text:
START CREATING YOUR DREAM LIFE NOW.
Enter your name and email to receive the 3 Must-Do's to Ignite Your Fierce Confidence.
I spent most of my life fantasizing about the way my life was supposed to be.
My thought process was, "When I ____ (lose 20lbs, get married, have the big house, lucrative career, adorable children…), then my life will be the way 'it's supposed to be.'"
I achieved a lot of what I set out to accomplish. I attended an Ivy League School, became an attorney, got married, built the big house, traveled extensively, had great friends and family, and to top it off had three beautiful daughters.
On paper my life looked like "I had it all." Yet, I felt trapped!
Although I had moments of fulfillment and happiness, they always felt fleeting or just beyond my reach because I was dealing with the same extra ten to twenty pounds, the same marriage that wasn't working, the same voices in my head that kept telling me what I should or shouldn't be doing, the need to be perfect, and that constant ache of wanting and knowing that "there had to be something more."
These feelings were the impetus for me to search for inner peace… and search I did! I read books, said affirmations, attended workshops, posted mantras on my bathroom mirror, did rebirthing ceremonies in warm pools, sweat in sweat lodges, had my aura cleansed by Indian Shamans, and went to more psychics and astrologers than I care to mention. I was looking for someone to give me my answers.
And while I had "aha" moments and periods of joy and self-love, they never lasted. Finally, I realized that nobody had my answers, a magical solution, or the ability to fix me. I needed to do the work myself and I needed to work from the inside out.
I came to realize that nothing in my external world — the weight, the marriage, that feeling that I was stuck on a gerbil wheel — was going to change until I shifted the way I felt about myself.
This was what brought me to The Ford Institute in 2002. Founded by the New York Times best-selling author Debbie Ford, The Ford Institute offers personal development courses and professional coaching training programs and has helped tens of thousands of people worldwide transform their lives in fulfilling and enriching ways.
As a student, I immersed myself in the work and witnessed my own life completely transform.
I let go of my marriage and worked through a difficult divorce and all of the emotions and changes that accompanied it.
I lost the weight I used as my protective shield, transformed my physique, and shifted my relationship with food and my body. I created a new home, a new career, and went from financial fear to freedom by stepping into new levels of responsibility in every area of my life.
I have amazing relationships and learned to open my heart and receive and give love in ways I never dreamed possible.
I have reached new levels of self-awareness and acceptance, and feelings of joy, purpose, and fulfillment that I never thought possible.
I have realized my purpose and feel free to be self-expressed, authentic, and fiercely confident in my passion to serve, empower, and liberate others.
Most importantly, I became the woman I aspired to be and have grown as a mother and role model for my three daughters!
It was my own healing and evolution that led me to become a Master Integrative Life Coach. I wanted to help others cross the bridge and share with them the amazing gift of liberation that I had been given. Shortly after getting certified, I was selected to be a teacher, core faculty member, and eventually leader of The Ford Institute.
This journey is what inspired me to write my book, The Integrity Advantage: Step into Your Truth, Love Your Life, and Claim Your Magnificence, a step-by-step guide that helps you shed all of the ways you have been out of integrity, empowers you to own that you are whole and complete, and guides you to live in alignment with your deepest truths and grandest desires.
Today, I am humbled to be an author, speaker, coach, and the CEO of The Ford Institute, supporting the evolution of thought leaders, influencers, and dynamic, motivated individuals around the globe.
"Before I attended The Shadow Process with The Ford Institute, I was sad that I would not be able to experience the teaching from Debbie Ford directly. I wondered how anyone other than her could possibly teach only what she could teach and share.
In a word, Kelley Kosow is a "badass."
After reading three of Debbie's books and doing all of the exercises. After watching the movie and videos Debbie generated. After completing The Shadow Process Workshop in LA with Kelley facilitating, I am complete and fully confident that Debbie is smiling from wherever she is, in the knowing that Kelley is not only continuing the work Debbie began, but is putting a spin on the process that only Kelley can do.
I could see in Kelley's eyes that she is fully committed to continuing the Divinely inspired work which Debbie Ford began."
—Greg Frucci
Kelley Kosow is an author, motivational speaker, and the Chief Executive Officer of the highly acclaimed Ford Institute. She continues the legacy of the late Debbie Ford, New York Times bestselling author and creator of The Shadow Process, and leads the development and teachings of The Ford Institute's transformational programs to tens of thousands of people across the globe.
Her book, The Integrity Advantage: Step into Your Truth, Love Your Life, and Claim Your Magnificence is praised as a "brand of brave insight and authentic wisdom [to] be who you want to be" and an "inspiration and catalyst to create the future of your dreams." Author Panache Desai says, "Kelley has the ability to elevate everyone that she meets into their highest expression. Her work transforms limitation in all forms and introduces people to the limitless power within them."
Known as a "kick-ass" coach to high-level executives, change makers, celebrities and dynamic, motivated individuals committed to personal transformation, Kelley blends her quick wit, laser sharp insight, and ruthless compassion to help people upgrade their lives on a cellular level.
While her gifts are many, she is remarkably skilled at awakening people to their limiting patterns, beliefs, and self-sabotaging behaviors and presenting the path of what is possible. Her coaching elevates the relationship her clients and students not only have with others but also with themselves.
Kelley is a graduate of Brown University and the University of Miami Law School and was formerly a practicing attorney and family law mediator. Though she achieved great success in her career, she felt "stuck" and was seeking more meaningful work when she discovered The Ford Institute. After Kelley began working with Debbie, she knew that a new path had opened up for her and became a staff member in 2007.
Prior to that, Kelley founded the company Go Goddess!™ Inc., which created games, books, and seminars to empower, inspire, and entertain women and girls. She has been featured in Oprah Magazine as someone who could "Dream it, Do it," as well as In Style, People, Working Mother, Latina, NY Times, Conde Nast Traveler, and LA Times. Kelley has also appeared on "The Balancing Act" and Better.tv.
Today, Kelley splits her time in Miami, New York City, and Los Angeles with family, friends, and her personal development community.
"Kelley is a very special human being who has the capacity to support others in a very non-judgmental and safe way. That is a very special gift. She is real, transparent and her desire to serve is apparent. I am very thankful we have crossed paths in this lifetime. She is a gift." —Eve Rosenberg
"Kelley is beautiful inside and out. She is strong, loving, compassionate, and genuine. She walks the talk, she lives the talk and the process. She is dedicated to this work. She carries on the work of Debbie Ford with pride, love, and a full understanding that she is here to do just that. How beautiful that must feel for her to know that she helps so many people and I can see in her that it is her true mission in this life. I can understand why Debbie left this work to her. She is the perfect fit." —Tammy
"Kelley Kosow has immersed herself in the work of Debbie Ford very deeply and carries on a beautiful legacy. She lovingly shares her vulnerability while maintaining great integrity as she skillfully guides others toward an inexplicable fullness of life that can only be attained through this integrative work."
—Lindarae Polaha
ASK KELLEY
Submit your questions about life, love, career, and more, and I'll answer them over The Fierce Life.
By clicking "SUBMIT" you are agreeing that we have the right to use your question and first name on The Fierce Life blog. Kelley may not respond to your message, or answer your question directly. If you are in need of medical or psychological help, call a professional immediately.


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GazetteerNews and Features
Farming Bartram's Garden
Mikel Young, a 10th grader at Bartram High School, shows off some of the harvest.
On the last Tuesday in July, two days before market day, 14-year-old Ryshawn Dobey mixed compost into a row of freshly tilled clover in Bartram's Garden in Southwest Philadelphia. For a moment he leaned on his hoe and surveyed the zucchini vines, collards, eggplants, peppers, black-eyed peas, okra, tomatillos, rattlesnake pole beans, and Sungold tomatoes whose profuse growth blocked the view of still other crops beyond them.
"I'm going to say my favorite thing I've eaten here was the squash," the stocky rising ninth-grader reflected. "Wait. No! It was the raspberries!"
He gazed up past a hill dotted with peach, pear, plum, cherry, apple, and nut saplings toward a bramble of raspberries that by this stage of the summer had been picked nearly clean. The view may have struck Dobey as particularly lovely, considering that he lives practically next-door in Bartram Village, a scruffy complex managed by the Philadelphia Housing Authority.
"My favorite thing to do," Dobey continued, "is to harvest. Especially curly kale like this," he said, swiveling his broad shoulders toward the row of plants growing behind him. "You make nice little bunches—and you always remember your bunch. When you're up at the market, you always remember, 'Yeah, I did that bunch. Buy this one!'"
For the moment, Dobey was on a field crew led by rising Penn junior Zoe Blickenderfer, an urban-studies major who spent the summer farming and mentoring local youth as part of a recent outgrowth of the Netter Center for Community Partnerships' Agatston Urban Nutrition Initiative (AUNI).
In October 2011, AUNI partnered with the Pennsylvania Horticultural Society, the city of Philadelphia's Parks & Recreation and Water departments, and Bartram's Garden to create the Community Farm and Food Resource Center at Bartram's Garden (CFFRC). The partnership transformed an underutilized ball field and a weed-conquered tennis court into a 3.5-acre farm site featuring a bit more than one acre under intensive cultivation, a community garden with around 55 individual plots, a solar-powered greenhouse for organic seedlings, and a nascent fruit orchard distinguished by historic heirloom varietals that harken back to the mid-18th century, when John Bartram cultivated North America's premiere botanic collection here on the Schuylkill River's right bank.
"Our main goals," says project director Ty Holmberg, "are to provide access to healthy, local, nutritious food; to develop tools for self-reliance and food sovereignty so people can learn how to [provide] for themselves; and to provide a space in the city where people can reconnect to the land, their food, and each other."
This summer, Holmberg and farm manager Christopher Bolden-Newsome oversaw eight Penn students and 22 local high-schoolers in an effort that dovetails with other aspects of AUNI's nationally recognized university-assisted community schools model.
The AUNI grew out of an academically-based community-service (ABCS) anthropology course taught in the early 1990s by Francis Johnston Gr'62. Johnston (now an emeritus professor) and his undergraduate students started out by teaching nutrition and health to 46 sixth-graders at a nearby middle school, with the aim of reducing childhood obesity. The endeavor gradually expanded to offer school-day, after-school, and summer learning opportunities for more than 10,000 students and their families at 20 public schools and community centers in Philadelphia, with an emphasis on hands-on opportunities to grow, cook, eat, and sell healthy foods.
The CFFRC has adopted an entrepreneurial approach to supporting that core mission and extending it. In the last year, the greenhouse produced some 80,000 transplants destined for community and school gardens throughout Philadelphia. The young students on the farm also market their produce at a weekly stand in Southwest Philadelphia, as well as at University City's larger Clark Park farmers market and through a small community-supported agriculture (CSA) subscription program. Cooking lessons and community feasts also figure into the summer routine for the youth participants, who are paid $7.25 an hour through a Philadelphia Youth Network grant administered by AUNI. For many of them, this is their first job.
The high-schoolers develop skills like public speaking and essay writing, and travel to a nearby public elementary school to teach younger summer-campers the basics of gardening, healthy eating, and food justice. (One of the program's most-discussed field trips involved a comparison of the produce selection and pricing at two Fresh Grocer supermarkets: one on the edge of Penn's campus at 40th and Walnut streets that offers a respectable array of fruit and vegetables, and one a mile-and-a-half away in the poorer Kingsessing neighborhood where, as Holmberg notes, "there are no organic options, there's no variety—there's like one type of apple—the quality is poor … even though it's the same exact company.")
As a project that makes use of public land and does not currently have a dedicated source of secure funding, the CFFRC is—like many of the Netter Center's initiatives in their infancy—a somewhat experimental enterprise. The program is subject to a five-year memorandum of understanding between the Netter Center, the Pennsylvania Horticultural Society, and the John Bartram Association governing shared responsibilities and the use of the site, whose long-term success will depend on continued support by the partners who helped to transform this slice of the Schuylkill River bank.
(To learn more about John Bartram's original use of the site—which some people have speculated was the location of Ben Franklin's famous kite-flying experiments, according to Bartram's Garden curator Joel Fry C'79 G'84—visit bartramsgarden.org.)
In April the CFFRC was honored with a Pennsylvania Governor's Award for Environmental Excellence that cited the program's "entrepreneurial jobs training and leadership development program for local high school students" in this low-income section of Philadelphia.
"The farm and garden at Bartram's captures all the key ideas and components of the Agatston Urban Nutrition Initiative," says Ira Harkavy C'70 Gr'79, the founding director of the Netter Center. "I think there are four academic courses that work with it, so it has that core academic health and nutrition partnership. It works with the community, with youth and adults, and with schoolchildren, which is crucial, because it has the active youth-development component of the Agatston Urban Nutrition Initiative."
The driving ethos is that the program's participants learn by being deliverers, not recipients, of valued services. For Penn students, that can mean anything from doing research toward a senior thesis to volunteering on a more ad hoc basis.
"The Netter Center's work with the university-assisted schools, AUNI, Bartram's Garden, all of them contain an approach in which students—in their academic courses, as volunteers, as work-study interns—can have an experience in which they engage in important civic work that makes a difference," says Harkavy. "It helps them develop as citizens."
The same goes for younger participants, he adds.
"They're seeing the products of their labor, and they're getting paid for it. That matters. And it's for positive work: it's socially valued, it's personally valued, it's transferable to their families, it gives them a sense of their own accomplishments. It's different than hamburger-flipping—it's learning work. They're learning new things and they're in touch with new people," Harkavy says.
"A lot of these kids, you can see that they have the potential to go one way or another," said Nina Kaledin, a junior classics major who opted to work for CFFRC instead of teaching sailing this summer, during a mid-morning break from the field. She reflected that the farm had recently hosted a visiting group of 13- and 14-year-olds whose number included two young teenagers wearing probation anklets.
"They could end up in trouble and on the streets and hustling," she said. "And programs like AUNI solidify their chances to go to college, and to change their situation. I feel that's such an important thing to do, especially in communities like Philadelphia, where the school systems aren't exactly excelsior right now."
A federal grant underwrites assessment of the program's success with regard to its health and nutritional goals. According to a 2009 case study authored by Francis Johnston, analyses carried out by Penn students as part of their ABCS course work have concluded that middle- and high-school students involved in AUNI programs eat significantly more servings of fruits and vegetables than their peers.
Recently, Holmberg has been working with partners at Children's Hospital of Philadelphia to evaluate "not just if this programming is affecting health, but if it's affecting the way that [the youth participants] see themselves in the community, their empowerment, their leadership skills, and things like that."
Given that the farm is only two-and-a-half years old, that will take time to determine. In the meantime, Ryshawn Dobey and his fellow farmhands have anecdotal evidence to light their way. In September, Dobey's older brother Rasheed, a two-year veteran of the Community Farm and Food Resource Center at Bartram's Garden, will matriculate at Voorhees College in South Carolina on a full scholarship.—T.P.
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Snack Brigade
Witness to a Demolition
Young Quakers

redpajama_set_name: RedPajamaCommonCrawl


text:
// Code generated by lister-gen. DO NOT EDIT.

package v1

import (
	v1 "k8s.io/api/core/v1"
	"k8s.io/apimachinery/pkg/api/errors"
	"k8s.io/apimachinery/pkg/labels"
	"k8s.io/client-go/tools/cache"
)

// EventLister helps list Events.
// All objects returned here must be treated as read-only.
type EventLister interface {
	// List lists all Events in the indexer.
	// Objects returned here must be treated as read-only.
	List(selector labels.Selector) (ret []*v1.Event, err error)
	// Events returns an object that can list and get Events.
	Events(namespace string) EventNamespaceLister
	EventListerExpansion
}

// eventLister implements the EventLister interface.
type eventLister struct {
	indexer cache.Indexer
}

// NewEventLister returns a new EventLister.
func NewEventLister(indexer cache.Indexer) EventLister {
	return &eventLister{indexer: indexer}
}

// List lists all Events in the indexer.
func (s *eventLister) List(selector labels.Selector) (ret []*v1.Event, err error) {
	err = cache.ListAll(s.indexer, selector, func(m interface{}) {
		ret = append(ret, m.(*v1.Event))
	})
	return ret, err
}

// Events returns an object that can list and get Events.
func (s *eventLister) Events(namespace string) EventNamespaceLister {
	return eventNamespaceLister{indexer: s.indexer, namespace: namespace}
}

// EventNamespaceLister helps list and get Events.
// All objects returned here must be treated as read-only.
type EventNamespaceLister interface {
	// List lists all Events in the indexer for a given namespace.
	// Objects returned here must be treated as read-only.
	List(selector labels.Selector) (ret []*v1.Event, err error)
	// Get retrieves the Event from the indexer for a given namespace and name.
	// Objects returned here must be treated as read-only.
	Get(name string) (*v1.Event, error)
	EventNamespaceListerExpansion
}

// eventNamespaceLister implements the EventNamespaceLister
// interface.
type eventNamespaceLister struct {
	indexer   cache.Indexer
	namespace string
}

// List lists all Events in the indexer for a given namespace.
func (s eventNamespaceLister) List(selector labels.Selector) (ret []*v1.Event, err error) {
	err = cache.ListAllByNamespace(s.indexer, s.namespace, selector, func(m interface{}) {
		ret = append(ret, m.(*v1.Event))
	})
	return ret, err
}

// Get retrieves the Event from the indexer for a given namespace and name.
func (s eventNamespaceLister) Get(name string) (*v1.Event, error) {
	obj, exists, err := s.indexer.GetByKey(s.namespace + "/" + name)
	if err != nil {
		return nil, err
	}
	if !exists {
		return nil, errors.NewNotFound(v1.Resource("event"), name)
	}
	return obj.(*v1.Event), nil
}

redpajama_set_name: RedPajamaGithub


How should minimum inhibitory concentrations (MICs) reported by the microbiology lab be interpreted?
MIC is the minimum inhibitory concentration of an antibiotic (AB) that inhibits an organism invitro, By itself, MIC does NOT take into account the pharmacokinetics (PKs) or pharmacodynamics (PDs) of an AB which ultimately determine its susceptibility cut-offs.
"Susceptible" implies that the isolate is inhibited by the usually achievable concentrations of the AB when recommended dosage is followed for the specific site of infection. "Intermediate" suggests that the MIC approaches usually attainable blood and tissue levels but at less- than-desirable expected clinical response rates, and generally should be avoided when an alternative AB exists. "Resistant" refers to isolates that are not inhibited by the usually achievable AB concentrations. In the absence of PK/PD data, comparing MICs can be misleading (i.e. lower MIC does not necessarily suggest a more potent AB).
Short answer: you can generally skip the MIC data and make antibiotic selection based on susceptibility report alone.


You target a vital area from a safe distance.
Prerequisite: Improved Precise Shot, Point-Blank Shot, Precise Shot, Intimidate 10 ranks.
Benefit: You can attempt a throat threat combat maneuver (see below) from up to 30 feet away. The normal requirements for throat threat apply except you must be wielding a piercing ranged weapon.
When you catch an enemy off-guard, you can take him hostage. Your blade remains pressed against his throat, a flick of your wrist away from a lethal cut. In melee combat, you can attempt to throat threat a flat-footed opponent as a standard action. Because your opponent must be flat-footed, this does not provoke an attack of opportunity. You cannot be threatened by any other foes when you initiate the throat threat and you must be wielding a slashing or piercing melee weapon (typically a dagger but not limited to it). Your target immediately becomes aware of you when you attempt to throat threat.
If successful, both you and the target gain the grappled condition. Although both creatures have the grappled condition, you can, as the creature that initiated the throat threat, release the throat threat as a free action, removing the condition from both you and the target. If you do not release the throat threat, you must continue to make a check each round, as a standard action, to maintain the hold. If your target does not break the throat threat, you get a +5 circumstance bonus on throat threat checks made against the same target in subsequent rounds. Your target remains flatfooted against you for as long as you maintain the throat threat. Unlike a grapple, while you throat threat a creature you can only perform one other action, a vital strike.
While maintaining a throat threat, you may make a single devastating attack, known as a vital strike, as an immediate action if your target attempts any action that you are aware of, or if any of your target's allies provoke an attack of opportunity from you or enter your threatened area. A vital strike automatically hits and scores a critical hit against your flat-footed opponent and your target must make a Fortitude save (DC equal to the damage dealt) or be stunned for one round. Your opponent may make a Stealth skill check to attempt an action without your noticing, including a move action that gets away from your throat threat, but you gain a +5 bonus on the opposed Perception check to notice. Creatures immune to critical hits are immune to throat threat. You can only throat threat a target your own size or one size category smaller than you. Creatures of a different type than you get a +5 circumstance bonus to their Fortitude save to resist being stunned.


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This is a Recipe for preparing at home spicy and mouthwatering Mutton Lonche (Meat Pickle) prepared in the authentic and traditional Konkani; Maharashtrian style of cooking Pickles. This Gosht Ka Achar lasts for a month or so if kept in a refrigerator.
First of all clean the Meat and then add all the above ingredients and mix it well.
After that cook for about 30 minutes on a slow sim. Cover with a stainless steel thali tightly adding some water over the thali so that it cooks on a slow flame.
When it cools down store in a bottle or jar.


A little while ago I wrote a post on how to set the partner of record in Office 365.
Since then, the Office 365 billing interface has changed so here's an updated tutorial on how to set the partner of record in Office 365 tenant.
You'll firstly need to login to the Office 365 web portal as an administrator with the appropriate rights.
Once you have logged onto the web console navigate to the Office 365 admin center using the app launcher. Towards the middle of this menu you will find a heading Billing which you will need to expand.
Below the Billing heading you should find an option Subscriptions which you need to select.
Now what actually appears here depends on what licenses you have in the Office 365 tenant but at first glance of the above screen shot the location to enter your partner of record is no very obvious. You may see a link in the lower right but in this case you don't see anything.
You need to select the More Actions pull down in the top left as shown above. When you do this a menu will appear.
In this menu option you will find the option Add partner of record.
Selecting this will slide an options screen from the right hand side of the page as shown above.
You can then enter you Microsoft Partner ID in that field and select the Check ID button.
if you have completed all the partner pre-requisites you should see that your organisation has been located and is displayed in all green indicating everything is good.
You now need to go to the bottom of this slide and Save the changes and apply that partner to this tenant.
When you do that, administrators in the tenant will be sent a confirmation email like that shown above indicating that a new partner of record has been set.
Remember, what you see in the subscriptions area may vary depending on what licenses have been added to the tenant. Some licenses don't support partner of record (i.e. Open). However, hopefully this makes it easy for you to set partner of record on those subscriptions that support it so you can start receiving commissions.


Amy Anne doesn't want any trouble. She doesn't even want very much attention. But when her favorite book gets pulled from the library shelf, she starts asking questions that lead to exactly that: trouble and attention. Between unfair treatment of siblings at home to creating a secret library of banned books at school, Amy Anne is poised to be an agent of change. The question is, can she speak up when it matters most?
This is a great read, and not just because I am biased in favor of librarians and reading. Amy Anne is a fantastic protagonist. Some readers might find her silence frustrating, but everybody who has ever wanted to stand up and couldn't find her voice (except inside her head) will relate to her. This is a character who reminds us that people who aren't loud can still have plenty of worthwhile things to say.
This story is a great example of a character taking positive action, especially since different points of view are considered, rather than villainized. Amy Anne is not just a righteous, one-dimensional crusader, either; she harbors some of her own biased assumptions about others. I also appreciate the honesty when students try some of the banned books and don't necessarily enjoy them. Overall, the book affirms the message that different kinds of books fit different readers.
The main character is in fourth grade, but this story fits 5th and 6th grade very well, especially with its themes of family and school injustice. There isn't inappropriate content for third or fourth graders who are ready to read this story. It would be a great choice for a school or library book club discussion group.
"I wanted all the books Mrs. Spencer had banned. I wanted a giant tower of books that filled my locker. And I wanted everyone to read them."


I know I'm late to the party, but I finally saw Alfonso Cuarón's space movie Gravity last night. Like Neil deGrasse Tyson and nearly everyone else, I really enjoyed it. That's why it's gnawing on me that a pivotal scene relied on some dubious physics.
It's the one in the promotional image to the left. (If you've haven't seen it yet, I'm shocked, but SPOILER ALERT.) Astronauts Dr. Ryan Stone (Sandra Bullock) and Matthew Kowalski (George Clooney) are in space suits, trying to board the International Space Station. Unfortunately, they approach it at high speed and ricochet around, at the risk of bouncing or sliding off into space, never to come back. Fortunately, some cable catches Stone's ankle, and she in turn catches a loose tether attached to Kowalski's suit, forming a chain. They stop in this position to have a conversation, but it's clear that Kowalski is being pulled out into space, and he eventually releases his tether in order to let Stone survive and return to the ISS.
Some have argued in favor of the physics in this scene, but even if there is some reasonable explanation having to do with momentum or centrifugal force, there's clearly something wrong when smart people like Bad Astronomer Phil Plait is in the audience wanting to scream, "'CLOONEY DOESN'T HAVE TO DIE!'"
It appears they are saved. Now all that's needed is for her to pull him to her, and for them to use the cable to get back to the ISS. But as she pulls, her leg makes a stray kick, accidentally releasing the cable; worse, kicking it just out of reach. Instead of Kowalski coming to her, she and Kowalski move together.
Now they are floating within spitting distance of the ISS (especially in space, where the spit would fly forward forever), but with no way to get there. He has no fuel in his jet pack, and she is quickly running out of oxygen. There's only one thing to do: He will push her toward the station so she can board it. As a result, he will go flying off in the other direction, never to be seen again. Just like in the original, he sacrifices himself to save her, but in a way that makes physical sense. As he floats away, they have the same touching conversation as in the film.
So that's my solution. I think it both makes the physics more realistic and avoids the clichéd cliffhanger scene that I have come to resent.
But, gosh, I could be wrong, either from the standpoint of physics or of dramatic integrity. As I was doing the necessary thought experiments to reimagine the scene, I realized that it's harder than it would seem to work out cause and effect in zero gravity. (I kept going back to the cool frictionless sleds we had in teacher Aaron's physics class at the fabulous Edmund Burke School in Washington, DC.) That gave me all the more respect for the rest of the film, which gets it really right a very large portion of the time. Seriously, it's spectacular.
So I very humbly submit this alternative to the interwebs, not so much in the spirit of a movie critique as in the spirit of fan fiction.


text:
Georgia Southern Ranger Challenge Wins State
Georgia Southern Army ROTC Videos
The Eagle Battalion Ranger Challenge team won the state competition Friday, October 21 at Fort Gordon, GA. The team competed in an Army Physical Fitness Test (APFT), triage, one-rope bridge, land navigation, written exam, and a 10K ruck march. Teams compete with nine members and must include at least one female and at least one Cadet from each MS level.
Team members include David Adler, Grant Allen, Luc Aviles, Aaron Bohan, John Dudley, Sean de la Torre, Caleb Herd, Dakota Jones, and Madison Stewart. Alternates were Jamie Arvey, Patrick Barnett, Tania Camacho, and William Eberhart.
Georgia Southern earned First Place in the APFT, One-Rope Bridge, Written Exam, and the 10K Ruck March.
The team will compete at the 6th Brigade Army ROTC competition at Camp Blanding, FL in January against the top teams from Alabama, Florida (2 teams), Louisiana, Mississippi, and Puerto Rico.
More photos: Georgia Southern University Army ROTC
Georgia Southern University, "Georgia Southern Ranger Challenge Wins State" (2016). University Videos. 506.


Rigid Audio has updated Aquiver, a cinematic sound module for Kontakt, to version 1.1.
Aquiver now comes with 1000 instruments and weights 3.7GB. There is also a new volume modulation knob and a new motion recording ping-pong switch for forward/backward playback of motion recordings.
This update is free for all current Aquiver customers.
Intro Price: $4.99 (New Reg. $99.99).


You don't have to use a vegan chocolate to make this decadent tart—any bittersweet baking bar will be great.
Preheat oven to 350˚. Pulse oats, whole wheat flour, coconut oil, agave, cocoa, salt, and cinnamon in a food processor until oats are coarsely ground and mixture looks like wet sand.
Firmly press into bottom and up the sides of tart pan. Bake until crust is golden brown and smells toasty, 20–25 minutes. Transfer to a wire rack; let cool.
Dissolve espresso powder in ¾ cup very hot water in a food processor. Add cocoa and let sit 5 minutes. Add melted chocolate, agave syrup, vanilla, ⅔ cup coconut oil, and ¼ tsp. kosher salt and process until mixture is very smooth and thick, about 30 seconds.
Scrape filling into cooled tart shell and smooth top (if making tart in a rectangular shell, you may have a little filling left over; save for another use, like truffles). Tap tart lightly against counter to pop any air bubbles in filling.
Cook oats and remaining 1 tsp. coconut oil in a small skillet over low heat, stirring constantly, until oats are toasted, about 3 minutes. Gradually add half of demerara sugar, stirring constantly, until sugar is melted, then remove from heat and stir in remaining demerara sugar just to coat. Season with kosher salt; let oat mixture cool.
Scatter oat mixture over tart, sprinkle with sea salt, and chill until filling is set, at least 1 hour.
Cut chilled tart into slices with a dry, hot knife; let sit at room temperature 15–20 minutes before serving.
Do Ahead: Tart can be made 2 days ahead. Once filling is set, cover and keep chilled.


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CU Presents - cu
Author: Kelly Dean Hansen Oct 27, 2017
DAILY CAMERA: Review: Eklund Opera's 'Merry Widow' among CU's finest productions
It was easy to be skeptical when the University of Colorado's Eklund Opera Program announced that its fall production would be yet another Viennese operetta following last year's memorable "Die Fledermaus." After all, this is a fairly obscure genre in the larger world of opera.
But program/stage director Leigh Holman and music director Nicholas Carthy have always planned their repertoire around their current student personnel, a strategy that has proved wise and successful. And Franz Léhar's "The Merry Widow" ("Die lustige Witwe") is many things that "Die Fledermaus" (which preceded it by 30 years) is not.
Where the earlier Johann Strauss work is mostly lightness, revenge pranks, and champagne, the 1905 "Widow" is a tender love story with real stakes for a small country — a human comedy in every way. Probably the closest point of contact to "Die Fledermaus" is a subplot involving a flirtatious, quasi-adulterous relationship that ultimately goes nowhere.
Eklund's production opens tonight at Macky Auditorium with repeat performances Saturday night and Sunday afternoon. The Saturday cast is different, as usual. Full dress rehearsals Tuesday and Wednesday indicated that this will be one of CU's best ever productions. Holman and Carthy keep raising their own bar, but they outdo themselves here in ways patrons should expect from them.
For starters, "Widow" is a show that has suffered from serious adaptation decay, even in Léhar's lifetime. In English-speaking countries, performances of the original libretto are uncommon, much less with the sung texts in the original German language. Unlike in "Fledermaus," CU opted to retain the German lyrics, with their exquisite meters and rhymes that perfectly fit Léhar's immortal melodies. Even professional American companies (including the Met) rarely do that. The production is authentic in other unusual ways too, including the settings and plots.
The spoken dialogue is in English (delivered crisply and with great exuberance), but the linguistic transitions are seamless, as they were in last spring's "Magic Flute." The Act I embassy set is lavish, the Act II outdoor set is gorgeous, and the Act III recreation of Maxim's in Paris is worth all of its 30 minutes.
The plot revolves around the French embassy of a nearly bankrupt Balkan country (called "Pontevedro" — the model was the very real country of Montenegro). A Pontevedrian widow has become exceedingly wealthy upon her aged husband's demise, and when she comes to Paris, it is up to the ambassador to keep those millions in Pontevedro — under no circumstances can she marry a Parisian.
The central five characters are sung and acted with excellence in both casts. The Saturday cast gives opportunities to singers who have done smaller parts in the past, while the Friday/Sunday leads generally have more experience.
The title role, Hanna Glawari, is the most demanding, and it is central to the operetta's success. In the Saturday cast, soprano Anna Whiteway — who did play the large role of Pamina in "Magic Flute" — really makes her mark here, delivering a genuinely tender portrayal of the widow. Her rendition of the famous "Vilja song" in Act II is crystalline in its beauty. As her former lover and current Pontevedrian hope Count Danilo, tenor Bryce Bartu makes a strong impact in his first major role.
Also given her first leading role is soprano Paige Sentianin as Valencienne, the ambassador's young, flirtatious and adorable wife. After making an excellent, but brief impact as Papagena in "Magic Flute," Sentianin shines here with a coquettish vivacity both in her acting and singing.
The Friday/Sunday cast uses more seasoned CU veterans in these three roles. Neila Getz was an imposing, forceful Rosalinda in "Fledermaus" and a menacing Queen of the Night in "Magic Flute." Her Hanna is perhaps more austere and melancholy than Whiteway's, but Getz's powerful voice is again in excellent form. Joshua DeVane — a baritone whose range allows him to venture into tenor territory — adds to his series of triumphant portrayals with a very human Danilo. Mary Kettlewell's Rosalinda was sassy, and her Valencienne here is no less delicious. Tenor Jacob Baker heroically takes on the demandingly high role of Camille de Rosillon in both casts. Rosillon is in love with Valencienne (whose resistance is tepid at best) and also Danilo's unwilling rival for Hanna's affections (it makes sense in context). Baker's top range is on brilliant display in his Act II duet with Sentianin and Kettlewell.
The ambassador, Baron Zeta, is a fine role, even though his singing is limited, and the character is played with gusto by Alex King on Saturday and Daniel Thompson (another returning favorite) in the Friday/Sunday cast.
The supporting cast is superb. Hanna's two French suitors (Erik Erlandson and Lane Melott Friday and Sunday; Steven Vinolas and Patrick Bessenbacher Saturday) provide terrific comic relief. They are joined by three Pontevedrian officials (Zachary Bryant, Karl Allen and Sklyer Schlenker) — two of whose wives have had dalliances with the Frenchman — along with Danilo and Zeta for the operetta's most rousing number, the Act II March-Septet (with typical sentiments about the confusing nature of women).
The six dancing "Grisettes" at Maxim's are also magnificent. And Grant Bowman deserves mention for his uproarious performance in the vital non-singing role of Njegus, secretary to the ambassador.
Carthy's orchestra is, as usual, phenomenal. They perform the rarely-used overture (which Léhar composed for the 400th performance) under a pantomime revealing the backstory of Hanna and Danilo.
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The Merry Widow (2017)
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Vienna's definitive romantic operetta uses laugh-out-loud comedy and lavish costumes to concoct the perfect musical confection. At a gala reception in...
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Opera Scenes (2017)
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Apr 26-29, 2018
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14:30 - 15:45 Merger & Acquisition: Ideal vs. Reality (ICC, Level 1, Dong Yu Grand Ballroom A) For Asian companies attempting to "go out", cheap and lucrative deals seem to be everywhere. However, the complexity and uncertainty of overseas M&A often results in a number of failures. Primarily, companies must fully understand the target enterprise, the legal and social circumstances and possible political barriers. Equally important, but often ignored, are post-M&A problems such as corporate cultural differences, management team frictions, trade union conflicts, community relations and environmental requirements. What experiences and lessons can be learned from those who have tested the water? Moderator: Martin SOONG, Anchor, CNBC Panelist: Mohamed Al-Mady, Vice Chairman & CEO, Saudi Basic Industries Corp.
21:00 – 22:30 Redefine the Role of Real Estate (ICC, Level 1, Dong Yu Grand Ballroom A) The Asian economy is facing challenges in restructuring and sustaining growth. How can the real estate industry redefine its role in such a transformation? Will the stimulus packages create another property bubble even before the economy gets back on track? Will exorbitant housing prices compromise consumption elsewhere, burden companies with increasing costs and reduce the competitiveness of a city? How should the housing market reform live up to people's expectations of affordable housing? Moderator: WANG Yongping, Secretary General, China Commercial Real Estate Association (CCREA) Panelists: CHEN Huai, Director General, Policy Research Center, Ministry of Housing and Urban-Rural Construction PAN Shiyi, Chairman, SOHO China Ltd.


The holidays don't last forever, and either will Winter White at The Avenue! Come stroll the streets!
The winter wont last forever, and thoughts of spring will come rushing in. But before we shed those coats, and long pants, The Avenue is presenting Winter White. Always a surprise is found tucked into one of the many shops on the streets. Come find yours!


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Q: Jacoco report : Not able to navigate to source file and see code coverage Tools :
Jacoco maven plugin
Issue :
I am working on a multi-module project.
The project structure is described as below -
Module1
Module1Test
Module2
Module2Test
I am able to generate the jacoco report for the Test module .
The jacoco report was not coming due to " Skipping JaCoCo execution due to missing classes directory" . But I managed to solve that error by following here . I copied source class files into target of test module.
Now report gets generated successfully. But I am yet not able to navigate to individual source files through report generated . The individual methods are not navigable to see which lines are covered and which are not.
Can anybody please advice what needs to be done to get navigation to source files enabled ?
Do I need to copy source files also in Test Folder  ?

redpajama_set_name: RedPajamaStackExchange


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Home > Blog entry > The devil in the details: Europe's low-carbon economy dream
The devil in the details: Europe's low-carbon economy dream
The increasing popularity of a 'low-carbon economy' rhetoric calls for robust assessments of the carbon intensity of EU funded projects. Otherwise the potential that lies in the concept may get diluted by conflicting interests.
, | 17 August 2012
In 2009, former British Prime Minister Gordon Brown heralded the beginnings of a "green revolution" that would be comparable in impact to the Industrial Revolution. The green revolution, said Brown, would lead to a new Ecological era in which the carbon footprint would be the basic criterion for assessing any human activity.
This epochal statement coming from the leader of one of the most carbon-intensive countries in the world is a clear sign that the need to take determined action against climate change has become mainstream. Political discourse has consequently shifted to reflect this new reality, with decision-makers including the concept of "low carbon economy" more and more often in their public interventions. And it is likely that, with the looming threat of climate change upon us, the low carbon economy will remain a top political goal for decades to come.
That is what fossil fuel industry lobbyists encourage us to do, celebrate marginal efficiency improvements while ignoring the fact that dirty production methods persist and might even expand.
The popularity of the low carbon economy among decision-makers is not only caused by environmental imperatives, but also because it is a framework which allows looking at issues such as climate change mitigation, energy savings, efficiency and rational resource use from an economic perspective.
In times of both economic and environmental crisis, politicians like to hear that you can, at the same time and using the same means, fight climate change and environmental degradation on the one hand and solve the problems of a collapsing economy on the other.
Thus, the low carbon economy has become a priority in numerous political programmes including the European Union's new Europe 2020 growth strategy, which includes a set of binding targets for a low-carbon economy. Furthermore, the European Commission has elaborated a Roadmap for moving to a low-carbon economy by 2050 and decarbonisation priorities have been included in separate strategies for the energy and transport sectors. Additionally, the EU's new Cohesion Policy (regional funds) will have as one of its main priorities "supporting the shift towards a low-carbon economy in all sectors" (pdf).
Individual members of the Union too are slowly becoming acquainted with the concept. For example, in recently elaborated documents, Slovak authorities have started including the concept of an "economy of green growth", although for the moment the expression seems to be used in a marginal and rather clumsy manner. But the government has announced it would come up with a "Low-carbon strategy for development until 2030" to be prepared by the Ministry of Environment by the end of this year.
Other countries too, even in Central and Eastern Europe, are slowly jumping on the low-carbon bandwagon, partly to fulfil commitments to the EU and secure European resources.
But a great risk lies in this growing popularity: the concept of a low-carbon economy may become diluted as more and more actors adapt it to their needs. The success of the low-carbon vision will naturally depend on what ends up being categorised as low-carbon.
For instance, the EU gas lobby has been trying to push for having gas included among the low-carbon fuels to receive European subsidies. The coal lobby too has been arguing that carbon capture and storage (CCS) and coal combustion technologies be considered low-carbon measures under the oxymoronic label "clean coal". Worryingly, the advocates of coal and gas have found support among EU decision-makers and hence there is a real risk that fossil fuel investments could be paid for with EU low-carbon budget funds.
Needless to say that nuclear advocates too present 'their' type of power as core to the low-carbon vision, because of its low greenhouse has emissions, regardless of its huge environmental and health hazards.
These examples show what is the danger here. The crux of the matter will be how we measure the carbon intensity of a specific project: if we concentrate only on chimneys and exhausts but neglect the whole production cycle we can come to a grossly distorted picture of what contributes to carbon emissions reductions and in what way. That is what fossil fuel industry lobbyists encourage us to do, celebrate marginal efficiency improvements while ignoring the fact that dirty production methods persist and might even expand. And, for this reason, the European Union and national authorities need to be very careful with how assessments of the carbon footprint of projects are completed, to make sure the entire real impact of the operations is taken into account.
The planning of a low-carbon transition in the EU has started. Despite of still lacking clarity over the concept and its implementation, more and more actors are rallying behind it.
And this is precisely why we should always remember that the problem with new concepts backed by huge amounts of money is that everyone learns fast how to use them – soon, everyone will declare their contribution to a competitive low-carbon economy, and we will be running the risk to make the concept meaningless or even dangerous. It is therefore important to keep a close eye on the evolution of this low-carbon vision and always remember that the devil is in the details.
Institution: EU Funds
Theme: Energy & climate | Resource efficiency
Tags: carbon footprint | climate action | corporate influence | fossil fuels | green economy


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Fifa 22 License Key Free Download [32|64bit] (Updated 2022) 🠪
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The assistant referee can even pick out potential sending-off situations, plus the referee can be given advice on potential penalty-taking situations by pressing the action button. A new "Bench View" will let the referee choose when to hold players back during a game. In addition, the referee will now have control of goal-line technology, which automatically informs the referee when certain scoring opportunities are present, and more.
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FIFA 22 is out today. For more on the game, visit: www.fifa.com
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The centerpiece of the documentary is Jon Otaku's story, which focuses on the "fukura," or pornographic artist's life. Otaku is a "connoisseur," who has mastered the non-mass production process
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FIFA 22 delivers a completely re-balanced Career Mode, which introduces the Transfer Market in the run-up to the 2017-18 football season. FIFA 22 introduces an all-new trading system, which enables the player to earn, spend, save and lend money in-game and determine their own progression to fantasy football. Players can now acquire squad players from friendlies at any time, for any price.
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The Berks, Bucks & Oxon Wildlife Trust is registered with the Fundraising Regulator.
Our Fundraising Promise is outlined below. We follow the Institute of Fundraising's Code of Practice and comply with the key principles embodied in the Code and this Promise.
The Berks, Bucks & Oxon Wildlife Trust (BBOWT) is committed to fundraising and communicating in an honest and transparent way.
BBOWT is the only voluntary organisation in the three counties that is concerned with all aspects of nature conservation. We rely on the generosity and enthusiasm of our members and supporters to fund the majority of our work to protect wildlife and inspire the next generation to care for wildlife too. We receive no core Government funding, so fundraising from the public is vital if we are to achieve our Vision: An environment rich in wildlife valued by all.
We aim to ensure that everyone who chooses to support us, whether by joining BBOWT, making a donation, giving their time to volunteer with us, or attend events, has a positive and rewarding experience and understands that their support is truly valued.
We publish information widely about our work, and how we spend people's donations and membership subscriptions. We are committed to keeping everyone informed. We communicate clearly why we need funds and what people's donations will be spent on, so that everyone can understand the benefits their donations will make for local wildlife. Read about our work on the Publications page.
We always treat your information in a safe, secure, sensitive and confidential way. Your data is safe with us. We take our obligations to look after your data very seriously. We will never sell your name, address or other personal information to third party organisations.
You can contact our Membership Team at any time on membership@bbowt.org.uk if you would like to change the way we contact you or to opt out of future communications.
If you do not want to make a donation to BBOWT, or you choose to withdraw your membership we will respect your decision.
If you tell us that you don't want to be contacted in a certain way, we will honour your request.
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The Berks, Bucks & Oxon Wildlife Trust is registered with the Fundraising Regulator. Our fundraising staff are members of the Institute of Fundraising.
BBOWT Trustees authorise all fundraising work and receive regular updates from the Chief Executive detailing the results of recent and current fundraising campaigns.
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2Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
The mTORC1 protein kinase complex plays central roles in regulating cell growth and metabolism and is implicated in common human diseases such as diabetes and cancer. The level of the amino acid leucine tells an organism a lot about its physiological state, including how much food is available, how much insulin is going to be needed, and whether new muscle mass can be made (see the Perspective by Buel and Blenis). Wolfson et al. identified a biochemical sensor of leucine, Sestrin2, which connects the concentration of leucine to the control of organismal metabolism and growth. When leucine bound to Sestrin2, it was released from a complex with the mTORC1 regulatory factor GATOR2, activating the mTORC1 complex. Saxton et al. describe the crystal structure of Sestrin2 and show how it specifically detects leucine. Aylett et al. determined the structure of human mTORC1 by cryoelectron microscopy and the crystal structure of a regulatory subunit, Raptor. The results reveal the structural basis for the function and intricate regulation of this important enzyme, which is also a strategic drug target.
Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.
It has long been appreciated that in addition to being a proteogenic amino acid, leucine is also a signaling molecule that directly regulates aspects of animal physiology, including satiety (1), insulin secretion (2), and skeletal muscle anabolism (3, 4). Because the liver has a low capacity to metabolize leucine, its concentrations in the blood fluctuate according to its consumption, so that dietary leucine can directly affect physiology (5–7). A key mediator of the effects of leucine is the mTOR complex 1 (mTORC1) protein kinase (8, 9), which regulates growth by controlling processes such as protein and lipid synthesis, as well as autophagy.
In addition to leucine, many environmental signals regulate the mTORC1 pathway, including other amino acids such as arginine, as well as glucose and various growth factors and forms of stress (10, 11). How mTORC1 senses and integrates these diverse inputs is not well understood, but it is clear that the Rheb and Rag guanosine triphosphatases (GTPases) have necessary but distinct roles. Rheb is a monomeric GTP-binding protein, and the Rags function as obligate heterodimers of RagA or RagB bound to RagC or RagD (12–14). Both the Rheb and Rag GTPases localize, at least in part, to the lysosomal surface (15–18), which is an important site of mTORC1 regulation (19). In a Rag-dependent manner, amino acids promote the translocation of mTORC1 to the lysosome, where Rheb, if bound to GTP, stimulates its kinase activity. Growth factors trigger the GTP-loading of Rheb by driving its GTPase activating protein (GAP), the tuberous sclerosis complex, off the lysosomal surface (18).
Regulation of the Rag GTPases by amino acids is complex, and many distinct factors have important roles (20). A lysosome-associated supercomplex containing Ragulator, SLC38A9, and the vacuolar adenosine triphosphatase (v-ATPase) interacts with the Rag GTPases and is necessary for the activation of mTORC1 by amino acids (21–24). Ragulator anchors the Rag heterodimers to the lysosome and has nucleotide exchange activity for RagA and RagB (21, 25). SLC38A9 is an amino acid transporter and a potential lysosomal arginine sensor (23), but the function of the v-ATPase in mTORC1 activation is unclear. Two GAP complexes stimulate GTP hydrolysis by the Rag GTPases, with GATOR1 acting on RagA and RagB (26), and folliculin–folliculin interacting protein 2 (FLCN-FNIP2) acting on RagC and RagD (27). The separate GATOR2 complex negatively regulates GATOR1 through an unknown mechanism and is necessary for mTORC1 activation (26). Last, the Sestrins are GATOR2-interacting proteins that inhibit mTORC1 signaling but whose molecular function is not known (28, 29). Previous reports argue that the Sestrins inhibit mTORC1 signaling through AMPK and TSC (30), but recent studies question this mechanism (28, 31).
The amino acid sensors upstream of mTORC1 have eluded researchers for many years. Whereas SLC38A9 is a strong candidate for sensing arginine at lysosomes (23), the long-sought sensor of leucine has thus far been unknown. Here, we present evidence that Sestrin2 is a leucine sensor for the mTORC1 pathway.
Activation of mTORC1 by amino acids requires the pentameric GATOR2 complex (26). Although its molecular function is unknown, epistasis-like experiments suggest that GATOR2 suppresses GATOR1, the GAP for and inhibitor of RagA and RagB (26). Within cells, Sestrin2 binds to GATOR2 in an amino acid–sensitive manner (28, 29); removal of all amino acids from the culture media induces the interaction, and readdition of the amino acids reverses it (28). Although several amino acids can regulate mTORC1 signaling, arginine and leucine are the best-established, and deprivation of either strongly inhibits mTORC1 in various cell types (8, 32, 33).
In human embryonic kidney–293T (HEK-293T) cells, removal of either leucine or arginine from the cell medium inhibited mTORC1 signaling to similar extents, as indicated by ribosomal protein S6 kinase 1 (S6K1) phosphorylation. However, only leucine depletion caused Sestrin2 to bind to GATOR2, inducing the interaction as effectively as complete amino acid starvation did (Fig. 1A). Leucine readdition rapidly reversed the binding, and amino acids did not affect the interaction between WD repeat–containing protein 24 (WDR24) and Mios, two core components of GATOR2 (Fig. 1A and fig. S1A).
Fig. 1 Leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction in cells and in vitro.
(A) Binding of Sestrin2 to GATOR2 in HEK-293T cells stably expressing FLAG-WDR24 (a component of GATOR2). Cells were deprived of leucine, arginine, or all amino acids for 50 min. Where indicated, cells were restimulated with leucine, arginine, or all amino acids for 10 min, and FLAG immunoprecipitates (IPs) were prepared from cell lysates. Immunoprecipitates and lysates were analyzed by immunoblotting for the indicated proteins and phosphorylation states. FLAG–methionine aminopeptidase 2 (metap2) served as a negative control. (B) Effects of leucine and arginine on the Sestrin2-GATOR2 interaction in ice-cold detergent lysates of amino acid–starved cells. HEK-293T cells stably expressing FLAG-metap2 or FLAG-WDR24 were deprived of all amino acids for 50 min. Leucine or arginine was added to the culture media or to cell lysates, and FLAG immunoprecipitates were prepared and analyzed as in (A). (C) Effects of individual amino acids on the purified Sestrin2-GATOR2 complex. FLAG immunoprecipitates were prepared from HEK-293T cells stably expressing FLAG-metap2 or FLAG-WDR24 and deprived of all amino acids for 50 min. Indicated amino acids (300 μM) were added directly to the immunoprecipitates, which, after re-washing, were analyzed as in (A). (D) Disruption of the purified Sestrin2-GATOR2 complex by leucine. The experiment was performed and analyzed as in (C), except that indicated concentrations of leucine (Leu) or arginine (Arg) were used. (E) Disruption of the Sestrin2-GATOR2 interaction by isoleucine (Ile) and methionine (Met). The experiment was performed and analyzed as in (C), except that the indicated concentrations of isoleucine, methionine, leucine, or arginine were used.
Sestrin2 is homologous to two other proteins, Sestrin1 and Sestrin3 (34–36); when overexpressed, all three can interact with GATOR2 (28). As with Sestrin2, leucine starvation and stimulation strongly regulated the interaction of endogenous Sestrin1 with GATOR2 (fig. S1B). In contrast, endogenous Sestrin3 bound to GATOR2 irrespective of leucine concentrations (fig. S1B), suggesting that this interaction is constitutive or regulated by signals that remain to be defined.
Although enzymatic events triggered by leucine may mediate the effects of leucine on the Sestrin2-GATOR2 interaction, it was tempting to consider the possibility that leucine might act directly on the complex. Consistent with this possibility, the addition of leucine, but not arginine, to ice-cold detergent lysates of cells deprived of all amino acids abrogated the interaction to the same extent as leucine stimulation of live cells did (Fig. 1B). Leucine also disrupted the interaction when added directly to immunopurified Sestrin2-GATOR2 complexes that were isolated from amino acid–deprived cells. Of the 18 amino acids tested at 300 μM each, only those most similar to leucine—methionine, isoleucine, and valine—had any effect on the Sestrin2-GATOR2 interaction in vitro (Fig. 1C).
When added to the purified complexes, leucine dose-dependently disrupted the Sestrin2-GATOR2 complex, with the half-maximal effect at about 1 μM (Fig. 1D). Methionine and isoleucine were considerably less potent, acting at concentrations about 10- and 25-fold greater than leucine, respectively (Fig. 1E). These values reflect only the relative potencies of these amino acids, owing to the fact that equilibrium conditions were not attained because the large assay volume precluded Sestrin2 from rebinding to GATOR2 once it had dissociated.
Given that leucine disrupts the purified complex, we reasoned that leucine might bind directly to Sestrin2 or GATOR2. To test this, we developed an equilibrium binding assay in which purified proteins immobilized on agarose beads were incubated with radioactive amino acids, and the bound amino acids were quantified after washing. Radiolabeled leucine bound to Sestrin2 but not to WDR24, the GATOR2 complex, or the control protein Rap2A (Fig. 2A), in a manner that was fully competed by excess nonradiolabeled leucine. In contrast, arginine did not bind to either Sestrin2 or Rap2A (fig. S2A). Consistent with the differential sensitivities to leucine of the Sestrin1- and Sestrin3-GATOR2 complexes, Sestrin1 bound leucine to a similar extent as did Sestrin2, whereas Sestrin3 bound leucine very weakly (Fig. 2B and fig. S2A). Drosophila dSestrin (CG11299-PD) also bound leucine, albeit at lower amounts than the human protein did (fig. S2, B and C).
Fig. 2 Sestrin2 binds leucine with a Kd of 20 μM.
(A) Binding of radiolabeled leucine to Sestrin2 but not to WDR24, GATOR2, or the control protein Rap2A. FLAG immunoprecipitates prepared from HEK-293T cells transiently expressing the indicated proteins or complexes were used in binding assays with [3H]leucine, as described in the supplementary materials. Unlabeled leucine was added where indicated. Values are means ± SD for three technical replicates from one representative experiment (n.s., not significant). SDS–polyacrylamide gel electrophoresis, followed by Coomassie Blue staining, was used to analyze immunoprecipitates that were prepared in parallel to those included in the binding assays. Asterisks in the right panel indicate breakdown products in the WDR24 and GATOR2 purifications. (B) Leucine-binding capacities of Sestrin1 (two isoforms), Sestrin2, and Sestrin3. FLAG immunoprecipitates were prepared and binding assays were performed and analyzed as in (A). (C) Leucine binds to bacterially produced Sestrin2 but not to the RagA/RagC heterodimer. Leucine binding assays were performed as described in the supplementary materials and analyzed as in (A) with polyhistidine (His)–mannose binding protein (MBP)–Sestrin2 or His–RagA/RagC bound to the Ni–NTA (nitrilotriacetic acid) resin. (D) Effects of leucine and arginine on the melting temperature of bacterially produced Sestrin2 in a thermal shift assay. His-MBP-Sestrin2 was incubated with Sypro Orange dye, with or without leucine or arginine. When the sample was heated, the change in fluorescence was captured and used to calculate melting temperatures (Tm) under the indicated conditions. Values are means ± SD for three replicates. (E) Sestrin2 binds leucine with a Kd of 20 μM. FLAG-Sestrin2 immunoprecipitates, prepared as in (A), were used in binding assays with 10 or 20 μM [3H]leucine and indicated concentrations of unlabeled leucine. In the representative graph, each point represents the normalized mean ± SD for n = 3 experiments in an assay with 10 μM [3H]leucine. Kd was calculated from the results of six experiments (three with 10 μM and three with 20 μM [3H]leucine). (F) Methionine can compete with the binding of leucine to Sestrin2. (G) Isoleucine can compete in the binding of leucine to Sestrin2. In (F) and (G), FLAG-Sestrin2 immunoprecipitates, prepared as in (A), were used in binding assays with 10 μM [3H]leucine and indicated concentrations of unlabeled methionine and isoleucine, respectively. In the graphs, each point represents the normalized mean ± SD for n = 3 experiments Ki values were calculated using data from the three experiments.
Because all of these proteins were expressed in and purified from HEK-293T cells, the above results did not rule out the possibility that an unidentified protein that copurifies with Sestrin2 (and Sestrin1) is the actual receptor for leucine. To address this possibility, we prepared human Sestrin2 in bacteria, which is a heterologous system that does not encode a Sestrin homolog or even a TOR pathway. Consistent with the results obtained with Sestrin2 prepared in human cells, radiolabeled leucine bound to bacterially produced Sestrin2 but not to the RagA-RagC heterodimer, which was used as a control (Fig. 2C). Furthermore, in a thermal shift assay, leucine, but not arginine, shifted the melting temperature of bacterially produced Sestrin2, but not of two control proteins, by up to 8.5° C (Fig. 2D and fig. S2, E and F). Collectively, these data strongly suggest that leucine binds directly to Sestrin2.
Although the thermal shift assay is valuable for assessing the capacity of a protein to bind a ligand, this method is not suitable for obtaining an accurate Kd (37). Therefore, we used a competition binding assay with increasing amounts of unlabeled leucine to determine that leucine has a Kd for Sestrin2 of 20 ± 5 μM (Fig. 2E). In comparison, methionine and isoleucine competed with leucine binding with inhibitory constants (Ki) of 354 ± 118 μM and 616 ± 273 μM, respectively (Fig. 2, F and G). These values are respectively about one-eighteenth and one-thirtieth the affinity of leucine for Sestrin2, and they correlate well with the relative potencies of leucine, methionine, and isoleucine in disrupting the Sestrin2-GATOR2 interaction in vitro (Fig. 1, D and E).
Consistent with leucine regulating mTORC1 by modulating the binding of Sestrin2 to GATOR2, 20 to 40 μM leucine had half-maximal effects on both the Sestrin2-GATOR2 interaction and mTORC1 activity in HEK-293T cells (Fig. 3, A and B). This concentration range encompasses the Kd of leucine for Sestrin2, indicating that the affinity of Sestrin2 for leucine is physiologically relevant.
Fig. 3 Sestrin2 regulates mTORC1 through GATOR2.
(A) Effects of varying leucine concentrations on mTORC1 activity, as measured by the phosphorylation of S6K1. HEK-293T cells were deprived of leucine for 50 min and restimulated with leucine at the indicated concentrations for 10 min. Cell lysates were analyzed via immunoblotting for the indicated proteins and phosphorylation states. (B) Effects of varying leucine concentrations on the Sestrin2-GATOR2 interaction. HEK-293T cells stably expressing the indicated proteins were starved as in (A) and FLAG immunoprecipitates were collected. The immunopurified complexes were treated with the indicated concentrations of leucine and then analyzed as in Fig. 1C. (C) Decreased GATOR2-binding capacity of the Sestrin2 S190W mutant. FLAG immunoprecipitates were prepared from HEK-293T cells transiently expressing the indicated proteins and were analyzed by immunoblotting for the indicated proteins. (D) Determination of the leucine-binding capacity of Sestrin2 S190W. Assays were performed and immunoprecipitates were analyzed as in Fig. 2A. (E) In Sestrin1, -2, and -3 triple-null cells expressing Sestrin2 S190W, the mTORC1 pathway cannot sense the absence of leucine. Wild-type HEK-293T cells and Sestrin1, -2, and -3 triple-null HEK-293T cells, generated with the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9) system, were used to express the indicated FLAG-tagged proteins. Cells were starved of leucine for 50 min and, where indicated, stimulated with leucine for 10 min; lysates were analyzed via immunoblotting.
To formally test whether Sestrin2 regulates mTORC1 by interacting with GATOR2, we identified a Sestrin2 mutant (S190W) that binds leucine but has a severely decreased capacity to bind GATOR2 (Fig. 3, C and D). In Sestrin1, -2, and -3 triple-null HEK-293T cells, mTORC1 signaling was active and unaffected by leucine deprivation (Fig. 3E). In these cells, expression of wild-type Sestrin2 restored the leucine sensitivity of the mTORC1 pathway, but expression of Sestrin2 S190W had no effect (Fig. 3E). Thus, Sestrin2 must be able to interact with GATOR2 for the mTORC1 pathway to sense the absence of leucine.
To test whether the leucine-binding capacity of Sestrin2 is necessary for mTORC1 to sense the presence of leucine, we identified two Sestrin2 mutants, L261A and E451A, which do not bind leucine to an appreciable degree (Fig. 4A). Leucine did not meaningfully affect the interaction of the mutants with GATOR2 in vitro, consistent with the role of Sestrin2 in mediating the effects of leucine on the Sestrin2-GATOR2 complex (Fig. 4B). Expression of wild-type Sestrin2 in the Sestrin1, -2, and -3 triple-null cells restored the leucine sensitivity of the mTORC1 pathway in these cells, but expression of either mutant inhibited signaling and rendered the mTORC1 pathway insensitive to leucine (Fig. 4C and fig. S3A). Furthermore, in Sestrin1, -2, and -3 triple-null cells that expressed the mutants, the localization of mTOR to lysosomes in the presence of leucine was decreased, whereas that of RagC was not affected (fig. S4, A to D). Thus, activation of mTORC1 by leucine requires the binding of leucine to Sestrin2.
Fig. 4 The capacity of Sestrin2 to bind leucine is required for the mTORC1 pathway to sense leucine.
(A) The Sestrin2 L261A and E451A mutants do not bind leucine. Binding assays were performed and immunoprecipitates were analyzed as in Fig. 2A. (B) Leucine insensitivity of the interactions of Sestrin2 L261A or E451A with GATOR2. FLAG immunoprecipitates were prepared from cells transiently expressing the indicated proteins. The immunoprecipitates were treated with the indicated concentrations of leucine and analyzed as in Fig. 1C (HA, hemagglutinin epitope). (C) In Sestrin1, -2, and -3 triple-null cells expressing Sestrin2 L261A or E451A, the mTORC1 pathway cannot sense the presence of leucine. Cells were generated and analyzed as in Fig. 3E. (D) Model showing how amino acid inputs from multiple sensors in distinct compartments impinge on the Rag GTPases to control mTORC1 activity.
Sestrin2 has several properties that are consistent with its being a leucine sensor for the mTORC1 pathway: (i) it binds leucine at affinities consistent with the concentrations at which leucine is sensed; (ii) Sestrin2 mutants that do not bind leucine cannot signal the presence of leucine to mTORC1; and (iii) loss of Sestrin2 and its homologs renders the mTORC1 pathway insensitive to the absence of leucine. Although we have not investigated Sestrin1 as thoroughly, it appears to behave similarly to Sestrin2, so we propose that Sestrin1 and Sestrin2 are leucine sensors upstream of mTORC1.
Given that Sestrin2 has appreciable affinity for methionine, it would not be surprising if, in contexts where leucine concentrations are low and methionine concentrations are high, Sestrin2 serves as a methionine sensor for the mTORC1 pathway.
Sestrin2 binds to and likely inhibits GATOR2, but how this leads to suppression of mTORC1 cannot be determined until the molecular function of GATOR2 has been clarified. In addition, structural studies are needed to understand how the binding of leucine to Sestrin2 disrupts its interaction with GATOR2, and why leucine binds very poorly to Sestrin3.
Because Sestrin1 and Sestrin2 are soluble proteins, it is likely that they sense free leucine in the cytosol. Although these concentrations are unknown, the Michaelis constant of the human leucyl–transfer RNA synthetase (LRS) for leucine has been reported to be 45 μM (38). This value is similar to the affinity of Sestrin2 for leucine, suggesting that cytosolic free leucine concentrations are within this range. Like Sestrin2, LRS binds isoleucine and methionine at lower affinities than it binds leucine (about 30-fold less in the case of LRS) (38). The similarities between the amino acid–binding characteristics of Sestrin2 and LRS support the notion that the affinity and specificity of Sestrin2 for leucine are sufficient for it to serve as a leucine sensor.
Our work suggests a model in which signals emerging from distinct amino acid sensors in different cellular compartments converge on the Rag GTPases at the lysosomal surface to regulate mTORC1 activity (Fig. 4D). The putative arginine sensor SLC38A9 probably monitors lysosomal contents, and Sestrin2 is almost certainly a cytosolic sensor. There must also be an amino acid sensor upstream of the FLCN-FNIP2 complex (the GAP for RagC and RagD), but its identity and cellular localization are unknown. A future challenge is to determine how the Rag GTPases integrate the inputs from the different sensors; this will likely require a much better understanding of the function of each Rag in the heterodimer. Moreover, in vivo characterization of the different sensors will be needed to comprehend how specific tissues adapt the amino acid sensing pathway to their particular needs.
Given that Sestrin2 (and Sestrin1) are likely to have leucine-binding pockets, these proteins may be targets for the development of small-molecule modulators of the mTORC1 pathway. Leucine attenuates the decrease in skeletal-muscle protein synthesis that occurs in the elderly and stimulates satiety (1, 37). Thus, small molecules that potently mimic the effects of leucine on Sestrin2 could have therapeutic value. Furthermore, caloric restriction inhibits mTORC1 signaling (40, 41) and is associated with increased health span and life span in multiple organisms (42, 43). Thus, small molecules that antagonize the effects of leucine on Sestrin2 might have caloric restriction–mimicking properties.
, p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008).
, Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159, 122–133 (2014).
Acknowledgments: D.M.S. is a founder, a member of the Scientific Advisory Board, a paid consultant, and a shareholder of Navitor Pharmaceuticals, which is targeting for therapeutic benefit the amino acid sensing pathway upstream of mTORC1. The His-MBP-Sestrin2 pMAL6H-C5XT plasmid is available from Navitor Pharmaceuticals under a materials transfer agreement with Navitor Pharmaceuticals. R.L.W., L.C., R.A.S., D.M.S., and the Whitehead Institute have filed two provisional patents that relate to the Sestrin2-GATOR2 interaction. We thank all members of the Sabatini Lab for helpful insights, in particular S. Wang for experimental advice; O. Levsh, from the laboratory of J.-K. Weng, for generously providing the control proteins used in the thermal shift assays; Navitor Pharmaceuticals for providing the His-MBP-Sestrin2 pMAL6H-C5XT plasmid; and Cell Signaling Technology for providing many antibodies. This work was supported by grants from NIH (R01 CA103866 and AI47389) and the Department of Defense (W81XWH-07-0448) to D.M.S.; fellowship support from NIH to R.L.W. (T32 GM007753 and F30 CA189333) and L.C. (F31 CA180271); and a grant from the Paul Gray Undergraduate Research Opportunities Program Fund to S.M.S. (3143900). K.S. is a Pfizer Fellow of the Life Sciences Research Foundation. D.M.S. is an investigator of the Howard Hughes Medical Institute.


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Rome, a mini guide to not miss anything
Judit Llordés
@juditllordes
SOURCES CONSULTED:
wikipedia.org, lonelyplanet.com
Rome in the course of history it has become one of the major capitals by extension of the territory. The city stands on seven hills and is crossed by two rivers the Tiber and the Aniene, moreover it is the only city in the world to host a foreign state within it. Vatican City.
Rome enjoys a temperate weather typically Mediterranean, warm summers and mild winters, therefore suitable for holidays all year round, obviously the best time in my opinion is spring.
As for transport, the city is served by two airports, the first intercontinental Leonardo da Vinci, but better known by the name of Fiumicino, name given by the municipality that hosts it about 30km from the city, then we have the international airport of Giovan Battista Pastine known as Ciampino. While in Fiumicino several companies land daily such as Alitalia ed Easyjet, in Ciampino you can only use low cost airlines such as Ryanair. As for transport, we remind you that Rome is the main railway hub in central Italy. In addition to the station Terms, there are other stations such as Tiburtina, Ostiense, Roma Trastevere and Roma Tuscolana.
The Rome metro has two lines: line A (yellow) and line B (blue), while lines B1 and C are currently being completed, in order to complete the network of connections in the city that will be added to the transport on rubber and rail already present.
Rome is full of museums, monuments and squares to visit among the main ones include the Vatican Museums with the Sistine Chapel, the Capitoline Museums, the oldest in the world open to the public since 1734, Piazza Navona, the Coliseum, the Pantheon, Piazza Venezia e Spanish Steps, without forgetting St. Peter's Basilica and the other hundreds of places that can be visited. But Rome is not only what we see on the surface, but under the city they develop for hundreds of kilometers catacombs, ancient Jewish and Christian cemetery areas dug into the tuff.
Rome hosts many every year private events which attract tourists from all over the world such as the International Film Festival held in autumn, the Biennial of International Art and the Roma Europa Festival.
Rome is also the capital of Shopping, in addition to the exclusive streets of the city, where the boutiques of the big names are concentrated, such as via Condotti, via del Babuino and via Ripetta, there are many shops and shopping centers, moreover there are two outlets outside Rome Castel Romano and Valmontone, ideal for making affordable purchases all year round.
The last thing I will talk about in this mini guide of Rome is the Roman cuisine. The most famous dishes are the bucatini all'amatriciana, based on bacon and tomato, spaghetti alla carbonara, with bacon, pecorino cheese and eggs, but also the various soups based on vegetables and legumes. Famous in Rome are also dishes such as tripe, kidney and offal.
Among the restaurants where it is possible to eat the typical dishes of the Roman tradition are the trattorias and the most famous is Sora Lella, a restaurant located on the Tiber Island in via Ponte Quattro Capi 16. Rome is also to be remembered for the Roman square, thin and crunchy compared to the Neapolitan one and here the prince of the square is undoubtedly Mustache, pizzeria in via del Governo Vecchio 114.
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Bloxorz is a straightforward yet addictive game - move a block around a floating platform using the arrow keys, dropping it through the square hole to finish the known level. That's it! Simple since it sounds, the known amounts get a growing number of taxing, though we are able to assure you they are all solveable actually! Later levels find you splitting your block into to controllable parts separately, utilize the spacebar to toggle between them. Besides that, the rest is pretty personal explanatory. Be warned - every single day start playing this you might find it hard to stop!