This is my newest creation, its a 1981 pontiac firebird with a 2jzgte engine. Its got a boostwerx adapter kit with a GM TH350 transmission, 4200 stall Coan converter, 76mm turbo built by Turbo Concepts, 950cc fuel injector clinic injectors, aeromotive 1000 pump, -8an fuel lines, fuel cell, Haltech EMS, Turbo concepts 38mm wastegate, Turbo concepts BOV, I did all the fab/install work myself. Tuning is being done by a friend. Its currently only tuned at 10psi but will be receiving more boost very soon!
Pontiac Firebird, 2JZGTE, Boostwerx, Turbo concepts, 76mm Turbo, Coan, Fuel injector clinic, Haltech, Aem, RB26DETT, 4G63, Talon, Civic, Tuning, Totota, Skyline, vg30dett, nissan, 300zx, drifting, drag, racing, boost, evo, s10, fast, supra, 240sx, 200sx,


text:
An associate’s degree in psychology can open up a wide range of career opportunities for graduates. While it may not be as comprehensive as a bachelor’s or master’s degree, an associate’s degree in psychology can still provide students with the foundational knowledge and skills necessary to pursue various careers related to mental health and human behavior.
What is an Associate’s Degree in Psychology?
An associate’s degree in psychology is a two-year undergraduate program that introduces students to the fundamental concepts, theories, and practices of psychology. The curriculum typically covers topics such as abnormal psychology, social psychology, human development, research methods, and statistics. Students may also have the opportunity to participate in fieldwork or internships where they can gain hands-on experience working with clients or research participants.
While an associate’s degree in psychology may not qualify graduates for certain positions that require higher levels of education and training (such as licensed counselor or psychologist), there are still many career paths that are open to those with this degree. Here are some examples:
1. Mental Health Technician
Mental health technicians work alongside psychiatrists and other mental health professionals to provide support and care for individuals with mental illnesses or disorders. They may assist with daily living activities, monitor patients’ behaviors and symptoms, administer medications under supervision, and help create treatment plans.
2. Social Services Assistant
Social services assistants work with social workers to help connect individuals and families with community resources such as housing assistance, food banks, and healthcare services. They may also assist with case management tasks such as maintaining client records and conducting assessments.
3. Research Assistant
Research assistants work alongside psychologists or other researchers in academic settings or private organizations to conduct studies on various topics related to human behavior. They may assist with data collection, analysis, literature reviews, and report writing.
4. Human Resources Specialist
Human resources specialists work in a variety of industries to recruit, train, and manage employees. Those with an associate’s degree in psychology may be well-suited for this field due to their knowledge of human behavior and motivation.
5. Substance Abuse Counselor
While becoming a licensed substance abuse counselor typically requires additional education and training beyond an associate’s degree, some entry-level positions may be available to those with this degree. Substance abuse counselors work with individuals struggling with addiction to develop treatment plans and provide support through the recovery process.
For those who wish to pursue higher levels of education and training in psychology, an associate’s degree can serve as a solid foundation for further study. Many universities offer bachelor’s degree programs in psychology that build upon the concepts covered in an associate’s program. Additionally, some master’s programs may accept students with an associate’s degree as long as they meet certain prerequisites and requirements.
- An associate’s degree in psychology can lead to various career opportunities related to mental health and human behavior.
- Career paths include mental health technician, social services assistant, research assistant, human resources specialist, and substance abuse counselor.
- An associate’s degree can also serve as a foundation for further study at the bachelor’s or master’s level.
In conclusion, while an associate’s degree in psychology may not provide graduates with all the necessary qualifications for certain positions in the field, it still offers many possibilities for those interested in working with people and understanding human behavior. From mental health technician to research assistant or social services assistant, there are many career paths open to those holding this degree. Additionally, for those who wish to continue their education, an associate’s degree can serve as a solid foundation for further study at the bachelor’s or master’s level.

domain: psychology


The source said that Casal had been "struggling on and off for the past year" with some personal issues, which his family and friends were helping him work through. He had been in the studio last week with Circles Around The Sun recording a new studio album and over the weekend they performed a well-received set at the LOCKN' Festival in Arrington, Virginia. "It appeared he was in a good head space. On Monday, however, he went home and stopped returning calls and texts from friends." The source said Casal's body was found on Monday evening.
The folk-influenced rocker and photographer was born in Denville, New Jersey, on Nov. 2, 1968 and began releasing solo albums in 1995 with Fade Away Diamond Time, the first of a dozen poetic, Americana-style solo efforts he released through 2011's Sweeten the Distance. He formed the trio Hazy Malaze in 2002, releasing three albums with bassist Jeff Hill and drummer Dan Fadel before joining Ryan Adams' band, The Cardinals, in 2005, touring with the group and appearing on five albums, including 2007's Easy Tiger and 2011's Class Mythology.
Beginning in 2012, he toured and recorded with former Black Crowes singer Chris Robinson's band, The Brotherhood, appearing on a dozen albums, including 2012's Big Moon Ritual and this year's Servants of the Sun. Casal's fluid, expansive playing was featured on albums by a wide variety of other acts, including Smashing Pumpkins guitarist James Iha's 1998 solo debut, as well as works by Lucinda Williams, The Fruit Bats, Duncan Sheik, Robert Randolph and the Family Band and Willie Nelson.
Adams paid loving tribute to his old friend on Instagram, writing, "Oh man. My heart is broken. It’s too much. What an honor to have known you, true believer. I love you, always. Go easy, brother. Go easy. Through thick and thin your heart was a lighthouse of kindness. Your eyes a mirror to a better world- your soul bled into ever note. I don’t know how to even feel right now. Grateful for your time. But immense loss. “I've seen things you people wouldn't believe. Attack ships on fire off the shoulder of Orion. I watched C-beams glitter in the dark near the Tannhäuser Gate. All those moments will be lost in time, like tears in rain."
Others paying tribute include Shooter Jennings, who wrote, "He was always my favorite picker in LA and we’d all just finished some beautiful music together."
A week ago, Casal announced on Instagram that he was producing a new album from one of his favorite singer/songwriters Kenny Roby of Six String Drag, soliciting help from anyone who would like to help out. See more tributes to Casal below.
If you or someone you know need help please contact the National Suicide Prevention Lifeline (1–800–273–8255) or visit SuicidePreventionLifeline.org to chat with someone online.
Finally, watch Casal performing at the LOCKN' Festival last weekend.


Friday, 2 February 2024, 15:29
Plans to make the most of the last drops of water out of the La Concepción reservoir are included in the latest drought decree approved by the Junta on Monday 29 January.
One of the actions published in the BOJA (official gazette of the Andalusian regional government) stated: "Optimisation and improvement of the dead reservoir facilities in La Concepción."
What does this mean? Sources told SUR that for the past year technicians have been maintaining a series of systems that will allow the maximum amount of water to be extracted from the dam, which now has a negligible "dead reservoir" area due to these works.
A reservoir is declared dead when it falls below 11% of its capacity or when it is impossible to continue extracting water from it, because what is left at the bottom is only mud.
And how has it been possible to improve the levels of this reservoir? It goes back to actions carried out during the severe droughts of 1982 and 1995. La Concepción had just five cubic hectometres in 1982 (it now has 13.1). Its 1982 level was below the level necessary to extract water for drinking. But that changed with the addition of pumps and other filtration systems.
In 1982, the pumping and piping station at the dam was adapted to be able to use 4 hm3 of the dead reservoir. Then, in 1995, it was possible to use a further 0.9 hectometres, 90% of what was left. But that same year, via a water transfer pump, it was then possible to use some 60,000 m3 of the approximate 100,000 m3 that remained.
By the time of this third step, at the end of September in 1995, only about 40,000 m3 remained unused. "This was of very poor quality, with excess sediment and contained a lot of iron and manganese," the sources said. But what was left unused was almost nothing, just the "swamp dregs". Today, for example, in the middle of a drought, just over 47,000 cubic metres a day is being extracted from La Concepción to be treated, 7,000 more than what was left at the bottom of the reservoir 29 years ago.
According to the Junta, 550 litres of water per second is extracted from the reservoir; 450 litres from the Marbella desalination plant, which is at full capacity, and some 100 litres per second come from the Fuengirola wells.
In the coming months, 100 litres per second will be extracted from the brackish wells at Guadalmansa and another 50 litres per second from boreholes in Fuengirola. By the summer the Marbella desalination plant will double its current production (from six to 12 cubic hectometres per year), according to the decree.
Permits for new desalination plants are made easier in the latest drought decree, with the delegates of the regional government in each province empowered to authorise portable desalination facilities. This includes, for example, the project in Estepona, which has already applied for permits and will be the first example of desalination in the municipality. It could be active by April and will contribute 2,900 cubic hectometres per day.
Exceptions to filling of pools and mixing of resources
According to the decree, the murky water left at the bottom of La Concepción can be mixed with water sourced elsewhere, such as the Lower Guadalhorce, Fahala and Aljaima, Guadalmansa, Fuengirola and El Traiphe, to improve its quality and make it usable.
Meanwhile farmers will be unable to start new areas of irrigated crops, and existing areas must be reduced by 75%, save exceptions agreed with associations of growers.
Fines for non-compliance with the rules range from 6,000 to 300,000 euros, depending on the infringement.
Interestingly, the new decree also details exceptions to the prohibition on filling swimming pools, but only with prior permission: "Partial filling of swimming pools with a water recirculation system will be allowed, in the quantities necessary to replace water losses due to evaporation and filter cleaning and to guarantee the sanitary quality of the water." Also permitted will be "the first filling of swimming pools of new construction or filling a pool following restoration or modification work" and in schools, "the complete or partial filling of children's dismantleable pools with a capacity of under 500 litres".
Te puede interesar


I don’t know what’s going on, and I can’t tell you what to believe, but I can report and let YOU decide.
That’s what we do here at WeLoveTrump.
And that’s why I like this guy Richard Citizen Journalist so much.
He does the same thing.
It looks like he either lives in D.C. or is staying in D.C. and he’s been doing some incredible citizen reporting recently.
His most recent is where he literally has his TV on live CNN and they are claiming a big live event is happening in the Rose Garden and then he turns the camera out his window looking down on the Rose Garden and it’s EMPTY.
Clearly no one there.
So what in the world is going on?
Are we all watching a show?
Watch it here safely on Rumble:
See it on Telegram here: https://t.me/ericfmoore/1922


text:
Researchers have found a new source for a key fat in infant development using hazelnuts! The University of Georgia researchers say that a mother’s breast milk is the best food for infants, but they have come up with a “designer fat” for bottle-fed babies based on hazelnut oil that provides essential nutrients usually found in mother’s milk.
This nutrient alternative provides the healthful omega-3 fatty acid DHA (Docosahexaenoic acid) and omega-6 fatty acid ARA (Arachidonic acid), both important for the development of the brain and other organs for infants during the last three months of pregnancy. Just one more reason hazelnuts are good for you!
These findings were published in the Journal of Agricultural and Food Chemistry–click here for more information.

domain: food


text:
Two bits of Nicki Minaj news today: First, the 31-year-old rapper has revealed that she does have plans to go on tour again in 2015. Second, listen to a new remix of August Alsina's 'No Love' featuring Minaj on vocals.
Adam Levine has enlisted the help of Fleetwood Mac singer Stevie Nicks to perform at his wedding today (July 19). Us Weekly reports that Nicks will be performing at Levine's ceremony, where he will wed Behati Prinsloo at a closed ceremony in Mexico.
Selena Gomez got an early birthday present yesterday from famed Italian singer Tony Renis, who serenaded the young star with an early Happy Birthday song. Click on the video above to watch Gomez getting swooned by Renis.
Drake put his comedic talents to work last night (July 16) as the host of the ESPY Awards. In addition to appearing in a sketch together with Chris Brown, the 'Started From the Bottom' rapper also impersonated boxer Manny Pacquiao hilariously trying to sing 'Let it Go' from 'Frozen.'
'Weird Al' Yankovic takes on Iggy Azalea's No. 1 hit 'Fancy' and much like Azalea, he's showing off his own swagger and style, but with a toilet plunger instead of high heels. 'Handy' is the fourth Weird Al parody video released this week off of his 'Mandatory Fun' album, which hit stores on Tuesday.
Jessica Simpson and former NFL star Eric Johnson tied the knot on July 5 in a lavish gathering at the San Ysidro Ranch in Montecito, Calif. People TV has a look inside Simpson and Johnson's wedding, including a look at the ceremony and the elegant reception.
Tracy Morgan's lawyers filed a lawsuit against Walmart on Thursday following the June car crash that left a friend of Morgan's dead, and Morgan himself in critical condition. The lawsuit is accusing Walmart of negligence which resulted in the crash.
After media reported yesterday that Kim Kardashian gave some controversial advice for pregnant women in regards to style, the 33-year-old reality star took to Twitter Saturday morning to defend herself, claiming her quote was made out of sarcasm, and was joking when she made the comment.
It appears that you already have an account created within our VIP network of sites on .
To keep your personal information safe, we need to verify that it's really you.
To activate your account, please confirm your password.
When you have confirmed your password, you will be able to log in through Facebook on both sites.
*Please note that your prizes and activities will not be shared between programs within our VIP network.
Welcome back to Q VIP
It appears that you already have an account on this site associated with . To connect your existing account just click on the account activation button below. You will maintain your existing VIP profile. After you do this, you will be able to always log in to http://kqvt.com using your original account information.

domain: entertainment


text:
Broadstone Lodge Guest House
No prices found through our partners. Please contact the business directly or check some of our recommended alternatives.
TripAdvisor Reviews Broadstone Lodge Guest House Inverness
Travel Blogs from Inverness
... guides. The wind was blustery and cold but the information in the audio guide was very informative and we enjoyed the walk.
This morning (Thursday) we went into Inverness to have a look around. Inverness city centre is, for the most part, very drab and the sandstone buildings are very dirty looking. We found the tourist information centre and, armed with maps, we went to the Museum and Art Gallery. We were very pleased that we ...
... 5. He also gave us a map of Inverness and told us where we could find a pub. So we got things settled and headed to The Castle View Pub just a block from Ardconnel. Larry and Erin had a pint of Belhaven's Best Ale and I had a lager shandy with Carlsburg lager.
Then we walked across the street to the Castle which is now law courts for the city and looked at the Ness River from up on the cliff. Then we went back to the B & B and went to bed.
... deep in countryside even though we remained within the bounds of the city of Inverness (which has half the population of Oxford.)
The canal follows the Great Glenn geological fault and joins Inverness on the East coast with Fort William on the West. One third of its 60 miles is man made, the remainder using Lochs Ness, Oich and Lochy.
... surround the lake.
Around 7:00, we finally headed to the hostel with a quick stop at Aldi to pick up dinner and snacks. The hostel is pretty nice and there is a car park right next door. We are in an eight bed dorm by ourselves right now. Cross your fingers that it stays that way. We seem to get the good places where we stay for only one night. Tomorrow we are going to see two girls from Ecuador that we used to work with.
# of countries: 34
Mid-trajectory, Alison exclaims with sudden alarm, "We forgot the flowers!!!" My goodness, to see the panic on her face, you could have believed the flowers represented some saintly cure for the damned, the Philosopher's Stone itself! I told her it was fine, let’s just get to the train. Now, bearing in mind I had already experienced a fairly overwhelming day, what ensued very nearly finished me off. We arrive at the ...

domain: travel


text:
I want to be awake. I had been racking my brain to find a way to get Tom Simpson to tell me where his birthmark was without alerting Bryce, and my innocent baby sister had discovered it unintentionally. Peat moss is a manufactured product for use in garden cultivation.
In March a very impressive eruption shook the volcano, with lava fountains higher than a kilometre. Just as Talon had been, in that dark, cold basement. You stayed with me all night. The room was bare but for some old metal shelving. I hopped to the front where the garage door was.
I was driving with a lead foot, and I reached Delta in less than ten minutes. But by the end of two days, we had the suite of measurements we needed. Of course, if you also want the wonderful benefits of minerals too, just add Guardian Of Eden Sea Soak.
They must be giving me lots of ibuprofen. And then she would leave me. Therefore, you should not expect that all of your personal information will be completely removed from our databases in response to your requests.
As concentration gradually reduces, its rate of decomposition slows. It will oxygenate the roots to protect against root rot and will kill bacteria and fungus, but will not harm garden worms.
The man finished binding my ankles. Blackness descended like a curtain around me. But here, our sampling quadcopter was temporarily grounded, and even the mighty STICK wasn't going to reach.
Use your head, Melanie.
Would their police station be open? My arms were braced, ready to break free when— My wrists suddenly appeared in front of me! Not as much fun anymore.
Water is h2o, meaning only 1 atom of oxygen. Each exposure means sooner than before.Subscribe now and save, give a gift subscription or get help with an existing subscription. Carbon (from Latin: carbo "coal") is a chemical element with symbol C and atomic number 6. It is nonmetallic and tetravalent—making four electrons available to form covalent chemical cytopix.com belongs to group 14 of the periodic table.
Three isotopes occur naturally, 12 C and 13 C being stable, while 14 C is a radionuclide, decaying with a half-life of about 5, years. Welcome to our NEW Swimming Pool & Hot Tub info page. Many of the beautiful pools and hot tubs of the rich and famous are professionally maintained upon the knowledge offered here.
Not necessarily. When exposed to air, ground beef undergoes a process known as lipid oxidation, which can cause spoilage over an extended period of time and typically is accompanied by discoloration.
Yahoo Lifestyle is your source for style, beauty, and wellness, including health, inspiring stories, and the latest fashion trends. Back to Carbon Dioxide Lasers Sub-Table of Contents.
Marking, Burning and Cutting Lasers, Costs Marking/Engraviing Lasers (From: Leonard Migliore ([email protected]).) If you want to make white marks on black or color anodize, a low-power (like 10 watts) CO2 laser does a good job.Download

domain: chemistry


text:
Spherical Google Nexus Q gets delayed due to negative feedback
Most people remember Google’s last I/O conference back in June for those video streaming glasses or Android Jelly Bean, but the Goog also unveiled another gadget called the Nexus Q at the event. Now we’re hearing that the spherical Nexus Q streaming device is getting pushed back after receiving a number of poor reviews.
Another Google Nexus hardware device
Google is traditionally a software company and all of its top products, such as Google search, Gmail, Android, YouTube, etc., reflect as much. However, the Mountain View tech giant is also increasingly getting involved in hardware, as demonstrated by its Nexus smartphones, or super ambitious projects like its self-driving car. At its last I/O conference, the Goog expanded the Nexus line-up to include the Nexus 7 tablet, as well as a media streaming device, the Nexus Q. However, whilst the Nexus tablet was met by near universal acclaim, the Nexus Q was regarded much differently.
Fails to fill a niche
The biggest problem facing the Nexus Q was arguably one of identity. Reviewers were unsure of its exact purpose and even Google didn’t really clarify things too much. Basically, the device can be used to stream content on your TV, although Google TV set top boxes already accomplish the same thing. The Android sphere can also be used to stream music to speakers, but you need to use a dedicated Android app (running on an Android device) to operate it to begin with. Not only is this an inconvenience, but it also kind of removes much of the purpose for using the Nexus Q, since you could instead simply opt to stream music on speakers with your Android smartphone or tablet.
Plagued by bugs
Beyond its identity issues, the Nexus Q was plagued by a number of other problems, including bugs. For one, the supposedly HD media streamer sadly streamed video content in less than fantastic quality. Aside from requiring an Android device to operate, the Google Nexus Q is also restricted to only using Google services, like YouTube, the Play Store or Google Music. Then bugs were widely reported, including the device randomly dropping connections. The final nail in the coffin was no doubt the Google music ball’s ridiculously high price of $299. With all that said, the Nexus Q did maintain a bright spot, with its creative design that was nearly universally praised.
Giving away free models to pre-orderers
Unlike Apple, Google is famous for releasing products to the public in ‘beta mode’ and then making improvements based on customer feedback. Of course, this strategy works a bit better with software, where fixing something is as simple as issuing an update, rather than hardware where you have to ship an entirely new fixed up version. Fortunately, Google has admitted that the Nexus Q is not ready commercially and is taking all the feedback to heart by delaying the product’s release until it’s ready (no ETA on this). Moreover, Google has also been nice enough to ship all those people who already pre-ordered the device, a free Nexus Q as a token of gratitude for their patience.

domain: news


text:
International Call for Scores 2015 - Schallfeld goes electronic
Ensemble Schallfeld in cooperation
with Kulturzentrum bei den Minoriten invited composers from all nationalities
born in or after 1974 to send in pieces for ensemble and electronics. The performance of the chosen pieces by Davide Gagliardi, Bnaya Halperin-Kaddari, Mariana Ungureanu took place in a concert at June 5th in the large Minoritensaal.
Since 2013 Schallfeld has been active in Graz and Austria as a young ensemble and platform for the promotion of contemporary music by international composers, mostly of the younger generation. Beyond being a "traditional ensemble", Schallfeld is active as a free artists' collective, consisting of musicians
with different backgrounds and interests. This leads to the great diversity of Schallfeld's activities, ranging from music theatre to sound art, chamber music, improvisation and educational activities.

domain: artistic


text:
6mm lapis and 4mm lapis rest upon a simple organic form. This hand sawn ring is made out of sterling silver making each one unique, no two will be alike. Each stone is hand set in fine silver and the entire piece has a brushed finish.
Lapis is a blue stone with specks of gold that represents vision, truth and awareness. Each stone is unique in itself, the stone you get may look slightly different then the stones in the photos. Please allow for variance.
*While I have some quantities in stock, most pieces are made to order and will ship within 5-10 business days. In stock items will ship within 1-3 business days. Please contact me if you want to know the availability or time frame of a piece.
*Please contact me if you would like to order a custom size or a custom item.
*100% designed and made by hand in my shop in Illinois.


text:
Audrey and James Hanson circa 1952It is said that Audrey claimed that her relationship with James Hanson was 'love at first sight' and was engaged to him in 1952 for a year. While filming Roman Holiday with Gregory Peck She approached the highly renowned Italian designers, the Fontana Sisters to design her gown. Sadly, that wedding was not meant to be as Audrey had other plans. At that point, she was reaching great heights in her career, and decided that “That the demands of their careers would keep them apart most of the time.” so she called the wedding off.
However, the dress that she had had made by the Fontana Sisters was still at their shop, and it needed to be dealt with, so what did Audrey do? She gave her gorgeous, custom made dress away...to a young Italian woman from the town of Latina, Italy. You see Audrey had asked the Fontana Sisters to give the dress away, saying “I want my dress to be worn by another girl for her wedding, perhaps someone who couldn’t ever afford a dress like mine, the most beautiful, poor Italian girl you can find.” So The Fontana Sisters found Amabile Altobella, a poverty stricken young Italian girl engaged to be married to a farm worker named Adelino Solda. Here is a quote from Amabile, “I have had a happy marriage, so the dress brought me luck.” What a lucky gal!
Just goes to show how generous, and kind Audrey was... and one of the many reasons why I admire her...
Courtesy of Kerry Taylor auctions.


Waterless coolant is pretty much snake oil when it comes to pressurised cooling systems. Its a less efficient coolant and requires much greater temperature changes to extract any given amount of heat.
With a pressurised water based cooling system you can arrange things so that most of the heat energy being taken out of the engine goes into trying to boil the water against the pressure head. As the energy needed to change the state of water from liquid to vapour is large a lot of heat can be absorbed without much change in coolant temperature. Which makes it much easier to keep the whole engine temperature stable. Theoretical ideal is for the hot coolant entering the radiator to have not quite enough energy to boil against the pressure head and the coolant leaving the radiator to be just a fraction below boiling point at that pressure. In a real system you make sure you have some margin but the temperature can be much more stable than with waterless coolant where any heat extracted from the engine goes directly into changing the coolant temperature.
The raison d'etre of waterless coolant is its much higher boiling point than unpressurised water. So it works pretty well in a crude, unpressurised or low pressure motor with a big cooling system and lots of metal in the block. A big metal block makes an effective heat sink smoothing out temperature variations between cold and hot ends. Lots of coolant rushing round allows the heat to be taken up without too much difference between hot and cold ends. But its still hard to arrange a nice smooth temperature gradient from the bottom of the block, where the coolant enters, up to the head where it leaves. With conventional coolant passage layout having water inlet and outlet at the same end of the motor with longitudinal galleries in block and head joined by vertical passages its very easy to have a short circuited system where the back end of the engine runs dangerously hotter than the front.
For all sorts of reasons our alloy V8 engines don't do well with internal temperature variations so are intrinsically unsuited to waterless coolants. It's a big cooling system so you can get away with it if you don't push too hard or in racing where high power, and high heat, normally goes with high speed so plenty of airflow over the radiator and in the engine compartment to help keep stuff cool. A modern motor designed for waterless coolant will have a rather different coolant passage layout.
Finally, unpleasant though boiling is with steam flying everywhere, it is very effective at pulling a lot of heat out of the motor very quickly. Just need to ensure coolant flow is continuous and all the passages are full to keep drawing the heat out. Much easier said than done. Which is why steam cooling where the coolant turns to vapour inside the motor has never been made to work reliably despite being much more efficient and needing far less coolant than a conventional system.
As usual there are darn good reasons for the conventional fuddy duddy engineering approach. You have to work hard to come up with something that is all round better.


text:
|Genre||Collection (Essays) (256 pp.)|
|Keywords||Communication, Freedom, Human Worth, Individuality, Religion, Science, Science Fiction, Society, Spirituality, Survival, Technology, Time|
The book begins with a "Twenty Question Multiple Choice Self-Help Quiz." Each question is actually a short chapter. For example, the first chapter deals with the "amnesic self" and asks why amnesia is a favorite device in fiction and especially soap operas. Other chapters deal with the nowhere self, the fearful self, the promiscuous self, and so forth.
The second part of the book is an essay on the nature of the self, complete with numerous diagrams and arrows. The third section presents discussions of various manifestations of the self as transcendent, orbiting, exempted, lonely, and demoniac. The last part is called "A Space Odyssey" and is captioned "What to do if there is no man Friday out there and we really are alone?"
Obviously, this summary says virtually nothing about what the book is about. Suffice it to say that Percy brings his playful humor to the central existential question of human meaning and he presents it in the form of a self-help manual.
|Commentary||This book is an imaginative mixture of fact and fiction, science and religion, history and current affairs, all of which are served up in a ruefully humorous style. The last two chapters ("A Space Odyssey") are particularly innovative. In them Percy spins yarns about two spaceships from Earth, one of which encounters sentient beings in a different star system, but has to turn back because human beings are considered too violent to make contact with. The other spaceship discovers no alien civilizations, but returns home to a devastated Earth 457 years after it took off.|
|Publisher||Farrar, Straus & Giroux|
|Place Published||New York|
|Annotated by||Coulehan, Jack|
|Date of Entry||09/16/97|

domain: library


text:
The textuality of my writing essay
This thesis examines the formative fiction of j m coetzee and his first book of essays, white writing: on the textuality & the land: reading 'white writing' and. Read this essay and over 1,500,000 others like it now sexuality/textuality in tristram shandy either by writing epistolary novels1. Seven standards of textuality: cohesive strategies - language in standards of textuality: cohesive strategies of textuality: cohesive strategies - language in use. Garde works characterised by complex textuality writing essays on love how do i start my essay my family college essay impact of web.
Narrative, literature, essay - intertextuality in writing and composition. Finished my carrer essay now i dont with four essays on textuality just wrote an essay over gmo to writing the essay on blackjazz for my university. If you are having issues with an academic writing assignment, our custom essay writing service is ready to help you in short terms we ensure a quick and efficient. Essay writing service because we do want you to enjoy college essay writing help from us, and want to see you back on our website as soon as possible.
“text” is an interesting lens to look at writing through there are literally brand-new spaces for writing being created by new technology and innovations still. Write my essay we are the most trusted essay writing service get the best essays childrens picture book review academic essay inter-textuality. Teaching of writing lab search working towards the final product of a formal essay, my students need to understand how to structure termed as textuality. Free essay: in the email above, though i was connecting my email with me, i didn’t include a picture i could have snapped a shot of myself the same day i. Over the past decade literary critic and editor jerome mcgann has developed a theory of textuality based in writing and essays extend his the textual condition.
Cohesion in composition in writing, cohesion is the use of repetition unity in paragraphs and essays. Essays and criticism on william shakespeare's othello - theatricality and textuality: the example of othello. Death of the author english literature essay the language of textuality itself will we provide top quality academic writing to assist with your essay and. Extract of sample how reading and writing has affected my to improve my writing abilities handbook and textuality in terms of educating.
- Cyberspace textuality: these essays are a wonderful introduction to the topic of cyberspace barbara page draws provocative parallels among women's writing.
- Greco-roman textuality and essay two main matters not given enough attention in previous assessments and writing in the ancient near east.
Writing the body: kafka, textuality and contemporary theories of embodiment uploaded by when the body is conceptualized in terms of writing and textuality. Book – material – text essays on the materiality, mediality and textuality of the (e)book. Page 2 russian formalism essay the form thus conveys the notion of textuality and how a work of art but instead it focused its critical writing on the novel.

domain: literature


text:
On 1 August 2017, a hard fork of bitcoin was created, known as Bitcoin Cash. Bitcoin Cash has a larger block size limit and had an identical blockchain at the time of fork. On 24 October 2017 another hard fork, Bitcoin Gold, was created. Bitcoin Gold changes the proof-of-work algorithm used in mining, as the developers felt that mining had become too specialized.
Press Contacts: San Francisco, CA, Kerryn Lloyd, [email protected] San Francisco, CA – August 28, 2018 –The Bitcoin Foundation has received a commitment of $200,000 for its 2018/2019 plan - $100,000 from Brock Pierce, a venture capitalist, philanthropist, serial entrepreneur and Chairman of the Bitcoin Foundation and a further $100,000 commitment [...]
Somewhere around 2017, the concept of web mining came to life. Simply put, web mining allows website owners to “hijack,” so to speak, their visitors’ CPUs and use them to mine Bitcoin. This means that a website owner can make use of thousands of “innocent” CPUs in order to gain profits. However, since mining Bitcoins isn’t really profitable with a CPU, most of the sites that utilize web mining mine Monero instead. Up until today, over 20,000 sites have been known to utilize web mining.
Bitcoin is a type of cryptocurrency: Balances are kept using public and private "keys," which are long strings of numbers and letters linked through the mathematical encryption algorithm that was used to create them. The public key (comparable to a bank account number) serves as the address which is published to the world and to which others may send bitcoins. The private key (comparable to an ATM PIN) is meant to be a guarded secret, and only used to authorize Bitcoin transmissions.
The Bitcoin mining network difficulty is the measure of how difficult it is to find a new block compared to the easiest it can ever be. It is recalculated every 2016 blocks to a value such that the previous 2016 blocks would have been generated in exactly two weeks had everyone been mining at this difficulty. This will yield, on average, one block every ten minutes.
^ Jump up to: a b "Bitcoin and other cryptocurrencies are useless". The Economist. 30 August 2018. Retrieved 4 September 2018. Lack of adoption and loads of volatility mean that cryptocurrencies satisfy none of those criteria. That does not mean they are going to go away (though scrutiny from regulators concerned about the fraud and sharp practice that is rife in the industry may dampen excitement in future). But as things stand there is little reason to think that cryptocurrencies will remain more than an overcomplicated, untrustworthy casino.
You can look at this hash as a really long number. (It's a hexadecimal number, meaning the letters A-F are the digits 10-15.) To ensure that blocks are found roughly every ten minutes, there is what's called a difficulty target. To create a valid block your miner has to find a hash that is below the difficulty target. So if for example the difficulty target is
Just like you don’t walk around with your savings account as cash, there are different Bitcoin wallets that should be used depending on how much money is being stored or transferred. Secure wallets like paper wallets or hardware wallets can be used as “savings” wallets, while mobile, web, and desktop wallets should be treated like your spending wallet.
Bitcoin cloud mining can be a tricky thing to determine if it’s completely safe in the Bitcoin world, and if it is, will it be cost effective? The return on your investment can be longer than other alternatives such as buying and selling Bitcoin. This can be due to the fees involved, the time it takes to mine, the upfront costs and the value of Bitcoin during that time. The upside is that if the costs are reasonable, the cloud mining operation has good rewards and the price of Bitcoin rises, you will more than likely end up making a healthy return on your investment.
The concept of a virtual currency is still novel and, compared to traditional investments, Bitcoin doesn't have much of a longterm track record or history of credibility to back it. With their increasing use, bitcoins are becoming less experimental every day, of course; still, after eight years, they (like all digital currencies) remain in a development phase, still evolving. "It is pretty much the highest-risk, highest-return investment that you can possibly make,” says Barry Silbert, CEO of Digital Currency Group, which builds and invests in Bitcoin and blockchain companies.
Difficulty increase per year: This is probably the most important and elusive variable of them all. The idea is that since no one can actually predict the rate of miners joining the network, neither can anyone predict how difficult it will be to mine in six weeks, six months, or six years from now. In fact, in all the time Bitcoin has existed, its profitability has dropped only a handful of times—even at times when the price was relatively low.
Across the Mid-Columbia Basin, miners faced an excruciating dilemma: cut their losses and walk, or keep mining for basically nothing in the hopes that the cryptocurrency market would somehow turn around. Many smaller operators simply folded and left town—often leaving behind trashed sites and angry landlords. Even larger players began to draw lines in the sand. Carlson started moving out of mining and into hosting and running sites for other miners. Others held on. Among the latter was Salcido, the Wenatchee contractor-turned-bitcoin miner who grew up in the valley. “What I had to decide was, do I think this recovers, or does the chart keep going like this and become nothing?” Salcido told me recently. We were in his office in downtown Wenatchee, and Salcido, a clean-cut 43-year-old who is married with four young kids, was showing me a computer chart of the bitcoin price during what was one of the most agonizing periods of his life. “Month over month, you had to make this decision: Am I going to keep doing this, or am I going to call it?”
During mining, your Bitcoin mining hardware runs a cryptographic hashing function (two rounds of SHA256) on what is called a block header. For each new hash that is tried, the mining software will use a different number as the random element of the block header, this number is called the nonce. Depending on the nonce and what else is in the block the hashing function will yield a hash which looks something like this:
Bitcoin is pseudonymous, meaning that funds are not tied to real-world entities but rather bitcoin addresses. Owners of bitcoin addresses are not explicitly identified, but all transactions on the blockchain are public. In addition, transactions can be linked to individuals and companies through "idioms of use" (e.g., transactions that spend coins from multiple inputs indicate that the inputs may have a common owner) and corroborating public transaction data with known information on owners of certain addresses. Additionally, bitcoin exchanges, where bitcoins are traded for traditional currencies, may be required by law to collect personal information.
Although BitFury claims to be producing chips whose performance is nearly identical to those used in the S9, the company has packaged them into a very different product. Called the BlockBox, it’s a complete bitcoin-mining data center that BitFury ships to customers in a storage container. Beijing’s Canaan Creative is still selling mining rigs to the public, but it offers only one product, the AvalonMiner 741, and it’s only half as powerful and slightly less efficient than the S9.
You’ll need a Bitcoin wallet in which to keep your mined Bitcoins. Once you have a wallet, make sure to get your wallet address. It will be a long sequence of letters and numbers. Each wallet has a different way to get the public Bitcoin address, but most wallets are pretty straightforward about it. Notice that you’ll need your PUBLIC Bitcoin address and not your private key (which is like the secret password for your wallet).
From a widespread adoption standpoint: for the typical consumer, Bitcoin is technically challenging and cumbersome to use for the inexperienced. They also forfeit the consumer protections afforded by traditional credit and debt cards. Merchants already have incentive to accept it in the form of reduced fees for accepting payments over typical payment processors.
This bizarre process might not seem like it would need that much electricity—and in the early years, it didn’t. When he first started in 2012, Carlson was mining bitcoin on his gaming computer, and even when he built his first real dedicated mining rig, that machine used maybe 1,200 watts—about as much as a hairdryer or a microwave oven. Even with Seattle’s electricity prices, Carlson was spending around $2 per bitcoin, which was then selling for around $12. In fact, Carlson was making such a nice profit that he began to dream about running a bunch of servers and making some serious money. He wasn’t alone. Across the expanding bitcoin universe, lots of miners were thinking about scaling up, turning their basements and spare bedrooms into jury-rigged data centers. But most of these people were thinking small, like maybe 10 kilowatts, about what four normal households might use. Carlson’s idea was to leapfrog the basement phase and go right to a commercial-scale bitcoin mine that was huge: 1,000 kilowatts. “I started to have this dream, that I was posting on online forums, ‘I think I could build the first megawatt-scale mine.’”
In exchange for securing the network, and as the “lottery price” that serves as an incentive for burning this energy, each new block includes a special transaction. It’s this transaction that awards the miner with new bitcoins, which is how bitcoins first come into circulation. At Bitcoin’s launch, each new block awarded the miner with 50 bitcoins, and this amount halves every four years: Currently each block includes 12.5 new bitcoins. Additionally, miners get to keep any mining fees that were attached to the transactions they included in their blocks.
Malachi Salcido: The Local Talent Salcido, a Wenatchee native and building contractor, studied other miners before launching his own bitcoin operation in 2014. He’s now one of the biggest miners in the basin, and has worked hard to convince the community that bitcoin and the blockchain could transform the region into a technology hub. “What you can actually do with the technology, we’re only beginning to discover,” says Salcido, pictured above in one of his mines. The basin is “building a platform that the entire world is going to use.” | Patrick Cavan Brown for Politico Magazine
Legal Gray Area. Major governments have largely remained on the sidelines, and this has created both a sense of potential and apprehension for Bitcoin proponents and critics respectively. Bitcoin isn’t backed by a regulatory agency and a government would technically be ceding power by supporting a decentralized currency. This has been largely officially unaddressed. Bitcoin’s price, however, tends to be very sensitive to any news concerning the US government’s opinion of cryptocurrencies. For example, when the SEC denied the approval of bitcoin-based exchange-traded-products—essentially bitcoin-backed assets on the stock market—in 2017, Bitcoin’s price dropped 18%. Yet while the price and adoption of Bitcoin would be affected by government action, governments are unable to criminalize Bitcoin. In fact, governments such as the United States and China have invested in it at some capacity.
As more miners join, the rate of block creation increases. As the rate of block generation increases, the difficulty rises to compensate, which has a balancing of effect due to reducing the rate of block-creation. Any blocks released by malicious miners that do not meet the required difficulty target will simply be rejected by the other participants in the network.
Bitmain gained an edge by supplying a superior product in large quantities, a feat that has eluded every other company in the industry. The Ordos facility is stuffed almost exclusively with Bitmain’s best performing rig, the Antminer S9. According to company specs, the S9 is capable of churning out 14 terahashes, or 14 trillion hashes, every second while consuming around 0.1 joules of energy per gigahash for a total of about 1,400 watts (about as much as a microwave oven consumes).
Controlling and monitoring your mining rig requires dedicated software. Depending on what mining rig you have, you’ll need to find the right software. Many mining pools have their own software, but some don’t. In case you’re not sure which mining software you need, you can find a list of Bitcoin mining software here. Also, if you want to compare different mining software, you can do it here.
The Ledger Nano is a smartcard based hardware wallet. Private keys are generated and signed offline in the smartcard’s secure environment. The Nano is setup using the Ledger Chrome Application. A random 24-word seed is generated upon setup and backed offline by writing it down on a piece of paper. In case of theft, damage or loss, the entire wallet can be recreated with the seed. A user selected PIN code is also assigned to the device to protect against physical theft or hacking.
To heighten financial privacy, a new bitcoin address can be generated for each transaction. For example, hierarchical deterministic wallets generate pseudorandom "rolling addresses" for every transaction from a single seed, while only requiring a single passphrase to be remembered to recover all corresponding private keys. Researchers at Stanford and Concordia universities have also shown that bitcoin exchanges and other entities can prove assets, liabilities, and solvency without revealing their addresses using zero-knowledge proofs. "Bulletproofs," a version of Confidential Transactions proposed by Greg Maxwell, have been tested by Professor Dan Boneh of Stanford. Other solutions such Merkelized Abstract Syntax Trees (MAST), pay-to-script-hash (P2SH) with MERKLE-BRANCH-VERIFY, and "Tail Call Execution Semantics", have also been proposed to support private smart contracts.


How many band shirts do you have in your closet? Yeah me to. When I was younger I bought a shirt at every show I went to. Many of them are from seeing Motley Crue, but I still have an Iron Maiden shirt from a show at Pershing Center a very long time ago. A recent study shows Metalheads are the most avid t-shirt collectors. Not a surprise to those of us with a closet full of black metal shirts.
Read the full story from MetalSucks


text:
Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2+ subtype of breast cancer. Using an isogeneic progression series of HER2+ breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2). Genetic depletion and overexpression approaches established that TG2 is both necessary and sufficient for acquisition of neratinib resistance. Mechanistically, we describe a pathway in which TG2-mediates activation of NF-κB signaling leading to upregulation of IL-6 in metastatic cells. This autocrine expression of IL-6 functions to maintain enhanced levels of TG2 via JAK:STAT3 signaling. This drug persistence feedback loop can be interrupted through the use of the JAK1/2 inhibitor ruxolitinib. In vivo application of ruxolitinib had no effect on tumor growth under non-treated conditions, but effectively prevented acquisition of resistance, leading to tumor regression upon coadministration with neratinib. Overall, our studies reveal a mechanism in metastatic breast cancer cells that predisposes them to acquisition of resistance to ErbB-targeted therapeutics. Clinically, immediate application of ruxolitinib could prevent acquisition of resistance and improve patient responses to HER2-targeted therapies.
Human epidermal growth factor receptor-2 (HER2) is overexpressed in approximately 20% of breast cancers. The ability to clinically identify this driver event has led the development and effective application of a growing variety of HER2-targeted agents including antibodies, antibody drug conjugates and kinase inhibitors . Despite the clinical success of HER2-targeting agents, the presence of drug persistent minimal residual disease and recurrence of fully drug resistant tumors frequently occurs in the metastatic setting [2,3,4].
Neratinib is a covalent kinase inhibitor approved for use in HER2+ breast cancer in 2017 . Neratinib is a highly potent compound that has significant inhibitory activity against EGFR, HER2 and ErbB4 . We have demonstrated that prolonged treatments with the first generation HER2/EGFR competitive kinase inhibitor, lapatinib, can result in spontaneous acquisition of resistance. In contrast, treatment with neratinib and the related covalent ErbB inhibitor, afatinib, fails to result in spontaneous resistance . The reasons for the sustained efficiency of neratinib are not completely clear, but neratinib does target an increased number of kinases outside of the ErbB family as compared to lapatinib. Additionally, unlike lapatinib, neratinib induces the degradation of HER2 [8, 9].
Tissue transglutaminase 2 (TG2) plays several roles in tumor biology where it is secreted and acts as a crosslinking enzyme capable of stabilizing the fibrillar nature of the extracellular matrix . We and others have also demonstrated that TG2 is present on tumor cell-derived extracellular vesicles and participates in the creation of pre-metastatic niches [11, 12]. In addition to the extracellular activities, TG2 is also active inside the cell where it crosslinks Iκbα making it unavailable for cytoplasmic sequestration of Nuclear factor-kappa-B (NF-κB) [13, 14]. Upregulation of proinflammatory NF-κB signaling plays important roles in sensing and contributing to changes in the tumor microenvironment (TME). Activation of NF-κB signaling has also been linked to lapatinib resistance and resistance to the anti-HER2 therapeutic antibody trastuzumab [15, 16]. Despite these findings the mediators of NF-κB activation and the function of this pathway in response to the next generation kinase inhibitors remained to be determined.
A critical downstream output of NF-κB activation is the upregulation of interleukin-6 (IL-6). This cytokine can be produced by a number of stromal cell types and acts on tumor cells in a paracrine fashion. In addition, tumor cells can also produce IL-6 to establish an autocrine signaling axis. IL-6 and downstream activation of JAK2/STAT3 signaling play critical roles in tumor progression, establishment of a stem-like phenotype, and drug resistance . Importantly, this pathway can be readily blocked via application of clinically approved IL-6 blocking antibodies and JAK inhibitors, such as ruxolitinib .
In the current study, we establish that in metastatic HER2+ breast cancer cells upregulation of TG2 is an initiating component of the NF-κB:STAT3 signaling loop allowing cells to persist in the presence of neratinib. We utilize a number of genetic and pharmacological approaches to demonstrate the importance of this feedback signaling loop in facilitating acquisition of neratinib resistance. Overall, our studies support the notion that combining ruxolitinib with HER2-targeted agents could inhibit the development of drug resistance in the metastatic setting and prolong patient response to ErbB-targeted agents.
Transglutaminase 2 facilitates acquired resistance to neratinib
Previous studies from our lab and others demonstrate that directed overexpression of HER2 is sufficient to transform the immortalized human mammary epithelial (HMLE) cell line [7, 18]. These HER2 transformed cells (HME2) are sensitive to treatment with ErbB inhibitors including neratinib, which potently inhibits HER2 phosphorylation and leads to degradation of the receptor (Fig. 1a and 1b) . In our previous studies, we utilized RNA sequencing analyses to characterize gene expression differences between the parental HME2 population and their isogenic derivatives that were isolated and subcultured from bone metastases (HME2-BM) [11, 19]. These analyses indicate that TG2 is part of a 1150 gene signature that is significantly regulated in the HME2-BM cells as compare the HME2 parental population. In addition to these mRNA analyses this increase in TG2 expression can also be readily observed at the protein level (Fig. 1c) . To characterize the functional role of TG2 in response to neratinib we depleted its expression in the BM cells and overexpressed it in the HME2 parental population (Fig. 1c) . In contrast to the HME2 parental population, the HME2-BM cells were capable of spontaneously developing resistance to neratinib upon prolonged drug treatment (Fig. 1d). Using a 3D culture approach we could readily observe the formation of drug resistant HME2-BM cell clusters upon 4 weeks of treatment with neratinib (Fig. 1d). Importantly, acquisition of neratinib resistance was abolished upon depletion of TG2 (Fig. 1d). Furthermore, directed overexpression of TG2 in the HME2 parental cells resulted in the formation of drug resistant cell clusters (Fig. 1d). Similar to what was observed using 3D culture, TG2 was both necessary and sufficient for acquisition of neratinib resistance under 2D culture conditions (Fig. 1e). Expansion of these neratinib resistant populations allowed us to quantify greater than tenfold increases in IC50 values compared to drug sensitive counterparts (Fig. 1f).
To validate the in vivo function of TG2 in drug resistance we engrafted TG2-manipulated HME2 and HME2-BM cells onto the mammary fat pad of NSG mice. Upon tumor establishment, mice were treated with neratinib via oral gavage, and the experiment was terminated when the non-treated tumors reached an average of 1000 mm3. The HME2 parental tumors required 39 days to reach 1000 mm3 (Fig. 2a-b). In contrast, the HME2-BM tumors only required 23 days (Fig. 2c-d). This differential primary tumor growth rate was not affected by TG2 expression as neither depletion of TG2 in the HME2-BM cells nor overexpression of TG2 in the HME2 parental cells affected untreated tumor weights (Fig. 2a and b). Treatment with neratinib abolished HME2-parental tumor formation at a dose that did not cause adverse effects to the animals (Fig. 2a-b). Overexpression of TG2 diminished the effectiveness of neratinib at this same dose (Fig. 2a-b). In contrast to the HME2-parental tumors, treatment of the HME2-BM tumors with neratinib did not significantly affect tumor growth, but depletion of TG2 allowed for a significant inhibition of tumor growth upon neratinib treatment (Fig. 2c-d). Taken together these data clearly indicate that TG2 facilitates acquisition of neratinib resistance under 2D, 3D, and in vivo conditions.
Transglutaminase 2 causes increased expression of IL-6
We next sought to identify signaling pathways, other than HER2, that are active in the HME2-BM cells as compared to the HME2-parental. To this end we conducted a kinase array on lysates derived from the two isogenic cell lines. This approach suggested increased phosphorylation of p53, Chk2, and STAT3 (Fig. 3a-b). Consistent with this increase in STAT3 phosphorylation, examination of our gene expression analyses comparing the HME2-parental and BM cells identified upregulation of interleukin 6 (IL-6) in the HME2-BM cells (GSE115255). The enhanced phosphorylation of STAT3 in the HME2-BM cells was verified by immunoblot, and this event was not affected by treatment with the HER2/EGFR inhibitor lapatinib, at concentrations that abolished downstream phosphorylation of Akt in both the HME2-parental and HME2-BM cells (Fig. 3c). Increased expression and secretion of IL-6 in the HME2-BM cells were validated using RT-PCR and AlphaLISA assays (Fig. 3d). These analyses also indicated that directed overexpression of TG2 increased IL-6 in the HME2-parental cells and depletion of TG2 decreased IL-6 expression in the HME2-BM cells (Fig. 3b). Finally, we verified the functionality of this signaling axis in the HME2 cells through treatment with exogenous IL-6 and the JAK1/2 inhibitor ruxolitinib . Clearly, both cells lines are capable of responding to IL-6 and the BM cells signal through JAK2 to phosphorylate STAT3 (Fig. 3e). Overall, these data indicate that increased expression of TG2 in metastatic cells can induce IL-6, leading to constitutive JAK:STAT3 signaling.
Transglutaminase 2-mediated activation of NF-κB is required for neratinib resistance
TG2 has previously been linked to activation of NF-κb and this pathway is a well-established mediator of IL-6 expression [20, 21]. Consistent with these studies, we observed a significant decrease in NF-κb activity when TG2 was depleted (Supplementary Fig. 1). To elucidate if NF-κB activation is the mechanism by which TG2 causes increased expression of IL-6 we overexpressed the super repressor (S.R.), a non-degradable form of IκBα that prevents NF-κB translocation into the nucleus. Indeed, expression of the S.R. reduced expression of IL-6 in both the HME2-BM cells and the TG2 overexpressing HME2 parental cells (Fig. 4a-b). Accordingly, expression of the S.R. reduced STAT3 phosphorylation in both the HME2-BM cells and the TG2-overexpressing HME2-parental cells (Fig. 4c). Importantly, expression of the S.R. prevented spontaneous acquisition of resistance to neratinib upon prolonged culture in the presence of drug (Fig. 4c-d). Taken together, these data suggest a mechanism by which TG2-mediated activation of NF-κB increases autocrine IL-6 expression leading constitutive activation of STAT3, allowing for acquisition of resistance to HER2-targeted therapies.
STAT3-driven expression of transglutaminase-2 drives drug resistance
Previous studies demonstrate that the TG2 proximal promoter contains both NF-κB and STAT3 binding elements and that TG2 expression can be driven by IL-6 [14, 22]. Consistent with these findings and our data in the previous figure, we observed decreased expression of TG2 in the HME2-BM cells when the S.R. was present (Fig. 5a). To directly interrogate the role of STAT3 in mediating TG2 expression we depleted STAT3 using an shRNA approach (Fig. 5b). Indeed, depletion of STAT3 also led to a diminution in TG2 levels (Fig. 5b). Depletion of STAT3 or co-administration of ruxolitinib also decreased the ability of HME2-BM cells to acquire neratinib resistance (Fig. 5c). Similar to depletion of STAT3, treatment of the HME2-BM cells with ruxolitinib also reduced expression of TG2 mRNA and protein (Fig. 5d-e). To evaluate the therapeutic potential of these findings we engrafted either control or STAT3 depleted HME2-BM cells onto the mammary fat pad and treated mice with neratinib, ruxolitinib or a combination of both compounds (Fig. 5f). Consistent with findings in Fig. 2, the HME2-BM cells quickly acquire resistance to neratinib, and tumors continued to grow in the presence of drug treatment (Fig. 5f). Similarly, treatment with ruxolitnib or depletion of STAT3 had no effect on tumor growth (Fig. 5f). In contrast, depletion of STAT3 or combination with ruxolitinib led to tumor regression upon treatment with neratinib (Fig. 5f). Taken together, these data clearly indicate that targeting JAK:STAT signaling in combination with ErbB inhibition can improve response to HER2-targeted therapies.
Expression of TG2 and IL-6 predict disease recurrence in HER2 + breast cancer
To examine the clinical applicability of our findings we analyzed several patient data sets. Consistent with our findings there is a significant correlation between IL-6 and TGM2 mRNA expression across the 1084 patient samples in the TCGA invasive breast cancer dataset (Fig. 6a). Analysis of the RPPA data included in this cohort also demonstrated that TGM2 mRNA is significantly increased in patient samples that have higher levels of STAT3 phosphorylation (Fig. 6a). Similarly, analysis of the 2509 patient samples in the METABRIC dataset also demonstrated a significant correlation between IL6 and TGM2 expression (Fig. 6b). Importantly, those patients with increased levels of TGM2 and IL6 received a significantly poorer prognosis index (Fig. 6b). To further investigate the importance of these factors in disease progression we analyzed relapse free survival in patients bearing increased levels of fibronectin, TGM2, and IL6 (Fig. 6c). These markers clearly predict for decreased patient survival, and breakdown of these findings into breast cancer subtypes indicated that this significance is derived from the HER2+ patients (Fig. 6c). Overall, these clinical findings support and are consistent with our mechanistic data suggesting a signaling loop in which STAT3 contributes to the expression of TGM2, leading to NF-κB-mediated upregulation of IL-6 (Fig. 6d). Overall, this signaling loop appears to play a role in facilitating resistance to neratinib and potentially other HER2-targeted agents.
Induction of epithelial-mesenchymal transition (EMT) is associated with acquisition of drug resistance . The processes of EMT lead to upregulation of bypass growth factor receptors and co-receptors that facilitate tumor growth in the presence of HER2 inhibitors [7, 24]. Indeed, previous studies from our lab demonstrate that prolonged treatment with the HER2-targeting drugs lapatinib and traztuzumab-DM1 results in the emergence of resistance cells that have upregulated fibroblast growth factor receptor (FGFR) and other mechanisms that serve as bypass pathways to achieve proliferative signaling [3, 25, 26]. However, as cells transition between these different growth programs we hypothesized that intermediate mechanisms are at play to allow cells to persist following initial drug challenge. To investigate this, we compared parental HER2-transformed cells (HME2) to their metastatic counter parts (HME-BM). These metastatic cells do not display increased expression of FGFR or other bypass mechanisms and transient dose response assays yielded similar sensitivity to HER2-targeting agents (Fig. 1) . However, upon prolonged neratinib treatment, the HME2-BM metastatic cells are able to spontaneously acquire resistance, an event not observed in their parental HME2 counterparts.
Along these lines, neratinib treatment prevents tumor formation in the HME2 parental cells, but in vivo growth of HME2-BM tumors is not affected by the same treatment. These data suggest that in addition to stable autocrine mechanisms, metastatic cells may also be engaging their microenvironment to resist drug treatment. Accordingly, use of ruxolitinib or depletion of STAT3 led to regression of tumor growth in vivo, suggesting that IL-6 or possibility other inducers of JAK:STAT signaling are clearly at play during in vivo acquisition of drug resistance. Indeed, the broad anti-inflammatory properties of ruxolitinib have been demonstrated in several conditions and drive its indication in graft-versus host disease. This type of response is also consistent the lack of efficacy of ruxolitinib as a single agent in solid tumors [27, 28]. A recent study demonstrates that addition of ruxolitinib to trastuzumab did not improve response in heavily pretreated patients . These clinical findings are consistent with the notion that the TG2:NF-κB:IL6:STAT3 loop is operant during acquisition of resistance, and targeting this pathway is incapable of re-sensitizing tumors that have already bypassed HER2 signaling via alternative growth factor pathways. Given that ruxoltinib is well tolerated by patients, the true clinical utility of this compound in the HER2 setting may be in upfront combination with HER2 targeted agents.
The relationship between Nf-κB:IL6:STAT3 is well established . Our studies add the intracellular function of TG2 as a key component in allowing this signaling loop to persist in an autocrine fashion. Numerous inhibitors of TG2 have been developed, but they are largely focused on blocking the extracellular crosslinking function of the enzyme . Additionally, small molecules are available for inhibition of Nf-κb signaling. However, several of these molecules also inhibit broad cellular functions such as nuclear transport or proteasome function . Specific inhibitors of IκB kinase (IKK), the kinase responsible for Iκ-Bα phosphorylation and degradation, do exist but TG2-mediated activation of NF-κB has been shown to be independent of IKK activity . Therefore, we chose to utilize the clinically approved compound ruxolitinib to break the TG2 drug persistence loop (Fig. 6d).
The use of immunocompromised mice is a drawback of our study. The acute use of ruxolitinib and its inhibition of JAK:STAT signaling leads to robust inhibition of cytokine signaling and blockade of inflammatory signaling utilized by cancer cells for tumor growth and progression. However, prolonged application of ruxolitinib is also associated with suppression of adaptive immunity. Whether this suppression of lymphoid function and immune surveillance will support emergence of underlying cancers remains to be determined .
The potency, covalent nature, and broad target spectrum of neratinib all contribute to its ability to effectively inhibit the growth of HER2-driven tumors. However, these characteristics also lead to significant toxicities associated with the compound. Tucatinib, a highly potent kinase inhibitor that has increased specificity for HER2, and trastuzumab-drug conjugates are emerging as additional standards of care for HER2 + patients . The enhanced specificity of these compounds for HER2 decreases systemic toxicities . However, the HER2 degradative properties of neratinib (Fig. 1a) suggest that the current mechanisms of persistence may be at play during any HER2-targeting event. Studies to determine if antibody-mediated drug delivery will be sufficient to overcome this persistence mechanism are currently underway in our laboratory.
Materials and methods
Human mammary epithelial cells (HMLE) stably transduced with firefly luciferase and slected for using Blasticidin. These bioluminescent cells were used to construct the parental HME2 cell line via lentiviral transduction of HER2 under puromycin selection. The HME2-BM cell line was isolated from bone metastases following mammary fatpad engraftment of the HME2 cells as previously described . Lentiviral transduction of pLV encoding shRNA’s targeting TGM2 or a scrambled shRNA as a control were used reduced expression of TG2 (VectorBuilder, Santa Clara, CA) encoding an. Human TGM2 or GFP as a control were also stably expressed following pLV transduction, as previously described . STAT3-targeted shRNA’s (shSTAT3#1: CTCAGAGGATCCCGGAAATTT, shSTAT3#2: GGCGTCCAGTTCACTACTAAA) were similarly expressed from pLV (VectorBuilder, Santa Clara, CA). Hygromycin selection was used for stable selection of the constructs above. Stable expression of the Iκbα was achieved through lenti-viral transduction of p-Babe-GFP- Iκbα (super repressor mutant (S.R)) or p-Babe-GFP as control followed by selection using FACS. Where indicated cells were treated with every third day until drug resistance was observed. HME2-BM and HME2-TG2 cells treated with neratinib were cultured as the BMNR and TG2NR populations respectively.
IACUC approval from Purdue University was received for conducting all in vivo assays. HME2 parental and HME2-BM cells were engrafted into the duct of the second mammary fat pad of 6–8-week old female, NSG mice (2 × 106 / 50 µl / mouse). When tumors reached 100 mm3, mice an oral gavage of neratinib (27 mg/kg/q.o.d). Neratinib was first solubilized in DMSO, and 0.25% Tween-80, 0.5% carboxymethyl cellulose solution was used for oral gavage at a final DMSO concentration of 10%. In separate experiments, female 8-week old NSG mice were engrafted with HME2-BM cells and treatment with neratinib (27 mg/kg/q.o.d) and/or ruxolitinib (40 mg/kg/q.o.d) was initiated when tumors were 100 mm3. The volume of mammary tumors were determined using digital calipers following the equation V = (length2)*(width)*(0.5).
3D hydrogel assays
Using a white-walled 96-well dish, 2000 cells were plated on 50 μl of solidified Cultrex basement membrane extract (BME) from (Trevigen, Gaithersburg, MD). Cells were plated in 10% FBS and 5% BME in DMEM. These cultures were treated with DMSO as a control or neratinib (100 nM) every three days. Growth was tracked every three days using bioluminescence and images were taken at Day 27.
A modified RIPA lysis buffer containing 150 mM NaCl, 50 mM Tris, 1.0% NP40, 0.1% SDS, 40 mM β-glycerolphosphate, 0.25% Sodium Deoxycholate, 10 mM activated sodium ortho-vanadate, protease inhibitor cocktail, and 20 mM sodium fluoride was used to lyse cells. Reducing, 10% SDS PAGE was used to separate proteins and membranes were probed for TG2 (Invitrogen CUB 7402, Mouse/Rat TGM2 antibody R & D systems, AF5418), phospho AKT (Ser 473) (CST Rabbit mAB#4060), total AKT (CST Rabbit 9272) phospho-STAT3 (Tyr705) (D3A7) (CST Rabbit mAB# 9145) and total STAT3 ((CST Rabbit mAB#2640), Iκbα (CST #) or β-tubulin (DSHB, Iowa City, IA). For the kinase profiling array whole cell lysates were generated from HME2-parental and HME2-BM cells under full growth media conditions. The phospho-kinase array was processed according to the manufactures instructions (R&D systems #ARY003C).
Isolated total RNA (Omega bio-tek, Norcross, GA), was reverse-transcribed (Thermo Fisher) and iQ SYBR Green was used for semi quantitative real-time PCR (Thermo Fisher). The reference gene was GAPDH. The following primers were used for the analysis. Human TG2: forward: ATAAGTTAGCGCCGCTCTCC, reverse: CTCTAAGACCAGCTCCTCGG and human IL-6: forward CCAGTACCCCCAGGAGAAGA Reverse: TGTTTTCTGCCAGTGCCTCT.
AlphaLISA IL-6 assay
IL-6 expression by each cell line was determined by using IL-6 (human) AlphaLISA detection kit. Cells were plated into 24 well plates (1 × 105 cells/well). Following overnight incubation, cells were incubated with serum free DMEM media. After 24 h incubation, culture supernatants were collected, centrifuged to pellet any detached cells and IL-6 was quantified using AlphaLISA detection kit.
Patient data analyses
Patient data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and cancer genome atlas (TCGA) were accessed through cBioportal. Relapse free survival based on differential gene expression was done using KM Plotter .
NF-κB Reporter assays
Cell expressing or depleted for expression of TG2 were transfected with pNifty2-Luc (InvivoGen) and pGL3 encoding renilla luciferase, containing no promoter sequence using TransIT LT1 transfection reagent (Mirus). 36 h after transfection cells were processed for renilla and firefly activity using the Dual luciferase Assay system (Promega).
2-sided T-tests and 2-way ANOVA were used to compare two groups when the variance was similar and all other data met the assumptions of these tests. Data were considered significant when P values were less then 0.05. Exclusion criteria were not utilized.
Availability of data and material
All data generated in this study are available within the manuscript and supplemental files.
Sodium dodecyl sulfate
Oral gavage every other day
Fluorescence activated cell sorting
Human mammary epithelial cells
HMLE cell transformed by HER2 overexpression
HME2 cells isolated from bone metastases
Fibroblast growth factor receptor
The Cancer Genome Atlas
Molecular Taxonomy of Breast Cancer International Consortium
Signal transducer and activator of transcription
Human epidermal growth factor receptor-2
Nuclear factor kappa B
Sidaway P. HER2-targeted agents overcome resistance. Nat Rev Clin Oncol. 2020;17:133–133. https://doi.org/10.1038/s41571-019-0325-y.
Hunter FW, Barker HR, Lipert B, Rothé F, Gebhart G, Piccart-Gebhart MJ, et al. Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Br J Cancer. 2020;122:603–12. https://doi.org/10.1038/s41416-019-0635-y.
Abdullah A, Akhand SS, Paez JSP, Brown W, Pan L, Libring S, et al. Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer. Oncogene. 2020;40:322–33. https://doi.org/10.1038/s41388-020-01530-6.
Akhand SS, Chen H, Purdy SC, Liu Z, Anderson JC, Willey CD, et al. Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy. NPJ Breast Cancer. 2021;7:1–11. https://doi.org/10.1038/s41523-020-00213-5.
FDA approves neratinib for extended adjuvant treatment of early stage HER2-positive breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-extended-adjuvant-treatment-early-stage-her2-positive-breast-cancer.
Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64:3958–65. https://doi.org/10.1158/0008-5472.CAN-03-2868.
Brown WS, Akhand SS, Wendt MK, Brown WS, SalehinAkhand S, Wendt MK. FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition. Oncotarget. 2016;7:83424–36. https://doi.org/10.18632/oncotarget.13117.
Zhang Y, Zhang J, Liu C, Du S, Feng L, Luan X, et al. Neratinib induces ErbB2 ubiquitylation and endocytic degradation via HSP90 dissociation in breast cancer cells. Cancer Lett. 2016;382:176–85. https://doi.org/10.1016/j.canlet.2016.08.026.
Collins DM, Conlon NT, Kannan S, Verma CS, Eli LD, Lalani AS, et al. Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer. Cancers (Basel). 2019;11:737. https://doi.org/10.3390/cancers11060737.
Gundemir S, Colak G, Tucholski J, Johnson GVW. Transglutaminase 2: A molecular Swiss army knife. Biochim Biophys Acta. 2012;1823:406–19. https://doi.org/10.1016/j.bbamcr.2011.09.012.
Shinde A, Paez JS, Libring S, Hopkins K, Solorio L, Wendt MK. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche. Oncogenesis. 2020;9:1–12. https://doi.org/10.1038/s41389-020-0204-5.
Antonyak MA, Li B, Boroughs LK, Johnson JL, Druso JE, Bryant KL, et al. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. PNAS. 2011;108:4852–7. https://doi.org/10.1073/pnas.1017667108.
Zhang H, Chen Z, Miranda RN, Medeiros LJ, McCarty N. TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy. Cancer Res. 2016;76:6410–23. https://doi.org/10.1158/0008-5472.CAN-16-0595.
Jia C, Wang G, Wang T, Fu B, Zhang Y, Huang L, et al. Cancer-associated Fibroblasts induce epithelial-mesenchymal transition via the Transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in Hepatocellular Carcinoma. Int J Biol Sci. 2020;16:2542–58. https://doi.org/10.7150/ijbs.45446.
Bailey ST, Miron PL, Choi YJ, Kochupurakkal B, Maulik G, Rodig SJ, et al. NF-κB Activation-Induced Anti-apoptosis Renders HER2-Positive Cells Drug Resistant and Accelerates Tumor Growth. Mol Cancer Res. 2014;12:408–20. https://doi.org/10.1158/1541-7786.MCR-13-0206-T.
Korkaya H, Kim G-I, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84. https://doi.org/10.1016/j.molcel.2012.06.014.
Fridman J, Nussenzveig R, Liu P, Rodgers J, Burn T, Haley P, et al. Discovery and Preclinical Characterization of INCB018424, a Selective JAK2 Inhibitor for the Treatment of Myeloproliferative Disorders. Blood. 2007;110:3538–3538. https://doi.org/10.1182/blood.V110.11.3538.3538.
Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15. https://doi.org/10.1016/j.cell.2008.03.027.
Shinde A, Hardy SD, Kim D, Akhand SS, Jolly MK, Wang W-H, et al. Spleen tyrosine kinase-mediated autophagy is required for epithelial-mesenchymal plasticity and metastasis in breast cancer. Cancer Res. 2019;79:1831–43. https://doi.org/10.1158/0008-5472.CAN-18-2636.
Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells. Breast Cancer Res. 2011;13:R96. https://doi.org/10.1186/bcr3034
TG2 and NF-kB signaling coordinates the survival of mantle cell lymphoma cells via IL-6-mediated autophagy. Cancer Res. 2016;76:6410–23. https://doi.org/10.1158/0008-5472.CAN-16-0595
Ai L, Skehan RR, Saydi J, Lin T, Brown KD. Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor κ light chain enhancer of activated B cells (NFκB) signaling controls basal and DNA damage-induced transglutaminase 2 expression. J Biol Chem. 2012;287:18330–41. https://doi.org/10.1074/jbc.M112.339317.
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–51. https://doi.org/10.1038/onc.2010.215.
Li G, Guo J, Shen B-Q, Yadav DB, Sliwkowski MX, Crocker LM, et al. Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells. Mol Cancer Ther. 2018;17:1441–53. https://doi.org/10.1158/1535-7163.MCT-17-0296.
Rexer BN, Arteaga CL. Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications. Crit Rev Oncog. 2012;17:1–16.
Azuma K, Tsurutani J, Sakai K, Kaneda H, Fujisaka Y, Takeda M, et al. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure. Biochem Biophys Res Commun. 2011;407:219–24. https://doi.org/10.1016/j.bbrc.2011.03.002.
Elli EM, Baratè C, Mendicino F, Palandri F, Palumbo GA. Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib. Front Oncol. 2019;9:1186. https://doi.org/10.3389/fonc.2019.01186.
Tavallai M, Booth L, Roberts JL, Poklepovic A, Dent P. Rationally Repurposing Ruxolitinib (Jakafi (®)) as a Solid Tumor Therapeutic. Front Oncol. 2016;6:142. https://doi.org/10.3389/fonc.2016.00142.
Kearney M, Franks L, Lee S, Tiersten A, Makower DF, Cigler T, et al. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer. Breast Cancer Res Treat. 2021;189:177–85. https://doi.org/10.1007/s10549-021-06306-4.
Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990;10:2327–34. https://doi.org/10.1128/mcb.10.5.2327-2334.1990.
Keillor JW, Apperley KYP, Akbar A. Inhibitors of tissue transglutaminase. Trends Pharmacol Sci. 2015;36:32–40. https://doi.org/10.1016/j.tips.2014.10.014.
Gilmore TD, Herscovitch M. Inhibitors of NF- κ B signaling: 785 and counting. Oncogene. 2006;25:6887–99. https://doi.org/10.1038/sj.onc.1209982.
Li J, Huang J, Jeong J-H, Park S-J, Wei R, Peng J, et al. Selective TBK1/IKKi dual inhibitors with anticancer potency. Int J Cancer. 2014;134:1972–80. https://doi.org/10.1002/ijc.28507.
Kulukian A, Lee P, Taylor J, Rosler R, de Vries P, Watson D, et al. Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models. Mol Cancer Ther. 2020;19:976–87. https://doi.org/10.1158/1535-7163.MCT-19-0873.
Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382:597–609. https://doi.org/10.1056/NEJMoa1914609.
Győrffy B, Surowiak P, Budczies J, Lánczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS ONE. 2013;8:e82241. https://doi.org/10.1371/journal.pone.0082241.
We acknowledge the use of the facilities within the Bindley Bioscience Center, a core facility of the NIH-funded Indiana Clinical and Translational Sciences Institute. We also kindly acknowledge the expertise of the personnel within the Purdue Center for Cancer Research Biological Evaluation Core. Schematic images were created in BioRender under publication agreement number JC23SAZH7K.
This research was supported in part by the National Institutes of Health (R01CA207751; R01CA232589; R21AA026675), the American Cancer Society (RSG-CSM130259), Purdue University Women’s Global Health Institute with support from The Catherine Peachey Fund: A Member of the Heroes Foundation Family to MKW, and the NIH (R00CA198929) to LS. We also acknowledge the support of the Purdue Center for Cancer Research via its NIH NCI grant (P30CA023168).
Ethics approval and consent to participate
All in vivo assays were conducted under IACUC approval from Purdue University, protocol number 1310000978.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Shinde, A., Kulkoyluoglu Cotul, E., Chen, H. et al. Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer. Mol Biomed 3, 19 (2022). https://doi.org/10.1186/s43556-022-00079-y
- Breast cancer
- Drug resistance

domain: health


text:
Lis Marti is a young pianist from Bern. Already at the beginning of her musical studies, she focused mainly on contemporary music. She has a particularly strong interest in electronic keyboard instruments, feminist art and cross-disciplinary projects. In her work, she strives to expand traditional performance and bring contemporary music to a mixed audience. An important part of her work therefore lies in collaborating with children and young people, be it in theatre projects or teaching piano and school music. Before her musical activities, Lis Marti completed an apprenticeship in an architectural office, which is why she has a strong connection to the visual arts in addition to music. Lis Marti is currently studying for a Master’s degree in Pedagogy at the Bern University of the Arts in the class of Antoine Françoise.
Photo © David Fürst


The whales and dolphins were out and about today, with 2 baleens species and a very special sighting of our Indian Ocean Humpback Dolphins. We started our tour by heading towards Danger Point to have a look out for some Humpback Whales, moving past the point and then making our way through the deep towards Dyer Island. We had plenty of pelagic seabirds in the area which gave away the presence of fish moving through the bay.
The fish attracted a slightly bigger visitor too, with us catching sight of a Brydes Whale. This whale was fairly sporadic, but we were able to get some great views of him, especially when he seemed to come towards us. We also got to see him put just a bit of his tail out the water, which was a super strange occurrence. The photo can be seen below where the whale looks almost like he’s avoiding something below him by lifting his body up.
We got lucky and found some Humpback Whales next, which is always a great find. We had two whales travelling along, with one whale doing some lobtailing as they surfaced. This is always and impressive sight and can be a form of communication. We moved parallel to the whales and moved with them for a while before deciding to take a stop over at Geyser Rock. On the way, we spotted two African Penguins bobbing about in the water.
The seals were enjoying the surf as we pulled into Shark Alley, with some surge coming in, the seals caught the waves in spectacular fashion before carrying on with their day. We watched as they frolicked and played before going into Sponge Bay where we tried to spot a couple more African Penguins.
Our last spot of the day was certainly a highlight, with a new member of our endangered Indian Ocean Humpback Dolphin family. This little guy was travelling very close to mom and another dolphin, but we managed to get a few good looks at this cutie. On his body, some lines that we call fetal folds which indicate that the calf is still very young.
What species did we see today?
Humpback Whale Brydes Whale Indian Ocean Humpback Dolphin
Humpback dolphins are an endangered species, with small populations living very close to shore, typically in water less than 25m deep and an average home range of 120km. Their proximity to land makes these animals particularly vulnerable to human influence.
Cape fur seal


text:
Original Story (06/10/20): Following the release of a red colorway to celebrate All-Star Weekend, a “Blue Cement”-style colorway of the Air Jordan 3 is now set to make its debut.
This colorway of Michael Jordan’s third signature sneaker features a Varsity Royal leather upper with matching Jumpman logos on its grey tongue. Cement-print overlays cover the toe and heel areas, while the heel itself features a grey Jumpman logo with “AIR” branding underneath.
Check out official images of the Air Jordan 3 “Varsity Royal” below. A release date of June 25th has been reported, but with all of the recent pushbacks, expect these to actually release later in the summer. Stay tuned to Modern Notoriety for updates.
Air Jordan 3 “Varsity Royal”
Color: Varsity Royal/Varsity Royal-Cement Grey
Style Code: CT8532-400
Release Date: June 25, 2020 (Asia)
Release Date: October 10, 2020 (NA)
Price: $190 USD
Update (09/28/20): Following an overseas debut back in June, the Air Jordan 3 “Blue Cement” will see a North American release via SNKRS and select retailers on October 10th. Previously released pairs can be found now on StockX and eBay for not much over retail.
Update (06/18/20): An overseas release date of the “Blue Cement” Air Jordan 3s has been confirmed. The pair has appeared on SNKRS Korea with a June 25th release date, while atmos and UNDEFEATED Japan are dropping on June 26th. Stay tuned for US release info.


text:
The Bachelor Battles Series
Tap a cover to be taken to that book's page for store links and other information.
Now of legal age to battle, one bounty hunter is going to challenge the tyrants who took her childhood sweetheart. If she wins, she might cause a revolution that leads to a future where the Network no longer exists. If she loses, they’ll both die. In this post-apocalyptic future, the Network Council makes the rules and these tyrants never play fair.
Here, you can:


text:
From £250 per week (low season) to £730 per week (high season)
Holiday Home Facilities
Beach front location we have lovely rattan garden table and chairs and the caravan is opposite the beach . .two tiolets doulbe glazed and central heating brand new 2014 complete with new veranda very light and spacious. 100 pounds refundable deposit will secure your booking this will be returned as long as no breakages or damage ,we also have the right to ask you to leave if there is at anytime any unsociable behaviour or damage caused to our caravan and we will hold any cost for any damage only the names on the booking will be aloud to stay in the caravan If this is found no to be the case we will have the right to ask them to leave. The caravan is a non smoking caravan and if we find smoking has been prohibited within the caravan we will send the cost of cleaning to the main name on the booking
Caravan is on a beach front location / Brand new caravan bought January 2014 is an ABI SUMMER BREEZE graded gold delux. Needs to be seen to be fully appreciated.
a home from home feel to our lovely caravan will give you a warm welcome
The caravan is in a prime sunny position opposite the beach and within a 2 minute walk away from the main oasis complex. With restaurants and indoor swimming pool, gym and sauna, shops children's club and arcade. At night time this comes alive with the main entertainment club showing (many famous acts through the season.
The caravan has a spacious living area with TV and fresh modern fabrics with subtle colours which create a relaxing *living environment for your stay.
The fully fitted Kitchen and beautiful bedrooms with fitted wardrobes, 2 twin rooms with two single beds in each room and the master bedroom with double bed and once again double fitted wardrobes. We have two toilets, one with double shower unit.
All rooms have central heating and all double glazed.
Duvets and pillows will be provided, we also will provide a welcome pack of tea and coffee
We also have a full length varanda on the caravan
Please book early for school holidays .
We are very proud of our caravan and know you will love it as much as we do. There is something here for all ages so if its a fun filled or peaceful holiday you want in a luxury caravan then contact us as West Sands has it all.
We do have august School holidays 2017 available..
Holiday Park Facilities
(Some facilities may require membership)
Pub/Club, Amusement Arcade, Tennis Court, Indoor Pool, Laundrette, Crazy Golf, Grocery Shop, Takeaway, Restaurant, Kids Club,
Funfair, Amusement Arcade, Fishing, Restaurant, Takeaway, Grocery Shop, Laundrette, The site offers a free road, train and bus service to all facilities on the site.


text:
Stowmarket: Muntons underpins growth by securing asset finance deal with RBS and Lloyds
- Credit: Dougy Blanks
Malt and malted ingredients manufacturer Muntons is on track to achieve annual sales of more than £100million after securing a new lending facility.
Stowmarket-based Muntons, which supplies more than 180,000 tonnes of malt products annually to food and drink producers around the world, has already increased its turnover from £54m in 2007 to more than £80m last year.
And sales are now on course to top £100m for the first time this year, with the firm having agreed a joint asset-based funding package with RBS Invoice Finance (RBSIF) and Lloyds TBS Commercial Finance.
The facility will be used to support exporting activity as well as the company’s UK operations, not least by strengthening its purchasing power in the market for barley where prices have doubled in recent years due to poor harvests and increases in demand.
Alan Ridealgh, managing director at Muntons, said: “The UK has experienced some unique weather over the past few years, with long periods of drought and then seemingly non-stop rain, which brings challenges not only for the farmers but also industries such as ours that rely on a ready supply of good quality cereals.
“With extreme weather comes cereal price volatility. We buy in excess of a quarter of a million tonnes of malting barley each year and when the price doubles having access to sufficient funding is an essential.
“The new arrangements we now have in place through RBS and Lloyds TSB Commercial Finance will provide us with the flexibility to cope with these demands and will enable us to grasp opportunities to grow our business profitably.”
- 1 Is this tearoom near Ipswich one of Suffolk’s best-kept secrets?
- 2 What time will the Red Arrows be flying over Suffolk this weekend?
- 3 Plans for two drive-through takeaways in Suffolk town
- 4 New landlord hopes to make Suffolk pub 'centre' of village community
- 5 The former Ipswich players looking for new clubs this summer
- 6 Woman in hospital with life-threatening injuries after serious A143 crash
- 7 WATCH: 'Unplayable' delivery from Suffolk bowler goes viral
- 8 Town boss McKenna adds ex-Manchester United player to coaching staff
- 9 New landlords take over award-winning pub and brewery in Suffolk village
- 10 Revealed: The top serious road crash hotspots in Suffolk
Chris Hawes, director of corporate at RBSIF, said: “Asset based lending is absolutely the correct financing structure given the nature of the Muntons business operation because it provides them with great flexibility and the ability to turn the value of their company assets into much needed working capital that supports the purchase of raw materials.
“We are proud to support UK manufacturing and Muntons are great example of how brand GB is being promoted overseas as they export worldwide via sales offices in Singapore and Seattle. The whole team at Muntons are passionate about what they do and strive to innovate and provide solutions to their customers.”
Ivor McTighe, director of business development, mid markets and global corporates at Lloyds TSB Commercial Finance, added: “Muntons has a solid management team that has worked hard to ensure the business’ growth escalates despite unexpected weather and volatile market conditions.
“This deal exemplifies our commitment to supporting strong British manufacturing businesses and the suitability of asset based lending for firms that need flexible cash flow to capitalise on expansion opportunities as they arise.”

domain: finance


text:
An excellent game
I think overall this is a pretty good game. The choices for music fit the game well and the graphics are very colorful, almost as if they we're from a painting. I liked the style of the game.
But to the gameplay. This is a basic difference game with some backstory added to it. It does add a purpose to the game, but it felt as if the plot and the characters were forgotten right after the intro, apart from the text bits after completing a screen.
Difference hunting in itself was quite the challenge. I did manage to beat the game, but I did take a long time on each screen. Some of the differences were subtle, which was okay, but the some of the differences were extremely difficult to see even when holding the cursor on top of a spot and comparing the two windows. While the flickering of the right screen made sense storywise, it made the job even harder. My eyesight is quite good, so I'd say some of the differences were way too small (small change in grass shape, slightly darker/ligher patch of grass within grass etc...) I still liked how the backup rune system didn't just give an easy way out, but challenged to look for the differences.
Overall, the style of the game is top notch. But, finding all the differences with just three backup runes can be extremely, and sometimes even unfairly difficult.

domain: hobby