text:
Dr. Bob's minions tire away endlessly to help the good Doctor in the name of science,
but with what little downtime they get they would like to share with you fine people!
Make Mine Marvel: Phase Two and Beyond
By Critch
The second Phase of the shared Marvel Cinematic Universe began as Phase One did: with an Iron Man movie. IRON MAN 3 was a unique entry for the series and superhero movies as a whole as it focused more on the man under the suit instead of the heroics themselves. After the events of THE AVENGERS Tony Stark is suffering PTSD, as he almost died in deep space delivering a nuclear bomb to the Chitauri aliens. Just as he's suffering through this, a terrorist known as The Mandarin is bombing random locations as an attack on America. Stark, attempting his usual bravado, calls him out and invites him to his home, which is summarily destroyed, along with his Iron Man suit. He manages to get back in form, with the help of a number of prototype suits, a kid, and War Machine, rooting out the true villain of the piece. IRON MAN 3 loosely adapted the Extremis comic storyline but went in a completely different and more humorous direction, but did start the questions about why the Avengers didn't get involved considering the terroristic threat along with the kidnapping of the President.
The next entry wasn't a movie at all. While the DVD releases typically included a short side-story set in the same universe, one of which eventually leading to AGENT CARTER, the universe didn't include any television until that fall when AGENTS OF S.H.I.E.L.D. came out on ABC. Following a mysteriously resurrected Agent Coulson and a new team of agents, the show focused on smaller parts of the fiction, such as other Asguardians, the Kree race, and fallout from the movies. The inclusion into the universe at this point has been sadly one-sided, as no major stars have shown up outside of a couple first-season visits from Nick Fury and the occasional guest Maria Hill, and the movies continue on as though Coulson is still dead, despite his team being responsible for finding a Helicarrier that would feature in the second Avengers film. For roughly half of the first season, S.H.I.E.L.D. struggled to find its place, building characters but never gelling into a consistent arc or rhythm. It turned out however that it was only biding its time until a futurecinematic entry, which turned the world on its head.
Meanwhile, the next actual movie was THOR: THE DARK WORLD. After some behind the scenes shenanigans that ended up replacing a director mid-production, THE DARK WORLD released, picking up immediately after THE AVENGERS with Thor taking Loki back to Asgard, where he is promptly placed in prison while the Cosmic Cube is placed into protection. It is revealed as the first of the Infinity Stones, one of six ancient artifacts that promise ultimate power to their holders. It isn't long before the second artifact is found on Earth by Thor's would-be girlfriend, which awakens the dark elves, a race that hungers for the Aether. With a universal alignment imminent, the Aether can snuff out almost all life and spread darkness to every corner of the realms. Thor's mother is killed, and he and Loki escape to stop them….And that's pretty much the plot. There's not a whole lot going on in this one other than Loki being funny and Thor doing Thor-like things. The main effects from this one end up being that Loki survives and ends up replacing his father on the throne of Asgard, while disgusing himself as Odin himself, and the Aether being hidden off Asgard with the mysterious Collector to prevent more than one Infinity Stone being in one place at the same time. That particular thread would be picked up two movies later…
With Iron Man and Thor accounted for, along with The Hulk showing up in an after-credits scene in IRON MAN 3, it was time to look in at the other major Avengers in CAPTAIN AMERICA: THE WINTER SOLDIER, featuring not only Cap, but also Black Widow. S.H.I.E.L.D. is beefing up their defenses with Project Insight, a set of three new Helicarriers, each of which with a predictive technology that can stop threats before they happen in a sort of Minority Report way. Captain America is against this, and raises some red flags which result in the apparent assassination of Nick Fury by a strange assassin with a metal arm. Alexander Pierce, Secretary of the World Security Council, also oversees S.H.I.E.L.D. but seems to be involved in the conspiracy to get the Helicarriers active without further delay. Captain America and Black Widow go on the run with the help of a fellow soldier who becomes The Falcon, and in the biggest twist the Marvel Universe so far reveal that Hydra, thought defeated with the Red Skull, is very much alive, controlled with an AI representation of Armin Zola. Hydra has shaped history with such events as the death of Tony Stark's parents, and using the Winter Soldier, revealed as Cap's friend Bucky, they plan on making sure Project Insight proceeds to be able to destroy their enemies, both on the wrong side of the law and the right side. Nick Fury is revealed to be alive, and Hydra is defeated, but not before all of S.H.I.E.L.D.'s secrets are revealed to the public and subsequently shut down. At the end of the movie, there is an uncertain future. A few more things of note happened. Stephen Strange, A.K.A. Doctor Strange had his name dropped for the first time, and during the end credits it was revealed that a separate Hydra base continued operating, doing experiments on Loki's scepter and creating superpowered beings: Quicksilver and the Scarlet Witch.
Back on AGENTS OF S.H.I.E.L.D., the events of WINTER SOLDIER left the team reeling as a major member revealed themselves to have been working for Hydra the whole time. Again, while the movies never directly reference the events of the show, this is a great example of how just existing in the same universe makes the storytelling possibilities endless for the show, as it can go deeper into things the movies just don't have the time to do. Between this and future alien happenings, the show continued to build steam and maintain quality from then on, and opened the door for future spinoffs, such as the two season AGENT CARTER, which appeared during the mid-season break during AGENT'S second season.
The next entry was possibly the riskiest thing that Marvel had done up to this point, but with the success of pretty much everything they had done thus far they were essentially playing with house money. GUARDIANS OF THE GALAXY was a loose adaption of a comic that had never had a long reach, and had no household names. Other than a beginning showing the kidnapping of a small child, it had no Earth connections, and included an almost all-alien cast, including a talking gun-happy raccoon and a walking tree who could only speak three words, "I am Groot", exclusively in that order. Proving that there was no such thing as 'Superhero fatigue' and continued Marvel's winning streakas Guardians was one of Marvel's biggest successes thus far. It opened up a whole new universe of possibilities. Just as THOR had made other worlds and aliens palatable to audiences as long as there was an Earth component, GUARDIANS proved that there didn't have to be any Earth at all. The film follows a band of light criminals; Star-Lord, the abducted human raised by thieves, Gamora, daughter of Thanos, Rocket Raccoon, an experiment, Groot, a tree, and Drax, an alien blinded by rage against Ronan, the villain. With unexpected humor and heart, the team chases down a payday by acquiring the third revealed Infinity Stone, which provides unlimited destructive power, whereas the Aether converts matter and the Cosmic Cube creates energy. Ronan is hired by Thanos to recover the stone, however he decides to keep it for himself to destroy his enemies. Through a series of adventures, Ronan is defeated, the team stays together for future mayhem, and a new franchise is born, just in time for the full Avengers team to return.
AVENGERS: AGE OF ULTRON begins with the full team of Avengers mopping up after WINTER SOLDIER, cleaning out the last Hydra base and recovering Loki's scepter, but not before the Scarlet Witch using her scepter given magic powers gives Stark a dark vision of the future. After revealing that inside the Scepter lies the fourth cosmic cube (Though one now must wonder why Thanos gave Loki one stone to just end up losing 2 stones, but it does put the stone at the same place as several other stones, so who knows), Stark and Banner use the new powers to try and transform the AI Jarvis into a new creation: Ultron, who they hope will be so advanced that the Avengers will no longer be needed. Ultron, of course, gets too smart too quickly, overrides Jarvis, and soon attempts to destroy the Avengers, taking the twins Quicksilver and The Scarlet Witch under his wing. Meanwhile, Thor leaves for a while to find out more, uncovering the Infinity Stones plaguing them, and they hide out at Hawkeye's house with his family. Nick Fury returns, and together, the Avengers form up to take out Ultron, managing to convince the twins whose side they should be really on. Saving the world from annihilation, Hulk leaves for unknown spaces, and Quicksilver sacrifices himself. Stark leaves the Avengers along with Thor, and a new team forms with Scarlet Witch, Captain America, The Falcon, War Machine, and the story moves forward, with a coda of Thanos recovering the fabled Infinity Gauntlet, which, with all the infinity stones, will give him control of the universe itself. So…Gulp.
Unlike Phase One, the Avengers did not close it out. Phase Two closes with a different style of Marvel movie, ANT-MAN, a more comedy focused less world-ending focused film. An ex-S.H.I.E.L.D. scientist, Hank Pym, had designed a shrinking suit for use in the field, but after S.H.I.E.L.D. began going directions he didn't like, and also the disappearance of his wife, he retired to take care of his daughter. Enter a thief who steals the suit, but ends up being talked into infiltrating Pym's old corporation to stop the new owner (Surprise, Hydra member!) from creating a new shrinking suit for the wrong hands. Protecting his daughter, the thief saves the day. The movie itself is more notable due to the behind the scenes mess, as the original director, Edgar Wright (Shaun of the Dead, Hot Fuzz) was working on it for almost a decade before Marvel finally moved on. It also revealed the Quantum realm, something that may come into play in future installments.
With that, Phase Two ended, and now we have officially entered Phase Three. Instead of an official Iron Man movie, we started off with CAPTAIN AMERICA: CIVIL WAR. After the events of AGE OF ULTRON, along with new flare ups with the surviving villain Crossbones (And the unsaid events happening on AGENTS OF S.H.I.E.L.D.), the United Nations decide that a new accord is needed, and the Sokovia Accords are created. Superheroes like The Avengers now need to register, something that Cap is against but Stark is all for. The issue is pressed when Bucky reappears, his memories slowly coming back but still possibly being controlled. After a public terrorist attack where he appears to be the cause, Cap leaps to his aid, facing off against the Black Panther, a king of the African nation Wakanda who also controls the world's supply of Vibranium, the most powerful metal known. The villainous Zemo, having lost his family at the hands of Ultron and thus the Avengers, gains control of Bucky, who busts out of captivity. After the chaos, Stark insists on Cap signing the accords, but Cap goes to save Bucky instead to find out what's really going on. Stark assembles a team to stop them. What follows is the greatest superhero battle scene in history. Heroes fighting heroes. And oh yes, the Marvel debut of SPIDER-MAN! It is a scene that should be watched rather than described here. Afterward, with almost all of Cap's forces held in an underwater prison known as The Raft, Stark goes after Cap and Bucky, having figured out something else is happening that he isn't privy too. Coming together in the frozen north, they discover Zemo, but Stark also finds out a secret Cap has been keeping: Bucky, as The Winter Soldier, killed his parents. Hero versus hero face off, with Cap the victor, but at the last moment keeps himself from killing Stark, and instead leaves with Bucky, now short his metal arm. In the end he sends a letter pledging that he'll be there if the world needs him, War Machine is crippled, and it is one of the rare instances where the villain wins, having destroyed The Avengers.
Lastly, we have the just-released DOCTOR STRANGE, which introduces the as-of-yet-unseen magical side of the Marvel Universe, with different dimensions and demons. I won't go into detail as the movie was just released, but it continues to move the Marvel universe forward.
Alongside the TV entry and the film entries has been the Netflix series, which has included the fantastic DAREDEVIL series, facing the origin of Daredevil facing off against the Kingpin and The Hand alongside Elektra and The Punisher starting in season two, JESSICA JONES as a damaged super-strong private detective fights against a villain with the ability to control others with a word, and LUKE CAGE, who uses his invulnerability to protect his neighborhood.
Phase Three continues next year with GUARDIANS OF THE GALAXY VOL. 2, SPIDER-MAN: HOMECOMING, and THOR: RAGNAROK, along with the TV series INHUMANS picking up after AGENTS OF S.H.I.E.L.D. Netflix continues as well with new seasons of DAREDEVIL, JESSICA JONES, and LUKE CAGE, along with new show IRON FIST. A Series combining the heroes, THE DEFENDERS, also will air. It'll close off in 2018 and 2019 with BLACK PANTHER, AVENGERS: INFINITY WAR, CAPTAIN MARVEL, ANT-MAN AND THE WASP, AVENGERS 4, SPIDER-MAN 2, And probably some more TV and Netflix productions, and maybe a DOCTOR STRANGE sequel considering the success of that entry.
Cinematic universes are the new big thing, with DC climbing on board with Justice League related films, and even Universal getting into the mix with a collection of same-universe monster movies. Hopefully they can keep the same quality that Marvel has displayed thus far, however Universal had already attempted the beginning of a universe with DRACULA UNTOLD and that went nowhere, and DC, while experiencing financial success with BATMAN V SUPERMAN: DAWN OF JUSTICE and SUICIDE SQUAD, has been floundering when it comes to the critics. Regardless, at least one universe is bright. Until next time, Make mine Marvel!
Previously on Minion Musings...


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The notorious, the fatuous, the misleading claim that '97% of climatologists' believe in ('catastrophic' implied/stated/assumed) anthropogenic global warming has been rebutted many times. Anyone with an elementary grasp of sample-survey techniques would have refused to publish the results, based as they are on a sloppy question, an imperfect frame, and a tiny subset of self-selected respondents of unknown qualifications. But perhaps when you are saving the planet, the means justifies the ends, or more clearly, 'let's not let scientific integrity get in the way of political impact.'
The WUWT site has a post dated 4th March from Jospeh D'Aleo, a meteorologist, reacting to another meteorologist still trotting out that egregious 97% as if it were a clincher instead of an embarassment, as per:
'Of the climatologists, a staggering 97% agreed to the same question… It's very difficult for me to understand the disdain for science that exists today.'
Oh the ironing! (as they say on the Daily Bayonet)
D'Aleo digs out an IceCap post from last December by Solomon, of the Canadian National Post, and reproduces part of it. Here is an extract, referring to a crude online survey sent to 10,257 'Earth scientists', of whom only 3,146 chose to respond, and of them a subset of 77 was extracted to create the 97%:
'This number will prove a new embarrassment to the pundits and press who use it. The number stems from a 2009 online survey of 10,257 earth scientists, conducted by two researchers at the University of Illinois. The survey results must have deeply disappointed the researchers - in the end, they chose to highlight the views of a subgroup of just 77 scientists, 75 of whom thought humans contributed to climate change. The ratio 75/77 produces the 97% figure that pundits now tout.'
Of course, with a mass media largely supine and uncritical under the whirling deluge of alarmist press releases, soundbites, and sundry spins, the '97%' grew wings and became something with which to impress the public. But the public is catching up. Teachers can contribute by ensuring that their pupils see that '97% ' as well-worthy of their disdain.
An SPPI report on the '97%' is available here: http://scienceandpublicpolicy.org/images/stories/papers/originals/consensus_opiate.pdf
Hat-tip: The Climate Science blog.
Added 7 March: There is analysis at Climate Quotes of the two questions used in the survey, noting that they could readily be answered in the affirmative by those who do not see any convincing evidence or arguments that AGW is a major and urgent threat: http://climatequotes.com/2011/02/10/study-claiming-97-of-climate-scientists-agree-is-flawed/
Added 19 July 2012. Barry Woods provides a lot more information and insight into fatuous 97% and 98% claims: http://wattsupwiththat.com/2012/07/18/what-else-did-the-97-of-scientists-say/#more-60090
Amongst other things, he tracked down an MSc thesis that was the source of one of the most widely quoted 97% figures: 'As this MSc thesis was the original source of the oft cited Doran paper
97% quote, I tracked it down (sometime ago now) and discovered in the
appendi that there was a great deal of email feedback and answers to
write in questions from the scientists that actually participated in the
survey, much of it critical and sceptical of the survey itself, the
methodology and the questions asked. Additionally, amongst those
environmental scientists that responded, were some very sceptical
sounding scientists with respect to man made climate change being the
dominant driver of climate change.'
As well as the Doran/Zimmerman survey, he reports on the later Anderegg 'survey', and notes scathing critiques of it:
'Paul Matthews: "Scott Denning needs to be more
careful if he and his fellow climate scientists are to be taken
seriously by scientists from other fields such as myself.
He loses credibility by referring to the ridiculous Anderegg et
al study, in which the authors put scientists into two different
pigeon-holes. '
A blog sharing information about materials presented to children on climate, highlighting those intended to frighten or mislead, and those which seek to inform and inspire rather than to recruit, even the very young, for an ill-founded political campaign around the threat of CAGW. A campaign which is irresponsible, destructive, divisive, and degrading. Search for 'climate catastrophe' online to see examples.
'There is no climate crisis, but there is a crisis of climate superstition, fraud, incompetence, and censorship. And it is being used to terrify children and threaten the future of western civilization.'
Tony Heller, https://realclimatescience.com/2019/11/there-is-no-climate-crisis/
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subset: commoncrawl


text: BUSINESS German fare proves tasty at MIPTV 5:00 AM PDT 4/9/2008 by Scott Roxborough , AP FACEBOOK TWITTER EMAIL ME Empty Complete MIPTV coverageCANNES -- Big-budget U.S. drama might still be king of the castle at the MIPTV market, but high-end international drama continues to storm the gates, with several significant deals, many of them coming from Germany. ZDF Enterprises, the commercial sales arm of German public broadcaster ZDF, reported record sales, with live-action teen-mermaid series "H20 -- Just Add Water" selling to France 2; Italy's RAI Sat; Antena 3 and Universal Pictures in Spain; and Canada's Vrak.TV. The show, produced in Australia, was recently picked up by Nickelodeon in the U.S. ZDF also scored big territory sales for its slate of crime dramas, with canine detective series "Here Comes Kalle" going to TF1 in France and RTBF in Belgium and long-running shows such as "The Old Fox" and "KDD" selling to Mediaset in Italy, AXN in Spain and Portugal and TF1 in France. Teutonic sales group Telepool sold RTL's mystery event telefilm "The Charlemagne Code" and Scandi crusades epic "Arn -- The Knight Templar" to France pay giant Canal Plus; licensed a package of German action series including "3 Wild Angels" and "Motorcycle Cops" to Italy's La Sette; and sold RTL's popular multicultural sitcom "Everybody loves Jimmy" to TV Catalunya in Spain. Bavarian Media Television sold Austrian cop series "Vienna Crime Squad" to RAI in Italy and inked eight package deals with broadcasters from Central and Eastern Europe for its diverse slate of Germanic fiction. German pubcaster ZDF, which produces virtually all of its local-language programming in-house, made a rare acquisition of a German series, picking up the first three seasons of the relaunched dog and cop show "Rex, A Cop's Best Friend" from Munich-based Beta Film. The show already airs on RAI Uno in Italy and on Austria's ORF. FACEBOOK TWITTER EMAIL ME Scott Roxborough firstname.lastname@example.com sroxborough AP email@example.com @thr


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text:
The Bankster - Ravi Subramanian10:30:00 PM
Price: Rs 250
Find the author at :
Website: http://www.
Facebook: http://www.facebook.
Twitter: https://twitter.com/
Slideshare: http://www.
Youtube: http://www.youtube.
~ Summary ~
You realize how cosmetic appearances go a LONG way, and not always for the good. You read about the insecurity and I could actually see it playing in my head as Harshita started to fall apart.
Wherever you go, from banks to corporate offices, there always are these basic problems that arise, and they will continue to arise, because yes, we have computers, and yes, we have brilliant advanced technology, but a human operates them at the end of the day.
Greed, lust, thirst for power, jealously, betrayal .. These are but basic human emotions!
When I read the withdrawal email (page 128) , I felt so bad for him.
It reminded me of those times when I was forced to apologize, when you're not really at fault, but you just HAVE to, and it is embarrassing and humiliating, but one's gotta do what one's gotta do eh?
There are moments when you are insulted, and then there are moments when you are just numb as you realize all you ever were, is a pawn. You try and plan this mega move, but you fail, miserably, and the way the author has depicted all of this, including the wife's dialogues as she tries to console and talk to her husband, I found it very realistic and beautiful.
One of the parts I liked the best, were related to the post mortem and the tides thing. It was right there in front of everyone, but they couldn't guess it. It was very probable, and it reminded me of Hermione in DH as she said that she wasn't super intelligent, just really precise and perspective.
Quite honestly, the culprits were a shock to me! One of them, I detested since the start, but the way they conducted it, it was quite an interesting read!
The best part about this book is that it isn't drab for a moment, there are so many things happening simultaneously that will scream for your attention.
Because once you start reading this book, these 358 pages will literally fly by!
Yatin Says :
Long back, when I was studying, I borrowed this book from a friend, "If God Was A Banker", the title was intriguing and my friend was praising the book too much, so I picked it up. Absolutely loved the book, recommended it as well to a lot of people. Post that, I never really kept a track of Ravi Subramanian's books, in fact, to be honest, I had no clue that the Ravi Subramanian who started following me on twitter around a month back is an author, till I checked his bio.
6 bookmarks
Its good to see some really nice thriller coming from Indian authors !ReplyDelete
liked this one !
Waiting to get it from you :D
okay!! I'm reading this book!!!ReplyDelete
I would've bought it myself but since BookAdda is already sending one to me. I'm just wondering what you'd do, since you're getting another one as well.. hahahahaha
This looks good.. waiting to read it.
Thanks FL and Nimue.ReplyDelete
Trust me this is happening with me for the Nth time. I either buy a book or publishers send me, or blogadda and I end up having multiple copies of the book and I give them away to people who wish to read them ! :P
oooh, ur so lucky,yatin! i love it that u included a picture of the signed copy. i am curious now; will read this if i can. :)ReplyDelete
Am getting this book from Blogadda too!! :P And am so envious that you got an author signed copy!! Lucky You!!ReplyDelete
Coming to your review,I loved it...am dying to get my hands on it... :)
Read it guys. Its a good book ! :)ReplyDelete


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Last week I joined Model Aeroplanes for a couple dates as they supported Motherwell band, The LaFontaines.
The first stop of the Scottish leg of the tour was a trip up to Inverness. Once into the hills, we were treated to some cracking scenery. Definitely one of the more scenic cigarette stops.
Model Aeroplanes
The LaFontaines
Our second day was at The Mash House in Edinburgh.
Model Aeroplanes
The LaFontaines
All images are © Gavin Craigie.


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#61 2017-09-23 13:29
Amazing visit! Thanks Dana and Chris. Your home is lovely and I enjoyed seeing all your antiques and decor, truly a step back in time in which elegance prevailed. Your welcoming hospitality and delicious breakfasts were much appreciated.Thanks, too, for the bag lunch you
packed for my train ride. A return visit is already on my calendar!
packed for my train ride. A return visit is already on my calendar!
#60 2017-06-20 12:03
Dana and Chris were super helpful in advance, ...uring us that they would find us a spot to change for our event even if we arrived before checkin. When we drove up we were a little worried when we saw the outside of the inn which is being resided. However once we looked at the beautiful grounds ,gardens and the lovely interior we were happy we had found this place.
Our room -4-was lovely clean and ready early.The location of the inn is in a beautiful neighborhood, very convenient to downtown.
Our hosts were super friendly and the cookies awaiting us on our return that evening and the wonderful breakfast The next morning made for a delightful visit.
Our room -4-was lovely clean and ready early.The location of the inn is in a beautiful neighborhood, very convenient to downtown.
Our hosts were super friendly and the cookies awaiting us on our return that evening and the wonderful breakfast The next morning made for a delightful visit.
#59 2017-06-20 12:02
My husband and I stayed 2 nights in October, 2016. Dana and Chris have done a fantastic job of making this inn beautiful inside and out. It is very clean and inviting. The renovations they have completed are wonderful and the ones in progress look great. Breakfast was out of this world! We were asked if we had any dietary restrictions, which we didn't but it was nice that they were mindful of those who might. Dana and Chris shared history of both the inn (fascinating!) and the surrounding area. We loved meeting the family dog, who was as sweet and low-key as can be. This was our first visit and we certainly hope to return!
#58 2017-02-17 05:18
We discovered the Stuart Avenue Inn, when our daughter moved to Kalamazoo to attend Western Michigan. Loved it the first time and continue to stay there when we visit our kids, who have since graduated, gotten married, and live in Kalamazoo. We are always welcomed with smiles, warm baked goods, a comfortable room and a wonderful breakfast. We highly recommend this B&B.
#57 2017-02-04 18:57
A perfect place to stay! Friendly, helpful, welcoming hosts. Very comfortable spacious room. Excellent breakfast. Nice neighborhood very close to popular bars and restaurants.
Not too far from Battle Creek. Great book collection. Highly recommend. Will definitely return.
Not too far from Battle Creek. Great book collection. Highly recommend. Will definitely return.
#56 2016-05-30 16:35
Chris and Dana were wonderful hosts. My room was very large and the bed was extra comfortable. I had a small refrigerator, a microwave, and a table from which I could work. The pancakes were so delicious that no syrup should be used. The flavor of the strawberries, blueberries, and the low carb base were perfect. And when you want a morning of relaxation then take your cup of coffee and walk through the beautiful garden that must cover at least half an acre. But I must say their thoughtfulness is outstanding. I did not have a car when I stayed and had my first ever gallstone attack at 11pm at night. Dana rushed me to the emergency room and made sure that I had her phone number. Chris and Dana are wonderful people.
And I didn't mention all of the beautiful interiors of the home---well you need to stay there if you want to know about it. :-)
And I didn't mention all of the beautiful interiors of the home---well you need to stay there if you want to know about it. :-)
#55 2015-09-20 22:50
Our group of 11 had a delightful stay. Chris and Dana are very accommodating especially for such a large group. The food and hospitality are wonderful. We would all recommend staying here.
#54 2015-06-22 18:19
Scott and I enjoyed another great weekend in Kalamazoo due in large part to the hospitality of Dana and Chris, and the wonderful atmosphere of the Stuart Avenue Inn. The delicious breakfasts contributed also! The Inn has become our home away from home.
#53 2015-01-20 06:12
I have stayed at the Stuart Avenue Inn 12 times. Dana and Chris are wonderful and helpful hosts. The home is beautiful and the rooms are warm, comfortable, and homey without being frilly or overdone. The dining room looks out over the lovely garden, and Dana's breakfasts are all made from scratch and delicious! I always look forward to my meals there. I will never stay anywhere else in Kalamazoo!
#52 2014-10-07 15:03
Best, most quiet night of sleep I've ever gotten at a B&B! Stuart Avenue Inn was very comfortable, quiet, and even better than we expected from what we saw on the web site. We stayed in Ruth's Room, which is actually nicer than the pictures communicate. All we could hear were the raindrops falling outside our room. Breakfast was good, and the Innkeepers kindly fulfilled our vegetarian request. Loved the private tables and the ability to enjoy breakfast when we wanted and as late at 10 AM, a great start to our day. Dana and Chris are lovely people; we felt like we were staying with very gracious friends! Can't wait to go back!
#51 2014-10-02 00:29
Stayed for a week and was the best vacation ever. Great atmosphere, superb food and very comfortable. Will return time and time again. Innkeepers Dana & Chris was warm and caring and immediately made us feel at home. When you are in or near Kalamazoo, MI, don't stay at a motel, stay at the Stuart Avenue Inn Bed and Breakfast, you will be glad you did.
#50 2014-06-22 04:36
I checked 4 other hotels for a room and couldn't find one. Then I called Stuart Ave Inn and my previous mood went from disappointment to astonishment. Dana almost insisted I let her pick my (stranded) daughter up at the train station to bring her to the Inn. Bear in mind, I had never met Dana nor even heard about the inn before that call. Then during the call Dana indicated she'd be asking my daughter what she wants for breakfast. Now, maybe I've led a sheltered life but, wow. The next day upon picking my daughter up I was blown away by the history, beauty and majestic size & style of the almost 130 year old home. When I walked in it was literally a spiritual feeling of rubbing elbows with 6 generations of guests and families. Don't even get me started about Dana & Chris' kindness and welcoming nature. I felt like I'd known them my whole life in the first 5 minutes. All I was looking for was a room. What I found however
#49 2013-11-12 00:27
We had a beautiful stay at the Bed and Breakfast for veterans day. Thank you for a quiet, clean and comfortable room. The breakfast was gourmet and out of this world. Please tell Belvedere thank you for being such a handsome host. We will definitely return to stay in other rooms.


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Happy New Year! We are looking forward to a great 2011. We have a great lineup of training planned, including our CSM and CSPO offerings, AgileEVM training, and some new trainings.
New Training Offerings
Along with our current training offerings around Certified ScrumMaster (CSM) and Certified Scrum Product Owner (CSPO) courses, we will also be offering training for:
- Agile Portfolio and Release Management using AgileEVM
- Managing Software Debt Workshop (based on our book)
- Online training and micro-consulting
Although we have been training these unofficially for some time now, these are new official offerings, we are looking for companies and individuals who are interested in taking these courses for a discount. Please let us know if you are interested in test-driving any of these offerings.
CSM and CSPO Training
Lets not forget our CSM and CSPO course listings. You can find a full list of our classes on the Scrum Alliance and on our web site. We will be holding CSM and CSPO classes back-to-back in San Francisco on the following dates:
- February 15-18
- March 22-25
- April 26-29
- June 14-17
- August 23-26
Of course, our CSPO course will include introductory training on the use of Innovation Games® to gather data from your customers and stakeholders. We feel strongly that a healthy relationship with your user community and stakeholders is essential to delivering great products.
AgileEVM Training
In fact, we have been working with our customers over the past 6 months on enhancing and improving our own product, AgileEVM. You can take a tour of AgileEVM on our training video page. Please register for a free account today if you don't already have one. You can manage up to 2 active releases with your free account so please try it out and let us know what you think at AgileEVM Support.
We are looking forward to a great year in 2011. Please let us know if you are interested in our training or consulting services at Sterling Barton.


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Law Journal articles, Legal blogs, information on my books, letters to the Times and a few other things
Friday, 8 June 2012
An ignoble day for the noble art
For Halsbury's Law Exchange
Recently on Halsbury's Law Exchange Simon Hetherington wrote a thoughtful piece on boxing. He stated candidly at the outset that he was not a boxing fan. For my own part, I admit to being an inveterate fan of the sport, although I haven't followed it closely for a few years now. Even the most avid boxing fan, however, has to admit that the activity gives rise to serious moral and legal questions. And even if one finds satisfactory answers to those questions in principle, no-one can be happy – from a legal, moral or sporting perspective – with the way in which boxing is run, as the embarrassing saga of the planned fight between David Haye and Dereck Chisora demonstrates.
The first question a lawyer might ask is why boxing is legal at all. Ordinarily, hitting someone with the intention to render them unconscious would amount to a serious criminal offence. The immediate riposte is that boxing is done by consent. But consent is usually no defence to a serious criminal offence, as the law student favourite of R v Brown [1993] 2 All ER 75 demonstrates. In that case the House of Lords found that the fact that the defendants had consented to sado-masochistic sexual activities was no defence to charges of unlawful and malicious wounding, and assault occasioning actual bodily harm (offences under ss 20 and 47 of the Offences against the Person Act 1861).
Is there a moral difference between damaging genitals for sexual gratification on the one hand, and damaging brains for sporting enjoyment, money and the entertainment of spectators on the other? If there is, it is not obvious. Of course, other activities (smoking or drinking for a start) and indeed other contact sports involve a risk to one's health. But only in boxing (or the various forms of full contact martial arts, which incidentally are usually regulated even more badly than boxing) is damaging another person's health the whole point of the activity rather than a risky side effect.
R v Brown was and remains a controversial decision, and one reached by a bare majority. For what it is worth, I think it was wrongly decided, and it would be interesting if someone challenged it with reference to the European Convention on Human Rights, under the right to a private life guaranteed by Art 8. But the case remains good law at least for now, and it is hard to square the underlying principle with the continuing legitimacy of boxing.
We therefore start with the fact that boxing is a moral and legal anomaly. How has it survived in an age of health and safety? I suggest there are four main reasons. First, it has the veneer of respectability conferred by the fact that it is a regulated activity. Secondly, it has been sanitised in the public eye by the Queensbury rules. Thirdly, it has a long history and accompanying tradition, which means there has been little public call for its abolition (though centuries of history and tradition did not save fox hunting). Fourthly, there is the natural resistance, particularly in England, to state paternalism - if people box voluntarily and with knowledge of the risks involved, most consider that it is not the state's business to stop them (this being the chief reason why R v Brown remains controversial).
A side note should be made about the Queensberry rules. They were not the first attempt at boxing rules (for example, in 1743 a set of rules known as the London Prize Ring Rules were published), but they were the reason why boxing took on its modern form, with a fixed number of rounds for each bout, restricted target areas and forms of striking, and compulsory gloves. Ironically these were only partially successful. Although potential injuries must have been reduced by the restrictions on possible forms of hitting, it is generally held that the use of gloves has actually increased the risk of death or serious injury. This is because in bare knuckle fights contestants would damage their hands quite quickly, especially with head punches, which thereafter limited the effectiveness of their blows (and thus explains why fights would last for dozens of rounds). Conversely, with gloves hand injuries are rare, even over 12 round fights, meaning punches can be thrown with maximum force throughout. While gloves cushion blows they do not reduce their force; the same brain injury will occur even if superficial injuries such as cuts will be reduced. Thus the Queensberry Rules are a good example of the law of unintended consequences.
Then there are the boxing associations which act as the sanctioning bodies and award titles in each weight division. Nowadays there is any number of competing associations, whose proliferation has led to a sometimes comical devaluation of the concept of "world champion". Many boxing fans will have never even heard of some of the fighters and some will not have even heard of all the soi-dissant authorities. So too with weight divisions: once upon a time there were only three ("heavyweight" started at ten stone ...) which was manifestly too few; nowadays there are manifestly too many.
Of greater legal interest however are the licensing authorities. In Britain the chief authority is the British Boxing Board of Control (BBBoC). Theoretically, only fights sanctioned by a recognised authority are lawful, although there are exceptions. The authorities seem to turn a blind eye to some forms of bare knuckle fights, for example, whilst two people who put on gloves and spar in an unlicensed gym will not likely attract the authorities' attention either.
But let us return to licensing authorities and the gaping regulatory hole which Simon Hetherington identifies. His article was prompted by the forthcoming fight between Haye and Chisora. The fight is not being sanctioned by the BBBoC. Nevertheless it is taking place in Britain, apparently legally, because it is being sanctioned by another board, that of Luxembourg. Can it be right, Mr Hetherington asks, that one country's authority can license a fight in another country, particularly when that other country's authority has explicitly refused to sanction it?
One thinks immediately of the tragic end to the greatest of all boxing greatest careers, that of Muhammad Ali. By 1981 he was a washed up has-been, a shadow of his former self, yet continued to rage against the dying of his sporting light, like so many boxers before and since. He wanted to fight the journeyman Trevor Berbick. No regulatory authority in America would have anything to do with it. But the shameless Bahamian boxing authorities did sanction the fight, which went ahead and was, as everyone predicted, an horrific spectacle as the once-great Ali was hammered by the young journeyman Berbick. To add to the disgrace the Bahamian organisers were so inept that no stopwatch or bell had been officially provided: a watch had to be borrowed and then someone improvised with a cowbell.
That "contest" was bad enough as an instance of greed above all else. But imagine how much worse – indeed, absurd – it would have been if the fight had been held in America under the auspices of a foreign authority, against the wishes of the duly constituted American authorities? That is the scenario that is threatening to occur with the Haye/Chisora fight.
Admittedly Haye against Chisora does not have the feel of an imminent disaster in the way that Ali v Berbick did; both fighters are presumed competent. But it has only come about because someone has managed to persuade the Luxemborg authority (which has no professional fighters under its jurisdiction) to licence the fight and a German company to promote it – on British soil. The British board does not want the fight to happen. Its reasons are not the point – if one disagrees with them, then one should appeal, or apply to review the decision by way of judicial review. One certainly should not have the option simply to rope in some other licensing authority to circumvent the inconvenience of one's own regulator.
If boxing is to have any credibility as a sport, let alone as an activity forming a glaring exception to the criminal law, then it has to be conducted in a respectable fashion. It does no one any credit or respect to be able to dodge the appropriate British regulatory authority on British soil with a small country's equivalent organisation. It would be embarrassing in other sports, if one could find one in which it would happen. But in boxing it should also be illegal – not simply unlawful, but as illegal as organising a criminal activity, which, after all, is precisely what unregulated boxing amounts to.
According to recent press reports, the European Boxing Union has threatened Luxembourg with expulsion for licensing the fight. Let us hope it is prepared to carry through with that threat, and that the whole tawdry affair is thereby brought to a swift and appropriate conclusion.
2 comments:
- Anonymous9 June 2012 at 20:42
The BBBoC is a disgusting, hypocritical organization and I hope Frank Warren's bold move destroys them. They object to Haye vs Chisora on moral grounds, yet had no problem allowing convicgted rapist Mike Tyson to fight in the UK after he bit Holyfield's ear off? They also had nothing to say about Lennox Lewis's outside the ring brawls with Hasim Rahman and Tyson, yet are supposedly outraged about Haye and Chisora's scuffle. This entire matter has been blown out of all proportion because of social media, which allows mountains to be made out of every molehill. Haye versus Chisora is a solid heavyweight fight between two evenly matched opponents, and all the hand-wringing over it is far more embarrassing than anything else. Even if Luxembourg pulls out, which it won't, there are six more boxing comissions ready to license the fight. The fight is not "unregulated boxing," it will be fought under the same rules as any other boxing match, and is sanctioned by both the WBO and WBA. There is nothing untoward about a out of the country comission licensing a fight in the UK - that is propaganda being put out by the BBBoC.ReplyDelete
This may all be true, and if so it rather confirms the aspersions I have cast on boxing management and organisation generally. But the point remains that either boxing is regulated properly by each country or it is not. If there is to be a British authority - and there should be - then it is meaningless if that authority can be circumvented whenever suits the promoters, so long as they can rope in an overseas authority. Assume the BBBoC are a hapless lot - the answer then is to replace them or reorganise them, not to circumvent them by going to Luxemborg.ReplyDelete


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Listener Did Some Random #PIMPINJOY On Behalf Of Amy
Amy is currently in Austin, Texas and spending a lot of time at Seton Northwest Hospital to be by her father's side during some difficult medical events. Amy shared with us that her dad is battling cancer and has had some complications post surgery.
Amy and her family have been spending a lot of time at the hospital and with the nurses. She said they have treated her family so well and they are really grateful for them, especially one in particular named Jen.
One listener took it upon themselves upon hearing about Amy's favorite nurse on-air and sent some flowers to the hospital on Amy's behalf.
The gesture is incredibly sweet and very #PIMPINJOY which is the definition of Amy and her family. Watch below to see the flowers and the sweet note to accompany them.
Whoever did this, thank you for being a bright light for Amy and her family during this difficult time.


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I have a doubt concerning firewire ports. I have seen there are two types so far: 400 and 800. How could I know what firewire type is my computer's firewire port?
I first read that as extinguish computer's firewire port...lol
Here's a picture of a FireWire 400 port:
And here's FireWire 800:
Super PIII | Unlocked ES Tualatin @ 1.8GHz (150x12, 1.65v), 512K L2
2GB PC2700 | 500GB | Radeon x1950Pro | Apollo Pro 266T | Win7 Pro


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Aldi Suisse AG
Aldi Suisse AG has had a presence with its product range in Switzerland since 2005. Aldi Suisse AG assumes its social responsibility not only with Fairtrade products, but has also supported the Caritas Markets for many years and, since 2011, helped children experiencing poverty and their families in Switzerland. During the Christmas period, Aldi Suisse AG sells Caritas Christmas goods such as gift wrapping paper, cards and tealight holders under the Caritas label, donating all the profits to the Caritas Children's Relief Fund. www.aldi-suisse.ch
Georg Fischer Clean Water Foundation
With its Clean Water Foundation, Georg Fischer AG is involved in improving the water supply in developing countries and in disaster regions. The foundation currently supports a drinking water project in Ethiopia. Clean Water Fondation
Sunstar Hotels
The Sunstar Hotel Group has hotels in the Grisons, the Bernese Oberland and Valais. In cooperation with Caritas, it offers poor families or individuals free holidays. www.sunstar.ch
Swiss Solidarity
Swiss Solidarity is an independent foundation established by the Swiss radio and TV company SRG SSR and supports Caritas' Humanitarian Aid with the donations it collects. www.glueckskette.ch
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The JTI Foundation supports disaster relief and risk reduction efforts worldwide. www.jtifoundation.org / Video: Disaster Risk Reduction Workshop in Bangkok
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ECHO is the European Commission's Directorate-General for Humanitarian Aid and Civil Protection. ECHO supports victims of humanitarian crises, including outside the European Union, through funding of partner organisations such as Caritas Switzerland. ec.europa.eu/echo
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Parliamentary body says government must now act to punish late payments in its supply chains, while introducing mandatory independent mechanisms to hold and manage retentions
Parliament's Business, Energy and Industrial Strategy (BEIS) Committee has urged the government to bring forward proposals to introduce mandatory project accounts with a mechanism to independently release cash retentions owed to contractors.
A new report from the committee into small businesses and productivity was critical of existing efforts to combat both late payments and the abuse of existing retentions systems, particularly in light of the collapse of Carillion that has seen building services specialists losing large amounts of money.
Addressing the issues of retentions and late payments have been the focus of an ongoing campaign for a range of industry bodies such as BESA, the ECA and the Specialist Engineering Contractors' (SEC) Group that have been pushing for regulatory reform. The same organisations have also supported MP Peter Aldous in introducing proposed regulation to parliament back in January that seeks to make the use of third part deposit schemes for holding retentions as a legal necessity.
It is in this environment that the BEIS Committee's report looked at concerns around payment practices in sectors such as construction and found that the introduction of independently managed project accounts for holding retentions would be a significant step to prevent future abuse.
However, current inaction within government on committing to such a proposal was a major source of concern in the findings.
The committee said, "The government is currently sitting on a review of this issue and we found the minister's stance that a lack of consensus was holding up progress disappointing."
"We recommend that the government should bring forward proposals as soon as possible to introduce compulsory project accounts so that retention money can be held independently and its release subject to fair and timely oversight."
The report noted that the principle of withholding retentions was necessary to ensure contractual responsibilities were being fulfilled in construction projects. However, the level of abuse of the system was a major concern, specifically from big companies that were increasingly building the practice of withholding retentions payments for as long as possible for financial gain into their business models.
The report said the significant damage to the supply chain from delayed and withheld retentions that were owed to contractors was highlighted even further by the liquidation of Carillion in January.
Prompt payment revamp
Late payment was another area of concern highlighted in the report that was found to adversely affect growth of UK SMEs as well as overall industry productivity.
The report said, "As we found with Carillion, late payments are built into the business models of too many companies, leading to many SMEs losing staff, profits and their businesses. This is totally unacceptable, unfair and constitutes a particularly disgraceful form of market abuse."
The committee once again called on government to take immediate action by granting the recently created position of Small Business Commissioner with new powers to fine companies found to be paying late. This would also require expanding the remit of the same commissioner to include the construction sector.
Industry response
Both BESA and the ECA, which have been campaigning for a number of years to make it mandatory for retentions to be held in accredited deposit schemes, welcomed the committee's calls concerning payment reforms.
BESA policy manager Alexi Ozioro said that the latest report highlighted the growing political momentum to ensure fairer payment practices. He also cited the Cabinet Office's announcement last week that it would next autumn consider backlisting companies with poor payment records from winning government contracts as a positive development.
Mr Ozioro said, "This highly influential report from the BEIS Select Committee and the Cabinet Office's intervention are highly significant especially with the anniversary of Carillion just a month away. This reflects growing political pressure to address behaviour that is not just morally wrong, but is also bad for the UK economy by putting perfectly good businesses at risk of insolvency."
"Connecting fair payment to procurement is a powerful statement from government, and a very welcome development."
Rob Driscoll, deputy director of policy and practice with the ECA, also praised the work of a Cabinet Office-established SME panel that had worked with civil servants to try and improve support for SMEs looking to work in the public sector.
He said, "These developments represent a significant milestone in the government realising its role as a responsible client in the post-Carillion era. They should be applauded."
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text: July 20, 2011 / Giveaway: Grant's Golden Brand Pomade Winner! By Well Groomed Posted in Giveaways Congrats, Ryan! Grant will contact you at your gmail address to get those tins of pomade to you. Feel free to send in a pic of your new 'do. Share this story About The Well Groomed


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Here's a quick and easy summer meal that comes together fast and doesn't heat up the whole house. By keeping this burrito simple, the light flavor of the shrimp and fresh salsa come through for a satisfying dinner that doesn't leave you feeling bloated. As if the heat weren't already enough.
For my Shrimp Burritos, you will need start with the salsa. Salsa in its simplest form is tomatoes, peppers, and onions. Many feel that cilantro is a must. While it does add a little palate-cleansing freshness, personally I can live without it. What I need in my salsa is citrus.
For tonight's salsa, I used heirloom cherry tomatoes, jalapenos, a little garlic, and a little shallot. I also learned why you should take inventory of your ingredients before you start cooking. Once I had everything cut and ready for the immersion blender, I realized that we had no citrus fruit in the house.
In a move that my counterpart is sure to comment on later, I added a splash of lemonade. Here's why this works: It adds the necessary zip that comes from citrus (lemon, lime, orange, whatever). But it also adds some sugar to cut the bitter in the peppers, garlic, and shallots without clashing with the sugar in the tomatoes or blunting the heat from the peppers. I pulsed the immersion blender about five times and placed the salsa in the fridge to chill.
For the shrimp, you will want to steam them on the stovetop. How long this takes will depend on the size and quantity of your shrimp. I used four tiger shrimp that were only partially defrosted. They cooked through in about 15 minutes. Also, you should steam your shrimp in the shells and shell them once they are cooked.
And, if you are using large shrimp like mine, you'll want to cut them up once they are shelled.
Once the shrimp is cooked and cut, you'll also need an avocado and some sour cream. Note that I am forgoing the beans and cheese ans they will weigh this down and won't taste right here. Well, maybe the right kind of cheese, but certainly not the beans. I am also omitting the cabbage slaw that usually adorns fish tacos. I consider the cabbage to be a proper culinary mistake on the tacos and certainly a disaster here.
To prep your tortilla, heat it in a flat skillet over low heat on the stovetop. You'll want to warm it so that it loses some of its stiffness. This will make it easier to roll and will prevent tearing.
To assemble the burrito, place the warm tortilla on a large plate. Add the avocado first, placing it in the center. Then place the shrimp on top of it. Spoon the sour cream on one side of the shrimp and the salsa on the other side. Carefully fold up the bottom over the filling. Then bring one of the sides over and line it up with the other and roll tightly, tucking in the bottom securely.
And that's it - avocado, shrimp, sour cream, and salsa. The whole thing came together for me in about 30 minutes.


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There's only two directions in Cape Town – from the mountain and to the mountain. And much the same, there's only two ways the Cape Town Skyline Wall Art by Native Decor can enhance your living space and that's exponentially and phenomenally. No matter where you are in the world, this piece of art will remind you of the beauty the mother city has to offer.
Material: Commercial Plywood


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Perched at the top of the residential buildings on the Overlook Level, The Penthouses offer 2,753 to 3,220-square-feet* of convenient single-story living. The expansive great room opens through glass walls to a spacious private deck capturing magnificent mountain views. Each four and five-bedroom floor plan features a master and junior master as well as en-suite baths in each room for the privacy and comfort of family and friends.
No Federal agency has judged the merits or value, if any, of this property. This is neither an offer to sell, nor a solicitation of offers to buy, any property in those states where such offers or solicitations cannot be made. Not available to residents in the State of New York. WARNING: THE CALIFORNIA DEPARTMENT OF REAL ESTATE HAS NOT INSPECTED, EXAMINED, OR QUALIFIED THIS OFFERING. Illustrations are artist's conceptual renderings only and are subject to change without notice. Amenities described herein are anticipated but not guaranteed and may not be completed by seller. Neither seller nor seller's agents assume responsibility for the accuracy of the information contained herein. Buyers should review the purchase agreement, public offering statement, and other offering materials provided by the seller prior to signing any contract to purchase a unit. ©Apex Park City Residences LLC. Unauthorized use of the images, artist renderings, plans or other depictions of the project or units is strictly prohibited.
The information contained herein is furnished by the owner to the best of their knowledge, but is subject to verification by the buyer. Seller's agent assumes no responsibility for accuracy. The sale offering is made subject to errors, omissions, changes of price to sale or withdrawn without notice. Elevations and floor plans are shown accurately at time of rendering. This information is subject to change without notice. Buyer is responsible to verify the accuracy of all information to the buyers own satisfaction.
© 2015 2016 BHH Affiliates, LLC. An independently owned and operated franchisee of BHH Affiliates, LLC. Berkshire Hathaway HomeServices and the Berkshire Hathaway HomeServices symbol are registered service marks of HomeServices of America, Inc.® Equal Housing Opportunity. Information not verified or guaranteed. If your home is currently listed with a Broker, this is not intended as a solicitation.


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Graphene In Heavy-duty Anti-Corrosion of Ocean
The first offshore wind power tower coated with graphene anti-corrosion system made by The Sixth Element (Changzhou) Materials Technology Co. Ltd has been in the Rudong sea area for more than 1 year. The anti-corrosion coatings with graphene-SE1132 from The Sixth Element creates a milestone in the marine heavy anti-corrosion. With 1% graphene in the primer, more than 2500 hours can be achieved in the salt spray test which redefined the anti-corrosion system: the heavy duty anti-corrosion system with 70%-80% zinc powder in the past is replaced by the new system of 25% zinc powder with 1% graphene. More than 50% zinc powder can be reduced.


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All the way from Finland travels Markus Luukkonen with his Finnish stories.
Our Amsterdam Brit Simon Hodges tells tells us the tall tales of Finn McCall
And Mezrab's own Irano-Dutch Sahand Sahebdivani tells stories of… of…. Dol-phins? Shark-fins? Fin-ishing last?
Come and find out!
Doors open at 19.00, stories start at 20.00 (don't be late)
All donations will go toward's Markus' international travel costs, so be kind.


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Cancer immunotherapy and its budding effectiveness at improving patient outcomes has revitalized our hope to fight cancer in a logical and safe manner. Immunotherapeutic approaches to reengage the immune system have largely focused on reversing immune checkpoint inhibitor pathways, which suppress the antitumor response. Although these approaches have generated much excitement, they still lack absolute success. Interestingly, newly described host-tumor sugar chains (glycosylations) and glycosylation-binding proteins (lectins) play key roles in evading the immune system to determine cancer progression. In this issue of the JCI, Nambiar et al. used patient head and neck tumors and a mouse model system to investigate the role of galactose-binding lectin 1 (Gal1) in immunotherapy resistance. The authors demonstrated that Gal1 can affect immune checkpoint inhibitor therapy by increasing immune checkpoint molecules and immunosuppressive signaling in the tumor. Notably, these results suggest that targeting a tumor's glycobiological state will improve treatment efficacy.
Asmi Chakraborty, Charles J. Dimitroff
Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid-derived suppressor cells (MDSCs). Using in vitro systems, murine tumor models in wild-type and genetically modified (β2-AR–/–) mice, and adoptive transfer approaches, we found that the degree of β2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues. It also modulates their expression of immunosuppressive molecules such as arginase-I and PD-L1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of β2-AR signaling in MDSCs were also found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the β2-AR–mediated increase in MDSC survival is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses, which reveal a greater expression of apoptosis-related genes in β2-AR–/– MDSCs. Our data reveal the potential of β2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs can be mitigated by treatment with β-AR antagonists, or enhanced by β-AR agonists. This strongly supports the possibility that reducing stress-induced activation of β2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.
Hemn Mohammadpour, Cameron R. MacDonald, Guanxi Qiao, Minhui Chen, Bowen Dong, Bonnie L. Hylander, Philip L. McCarthy, Scott I. Abrams, Elizabeth A. Repasky
Eileen P. Scully, Ethel D. Weld, Joel N. Blankson
The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.
Monica Chang-Panesso, Farid F. Kadyrov, Matthew Lalli, Haojia Wu, Shiyo Ikeda, Eirini Kefaloyianni, Mai M. Abdelmageed, Andreas Herrlich, Akio Kobayashi, Benjamin D. Humphreys
Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.
Dhanya K. Nambiar, Todd Aguilera, Hongbin Cao, Shirley Kwok, Christina Kong, Joshua Bloomstein, Zemin Wang, Vangipuram S. Rangan, Dadi Jiang, Rie von Eyben, Rachel Liang, Sonya Agarwal, A. Dimitrios Colevas, Alan Korman, Clint T. Allen, Ravindra Uppaluri, Albert C. Koong, Amato Giaccia, Quynh Thu Le
The microphthalmia family of transcription factors (MiT/TFEs) controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. However, the mechanisms by which cells with constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we found that epidermal Tsc1 deletion resulted in a phenotype characterized by wavy hair and curly whiskers, and was associated with increased EGFR and HER2 degradation. Unexpectedly, constitutive mTORC1 activation with Tsc1 loss increased lysosomal content via upregulated expression and activity of MiT/TFEs, whereas genetic deletion of Rheb or Rptor or prolonged pharmacologic mTORC1 inactivation had the reverse effect. This paradoxical increase in lysosomal biogenesis by mTORC1 was mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE downregulation. Thus, inhibiting hyperactive AKT signaling in the context of mTORC1 loss-of-function fully restored MiT/TFE expression and activity. These data suggest that signaling feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling, respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.
Kaushal Asrani, Sanjana Murali, Brandon Lam, Chan-Hyun Na, Pornima Phatak, Akshay Sood, Harsimar Kaur, Zoya Khan, Michaël Noë, Ravi K. Anchoori, C. Conover Talbot Jr., Barbara Smith, Michael Skaro, Tamara L. Lotan
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases — where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele — is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3–4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.
Kathryn H. Morelli, Laurie B. Griffin, Nettie K. Pyne, Lindsay M. Wallace, Allison M. Fowler, Stephanie N. Oprescu, Ryuichi Takase, Na Wei, Rebecca Meyer-Schuman, Dattatreya Mellacheruvu, Jacob O. Kitzman, Samuel G. Kocen, Timothy J. Hines, Emily L. Spaulding, James R. Lupski, Alexey Nesvizhskii, Pedro Mancias, Ian J. Butler, Xiang-Lei Yang, Ya-Ming Hou, Anthony Antonellis, Scott Q. Harper, Robert W. Burgess
Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.
Tianyu He, Cuiling Xu, Noah Krampe, Stephanie M. Dillon, Paola Sette, Elizabeth Falwell, George S. Haret-Richter, Tiffany Butterfield, Tammy L. Dunsmore, William M. McFadden Jr., Kathryn J. Martin, Benjamin B. Policicchio, Kevin D. Raehtz, Ellen P. Penn, Russell P. Tracy, Ruy M. Ribeiro, Daniel N. Frank, Cara C. Wilson, Alan L. Landay, Cristian Apetrei, Ivona Pandrea
CD8 cytotoxic T lymphocytes (CTLs) rely on rapid reorganization of the branched F-actin network to drive the polarized secretion of lytic granules, initiating target cell death during the adaptive immune response. Branched F-actin is generated by the nucleation factor actin-related protein 2/3 (Arp2/3) complex. Patients with mutations in the actin-related protein complex 1B (ARPC1B) subunit of Arp2/3 show combined immunodeficiency, with symptoms of immune dysregulation, including recurrent viral infections and reduced CD8+ T cell count. Here, we show that loss of ARPC1B led to loss of CTL cytotoxicity, with the defect arising at 2 different levels. First, ARPC1B is required for lamellipodia formation, cell migration, and actin reorganization across the immune synapse. Second, we found that ARPC1B is indispensable for the maintenance of TCR, CD8, and GLUT1 membrane proteins at the plasma membrane of CTLs, as recycling via the retromer and WASH complexes was impaired in the absence of ARPC1B. Loss of TCR, CD8, and GLUT1 gave rise to defects in T cell signaling and proliferation upon antigen stimulation of ARPC1B-deficient CTLs, leading to a progressive loss of CD8+ T cells. This triggered an activation-induced immunodeficiency of CTL activity in ARPC1B-deficient patients, which could explain the susceptibility to severe and prolonged viral infections.
Lyra O. Randzavola, Katharina Strege, Marie Juzans, Yukako Asano, Jane C. Stinchcombe, Christian M. Gawden-Bone, Matthew N.J. Seaman, Taco W. Kuijpers, Gillian M. Griffiths
Tumor-induced immunosuppression is a common obstacle for cancer treatment. Adrenergic signaling triggered by chronic stress participates in the creation of an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) proliferation and activation. In this issue of the JCI, Mohammadpour et al. elegantly delve into the mechanisms underlying MDSC contribution to tumor development. They used in vitro and in vivo mouse models to demonstrate that chronic stress results in MDSC accumulation, survival, and immune-inhibitory activity. Of therapeutic relevance, the authors showed that propranolol, a commonly prescribed β-blocker, can reduce MDSC immunosuppression and enhance the effect of other cancer therapies.
Ignacio Iñigo-Marco, Marta M. Alonso
microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.
Mahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta, Yana K. Reshetnyak, Raman Bahal, Paolo Fiorina, Peter M. Glazer, David L. Rimm, Carlos Fernández-Hernando, Yajaira Suárez
Deep venous thrombosis (DVT) and secondary pulmonary embolism cause approximately 100,000 deaths per year in the United States. Physical immobility is the most significant risk factor for DVT, but a molecular and cellular basis for this link has not been defined. We found that the endothelial cells surrounding the venous valve, where DVTs originate, express high levels of FOXC2 and PROX1, transcription factors known to be activated by oscillatory shear stress. The perivalvular venous endothelial cells exhibited a powerful antithrombotic phenotype characterized by low levels of the prothrombotic proteins vWF, P-selectin, and ICAM1 and high levels of the antithrombotic proteins thrombomodulin (THBD), endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI). The perivalvular antithrombotic phenotype was lost following genetic deletion of FOXC2 or femoral artery ligation to reduce venous flow in mice, and at the site of origin of human DVT associated with fatal pulmonary embolism. Oscillatory blood flow was detected at perivalvular sites in human veins following muscular activity, but not in the immobile state or after activation of an intermittent compression device designed to prevent DVT. These findings support a mechanism of DVT pathogenesis in which loss of muscular activity results in loss of oscillatory shear–dependent transcriptional and antithrombotic phenotypes in perivalvular venous endothelial cells, and suggest that prevention of DVT and pulmonary embolism may be improved by mechanical devices specifically designed to restore perivalvular oscillatory flow.
John D. Welsh, Mark H. Hoofnagle, Sharika Bamezai, Michael Oxendine, Lillian Lim, Joshua D. Hall, Jisheng Yang, Susan Schultz, James Douglas Engel, Tsutomu Kume, Guillermo Oliver, Juan M. Jimenez, Mark L. Kahn
Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of β-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-β (RARβ) expression by reducing the interaction between RARα and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RARβ expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARβ expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARβ had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARβ are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.
Junhee Park, Xianglan Zhang, Sun Kyoung Lee, Na-Young Song, Seung Hwa Son, Ki Rim Kim, Jae Hoon Shim, Kwang-Kyun Park, Won-Yoon Chung
While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.
Scott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan
Excessive alcohol consumption is associated with spontaneous burning pain, hyperalgesia, and allodynia. Although acetaldehyde has been implicated in the painful alcoholic neuropathy, the mechanism by which the ethanol metabolite causes pain symptoms is unknown. Acute ethanol ingestion caused delayed mechanical allodynia in mice. Inhibition of alcohol dehydrogenase (ADH) or deletion of transient receptor potential ankyrin 1 (TRPA1), a sensor for oxidative and carbonyl stress, prevented allodynia. Acetaldehyde generated by ADH in both liver and Schwann cells surrounding nociceptors was required for TRPA1-induced mechanical allodynia. Plp1-Cre Trpa1fl/fl mice with a tamoxifen-inducible specific deletion of TRPA1 in Schwann cells revealed that channel activation by acetaldehyde in these cells initiates a NADPH oxidase-1–dependent (NOX1-dependent) production of hydrogen peroxide (H2O2) and 4-hydroxynonenal (4-HNE), which sustains allodynia by paracrine targeting of nociceptor TRPA1. Chronic ethanol ingestion caused prolonged mechanical allodynia and loss of intraepidermal small nerve fibers in WT mice. While Trpa1–/– or Plp1-Cre Trpa1fl/fl mice did not develop mechanical allodynia, they did not show any protection from the small-fiber neuropathy. Human Schwann cells express ADH/TRPA1/NOX1 and recapitulate the proalgesic functions of mouse Schwann cells. TRPA1 antagonists might attenuate some symptoms of alcohol-related pain.
Francesco De Logu, Simone Li Puma, Lorenzo Landini, Francesca Portelli, Alessandro Innocenti, Daniel Souza Monteiro de Araujo, Malvin N. Janal, Riccardo Patacchini, Nigel W. Bunnett, Pierangelo Geppetti, Romina Nassini
Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27–mediated spliced X-box–binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27–mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.
Chin-Hsiu Liu, Sengupta Raj, Chun-Hsiung Chen, Kuo-Hsuan Hung, Chung-Tei Chou, Ing-Ho Chen, Jui-Teng Chien, I-Ying Lin, Shii-Yi Yang, Takashi Angata, Wen-Chan Tsai, James Cheng-Chung Wei, I-Shiang Tzeng, Shih-Chieh Hung, Kuo-I Lin
Manganese (Mn) participates in a variety of distinct physiological processes, including acting as a cofactor for several enzymes and metalloenzymes, in addition to playing a role in immune function, endocrine function, hematopoiesis, and oxidative stress regulation. Mn homeostasis is tightly regulated via intestinal absorption and hepatobiliary and intestinal excretion. In this issue of the JCI, Mercadante and colleagues explored the role of the metal transporter Slc30a10 in vivo using a mouse model system. The authors used whole-body and tissue-specific gene knockouts to show that Slc30a10 is paramount for Mn excretion in the liver and small intestines. These findings provide further insights into mechanisms for Mn homeostasis as well as potential targets for addressing Mn-associated disorders or environmental exposures.
Nathan Katz, Daniel J. Rader
Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.
Arjan C. Houweling, Glenda M. Beaman, Alex V. Postma, T. Blair Gainous, Klaske D. Lichtenbelt, Francesco Brancati, Filipa M. Lopes, Ingeborg van der Made, Abeltje M. Polstra, Michael L. Robinson, Kevin D. Wright, Jamie M. Ellingford, Ashley R. Jackson, Eline Overwater, Rita Genesio, Silvio Romano, Letizia Camerota, Emanuela D'Angelo, Elizabeth J. Meijers-Heijboer, Vincent M. Christoffels, Kirk M. McHugh, Brian L. Black, William G. Newman, Adrian S. Woolf, Esther E. Creemers
Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we focused on an ADAR2-catalyzed RNA editing site within the miR-379-5p seed region. This site was under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrated that in contrast to wild-type miRNA, edited miR-379-5p inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro, which was due to the ability of edited but not wild-type miR-379-5p to target CD97. Importantly, through nanoliposomal delivery, edited miR-379-5p mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as a new class of cancer therapeutics.
Xiaoyan Xu, Yumeng Wang, Kamalika Mojumdar, Zhicheng Zhou, Kang Jin Jeong, Lingegowda S. Mangala, Shuangxing Yu, Yiu Huen Tsang, Cristian Rodriguez-Aguayo, Yiling Lu, Gabriel Lopez-Berestein, Anil K. Sood, Gordon B. Mills, Han Liang
Manganese (Mn), an essential metal and nutrient, is toxic in excess. Toxicity classically results from inhalational exposures in individuals who work in industrial settings. The first known disease of inherited Mn excess, identified in 2012, is caused by mutations in the metal exporter SLC30A10 and is characterized by Mn excess, dystonia, cirrhosis, and polycythemia. To investigate the role of SLC30A10 in Mn homeostasis, we first generated whole-body Slc30a10–deficient mice, which developed severe Mn excess and impaired systemic and biliary Mn excretion. Slc30a10 localized to canalicular membranes of hepatocytes, but mice with liver Slc30a10 deficiency developed minimal Mn excess despite impaired biliary Mn excretion. Slc30a10 also localized to the apical membrane of enterocytes, but mice with Slc30a10 deficiency in small intestines developed minimal Mn excess despite impaired Mn export into the lumen of the small intestines. Finally, mice with Slc30a10 deficiency in liver and small intestines developed Mn excess that was less severe than that observed in mice with whole-body Slc30a10 deficiency, suggesting that additional sites of Slc30a10 expression contribute to Mn homeostasis. Overall, these results indicated that Slc30a10 is essential for Mn excretion by hepatocytes and enterocytes and could be an effective target for pharmacological intervention to treat Mn toxicity.
Courtney J. Mercadante, Milankumar Prajapati, Heather L. Conboy, Miriam E. Dash, Carolina Herrera, Michael A. Pettiglio, Layra Cintron-Rivera, Madeleine A. Salesky, Deepa B. Rao, Thomas B. Bartnikas


text: I don't know about you, but I was always fond of cold weapons, like, you know, bows, knives and swords. Especially when some hot girl wielding it! I can still remember of Red Sonja and Xena, and some girls from video games…mmm, sweet memories. Also, I've read few posts on the net that says that the girls with swords are passe – and I disagree. These babes look dangerous with the weapon in their hands, and dressed like this – they look sooo hot! This gallery is for fans, so just enjoy this pics.


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SILICON SLOPES, UT — October 1, 2015 — Workfront, the leading provider of cloud-based Enterprise Work Management solutions, today announced that Sue Fellows has joined the company as its new executive vice president of Customer Success and a member of the executive leadership team.
As Workfront's EVP of Customer Success, Fellows will be responsible for managing the Workfront customer organization, including: Customer Success, Education & Training, Customer Success Operations, Strategic Services, and Technical Support.
Fellows brings nearly two decades of experience working with customers to drive value and customer satisfaction. Prior to Workfront, Sue was the Vice President of Global Customer Excellence at Apttus. During her tenure at Apttus, Fellows' contributions in building the customer success and support functions resulted in increased customer satisfaction scores, as well as higher renewal rates for the organization. Sue has worked for both start up and enterprise technology companies including RightNow Technologies and Oracle, and held leadership roles in Professional Services, Operations and Customer Success Management.
"Sue is a great addition to the Workfront team due to her proven success in developing and implementing processes, tools, and teams designed to provide SaaS customers with world-class service," said Eric Morgan, CEO of Workfront. "Sue's leadership will be a driving force in the retention and growth of Workfront's customer base and the continued ability to provide our customers with excellent customer service."
Fellows joins Workfront at an exciting time as the company just announced $33 million in funding and the acquisition of ProofHQ. Workfront was also recently listed as a Leader in the Gartner Inc., 2015 Magic Quadrant for Cloud-Based IT Project and Portfolio Management Services and a Challenger in the Gartner Inc, 2015 Magic Quadrant for Marketing Resource Management .
To find our more about Workfront, visit www.Workfront.com.
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About Workfront
Workfront is a cloud-based Enterprise Work Management solution that helps marketing, IT, and other enterprise teams conquer the chaos of excessive email, redundant status meetings, and disconnected tools. Unlike other tools, Workfront Enterprise Work Cloud is a centralized, easy-to-adopt solution for managing and collaborating on all types of work through the entire work lifecycle, which improves team productivity and executive visibility. Workfront is trusted by thousands of global enterprises, like Cars.com, Cisco Systems, Comcast, iProspect, Schneider Electric and Trek. To learn more, visit www.workfront.com or follow us on Twitter @Workfront_Inc.