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The Oscars' most confusing categories, explained
By Emily St. James@emilyvdw Feb 19, 2015, 10:00am EST
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The Oscars are not actually this large. That would be hard to carry.
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One of the things that allows the Oscars to maintain their prominence as not just the preeminent film award but the preeminent entertainment award period is their relative paucity of trophies. The Oscars hand out awards in just 24 categories, all during their televised ceremony. Compared to, say, the Grammys' 83 prizes, the Oscars are relatively stingy — making each reward precious.
And yet it's not uncommon to have absolutely no idea what some of these awards mean. Sure, most of us know what it means to win an award for acting, and the term "Best Costume Design" is self-explanatory. But what's the difference between Sound Design and Sound Editing? How long is a short film? And just what does a director do anyway?
Read on, for we have answered your Oscar category questions.
So who wins Best Picture anyway?
Glamorous actors are the center of attention on Oscar night, but the biggest award of all is placed in the hands of producers who are typically obscure to the mass public. This is a throwback to the Academy's roots in the Hollywood of the late silent era, when producers were the most important figures in the film industry. (That description would largely hold — give or take a particularly prominent director — until the 1960s and '70s.)
Think of Gone with the Wind, for instance, which was long the film that had won the most Oscars. Directed by Victor Fleming (who actually replaced original director George Cukor), it was producer David O. Selznick who made adapting the novel into his passion project and got the biggest film of the era made, and it was Selznick who took home the Best Picture trophy (via his Selznick International Pictures company).
Today's films often have dozens of producers — occasionally just people who sign on to help secure funding, or help a movie get made — so the Academy has instituted a couple of regulations. To win, a producer must have a "producer" or "produced by" credit on the film, and only the three producers who have done the most work to make the film a reality (determined by the Academy) are nominated.
If you look at this year's ballot, however, you'll notice several films with four producers nominated — and American Sniper has five. The explanation here is that a team of two producers who are credited as a team and work closely together count as one producer, from the Academy's point of view. So, ultimately, three two-person teams could be nominated, thus allowing for a maximum of six nominees for a film.
So, um, what does a director do, anyway?
Don't be embarrassed! The answer to this question isn't necessarily intuitive, because the popular understanding of "director" is just "the person who's in charge on a movie set." And that's not wrong, but it also doesn't really dig into what a director does beyond bossing people around.
The simple answer for this is that in the '60s and '70s, the director replaced the producer as the most important person working on a film, in the understanding of the industry. (Many proponents of auteur theory would argue the director had always been the most important person working on a film, and it just took that long to catch up. But that's neither here nor there.) The director is responsible for the overall look, feel, and tone of a film. And assuming she has final cut, she's the ultimate decider, on everything from script notes to the edit that's released to theaters. (Yes, the studio will have some say in this, but the studio also doesn't get the Oscar.)
The thing that makes the job difficult to describe, ultimately, is that different directors handle the job in different ways. At a recent Q&A session I attended, Oscar-winning director William Friedkin argued the most important part of a director's job is getting the right cast and turning them loose. Robert Altman (director of MASH and Nashville, among others) assembled huge ensemble casts and allowed for ample room for improvisation and exploration. British director Mike Leigh (of the recent Mr. Turner) comes up with his scripts in conjunction with his actors, who improvise until the screenplay is arrived at, then begin the shoot.
But the most basic part of a director's job is making calls about what the film is going to look like. As a visual medium, the images are incredibly important to film, and the great directors have immediately recognizable, signature styles. Think of, say, the many times Steven Spielberg has shot characters staring at something in wonder, or the many times Martin Scorsese has employed bravura tracking shots that follow the character through his or her native environment.
What makes a screenplay original or adapted?
On its face, the answer to this is easy: adapted screenplays are based on other works, while original screenplays are based on the writer's own idea. In practice, it's (you guessed it) more complicated.
This year's nominees for Original Screenplay, for instance, include Foxcatcher, a film that is based on a true story. And yet because the script was written from screenwriters E. Max Frye and Dan Futterman's original research, it counts as original. If it had been based on one primary source, as with The Imitation Game, based on a biography of Alan Turing, then it would be in the Adapted category. Why do this? Studios or producers often buy the rights to specific books or articles, then hire screenwriters to turn them into scripts.
Making things even more confusing is that the Adapted category is also where all sequels go by default. Before Sunset and Before Midnight both ended up here, because they were based on characters from Before Sunrise, as did Toy Story 3. Even though the stories and scenarios of all three films were completely original, the Academy counted them as adapted because the characters in them had appeared in prior films.
All of which brings us to Whiplash's nomination for Best Adapted Screenplay. The Academy's decision to place it here is because director and writer Damien Chazelle made a short film from one of the script's scenes before making a feature. But even though the script for the feature version of Whiplash predates the short film version, the Academy still ruled that the feature is "based on" the short, landing it here.
Confused? So was the film's studio, Sony Pictures Classics, which only found out it was competing in Adapted when journalist Mark Harris did. (The Academy decides which screenplays go where in toss-up calls like this.)
Who decides whether an actor is lead or supporting?
This is the complete opposite of the screenplay categories. The Academy does not make hard rulings on who's lead and supporting. The actors and studios running their campaigns suggest where they would like to compete, but it's ultimately up to the voters, who can make up their own minds on category placement.
The Academy has all sorts of restrictions placed on actors — you can't be nominated if all of your dialogue was dubbed, you can't be nominated twice in the same category, etc. — but its regulations don't spell out any real differentiation between lead and supporting. Yes, it would have been ridiculous for Bradley Cooper to argue he was a supporting player in American Sniper, but Meryl Streep quite possibly could have gone lead or supporting for Into the Woods.
Where this really trips up the Oscars is in two particular cases. The first involves child performers, who are often slotted into supporting by default, even if they're the lead of a film. (The most recent example of this is Hailee Steinfeld in True Grit. She's the lead actress of that film but was nominated in supporting.) This campaign tactic doesn't always work, however. Keisha Castle-Hughes campaigned as supporting for Whale Rider in 2003, but the voters decided (accurately) to nominate her in lead.
The other instance comes when an actor has two roles they're winning acclaim for in a given year and doesn't want to split votes between them. (Remember: an actor can only be nominated once per category.) Thus, the studios involved usually agree to campaign one performance as lead and one as supporting. In 2008, for instance, Kate Winslet ran as lead for Revolutionary Road and supporting for The Reader. She ended up getting just one nomination, for The Reader, for which she was placed in lead, instead of supporting. She ended up winning, however, so probably she didn't mind.
Finally, if a performance receives votes in both lead and supporting (or if an actor receives multiple votes for multiple roles in the same category), the nomination goes to whichever category the actor qualifies in first.
Who wins the foreign film award?
The person you see giving the speech for the foreign film Oscar is almost always the film's director, and that's the person who will almost always take the prize home. But technically, the award goes to the film's country of origin.
Every country that's not the United States is allowed to choose one film from its local film industry to submit for Academy consideration, provided the film is not in English and was released in its country of origin between October 1 and September 30. (The foreign film calendar is slightly earlier than the Academy calendar.)
Thus, the United Kingdom is unlikely to win this award, but could if it submitted a film in Welsh. Indeed, Canada has won this award, for The Barbarian Invasions, a film in French.
Foreign films are eligible for all other Oscars, but only provided they meet the Oscars' general eligibility requirements (playing in at least one theater in Los Angeles Country for a week within the calendar year being awarded). If they don't, then nominated foreign films are ineligible for any further Oscars at future awards.
What is cinematography?
Technically (and to be incredibly pedantic about it), it's the ability to manipulate light to create images within film cameras. But functionally, the award is for much more than that.
A cinematographer is usually known as a "director of photography," and that name may be easier to immediately grasp. Within the industry, cinematography usually is understood to mean everything having to do with the camera — its movement, the images it captures, the light it receives, etc.
That's how the last several awards (Gravity, Life of Pi, Hugo) have gone to impressive camera feats that, while beautiful, were created in computers. (This is to take nothing away from the cinematographers who created those images, simply to say that they're often not as "pure" as they might appear.) This year's award might very well go to Birdman, which is all about the restless movement of the camera and appears to take place in one long shot. (Clever edits mask the cuts.)
The cinematographer and director often work closely together to create the images you see, but the Oscar for cinematography is usually one meant to express a film's visual beauty or, occasionally, its movement and momentum. In the 1980s and '90s, the award went to films with beautiful exterior landscapes; now, it goes to the creation of painterly images within computer-assisted visual effects.
What does a film editor do?
This one is simple — the film editor takes all of the footage shot and assembles it into the movie you see. They determine the rhythm of scenes, when you see certain camera angles, and what stays in or gets cut. They, too, work closely with the director, but instead of doing so on set (as the cinematographer does), they're present throughout the post-production process. Many directors with long-trusted editors — like, say, Martin Scorsese and editor Thelma Schoonmaker — will have those editors assembling footage into rough cuts even while filming continues.
Ultimately, the decision of final cut rests with the director or studio executives (usually the latter), but the editor is the person with the technical know-how to make that final cut happen. And they often have ideas of their own to contribute to this process.
What is production design?
This used to be called "Best Art Direction — Set Decoration," and that second term should tip you off. This is an award given to the sets you see in movies.
The production designer (or art director) can be better understood as a "set designer" (even if she doesn't always build the actual sets herself), while the set decorator places props and other items upon those sets to make them come to life. The category was originally called "Best Interior Decoration," and that's another good hint as to what's being rewarded here.
What's the difference between sound mixing and sound editing?
The Academy, as mentioned, is extra-judicious in what it rewards. So why are there two seemingly interchangeable awards for sound design?
The answer is that they reward two completely different things, weird as that might seem. The award for sound mixing used to just be called Best Sound. It rewards the overall soundscape — or soundtrack — of the film. In short, everything you hear in the film has to be mixed together and set to certain levels, to the director's specifications, and that job falls to the sound mixers. The nomination for Interstellar here has proved somewhat controversial, because that film's dialogue was famously difficult to understand, due to the booming noise from other parts of the soundtrack.
Sound editing, meanwhile, used to be called "sound effects editing," and that's a good clue as to what this award is given for. All of the sound effects you hear in a film have to be created, of course, and this prize goes to the best created sound effects.
Who decides if something is an original song?
The award for original song (and original score) is just what it sounds like — music written for the film specifically, rather than for something else. For instance, Jennifer Lawrence's performance of "The Hanging Tree" from the latest Hunger Games movie was ineligible, because its lyrics were written by Suzanne Collins for the book series. The music was original, but that's not enough.
Original songs also have to be important to the film they appear in. They must appear within the movie itself, or as the first song over the closing credits. And that "important" clause often means that songs by prominent artists are nevertheless snubbed, because they don't play in a major montage or musical number within the film. Indeed, the recent trend in the category has been to move away from songs that play over the closing credits. (That said, ironically, this year's award will probably be won by "Glory" from Selma — the first song that plays over the film's closing credits.)
How short is a short film? And why do they still give short films Oscars?
We'll tackle the first question first, because it's the easiest. A short film is 40 minutes or less, including credits. The award used to be split up by how many reels of film it used, with awards for "short subject — one reel" and "short subject — two reel," but those were collapsed into the two awards (for animated and live-action shorts) we now have. (The Documentary Short Subject also has a running time of 40 minutes or less, but that award is administered by the documentary branch of the Academy.)
The three shorts categories are often the ones suggested for elimination when questions of how to reduce the running time of the overall show are suggested. (It's also been floated that the awards be given at a separate ceremony.) And to be sure, the fact that the Oscars have awards for shorts is somewhat archaic. The prizes stem from the days when going to the movies meant seeing a short or two before the main feature, something that rapidly died out with the advent of television.
But short films are still an important way for up-and-coming filmmakers to break into the industry. Indeed, there's a clause in the Academy's regulations for these prizes that allow for award-winning student films to compete. So long as this remains true, the short film awards are unlikely to go anywhere.
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Lucas Herbert has bounced back from a slow start to the Abu Dhabi HSBC Championship to record a second round of 65 and improve 53 places from his opening round standing.
Herbert, who is in his first season as a full European Tour cardholder after his successful year playing on invite in 2018, produced eight birdies in his morning round on day two and he now finds himself in a share of 9th place and four shots from the leader, Ireland's Shane Lowry.
Lowry leads by one over South Africans Louis Oosthuizen and Richard Sterne with Lee Westwood another shot back in 4th place.
Herbert moved from 226th to 82nd in the world ranking courtesy of his outstanding last twelve months and is establishing himself with a level of consistency that will see him move much higher in the years to come.
Jason Scrivener is the next best of the Australians after Herbert, he too adding a second round of 65 to be in a share of 13th.
Scott Hend, Sam Brazel and Ryan Fox are the next best of the Australasians and the only others to make the cut, that trio sharing 32nd place and seven shots from the lead.
The tournament carries prizemoney of US$7 million and is one of the lucrative Rolex Series on the European Tour.


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CannaRoyalty Revenue Jumps 266% In Second Quarter To C$3.5 Million
StaffAugust 23, 20184min26460
CannaRoyalty
Canadian-based CannaRoyalty (CNNRF) reported its second-quarter earnings for the period ending June 30, 2018, with revenues increasing 266% to C$3.5 million versus last year's revenues of C$960,157. In addition to that, CannaRoyalty made huge strides by delivering net income of C$9.3 million for the quarter versus last year's net loss of C$2 million. The net income per diluted share was $0.17 as compared to a net loss per diluted share of $0.05 for the same time period in 2017.
"Q2 marked a turning point for CannaRoyalty and its shareholders as the team translated strategy and execution into record financial performance. The Company generated earnings per share of $0.18 primarily by delivering on its stated objective of rationalizing early passive investments. The Company also generated a record adjusted EBITDA result for a Canadian-listed cannabis company2," said Marc Lustig , CEO of CannaRoyalty. "Q2 is the beginning of a multi-quarter parabolic step change in revenue, powered by sequential acquisitions and organic growth. CannaRoyalty generated a record $3.5 million in revenue this quarter, a 446% increase from Q1 and more than the Company generated in all of 2017."
Gross margins increased 95% to C$820,935 over last year's C$421,681 for the same time period. Operating expenses rose 129% to C$6.3 million versus last year's C$2.7 million.
Since The Quarter Closed
Following the close of the second quarter, CannaRoyalty acquired FloraCal Farms for $1 million and 35,088 CannaRoyalty Class A Compressed Shares, as well as up to an additional US$3 million in cash and 35,088 Compressed Shares to be paid over 3 years. The company also acquired a licensed distribution and manufacturing facility, RVR Distribution, in the city of Cotati in Sonoma County, California for $2.4 million to support its push into the California market.
July continued to be a busy month for the company as it then purchased the exclusive rights to distribute and manufacture California's infused pre-roll company Pacific Remedy. In August, CannaRoyalty also closed on its deal to sell its pre-roll technology to Aurora (ACBFF) for C$7 million in Aurora common shares.
Lustig added, "These results reflect the successful initiation of the company's strategic focus on building its Californian distribution and brands platform. This growth is expected to continue in Q3 and Q4 as FloraCal and RVR are added to the Company's financials and as our team continues to grow market share and expand the Company's supporting manufacturing and value-add services footprint. Both RVR and FloraCal are performing above expectations, and we are actively executing our plans to increase the revenue generating capacity of both companies."
Financial Moves
CannaRoyalty reaped the benefits of its stake in Anandia Inc., which was acquired by Aurora and was valued at approximately C$115 million in common shares and warrants of Aurora. CannaRoyalty's equity stake in Anandia was reported at approximately $26.4 million as of June 30, 2018.
On July 12, 2018, CannaRoyalty announced that it had closed a fully marketed private placement of unsecured convertible debentures raising aggregate gross proceeds of $ 32,980,000.
The stock was lately trading at $4.00 on the OTC Markets, not too far from the company's year high of $4.58.
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Frontiers in Pharmacology
Pharmacology of Ion Channels and Channelopathies
CaMKII in Cardiac Health and Disease View all 19 Articles
Models of Ca2+/CaM-Dependent CaMKII Activation and Regulation
Models of Oxidative CaMKII Activation and Regulation
Front. Pharmacol., 03 April 2014 | https://doi.org/10.3389/fphar.2014.00060
Modeling CaMKII-mediated regulation of L-type Ca2+ channels and ryanodine receptors in the heart
Joseph L. Greenstein*, Panagiota T. Foteinou, Yasmin L. Hashambhoy-Ramsay† and Raimond L. Winslow
Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
Excitation-contraction coupling (ECC) in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca2+ transport. Voltage- and Ca2+-dependent L-type Ca2+ channels (LCCs) allow for Ca2+ entry into the myocyte, which then binds to nearby ryanodine receptors (RyRs) and triggers Ca2+ release from the sarcoplasmic reticulum in a process known as Ca2+-induced Ca2+ release. The highly coordinated Ca2+-mediated interaction between LCCs and RyRs is further regulated by the cardiac isoform of the Ca2+/calmodulin-dependent protein kinase (CaMKII). Because CaMKII targets and modulates the function of many ECC proteins, elucidation of its role in ECC and integrative cellular function is challenging and much insight has been gained through the use of detailed computational models. Multiscale models that can both reconstruct the detailed nature of local signaling events within the cardiac dyad and predict their functional consequences at the level of the whole cell have played an important role in advancing our understanding of CaMKII function in ECC. Here, we review experimentally based models of CaMKII function with a focus on LCC and RyR regulation, and the mechanistic insights that have been gained through their application.
Cardiac electrophysiology is a discipline with a rich and deep history dating back more than a half-century. Much of our understanding of fundamental biological mechanisms in this field comes from experimental research coupled with integrative mathematical modeling. The goal of this modeling has been to achieve a quantitative understanding of the functional mechanisms and relationships that span from the level of molecular structure and function to integrated cardiac myocyte behavior in health and disease. Advances in computational techniques and hardware have led to the recent development of many sophisticated large-scale models of heart tissue, in which these electrophysiological myocyte models are the fundamental building blocks. Some of the most fundamental advances in computational cell biology, including formulation of dynamic models of voltage-gated ion channels, mitochondrial energy production, membrane transporters, intracellular Ca2+ dynamics, and signal transduction pathways have emerged from this field. One such signaling pathway is that involving the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMKII), which targets and functionally regulates a number of proteins that are central to cardiac excitation-contraction coupling (ECC), and has been identified as a promising new target for antiarrhythmic therapy in patients with heart failure (Rokita and Anderson, 2012). This review focuses on the role of experimentally based models of CaMKII function with a focus on L-type Ca2+ channel (LCC) and ryanodine receptor (RyR) regulation, and the mechanistic insights that have been gained through their application.
The nature of ECC is linked closely to the micro-anatomical structure of the cell. Sarcomeres, the basic units of contractile proteins, are bounded on both ends by the t-tubular system (Soeller and Cannell, 1999; Bers, 2001). The t-tubules extend deep into the cell and approach the sarcoplasmic reticulum (SR), an intracellular luminal organelle involved in the uptake, sequestration and release of Ca2+. The junctional SR (JSR) is the portion of the SR most closely approximating (within 12–15 nm Franzini-Armstrong et al., 1999) the t-tubules. The close proximity of these two structures forms a microdomain known as the dyad. RyRs are Ca2+-sensitive Ca2+-release channels which are preferentially located in the dyadic region of the JSR membrane. In addition, LCCs are preferentially located within the dyadic region of the t-tubules, where they are in close opposition to the RyRs. The process by which Ca2+ enters the myocyte during the initial depolarization stages of the action potential (AP) via voltage-gated LCCs and triggers the opening of RyRs, and hence JSR Ca2+ release, is known as Ca2+-induced Ca2+ release (CICR) and comprises the initial transduction event of ECC. Recent imaging studies have demonstrated that dyadic clefts are small, where junctions contain an average of 14 RyRs, with some clusters incompletely filled with RyRs, and with a large fraction of clusters closely spaced within 20–50 nm, suggesting that smaller clusters may act together to function as a single site of CICR (Baddeley et al., 2009; Hayashi et al., 2009).
The elucidation of CICR mechanisms became possible with the development of experimental techniques for simultaneous measurement of L-type Ca2+ current (ICaL) and Ca2+ transients, and detection of local Ca2+ release events known as Ca2+ sparks (Cheng et al., 1993). The evidence for tight regulation of SR Ca2+ release by triggering LCC current (for a review see Soeller and Cannell, 2004) gave rise to and later verified the local control theory of ECC (Stern, 1992). The mechanism of local control predicts that tight regulation of CICR is achieved because LCCs and RyRs are regulated by local dyadic Ca2+. It is now widely accepted that CaMKII, a ubiquitous Ca2+-dependent protein that can become highly activated in the dyad (Currie et al., 2004; Hudmon et al., 2005; Maier, 2005), can modulate CICR via phosphorylation of a number of ECC proteins including LCCs and RyRs (Maier and Bers, 2007). CaMKII modulates LCCs via a Ca2+-dependent positive-feedback regulatory mechanism known as ICaL facilitation (Anderson et al., 1994; Xiao et al., 1994; Yuan and Bers, 1994). This is observed as a positive staircase in current amplitude in combination with a slower rate of ICaL inactivation upon repeated membrane depolarization. Although multiple mechanisms have been suggested to underlie ICaL facilitation, experiments from Dzhura et al. (2000) demonstrated that CaMKII-dependent ICaL facilitation alters the behavior of LCCs such that high activity gating modes with prolonged open times are more likely to occur. The specific functional effects of CaMKII phosphorylation of RyRs remain controversial. CaMKII has been shown to increase (e.g., Wehrens et al., 2004) or decrease (e.g., Lokuta et al., 1995) the channel open probability. Inconsistencies in experimental findings regarding the role of CaMKII on RyR function may not be surprising given the methodological differences between the studies. In addition, the high sensitivity of RyR gating to both cytosolic and SR Ca2+ makes it difficult to interpret experiments in which these Ca2+ concentrations are not tightly controlled. In one well designed study, Guo et al. (2006) developed an experimental protocol that overcame this challenge and provided strong evidence that CaMKII mediated phosphorylation of RyRs increases channel open probability. Such an increase is also consistent with transgenic studies of CaMKII overexpression which report increased Ca2+ spark frequency in response to elevated CaMKII activity (Maier et al., 2003; Kohlhaas et al., 2006).
The CaMKII holoenzyme exists as an elaborate macromolecular complex consisting of two stacked ring-shaped hexamers (Hudmon and Schulman, 2002). Each of the holoenzyme's 12 subunits can be activated through the binding of Ca2+-bound CaM (Ca2+/CaM) to the CaMKII regulatory domain in response to beat-to-beat transient increases of intracellular Ca2+ concentration. In cardiac myocytes, an activated CaMKII molecule can undergo autophosphorylation by neighboring subunits at threonine amino acid residues in its regulatory domain, which allows the kinase to retain activity even upon dissociation of Ca2+/CaM (Meyer et al., 1992). An alternative mechanism of oxidative CaMKII activation has also been identified (Erickson et al., 2008). As a result of the fact that CaMKII regulates multiple protein targets (both directly and indirectly involved in ECC), and that the effect of CaMKII mediated phosphorylation on any particular target protein may involve complex alterations in biophysical function (e.g., mode-switching behavior of LCCs), the task of elucidating its role in cardiac function in both normal and failing hearts continues to present great challenges and cannot be accomplished via experiments alone. Some recent advances in understanding the mechanisms of CaMKII-dependent function in cardiac myocytes have been discovered by coupling mathematical models to experimental observations. In this review we will focus on key models of CaMKII-mediated regulation of LCCs and RyRs arising from both Ca2+/CaM-dependent as well as oxidative activation pathways, the integration of such models into whole-cell models, and the mechanistic insights that have been obtained from this work. A summary of the models covered here is provided in Table 1.
Table 1. Key features of CaMKII models in cardiac ECC.
The first model of CaMKII signaling within the context of ECC integrated into the cardiac myocyte was presented by Hund and Rudy (2004). This model, known as the HRd model, incorporates a scheme based on the work of Hanson et al. (1994), where a single population of CaMKII transitions from an inactive to active state in response to elevated subspace Ca2+ levels. CaMKII activity is assumed to modify the function of LCCs and RyRs by slowing their inactivation kinetics, thereby enhancing ICaL and JSR Ca2+ release, respectively. SR Ca2+ uptake was also enhanced by CaMKII activity via its action on phospholamban (PLB) and the SR Ca2+-ATPase (SERCA). The model predicted that CaMKII plays a critical role in the rate-dependent increase of the cytosolic Ca2+ transient by increasing ECC gain, but that it does not play a significant role in rate-dependent changes of AP duration. Similar results were obtained in the human cardiac AP model of O'hara et al. (2011), which incorporates the role of CaMKII phosphorylation on LCCs, the fast Na+ current (INa), and the transient outward K+ current (Ito1). The HRd model was later updated and used to investigate the role of altered CaMKII signaling in the canine infarct border zone (Hund et al., 2008). Experimentally measured elevation of CaMKII autophosphorylation in this region is reproduced by the model, which indicates that hyperactive CaMKII impairs Ca2+ homeostasis by increasing Ca2+ leak from the SR. A number of additional modeling studies have focused on the role of CaMKII on various aspects of intracellular Ca2+ dynamics. Iribe et al. (2006) incorporated a conceptual CaMKII model into their previous myocyte model (Noble et al., 1991) combined with a model of mechanics (Rice et al., 1999) in order to investigate its role on SR Ca2+ handling and interval-force relations. They found that a relatively slow time-dependent inactivation of CaMKII allowed for the reconstruction of a variety of interval-force relations, including alternans. Koivumaki et al. (2009) built a model of the murine cardiac myocyte to analyze genetically engineered heart models in which CaMKII-mediated phosphorylation of LCCs is disrupted or CaMKII is overexpressed. They demonstrated how these genetic manipulations lead to the observed experimental phenotypes as a result of autoregulatory mechanisms that are inherent in intracellular Ca2+ cycling (e.g., steady-state regulation of SR content via Ca2+ release dependent inactivation of LCCs), and that disruption of the regulatory system itself (e.g., via CaMKII overexpression) leads to the most aberrant physiological phenotypes. Livshitz and Rudy (2007) formulated a new model of SR Ca2+ release kinetics and incorporated it into the HRd model in order to better understand regulation of Ca2+ and electrical alternans under various pacing protocols. They found that increased CaMKII activity leads to increased alternans magnitude as well as the appearance of both Ca2+ and electrical alternans at lower pacing rates (where they would not normally occur). This model identifies Ca2+ alternans as the underlying mechanism for electrical alternans, both of which were eliminated with CaMKII inhibition, suggesting this as an antiarrhythmic strategy. Zang et al. (2013) recently developed a new canine myocyte model, also based on the HRd model, to study the role of upregulated CaMKII in heart failure. Similarly, they find that enhanced RyR Ca2+-sensitivity and SR Ca2+ leak mediated by CaMKII overexpression alters Ca2+ handling in a manner that promotes alternans, while AP prolongation occurs primarily due to an associated down regulation of K+ currents. Interestingly, they find that blocking SR Ca2+ leak restores contraction and relaxation function, but does not eliminate alternans completely.
Grandi et al. (2007) developed a model of CaMKII overexpression in the rabbit ventricular myocyte, which incorporates the functional effects of CaMKII-mediated phosphorylation of LCCs, as well as INa and Ito1. This model shows that while CaMKII-mediated action on LCCs prolongs the AP, the combined effect of CaMKII on all three of the targets studied leads to AP shortening. While this study was primarily motivated by and focused on the functional role of CaMKII-mediated regulation of INa (see accompanying article in this series by Grandi and Herren), it clearly demonstrates that the multiple targets of CaMKII interact to produce net alterations of integrated cellular function which are difficult to predict from knowledge if its functional effects on isolated individual targets. Saucerman and Bers (2008) developed and incorporated models of CaM, CaMKII, and calcineurin (CaN) into the rabbit ventricular myocyte model of Shannon et al. (2004) in order to better understand the functional consequences of the different affinities of CaM for CaMKII and CaN during APs. The model predicts that the relatively high Ca2+ levels that are achieved in the cardiac dyad lead to a high degree of CaM activity which results in frequency-dependent CaMKII activation and constitutive CaN activation, whereas the lower Ca2+ levels in the cytosol only minimally activate CaM, which allows for gradual CaN activation, but no significant activation of CaMKII. The prediction that robust beat-to-beat oscillations of CaMKII activity occur in the dyad (i.e. in the vicinity of RyRs and LCCs) but not in the cytosol is a key factor that would influence the way in which local signaling mechanisms would be incorporated into models that followed that included detailed reconstruction of dyadic Ca2+ dynamics. In one such model, Soltis and Saucerman (2010) integrated dynamic CaMKII-dependent regulation of LCCs, RyRs, and PLB with models of cardiac ECC, CaMKII activation, and β-adrenergic activation of protein kinase A (PKA). In this model phosphorylation of all CaMKII substrates exhibits positive frequency dependence similar to that observed in experiments (De Koninck and Schulman, 1998). However, both CaMKII activity and target protein phosphorylation levels adapt to changes in pacing rate with distinct kinetics (see Figure 2 of Soltis and Saucerman, 2010). CaMKII-mediated phosphorylation is relatively fast at LCCs, slower at RyRs, and very slow at PLB. Additionally, the model predicts a high degree of phosphorylation of LCCs in control conditions, but a moderate amount of phosphorylation of RyRs and PLB (e.g., PLB phosphorylation <10% at all frequencies). In addition, this study predicts a novel mechanism in which CaMKII and PKA synergize to form a positive feedback loop of CaMKII-Ca2+-CaMKII regeneration. Furthermore, this model predicts that CaMKII-mediated hyperphosphorylation of RyRs, which renders them leaky, may be a proarrhythmic trigger via induction of delayed afterdepolarizations (DADs). Recently, Morotti et al. (2014) modified the Soltis and Saucerman (2010) rabbit model to further investigate the arrhythmogenic role of another synergistic interaction in mouse ventricular myocytes. This synergism is that of the positive feedback loop of CaMKII-Na+-Ca2+-CaMKII in which CaMKII-dependent increases in intracellular Na+ level perturbs Ca2+ homeostasis and CaMKII activation. Simulation results from Morotti et al. (2014) demonstrate that the feedback between disrupted Na+ fluxes and CaMKII signaling is exaggerated when CaMKII is overexpressed. Under this condition, and upon an increase in intracellular Na+ concentration, the model predicts Ca2+ overload and enhancement of CaMKII activity which in turn increases spontaneous Ca2+ release events via an increase in RyR phosphorylation. This CaMKII-dependent hyperphosphorylation of RyRs exacerbates the associated electrophysiological instability as simulated by the occurrence of DADs (see Figure 7 of Morotti et al., 2014). In this model, the DADs do not occur when CaMKII target phosphorylation is clamped to basal levels.
Recently, Hashambhoy et al. (2009) developed a biochemically and biophysically detailed model of CaMKII-mediated phosphorylation of LCCs. The model includes descriptions of the dynamic interactions among CaMKII, LCCs, and phosphatases as a function of dyadic Ca2+ and CaM levels, and has been incorporated into an integrative model of the canine ventricular myocyte with stochastic simulation of LCC and RyR channel gating within a population of release sites based on the theory of local control of ECC (Greenstein and Winslow, 2002). A schematic representation of one such model Ca2+-release site is shown in Figure 1A. This CaMKII-LCC model is formed by the integration of three modules: a CaMKII activity model which reflects the different structural and functional states of the kinase based on the work of Hudmon and Schulman (2002) and Dupont et al. (2003), an LCC phosphorylation model derived from studies of facilitation in LCC mutants (Grueter et al., 2006; Lee et al., 2006), and a previously developed LCC gating model (Jafri et al., 1998; Greenstein and Winslow, 2002). In this model it is assumed that there is one 12-subunit CaMKII holoenzyme tethered to each LCC (Hudmon et al., 2005), each CaMKII monomer can transition among a variety of activity states (see Figure 2 of Hashambhoy et al., 2009), and CaMKII monomers can catalyze phosphorylation of individual LCCs. The LCC gating model reflects two forms of channel gating, mode 1 (normal activity) and mode 2 (high activity with long openings). In the model, LCC phosphorylation promotes transitions of LCCs from mode 1 to mode 2 gating, based on experimental observations with constitutively active CaMKII (Dzhura et al., 2000). This model demonstrates that these CaMKII-dependent shifts of LCC gating patterns into high activity gating modes may be the underlying mechanism of ICaL facilitation. In addition, the model predicts that this CaMKII-mediated shift in LCC gating leads to an apparent increase in the speed of both ICaL inactivation and recovery from inactivation, both of which are experimentally associated with ICaL facilitation, with no change to the underlying intrinsic LCC inactivation kinetics. Hashambhoy et al. (2010) further expanded this model to include CaMKII-dependent regulation of RyRs. In this model update, RyR phosphorylation is modeled as a function of dyadic CaMKII activity and it is assumed that RyR sensitivity to dyadic Ca2+ is increased upon phosphorylation, the degree to which is constrained by experimental measurements of Ca2+ spark frequency and steady state RyR phosphorylation (Guo et al., 2006). This study demonstrated that under physiological conditions, CaMKII phosphorylation of LCCs ultimately has a greater effect on ECC gain, RyR leak flux, and AP duration as compared with phosphorylation of RyRs (Figure 1B). AP duration at 90% repolarization (APD90) correlates well with a CaMKII-mediated shift in modal gating of LCCs (Figure 1C). A modest additional increase in LCC phosphorylation, and hence mode 2 gating, beyond that shown in Figure 1C leads to the appearance of early afterdepolarizations (EADs) in simulated APs (see Figure 5 of Hashambhoy et al., 2010). The results of these model analyses suggest that LCC phosphorylation sites may in fact prove to be a more effective target than those on the RyR for modulating diastolic RyR-mediated Ca2+ leak and preventing abnormal proarrhythmic cellular depolarization.
Figure 1. (A) Schematic representation of the cardiac dyad. Ca2+ ions pass through the LCC and enter the dyad, where they bind to RyRs, triggering CICR. The activity of each CaMKII monomer is a function of dyadic Ca2+ levels. Ca2+ ions released from the SR diffuse out of the dyad into the bulk myoplasm. (B) Simulated results from a 1-Hz AP-pacing protocol under different LCC and/or RyR phosphorylation conditions. (C) APD90 as a function of average LCC phosphorylation levels. Fully phosphorylated LCCs gate in mode 2, which exibit long-duration openings. (A) Reprinted with permission from Hashambhoy et al. (2009). Copyright 2009 Elsevier. (B,C) Reprinted with permission from Hashambhoy et al. (2010). Copyright 2010 Elsevier.
The modeling studies described above focus on the role of CaMKII-mediated regulation of its targets via the classical Ca2+/CaM-dependent activation pathway which involves CaMKII autophosphorylation. Recently a novel mechanism for oxidative CaMKII activation was discovered in the heart (Erickson et al., 2008). This alternative oxidation-dependent pathway involves the oxidation of CaMKII at specific methionine residues, which has been shown to produce persistent kinase activity and increase the likelihood of arrhythmias (Xie et al., 2009; Wagner et al., 2011). These new findings implicate oxidative CaMKII activation as a putative mechanistic link between the accumulation of reactive oxygen species (ROS) and life-threatening cardiac arrhythmias (Erickson et al., 2011). Therefore, developing a quantitative understanding of the role of CaMKII oxidation in regulating cardiac ECC requires the integration of computational models that link cellular ROS and redox balance, CaMKII activity and function, ECC, and whole-cell electrophysiology. Such models will prove to be powerful tools for teasing out important mechanisms of arrhythmia in heart disease.
In one recent study, Christensen et al. (2009) developed a deterministic model of oxidative CaMKII activation based on their own experimental findings to study the role of this signaling pathway in the canine infarct border zone following myocardial infarction. A new simplified model of CaMKII activation was developed based on the work of Dupont et al. (2003), and incorporated into a model of a single cardiac fiber. Each myocyte within the fiber model was represented by the Hund et al. (2008) model, which as noted above, incorporates CaMKII effects on INa, ICaL, SR Ca2+ leak and uptake, as well as ion channel remodeling associated with the infarct border zone. Simulation results demonstrate that enhanced oxidative CaMKII activity is associated with reduced conduction velocity, increased refractory periods, and a greater likelihood of conduction block formation. Furthermore, CaMKII inhibition in the model improves conduction and reduces vulnerability to conduction block and reentry. The results of Christensen et al. (2009) are attributed primarily to CaMKII-mediated regulation of INa kinetics and availability. They note that CaMKII activation will also impact ECC proteins in ways that may promote arrhythmias, but these mechanisms were not explored in detail in this model.
Along these lines, Foteinou et al. (2013) have recently developed a novel stochastic model of CaMKII activation (Figure 2A) that reflects the functional properties of the cardiac isoform including both the canonical phosphorylation-dependent activation pathway and the newly identified oxidation-dependent pathway. This model builds upon the work of Hashambhoy et al. (2010, 2011) in order to incorporate recent experimental data for CaM affinity and autophosphorylation/oxidation rates measured specifically for the cardiac isoform of CaMKII (Gaertner et al., 2004; Erickson et al., 2008). Predicated upon this, the authors implemented the four-state deterministic activation model of Chiba et al. (2008) within a stochastic framework that is constrained by the geometry of the CaMKII holoenzyme. This was accomplished by restricting CaMKII autophoshorylation events to occur only between adjacent CaMKII subunits. The stochastic activation model was further modified by including oxidized active states in addition to a Ca2+/CaM-bound active state, an autophosphorylated Ca2+/CaM-bound state, and an autophosphorylated Ca2+/CaM-dissociated state (i.e., an autonomous active state). Following incorporation into the canine cardiac myocyte model (Hashambhoy et al., 2011), Foteinou et al. (2013) obtain steady state APs at a pacing cycle length (PCL) of 2 s as illustrated in Figure 2B. This model predicts increased likelihood of EADs under this protocol upon increased oxidative stress (application of 200 μM H2O2, which is at the high end of pathophysiological levels), as shown in Figure 2C. Notably, the model simulates no EADs in the presence of ROS at a PCL of 1 s, which is consistent with the experimentally measured rate-dependence of EADs in the presence of 200 μM H2O2 (Zhao et al., 2012). The model predicts that EADs result from both enhanced CaMKII-dependent shifts of LCCs into highly active mode 2 gating and a progressively increased late component of Na+ current (INaL). The simulated increase in ICaL via oxidized CaMKII corroborates the experimental findings of Song et al. (2010) who demonstrated that oxidative CaMKII activation is involved in the regulation of LCCs. In particular, the in silico model of H2O2 exposure discussed here predicts that the fraction of LCCs gaiting in mode 2 will shift from 5% in control (absence of ROS) to 7% upon this increase in ROS. Using this model, the simulated diastolic RyR leak also increases in response to oxidative stress (~44%) primarily as an indirect consequence of increased Ca2+ influx via LCCs. Wagner et al. (2011) recently observed a ~15-fold H2O2-mediated increase in SR Ca2+ leak, which is far greater than that produced in this model (<2-fold). They, however, provide additional evidence indicating that their observed increase in Ca2+ leak does not require the presence of CaMKII, suggesting an important role for CaMKII-independent mechanisms of ROS-mediated alteration of cardiac ECC as well.
Figure 2. (A) State diagram of the stochastic CaMKII activation model of Foteinou et al. (2013). Prior to the introduction of Ca2+/CaM, all of the CaMKII subunits are in the inactive form (state I). Activation occurs upon binding of Ca2+/CaM (state B), autophosphorylation (state P), and oxidation (state OxB). Autonomous active states (Ca2+/CaM-unbound) can be either autophosphorylated (state A) or oxidized (state OxA). The model also includes an active state that is both oxidized and phosphorylated (state OxP). (B) Simulated steady state APs under control conditions (0 μM H2O2). (C) Simulated APs, some of which exhibit EADs, under conditions of elevated oxidant stress (200 μM H2O2). Simulated APs are from a 2 s PCL pacing protocol (ensemble of 12500 calcium release units). For each condition, results for 10 consecutive APs following an initial 10 s of pacing are shown.
As these ROS-mediated effects need to be further examined, future studies will focus on establishing quantitative links between cellular ROS and redox balance, CaMKII activity and function, ECC, and whole-cell electrophysiology. Recently, Gauthier et al. (2013a,b) developed mechanistic models of ROS production and scavenging to investigate how these two competing processes control ROS levels in cardiac mitochondria. Simulations confirm the hypothesis that mitochondrial Ca2+ mismanagement leads to decreased scavenging resources and accounts for ROS overflow as is believed to occur in heart failure (Hill and Singal, 1996). Notably, the ROS regulation module of Gauthier et al. (2013b) enables its use in larger scale heart models designed to simulate and study how mitochondrial ROS and the functional consequences of its accumulation, such as CaMKII oxidation, regulate cellular physiological function, AP properties, and arrhythmogenesis.
Integrative modeling of cardiac ECC, cell signaling, and myocyte physiology has played a critical role in revealing mechanistic insights across a range of biological scales. With respect to CaMKII function at the smallest scale, models have shed light on how Ca2+ ions, CaM, CaMKII, LCCs, and RyRs interact in the cardiac dyadic junction both at rest and during triggered ECC events. On an intermediate scale, models have predicted the consequences of normal and abnormal CaMKII signaling on whole-cell Ca2+ cycling, effects of ROS imbalance, AP shape, and the generation of cellular arrhythmias such as EADs. Incorporation of these cellular models into higher scale tissue simulations has provided important insight into the relationship between CaMKII function, electrical wave conduction velocity, and the emergence of arrhythmogenic substrates in diseased tissue. The continuum of biological scales spanned by these models allows for the development of multiscale approaches whereby we can predict and understand the emergence of macroscale phenotypes as a consequence of CaMKII-mediated molecular signaling events. A great deal of evidence now implicates CaMKII as a nexus point linking heart failure and arrhythmias (Swaminathan et al., 2012), identifying it as a prime target for antiarrhythmic therapies (Fischer et al., 2013). Despite this growing body of evidence, the modeling studies presented here demonstrate that it remains difficult to identify which of the many CaMKII target proteins are primarily responsible for the functional changes that increase the likelihood of arrhythmia development. Some studies (Hund et al., 2008; Soltis and Saucerman, 2010; Zang et al., 2013; Morotti et al., 2014) identify phosphorylation of RyRs, which leads to elevated SR Ca2+ leak and/or increased likelihood of spontaneous Ca2+ release events and DADs, as the key mechanism underlying arrhythmogenesis. Others (Hashambhoy et al., 2010; Foteinou et al., 2013) predict that LCC phosphorylation, which leads to elevated channel open probability via high activity gating, plays the predominant role by altering whole cell Ca2+ levels and AP properties, including the appearance of EADs. These mechanisms may co-exist in heart failure, and it is likely that both play an important role. Moreover, CaMKII modulation of other targets such as PLB, INa, and K+ currents, many of which have been incorporated into the above cell models, adds additional layers of complexity to the task of interpreting and predicting the mechanisms by which CaMKII signaling alters cardiac function in health and disease. As a result of the breadth and diversity of CaMKII targets, strategies that involve broad inhibition of CaMKII activity will impact and alter the function of many cellular subsystems, with complex consequences that may not all be beneficial. As mathematical models of CaMKII signaling in the cardiac dyad and beyond are further developed, they will play a key role in identifying target-specific therapeutic strategies for improving myocardial function and reducing arrhythmias.
Supported by National Institutes of Health grants HL087345, HL105239, and HL105216.
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Zhao, Z., Wen, H., Fefelova, N., Allen, C., Baba, A., Matsuda, T., et al. (2012). Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: predominant by Ca waves or Ca currents? Am. J. Physiol. Heart Circ. Physiol. 302, H1636–H1644. doi: 10.1152/ajpheart.00742.2011
Keywords: cardiac myocyte, excitation-contraction coupling, cell signaling, CaMKII, computational modeling
Citation: Greenstein JL, Foteinou PT, Hashambhoy-Ramsay YL and Winslow RL (2014) Modeling CaMKII-mediated regulation of L-type Ca2+ channels and ryanodine receptors in the heart. Front. Pharmacol. 5:60. doi: 10.3389/fphar.2014.00060
Received: 31 January 2014; Accepted: 18 March 2014;
Eleonora Grandi, University of California Davis, USA
Henggui Zhang, The University of Manchester, UK
Stefano Morotti, University of California Davis, USA
Copyright © 2014 Greenstein, Foteinou, Hashambhoy-Ramsay and Winslow. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Joseph L. Greenstein, Institute for Computational Medicine, Johns Hopkins University, 3400 N Charles Street, Hackerman Hall, Baltimore, MD 21218, USA e-mail: jgreenst@jhu.edu
†Present address: Yasmin L. Hashambhoy-Ramsay, Merrimack Pharmaceuticals, Cambridge, USA


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NaNoFeed: My Wicked Grandma, or encouragement from literary ancestors
Posted on November 16, 2011 by epbeaumont
In "real life," which is to say in my biological family tree, I have a grandma and a great-aunt who ran off to Hollywood in the 1930s to be chorus girls. In my literary family tree, I have a wicked grandma too: Aurore Dudevant nee Dupin, known to posterity as George Sand.
She was one of the pulp writers par excellence of the nineteenth century, along with Dickens, Balzac and Dostoevsky. By a multiplicity of routes she was the godmother of Russian literature and via that connection, an influence on twentieth-century African-American literature as well. Isabelle Naginski's study George Sand: Writing for her Life was positively inspirational, along with Francoise Genevray's George Sand et ses contemporains russes, which taught me that one's greatest influence is not necessarily in one's home country. In the age of the internets, I definitely take that to heart!
There's a huge piece of her oeuvre that would be classified as nineteenth-century "chick lit." She also wrote metaphysical thrillers, show-biz road movies, and political soap operas that sneaked past the censors in czarist Russia because they were "only stories" written by someone who was "just a woman."
She wrote a variety of utopian fiction, some of which shared turf with the science-fiction of the time. She was a serious Jules Verne fan, and her request for a sea story was apparently the genesis of 20,000 Leagues Under the Sea, which makes her one of the grandmothers of steampunk.
She's seriously neglected even now; I first heard about her in music class, via her long-term relationship with Frederic Chopin. (That was actually my first model for a working partnership of two artists; once I'd seen the example of the two of them working side by side, she at her desk and he at his piano, standard-issue marriage did not appeal.)
She didn't worry about genre and she wrote the story she wanted to write, in spite of many struggles with publishers (she ran through several!) about what was marketable as a "George Sand novel." When her publisher wouldn't put out her latest work, she went independent and serialized it herself in the progressive newspaper she founded to lobby for reform in her home province. Vastly successful, incredibly prolific (60-70 novels!), independent… what more could one hope for in a literary wicked grandma?
This entry was posted in NaNoWriMo, Writing and tagged NaNoFeed, Writing. Bookmark the permalink.


text: 32 PROCTOR | April 2018 Reduce risk & enhance results of your litigation, commercial & family law cases... With a forensic accountant that is easy to access, understands complex financial data and presents findings clearly. The truth behind the numbers. For more information visit ultonforensics.net or call (07) 4154 0400 Forensics Guns and judges: Antonin Scalia and the right to bear arms with Supreme Court Librarian David Bratchford Please join us for the first lecture in the 2018 Selden Society lecture series, presented by Justice Glenn Martin AM. Thursday 3 May 5.15 for 5.30pm – followed by refreshments Banco Court, Queen Elizabeth II Courts of Law Level 3, 415 George Street, Brisbane CPD points: 1 point per hour, self-assessed To register please visit sclqld.org.au/selden Antonin (Nino) Scalia was, for many years, the best known member of the Supreme Court of the United States. He was charming, mercurial, polarising and stubborn. Scalia was a member of the court for nearly 30 years until his unexpected death in 2016 at the age of 79. Justice Scalia collected numerous awards and achievements on his way to the Bench. At Harvard he graduated magna cum laude and became a Sheldon Fellow. His legal career began in 1961 in a respected firm in Cleveland, Ohio, but because he wanted to teach he took up a post as professor of law at the University of Virginia in 1967. Four years later he entered public service in the Nixon administration, becoming an Assistant Attorney-General in 1974. It was in that role that he argued his only case before the Supreme Court, Alfred Dunhill of London v Republic of Cuba. His judicial career began in 1982 when President Reagan appointed him to the United States Court of Appeals for the District of Columbia Circuit. Four years later he was unanimously confirmed by the Senate as an Associate Justice of the Supreme Court. Many commentators suggested that Scalia would unite the conservative justices on the court, but they were wrong. Scalia was more concerned with being true, as he saw it, to the principles of textualism and originalism than with forming coalitions of like-minded judges. He wanted to win each argument, and his frustration with the reasoning of other members of the court would often lead him to engage in ferocious and destructive dissents. He was, as Bruce Murphy observed in Scalia — A Court of One, "driven to be right rather than influential". But he was influential in other ways. His dissents helped promote 'originalism' as a means of interpreting the US Constitution. In one of the most influential decisions of the last 25 years, Scalia wrote the majority opinion in District of Columbia v Heller. It was the first extensive decision on the Second Amendment and the right to bear arms. In it he engaged in a lengthy historical exposition and a grammatical analysis of the amendment. This decision changed the previously accepted understanding of the amendment and it is often mistakenly thought to support the abolition of all restrictions on gun ownership. About the speaker Justice Glenn Martin AM was in practice as a barrister from 1979 until his appointment as a judge of the Supreme Court in 2007. In 2013 he received additional appointments as president of the Industrial Court of Queensland and the Queensland Industrial Relations Commission. Your library


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SHADOWPLAY - SIMULATED CHILD ABDUCTIONS: #LisaIrwin : Valhall - The Cell Phone Records.
So the cell phone records have been analyzed by the FBI, Wild-Bill Stanton's "people", and FOX news. According to John Picerno, the new local attorney for Jeremy Irwin and Deborah Bradley, the FBI, in a 3 hour meeting, went over the records and the pings for the phones. Megyn Kelly interviewed both Bill Stanton and John Picerno about this latest development. Let's see what they had to say…and what they didn't say.
11:57 pm – outbound call to Megan Wright's phone number from Deborah's phone.
3:17 am – attempted call to Deborah's voicemail from Deborah's phone.
3:32 am – attempted call to Deborah's voicemail from Deborah's phone.
times unknown – five attempts at accessing the internet from Deborah's phone.


"Processing the Scape", SIM and Hvítahús Artist Residencies, Iceland was a sabbatical-related research activity that included two artist residencies in Iceland: SIM Residency Program in Reykjavík (February 2016) and Hvítahús Artist Residency near Hellisandur (March 2016). The objective for the sabbatical period and artist residencies was to conduct studio research in the form of paintings, drawings, and installations with an emphasis on examining new sources for the environments within the work. An extension of my previous studio research, this included the use of serial painting and installations (on plastic) as a way to wade through philosophical and formal questions, explored through the additive and subtractive act of painting and a resulting, recurring figure held in expressly ambiguous spaces. The core of the work at both the SIM and Hvítahús residencies occurred through a direct response to the extremes and the subtleties particular to the Icelandic 'scape' and the processing of that fresh input toward the needs of each new piece and larger body of work.
My expectations for what this would mean were exceeded exponentially. I thought that the Icelandic environments would be dramatic, and they were, but they were also more engaging and more intense – to a degree beyond what I could have known ahead of time. The visuals are extreme and constantly changing, and incredibly beautiful. Iceland has an energy that is palpable – one that can induce fear (people died while I was there and in places I would soon go or had just been) or awe (I found myself often unable to look away as a sky and sea would rapidly go from one state to another) or a sense of meditative repetition (watching the fishing boats, working boats, make their daily movement methodically across my horizon day and night).
My work usually preferences the 'figure' – in my case literally, as large bodies dominate my works, acting within vague, psychological land/seascapes that were formerly based on input from Seattle and Greece. My goal in Iceland was to shift this and instead preference the 'ground', shifting scale and submitting these smaller figures to the forces of nature. As a long distance runner, this was compounded as my body was subjected to ice and snow, cold, hail, and the ever-present winds, particularly extreme during the second month on the Snæfellsnes Peninsula. As such, my work was informed not only by the visual input but also by what affected me to my physical core – I felt it – and worked to translate it through the act of painting.
The flow between the two residencies worked out perfectly. For the first month, I worked and lived with nine other artists from all over the world (France, Egypt, Italy, Australia, South Korea, and Sweden) within the city of Reykjavík. This allowed me to acclimate to Iceland, have a daily discourse with other artists, and take advantage of Reykjavík activities, including exhibitions and other cultural opportunities. Two examples that stand out were being able to sketch from the sculptures of Einar Jónsson and participating in a dance workshop during the Reykjavík Dance Festival. Einar Jónsson, known as Iceland's first sculptor, created figurative works of uncommon drama, physicality, and flow. I was able to go back to the Einar Jónsson Museum several times and found a kinship with his sculptural expression of the human body entwined with Icelandic mythology. These found their way into my painted works through the sketches completed on-site. The dance workshop was also an unexpectedly perfect fit for the questions I was asking in my paintings. It was led by Danish choreographer, Marie Topp. Just as I am a process painter, she is a process choreographer, needing dancers in person to physically work out her ideas and develop her work. Our ideas and ways correspond very closely – her goals include work that investigates "forces against the body" found through a "physicality that leads to form/narrative". This is exactly what I am doing through my paintings.
The work I created at SIM was a response to the water and landscapes from just outside the residency (two blocks from the sea and surrounded by mountain ranges) as well as from a trip to the southwest of Iceland, which included seeing the Gullfoss waterfall (a huge series of waterfalls frozen in their February state) and the deep, glowing crevasses of the Sólheimajökull Glacier. I would take photos but also just look and take in what I saw and then respond through painting and drawing once back in my studio. These developed as fragments and accumulations, building as layers of information that formed their own logic and meanings or connections. The figures shrunk and became even more embedded within their landscapes, pressured by the forces of their environments. The color, too, while an extension of my former palette, shifted and pared down while in Iceland, a response to the white of the snow and ice, the deep dark of the silhouetted mountains, and to the constantly changing blue/green/teal of the ocean and sky. This palette was punctuated with moments of orange and red, signifying a body or a movement, struggling within the vast scapes.
For the second month, I shifted from Reykjavík to the Hvítahús Artist Residency on the Snæfellsnes Peninsula. This is a remote location, on the very edge of the Snæfellsnesþjóðgarður National Park, with a few small towns nearby. The residency is housed in a former icehouse (used to store fish) and is the last remaining building from the Krossavík harbor, which relocated in the 1940s. Remnants of the fishing village remain visible as stone walls projecting into the Atlantic Ocean and other land works that had defined the town. The studio was a large two-story space, ideal within which to expand on the research begun over the previous month.
The main goals of this second residency were to work (paint) and run. The running allowed me to experience this West Fjord environment and landscape in a particular, intimate way. The weather during March was extreme on the peninsula, adding to the forces that I was already investigating in my work. I encountered winds so fierce that I had to use every bit of strength to just move forward and stay on my feet (not always successfully). I ran with views that shifted from a moon-like scape dotted with blocks of volcanic rock, to a huge glacier atop a series of volcanic mountains that all gathered into one stunning form, to the Atlantic Ocean with its waves suddenly, forcibly crashing up stacks of black, basalt cliffs. I took photos everywhere I explored and fed those, and my actual experience of each place, back into the work in the studio. There was also a three-day storm with winds so strong they tore the asphalt off a road just 30 kilometers from where I was. I did not go out for those three days and instead painted through the unnerving sounds assaulting my icehouse and the fear it induced.
I think my battle-type process, where sources are sieved through the physical struggle of marks in continual negotiation, fought hard, made sense for responding to Iceland in particular and I hope a poetry was found in each truce.
The idea, whether in Iceland, or back in my U.S. studio, is to find each painting and its imagery through the rhythms of formal questioning, as well as through the resistance any artist feels when moving toward intention. It is a searching, a responding, to make sense of meanings that begin to be revealed in each single piece and across the many happening at the same time. Each painting is the residue of the act of working toward a semblance of meaning and are about, come from, a type of grasping.
I would like to end with a large and heart-felt thank you to all those I met and worked with in Iceland, to my partner, CJ, for taking care of everything (and everyone) at home, and for the support I received through an International Activities Grant from the WKU Office of International Programs and a QTAG Award from Potter College of Arts & Letters.
This post includes images from a March 2016 artist residency at Hvítahús on the Snaefellsnes Peninsula, Iceland. Studio images (of me) taken by Sigurdur Bragason.
This post includes images of works in progress throughout the month of February and our final group exhibition, Between Oceans: SIM Artists in Residence February '16.
This is the start of the work I'll be making at the first of two artist residencies in Iceland (for sabbatical research titled Processing the Scape). The residencies: SIM Artist Residency in Reykjavik (February 2016) and Hvitahus Artist Residency near Hellissandur (March 2016). The goal is to use drawings, paintings, and installations to examine new sources for the environments in my work, particularly by responding to and processing the Icelandic 'scape' and its extremes and subtleties. A big thank you for support from an International Activities Grant from the WKU Office of International Programs and a QTAG award from Potter College of Arts & Letters.


text:
namespace extensions {

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// ExtensionMessageBubbleController::Delegate

ExtensionMessageBubbleController::Delegate::Delegate() {
}

ExtensionMessageBubbleController::Delegate::~Delegate() {
}

////////////////////////////////////////////////////////////////////////////////
// ExtensionMessageBubbleController

ExtensionMessageBubbleController::ExtensionMessageBubbleController(
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      profile_(profile),
      user_action_(ACTION_BOUNDARY),
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}

ExtensionMessageBubbleController::~ExtensionMessageBubbleController() {
}

std::vector<base::string16>
ExtensionMessageBubbleController::GetExtensionList() {
  ExtensionIdList* list = GetOrCreateExtensionList();
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    return std::vector<base::string16>();

  std::vector<base::string16> return_value;
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    const Extension* extension = service_->GetInstalledExtension(*it);
    if (extension) {
      return_value.push_back(base::UTF8ToUTF16(extension->name()));
    } else {
      return_value.push_back(
          base::ASCIIToUTF16(std::string("(unknown name) ") + *it));
      // TODO(finnur): Add this as a string to the grd, for next milestone.
    }
  }
  return return_value;
}

const ExtensionIdList& ExtensionMessageBubbleController::GetExtensionIdList() {
  return *GetOrCreateExtensionList();
}

void ExtensionMessageBubbleController::Show(ExtensionMessageBubble* bubble) {
  // Wire up all the callbacks, to get notified what actions the user took.
  base::Closure dismiss_button_callback =
      base::Bind(&ExtensionMessageBubbleController::OnBubbleDismiss,
      base::Unretained(this));
  base::Closure action_button_callback =
      base::Bind(&ExtensionMessageBubbleController::OnBubbleAction,
      base::Unretained(this));
  base::Closure link_callback =
      base::Bind(&ExtensionMessageBubbleController::OnLinkClicked,
      base::Unretained(this));
  bubble->OnActionButtonClicked(action_button_callback);
  bubble->OnDismissButtonClicked(dismiss_button_callback);
  bubble->OnLinkClicked(link_callback);

  bubble->Show();
}

void ExtensionMessageBubbleController::OnBubbleAction() {
  DCHECK_EQ(ACTION_BOUNDARY, user_action_);
  user_action_ = ACTION_EXECUTE;

  delegate_->LogAction(ACTION_EXECUTE);
  delegate_->PerformAction(*GetOrCreateExtensionList());
  AcknowledgeExtensions();
}

void ExtensionMessageBubbleController::OnBubbleDismiss() {
  DCHECK_EQ(ACTION_BOUNDARY, user_action_);
  user_action_ = ACTION_DISMISS;

  delegate_->LogAction(ACTION_DISMISS);
  AcknowledgeExtensions();
}

void ExtensionMessageBubbleController::OnLinkClicked() {
  DCHECK_EQ(ACTION_BOUNDARY, user_action_);
  user_action_ = ACTION_LEARN_MORE;

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  Browser* browser =
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  AcknowledgeExtensions();
}

void ExtensionMessageBubbleController::AcknowledgeExtensions() {
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       it != list->end(); ++it)
    delegate_->AcknowledgeExtension(*it, user_action_);
}

ExtensionIdList* ExtensionMessageBubbleController::GetOrCreateExtensionList() {
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    return &extension_list_;  // Can occur during testing.

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         it != extension_set->end(); ++it) {
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      if (!delegate_->ShouldIncludeExtension(id))
        continue;
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    }

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    initialized_ = true;
  }

  return &extension_list_;
}

}  // namespace extensions

redpajama_set_name: RedPajamaGithub


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Don't Crack Under Job-Offer Pressure
by Mark Feffer September 6, 2016 5 min read
cover letterInterviewingJob Huntingresume
The technology industry's unemployment rate hit 2.4 percent in August, and tech employers are feeling enormous pressure to find tech pros with the right combination of skills and experience. Meanwhile, candidates have their pick of offers, and those with top backgrounds can demand considerable salaries and perks.
In that sort of environment, job candidates might find themselves under a lot of pressure from a prospective employer to accept an offer. In a certain way, this behavior is understandable: executives aren't very sympathetic when managers complain about the difficulty of meeting deadlines with short-handed teams, so those managers often press job candidates to say "yes" to the job as quickly as possible.
But recruiters and career coaches offer the same advice to tech pros in such situations: Don't knuckle under. Take your time.
"Yes, people should leave themselves breathing room," said Lorne Epstein, an Arlington, Va., recruiter and author of You're Hired: Interview Skills to Get the Job. "It's a big decision and it needs to be thought through."
Mary Cavanaugh, vice president of the Boston-based outsourcing and career-coaching firm Keystone Associates, agrees with that sentiment. "No matter what, the interview process is a protracted process," she observed. "The acceptance process should take time, as well."
"Recruiters create a lot of heat and excitement," Epstein added. "But if you get an offer, you should take a week to think about it. That's a reasonable amount of time to do your due diligence."
Know the Company… and Yourself
Due diligence? Haven't you already researched the company to decide whether it's a place where you'd want to work? Even though most career coaches advise doing that research before you start interviewing, Epstein notes that many candidates don't engage in as much as much pre-vetting as they should. "If you haven't researched the company, now's the time to do it," he said.
Even if you feel like you know the prospective employer well, Cavanaugh believes that, especially today, evaluating an offer requires real time and attention. "You should be looking at the whole offer, not just compensation," she said. "It's also about culture, about the team, about growth potential. You need to look at the offer more holistically."
How a company treats you after it's made an offer is a reflection of its culture. "You should never hesitate to tell the recruiter or hiring manager, 'I need the time,'" Cavanaugh added. If they're leaning on you now, imagine what it will be like when deadlines are looming.
Set Expectations Early, and Nicely
Of course, you never want to be rude to a potential employer, especially when an offer is on the table. The key to handling the situation gracefully is to be honest and courteous from the start.
For example, if you're not actively looking for work when a recruiter approaches you—which happens a lot in tech these days—level-set their expectations right away, Epstein said. Give them a timeframe you regard as realistic for deciding to make a move, and an idea of what your main considerations for a job-switch might be. Your family's opinions may carry much weight, for instance, especially if relocation is involved.
Also, most employers think it's perfectly reasonable to ask for five business days to weigh your decision. "They're not going to pull their offer because you want five days," Epstein said. "They've spent a lot of time on pursuing you already." And, he pointed out, "Employers are paying a lot more attention to onboarding." That means they don't want to put a bad taste in your mouth by balking as a reasonable request; they want you to start the job in a happy state of mind.
That's true even when you've got more than one offer on the table. "Always express gratitude, but don't be afraid to say you have other options you need to evaluate," said Cavanaugh. Tell the employer you want to be thorough, "so [you] can come to this role excited and ready to go."
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Mark Feffer
Mark Feffer started as a videotape editor back when there was videotape to edit, then joined the news desk at Dow Jones News/Retrieval, the company's first online product. He produced The Wall Street Journal's first multimedia CD-ROMs and published his novel, "September," in 2006. He lives in Pennsylvania with his wife, their fierce terrier, and a schnauzer who wonders why she ever left California. He's a member of the Project Management Institute.