Comradde PhysioProffe

Setraline is the chemical name for Zoloft, a commonly prescribed antidepressant. An independent scientist currently unaffiliated with any academic or industrial research entity named Ethan Perlstein has been recently soliciting funds via “crowdsourcing” to continue his studies on the mechanisms by which sertraline is toxic to yeast, with the goal of shedding light on antidepressant function in the human brain.

The experimental foundation for his research plan that he has been soliciting funds to pursue is a paper he published in 2007 in the journal Genetics. This paper describes the isolation and characterization of yeast mutants that are resistant to sertraline-induced toxicity.

In this post, my goal is to enumerate various experimental findings that may be considered germane to the likelihood that his research will succeed at its stated goal of shedding light on antidepressant function in the human brain.

(1) Sertraline is, as pointed out in the Genetics paper, a “cationic amphiphile”. That means that it has both a hydrophobic component and a hydrophilic component that is positively charged under physiological conditions. The paper also points out that cationic amphiphiles “[have] long been recognized [to] interact with phospholipid membranes”. This is, of course, not at all surprising, since cationic amphiphiles are basically detergents.

(2) In human patients, the total concentration of sertraline in plasma at therapeutic doses has been estimated as 80-165 nM, that is bioavailable in the plasma (i.e., unbound to albumin and other proteins) has been estimated as 1.5-3 nM, and that is bioavailable in brain has been estimated as similar to plasma 2-4 nM. This means that in human patients taking sertraline, their brain neurons are probably exposed to a concentration of sertraline somewhere between 1.5 and 4 nM. (These estimates come from this paper.)

(3) According to the Genetics paper, the concentration of sertraline employed in the screen for resistant yeast mutants is “∼45 μm sertraline, which is approximately three times the IC50 of sertraline as determined by dose–response experiments in liquid culture”. The paper also notes that “lowering the selection concentration from ∼45 to ∼42 μm resulted, on average, in a 10-fold increase in the number of resistant colonies”. This indicates that the dose employed is nowhere near saturating with respect to sertraline’s physiological target in yeast cells, and is rather near the lower bound for having any physiological effect.

(4) Since the yeast are plated on a growth medium (YPD) that contains no intact proteins or long peptides, the yeast cells are likely exposed to close to 45 μm sertraline. This means that the yeast cells are likely being exposed to somewhere between 11,250 and 30,000-fold greater concentrations of sertraline than the brain neurons of human patients being treated with sertraline.

(5) As discussed in detail in the Genetics paper, the yeast clones resistant to this dose of sertraline have spontaneous mutations/polymorphisms in genes that encode proteins important for cellular lipid membrane homeostasis and trafficking.

(6) As discussed in detail in the Genetics paper, the dose of sertraline used for the resistance screen induces severe defects in the intracellular membrane structures within the yeast cells.

Based on all of the above, these conclusions follow:

(3) Continued study of the effects of sertraline and other amphiphilic compounds at astronomical doses on yeast cells is likely a waste of time and effort vis a vis the goal of elucidating antidepressant actions in the human brain.

Is there a reason having to do with the way plays generally set up that there is almost never any offensive player in position to pull down an offensive rebound off a three-point shot?

Why do automated teller machines require that you enter your withdrawal amount to the motherfucken cent, when the fucken machine only has motherfucken twenty dollar bills to dispense? Every time I type in those two zeroes, I want to be punching someone in the fucken dicke instead.

Parenting in a pathologically competitive, information-saturated city can make anyone crazy, even those parents lucky enough to be worried about fennel burgers in school lunches. And while Avenues offers its students every imaginable educational benefit — a 9-to-1 student-to-teacher ratio, a Harvard-designed “World Course” — it has also tapped into an even deeper, more complicated parental anxiety: the anxiety of wanting their kids to have every advantage, but ensuring that all those advantages don’t turn them into privileged jerks.

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Whether it’s snack time or a field trip to a Chelsea gallery, everything at Avenues feels designed to assuage parental anxiety. The school has distributed a handout to parents that explains what kids are learning when they are doing various things: For instance, when they are making bridges out of blocks, they are really learning to build with shapes (and honing math skills); planning ahead (which helps with study skills); and recreating structures (thereby working on geography skills). On the first day of school, Topher Collier, one of New York’s top child psychologists and head of Avenues’ student success team, gave his advisees a package with 21 items and a printout that detailed the meaning of each. It included a star streamer ball. (“With proper goal setting, effort, monitoring and reflection, your goals are in reach.”) There was also a mini-parachute. (“Make mistakes . . . you’ve got a safety net. Sometimes our greatest achievements can come from failure.”)

* * *

The better question might be: How do you build humility at a school that costs $43,000 a year? Where students are tended to by a 10-person success team and are expected to find a passion — any passion — around which expertise, confidence and college admission may come? As the Kims spoke in their West Village town house, their son, Jackson, emerged in checkered pajamas from playing a “Star Wars” game on a Mac and broke into a number of songs in Mandarin, including “Head, Shoulders, Knees and Toes.” His aquarium was buzzing in the background, and his scooters, strollers and bikes filled up the entryway. The Kims may be concerned with ensuring that Jackson is humble, but they are also acutely aware of the advantages that speaking Mandarin will give him. “He will have such a leg up compared to his peers,” Ella said. “He’ll be so marketable coming out of college with that language fluency. There’s enough competition domestically!”

Android Software Engineer, Dianne Hackborn.

What the fucken fucke is the dealio with the cars zooming around in pairs with one car pushing the other? This is obviously some kind of tactical dealio, but what are the specifics?

INGREDIENTS
half medium white onion, chopped
six garlic cloves, chopped
one large can diced san marzanos
olive oil
salt
fresh-ground black pepper
red chile pepper flakes
dried oregano
dried thyme
half cup dry white wine
half pound penne
parmigiano reggiano

Sautee the onions and garlic with black and red pepper, oregano, and thyme, until they are starting to soften.

Deglaze with the wine and reduce until all the alcohol is gone.

Add the tomatoes and simmer with the lid offe for about an hour, salting to taste.

Sauce is done.

Boil the penne in salty water until very molto al dente, add some pasta water to the sauce, throw in the drained penne, and finish on medium high for a minute or two.

So simple! Yet so delicious!

Pinkberry for dessert!

Extremist right-wing filth senators have so fucked uppe the senate that no one even wants to be a fucken senator anymore. These republican scummebagges are like the ugly, stupid, vicious little bully that everyone hates who purposely takes a fucken shitte in the goddamn sandbox.

Lieberal lamestream media hard at work:

The two bombs that exploded near the finish line of the Boston Marathon on April 15 were the worst attack on U.S. soil since the Sept. 11 2001, attacks.

Either mass shooting by white christian d00ds is not an “attack on U.S. soil”, or killing three people with a bomb is worse than killing six or twenty-six or twelve with guns. (And that was the white christian d00d mass-shooting death toll for just one year.)