neurosciencestuff:

Scientists Link ALS Progression to Increased Protein Instability
A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.
“Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff.
Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates.
“The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Getzoff.
Striking in the Prime of Life
ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association’s Ice Bucket Challenge has enhanced public awareness of the disease.
ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms.
SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary “sporadic” ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don’t agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease.
One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations.
In 2003, based on their and others’ studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the “framework destabilization” hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up—and that accumulating SOD aggregation somehow triggers disease.
Faster Clumping, Worse Disease
In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS “hotspot” affect SOD protein stability.
To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, “wild-type” SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab’s SIBYLS beamline.
“We could detect differences between the two proteins even before we accelerated the aggregation process,” said David S. Shin, a research scientist in Tainer’s laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley.
The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS.
Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS.
What could explain these SOD mutants’ diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions—and this ability was lower for the SOD mutants associated with more severe ALS.
“There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions,” said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab.
Toward New Therapies
In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions—and thus are more likely to misfold and stick together in aggregates.
Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons.
“Because mutant SODs get bent out of shape more easily,” said Getzoff, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.”
The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants.
“If our hypothesis is correct,” said Shin, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”

neurosciencestuff:

Scientists Link ALS Progression to Increased Protein Instability

A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

“Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff.

Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates.

“The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Getzoff.

Striking in the Prime of Life

ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association’s Ice Bucket Challenge has enhanced public awareness of the disease.

ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms.

SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary “sporadic” ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don’t agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease.

One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations.

In 2003, based on their and others’ studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the “framework destabilization” hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up—and that accumulating SOD aggregation somehow triggers disease.

Faster Clumping, Worse Disease

In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS “hotspot” affect SOD protein stability.

To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, “wild-type” SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab’s SIBYLS beamline.

“We could detect differences between the two proteins even before we accelerated the aggregation process,” said David S. Shin, a research scientist in Tainer’s laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley.

The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS.

Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS.

What could explain these SOD mutants’ diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions—and this ability was lower for the SOD mutants associated with more severe ALS.

“There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions,” said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab.

Toward New Therapies

In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions—and thus are more likely to misfold and stick together in aggregates.

Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons.

“Because mutant SODs get bent out of shape more easily,” said Getzoff, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.”

The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants.

“If our hypothesis is correct,” said Shin, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”

medicalschool:

Scientists See Chemical Bonds Between Atoms
In an amazing work of microscopy, scientists have gotten a high-resolution view of a molecule and its chemical bonds. What’s more, the Lawrence Berkeley National Laboratory researchers got a peek at the molecule as it broke and reformed bonds after undergoing a chemical reaction.
Their images show a molecule, on the left above, which has 26 carbon and 14 hydrogen atoms structured as three connected benzene rings. The molecules on the right are the two most common products that result after the molecule is heated to 90 degrees Celsius.

Read More

medicalschool:

Scientists See Chemical Bonds Between Atoms

In an amazing work of microscopy, scientists have gotten a high-resolution view of a molecule and its chemical bonds. What’s more, the Lawrence Berkeley National Laboratory researchers got a peek at the molecule as it broke and reformed bonds after undergoing a chemical reaction.

Their images show a molecule, on the left above, which has 26 carbon and 14 hydrogen atoms structured as three connected benzene rings. The molecules on the right are the two most common products that result after the molecule is heated to 90 degrees Celsius.

Read More

anerdyfeminist:

kk-maker:

2spoopy5you:

lohelim:

winterthirst:

sabacc:

Steve Rogers did, in fact, realize that something was off when he saw the outline of the woman’s odd bra (a push-up bra, he would later learn), but being an officer and a gentleman, he said that it was the game that gave the future away.

 (via)

No, see, this scene is just amazing. The costume department deserves so many kudos for this, it’s unreal, especially given the fact that they pulled off Peggy pretty much flawlessly.

1) Her hair is completely wrong for the 40’s. No professional/working woman  would have her hair loose like that. Since they’re trying to pass this off as a military hospital, Steve would know that she would at least have her hair carefully pulled back, if maybe not in the elaborate coiffures that would have been popular.

2) Her tie? Too wide, too long. That’s a man’s tie, not a woman’s. They did, however, get the knot correct as far as I can see - that looks like a Windsor.

3) That. Bra. There is so much clashing between that bra and what Steve would expect (remember, he worked with a bunch of women for a long time) that it has to be intentional. She’s wearing a foam cup, which would have been unheard of back then. It’s also an exceptionally old or ill-fitting bra - why else can you see the tops of the cups? No woman would have been caught dead with misbehaving lingerie like that back then, and the soft satin cups of 40’s lingerie made it nearly impossible anyway. Her breasts are also sitting at a much lower angle than would be acceptable in the 40’s.

Look at his eyes. He knows by the time he gets to her hair that something is very, very wrong.

so what you are saying is S.H.E.I.L.D. has a super shitty costume division….

Nope, Nick Fury totally did this on purpose.

There’s no knowing what kind of condition Steve’s in, or what kind of person he really is, after decades of nostalgia blur the reality and the long years in the ice (after a plane crash and a shitload of radiation) do their work. (Pre-crash Steve is in lots of files, I’m sure. Nick Fury does not trust files.) So Fury instructs his people to build a stage, and makes sure that the right people put up some of the wrong cues.

Maybe the real Steve’s a dick, or just an above-average jock; maybe he had a knack for hanging out with real talent. Maybe he hit his head too hard on the landing and he’s not gonna be Captain anymore. On the flipside, if he really is smart, then putting him in a standard, modern hospital room and telling him the truth is going to have him clamming up and refusing to believe a goddamn thing he hears for a really long time.

The real question here is, how long it does it take for the man, the myth, the legend to notice? What does he do about it? How long does he wait to get his bearings, confirm his suspicions, and gather information before attempting busting out?

Turns out the answer’s about forty-five seconds.

This is super interesting.

immortalcomanche:

Aperture Laboratories Logo

"And thus it was, a Fourth Age of Middle-earth began. And the Fellowship of the Ring, though eternally bound by friendship and love, was ended.”

A message from Anonymous
Meant to ask xxiv, not xxvi, in my last post. Whoops. :P

Heh, it’s all good, don’t worry about it. XD

24. Have you ever felt like you had a “mind-meld” with someone?

Hm, probably at some point. Not sure about having the exact same ideas or thinking the exact same way as another person, but I definitely have people that I’m close enough to that we’re practically able to communicate with out using any intelligible words. My current roommate and I are like this. We’ve been known to confuse people who aren’t quite as fluent in our … verbal shorthand. :P

A message from goldpond
really interested in your last post. i also see clara as a free agent; i actually find that she's almost manipulating the doctor more than he's "turning her into a weapon" (i don't see that at all tbh). i love her & i think she's one of the more intense/scarier companions we've had. she's completely changed the companion/doctor dynamic. it's fascinating & brilliant (but selfishly i'm not sure i really LIKE it). anyway, i love reading your thoughts, i wish tumblr had more dw fandom discussion x

queenmegmasters:

tillthenexttimedoctor:

(Thank you! I think my last post was this one, right? I think tumblr has plenty of dw fandom discussions, there’s a lot of meta being written… and a lot of arguments taking place. It’s a rich environment if you know where to look.)

I’ve got to admit, I don’t quite see the manipulation angle. Except maybe the lies she is telling, to keep up the appearance of everything being fine. But he’s catching on there… and he’s not willing to give this up anymore than she is, he’s just suddenly the more honest person in this friendship.

I never thought I’d see the day where it would be feasible to call Clara “one of the more intense/scarier companions we’ve had”. But you are right. In a way, she even transcends River Song here. River might have almost destroyed the universe once and can make a Dalek beg for mercy, but she also became more compassionate, less destructive, less impulsive, as she developed and grew. She did not start out as Clara Oswald, who wanted to be caring and heroic and responsible and good. There is an underlying uncertainty of just what Clara can be capable of in time which in its own way is more unsettling than “used to be a super assassin”.

(hijacking this post bc yes hello I have 50 billion dark!dw headcanons)

(im putting this under a read more actually. it got way longer than i thought it would)

Read More

A message from Anonymous
v, xxi, xxii, xxvi.

5. Do you think of yourself as a human being or a human doing? Do you identify yourself by the things you do?

A human being, I think. In the end, what we do - while extremely important - is only a small of the whole of who we are.

21. Do you love easily?

Not really. I can get infatuated fairly easily, I guess, with both people and things. But actual loving is usually deeper and feels more … reasoned, in a way. Like a predetermined action. And love is a lot less likely to change for me than infatuation is.

22. List the top five things you spend the most time doing, in order.

Class
Sleep
Talking to/spending time with/hanging out with friends
Studying
Watching movies/TV episodes and reading (both books and online)

26. How would you describe your gender/sexuality?

I’m a heterosexual cis female.

Thanks! These were fun to answer. :)

sinfultragedy:

4 GIFS || Fred & Wesley
(Requested by sunnydalehighh)