sábado, 23 de septiembre de 2017, 22:25
Sitio: Ontological Design: The Road to the Planetary Synapse
Curso: Ontological Design: The Road to the Planetary Synapse (Neuroscience & Biotechnology)
Glosario: Neurociencia | Neuroscience
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A neural portrait of the human mind [907]

de System Administrator - sábado, 4 de octubre de 2014, 21:39
 

Nancy Kanwisher: A neural portrait of the human mind

 

TED2014

Brain imaging pioneer Nancy Kanwisher, who uses fMRI scans to see activity in brain regions (often her own), shares what she and her colleagues have learned: The brain is made up of both highly specialized components and general-purpose "machinery." Another surprise: There's so much left to learn.

Video

0:11 - Today I want to tell you about a project being carried out by scientists all over the world to paint a neural portrait of the human mind. And the central idea of this work is that the human mind and brain is not a single, general-purpose processor, but a collection of highly specialized components, each solving a different specific problem, and yet collectively making up who we are as human beings and thinkers. To give you a feel for this idea,

0:42 - imagine the following scenario: You walk into your child's day care center. As usual, there's a dozen kids there waiting to get picked up, but this time, the children's faces look weirdly similar, and you can't figure out which child is yours. Do you need new glasses? Are you losing your mind? You run through a quick mental checklist. No, you seem to be thinking clearly, and your vision is perfectly sharp. And everything looks normal except the children's faces. You can see the faces, but they don't look distinctive, and none of them looks familiar, and it's only by spotting an orange hair ribbon that you find your daughter.

1:22 - This sudden loss of the ability to recognize faces actually happens to people. It's called prosopagnosia,and it results from damage to a particular part of the brain. The striking thing about it is that only face recognition is impaired; everything else is just fine.

1:39 - Prosopagnosia is one of many surprisingly specific mental deficits that can happen after brain damage.These syndromes collectively have suggested for a long time that the mind is divvied up into distinct components, but the effort to discover those components has jumped to warp speed with the invention of brain imaging technology, especially MRI. So MRI enables you to see internal anatomy at high resolution, so I'm going to show you in a second a set of MRI cross-sectional images through a familiar object, and we're going to fly through them and you're going to try to figure out what the object is. Here we go.

2:23 - It's not that easy. It's an artichoke.

2:25 - Okay, let's try another one, starting from the bottom and going through the top. Broccoli! It's a head of broccoli. Isn't it beautiful? I love that.

2:34 - Okay, here's another one. It's a brain, of course. In fact, it's my brain. We're going through slices through my head like that. That's my nose over on the right, and now we're going over here, right there.

2:45 - So this picture's nice, if I do say so myself, but it shows only anatomy. The really cool advance with functional imaging happened when scientists figured out how to make pictures that show not just anatomy but activity, that is, where neurons are firing. So here's how this works. Brains are like muscles.When they get active, they need increased blood flow to supply that activity, and lucky for us, blood flow control to the brain is local, so if a bunch of neurons, say, right there get active and start firing, then blood flow increases just right there. So functional MRI picks up on that blood flow increase, producing a higher MRI response where neural activity goes up.

3:28 - So to give you a concrete feel for how a functional MRI experiment goes and what you can learn from itand what you can't, let me describe one of the first studies I ever did. We wanted to know if there was a special part of the brain for recognizing faces, and there was already reason to think there might be such a thing based on this phenomenon of prosopagnosia that I described a moment ago, but nobody had ever seen that part of the brain in a normal person, so we set out to look for it. So I was the first subject. I went into the scanner, I lay on my back, I held my head as still as I could while staring at pictures of faces like these and objects like these and faces and objects for hours. So as somebody who has pretty close to the world record of total number of hours spent inside an MRI scanner, I can tell you that one of the skills that's really important for MRI research is bladder control. (Laughter)

4:28 - When I got out of the scanner, I did a quick analysis of the data, looking for any parts of my brain that produced a higher response when I was looking at faces than when I was looking at objects, and here's what I saw. Now this image looks just awful by today's standards, but at the time I thought it was beautiful. What it shows is that region right there, that little blob, it's about the size of an olive and it's on the bottom surface of my brain about an inch straight in from right there. And what that part of my brain is doing is producing a higher MRI response, that is, higher neural activity, when I was looking at facesthan when I was looking at objects. So that's pretty cool, but how do we know this isn't a fluke? Well, the easiest way is to just do the experiment again. So I got back in the scanner, I looked at more faces and I looked at more objects and I got a similar blob, and then I did it again and I did it again and again and again, and around about then I decided to believe it was for real. But still, maybe this is something weird about my brain and no one else has one of these things in there, so to find out, we scanned a bunch of other people and found that pretty much everyone has that little face-processing region in a similar neighborhood of the brain.

5:49 - So the next question was, what does this thing really do? Is it really specialized just for face recognition?Well, maybe not, right? Maybe it responds not only to faces but to any body part. Maybe it responds to anything human or anything alive or anything round. The only way to be really sure that that region is specialized for face recognition is to rule out all of those hypotheses. So we spent much of the next couple of years scanning subjects while they looked at lots of different kinds of images, and we showed that that part of the brain responds strongly when you look at any images that are faces of any kind, and it responds much less strongly to any image you show that isn't a face, like some of these.

6:34 - So have we finally nailed the case that this region is necessary for face recognition? No, we haven't.Brain imaging can never tell you if a region is necessary for anything. All you can do with brain imaging is watch regions turn on and off as people think different thoughts. To tell if a part of the brain is necessary for a mental function, you need to mess with it and see what happens, and normally we don't get to do that. But an amazing opportunity came about very recently when a couple of colleagues of mine tested this man who has epilepsy and who is shown here in his hospital bed where he's just had electrodes placed on the surface of his brain to identify the source of his seizures. So it turned out by total chancethat two of the electrodes happened to be right on top of his face area. So with the patient's consent, the doctors asked him what happened when they electrically stimulated that part of his brain. Now, the patient doesn't know where those electrodes are, and he's never heard of the face area. So let's watch what happens. It's going to start with a control condition that will say "Sham" nearly invisibly in red in the lower left, when no current is delivered, and you'll hear the neurologist speaking to the patient first. So let's watch.

7:52 - (Video) Neurologist: Okay, just look at my face and tell me what happens when I do this. All right?

7:59 - Patient: Okay.

8:01 - Neurologist: One, two, three.

8:06 - Patient: Nothing. Neurologist: Nothing? Okay. I'm going to do it one more time. Look at my face. One, two, three.

8:19Patient: You just turned into somebody else. Your face metamorphosed. Your nose got saggy, it went to the left. You almost looked like somebody I'd seen before, but somebody different. That was a trip.(Laughter)

8:38 - Nancy Kanwisher: So this experiment — (Applause) — this experiment finally nails the case that this region of the brain is not only selectively responsive to faces but causally involved in face perception. So I went through all of these details about the face region to show you what it takes to really establish that a part of the brain is selectively involved in a specific mental process. Next, I'll go through much more quickly some of the other specialized regions of the brain that we and others have found. So to do this, I've spent a lot of time in the scanner over the last month so I can show you these things in my brain.

9:17 - So let's get started. Here's my right hemisphere. So we're oriented like that. You're looking at my head this way. Imagine taking the skull off and looking at the surface of the brain like that. Okay, now as you can see, the surface of the brain is all folded up. So that's not good. Stuff could be hidden in there. We want to see the whole thing, so let's inflate it so we can see the whole thing. Next, let's find that face area I've been talking about that responds to images like these. To see that, let's turn the brain around and look on the inside surface on the bottom, and there it is, that's my face area. Just to the right of that is another region that is shown in purple that responds when you process color information, and near those regions are other regions that are involved in perceiving places, like right now, I'm seeing this layout of space around me and these regions in green right there are really active. There's another one out on the outside surface again where there's a couple more face regions as well. Also in this vicinity is a region that's selectively involved in processing visual motion, like these moving dots here, and that's in yellow at the bottom of the brain, and near that is a region that responds when you look at images of bodies and body parts like these, and that region is shown in lime green at the bottom of the brain.

10:31 - Now all these regions I've shown you so far are involved in specific aspects of visual perception. Do we also have specialized brain regions for other senses, like hearing? Yes, we do. So if we turn the brain around a little bit, here's a region in dark blue that we reported just a couple of months ago, and this region responds strongly when you hear sounds with pitch, like these. (Sirens) (Cello music) (Doorbell) In contrast, that same region does not respond strongly when you hear perfectly familiar sounds that don't have a clear pitch, like these. (Chomping) (Drum roll) (Toilet flushing)

11:17 - Okay. Next to the pitch region is another set of regions that are selectively responsive when you hear the sounds of speech.

11:25 - Okay, now let's look at these same regions. In my left hemisphere, there's a similar arrangement — not identical, but similar — and most of the same regions are in here, albeit sometimes different in size.

11:35 - Now, everything I've shown you so far are regions that are involved in different aspects of perception,vision and hearing. Do we also have specialized brain regions for really fancy, complicated mental processes? Yes, we do. So here in pink are my language regions. So it's been known for a very long timethat that general vicinity of the brain is involved in processing language, but we showed very recently that these pink regions respond extremely selectively. They respond when you understand the meaning of a sentence, but not when you do other complex mental things, like mental arithmetic or holding information in memory or appreciating the complex structure in a piece of music.

12:20 - The most amazing region that's been found yet is this one right here in turquoise. This region respondswhen you think about what another person is thinking. So that may seem crazy, but actually, we humans do this all the time. You're doing this when you realize that your partner is going to be worried if you don't call home to say you're running late. I'm doing this with that region of my brain right now when I realize that you guys are probably now wondering about all that gray, uncharted territory in the brain, and what's up with that?

12:57 - Well, I'm wondering about that too, and we're running a bunch of experiments in my lab right now to try to find a number of other possible specializations in the brain for other very specific mental functions. But importantly, I don't think we have specializations in the brain for every important mental function, even mental functions that may be critical for survival. In fact, a few years ago, there was a scientist in my labwho became quite convinced that he'd found a brain region for detecting food, and it responded really strongly in the scanner when people looked at images like this. And further, he found a similar responsein more or less the same location in 10 out of 12 subjects. So he was pretty stoked, and he was running around the lab telling everyone that he was going to go on "Oprah" with his big discovery. But then he devised the critical test: He showed subjects images of food like this and compared them to images with very similar color and shape, but that weren't food, like these. And his region responded the same to both sets of images. So it wasn't a food area, it was just a region that liked colors and shapes. So much for "Oprah."

14:11 - But then the question, of course, is, how do we process all this other stuff that we don't have specialized brain regions for? Well, I think the answer is that in addition to these highly specialized components that I've been describing, we also have a lot of very general- purpose machinery in our heads that enables us to tackle whatever problem comes along. In fact, we've shown recently that these regions here in whiterespond whenever you do any difficult mental task at all — well, of the seven that we've tested. So each of the brain regions that I've described to you today is present in approximately the same location in every normal subject. I could take any of you, pop you in the scanner, and find each of those regions in your brain, and it would look a lot like my brain, although the regions would be slightly different in their exact location and in their size.

15:04 - What's important to me about this work is not the particular locations of these brain regions, but the simple fact that we have selective, specific components of mind and brain in the first place. I mean, it could have been otherwise. The brain could have been a single, general-purpose processor, more like a kitchen knife than a Swiss Army knife. Instead, what brain imaging has delivered is this rich and interesting picture of the human mind. So we have this picture of very general-purpose machinery in our heads in addition to this surprising array of very specialized components.

15:42 - It's early days in this enterprise. We've painted only the first brushstrokes in our neural portrait of the human mind. The most fundamental questions remain unanswered. So for example, what does each of these regions do exactly? Why do we need three face areas and three place areas, and what's the division of labor between them? Second, how are all these things connected in the brain? With diffusion imaging, you can trace bundles of neurons that connect to different parts of the brain, and with this method shown here, you can trace the connections of individual neurons in the brain, potentially someday giving us a wiring diagram of the entire human brain. Third, how does all of this very systematic structure get built, both over development in childhood and over the evolution of our species? To address questions like that, scientists are now scanning other species of animals, and they're also scanning human infants.

16:47 - Many people justify the high cost of neuroscience research by pointing out that it may help us somedayto treat brain disorders like Alzheimer's and autism. That's a hugely important goal, and I'd be thrilled if any of my work contributed to it, but fixing things that are broken in the world is not the only thing that's worth doing. The effort to understand the human mind and brain is worthwhile even if it never led to the treatment of a single disease. What could be more thrilling than to understand the fundamental mechanisms that underlie human experience, to understand, in essence, who we are? This is, I think, the greatest scientific quest of all time.

17:33 - (Applause)

Brain researcher
Using fMRI imaging to watch the human brain at work, Nancy Kanwisher’s team has discovered cortical regions responsible for some surprisingly specific elements of cognition.
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A SEARCH BETWEEN RISING DISORDER AND COMPLEXITY [626]

de System Administrator - viernes, 1 de agosto de 2014, 23:10
 

THE END OF THE UNIVERSE: A SEARCH BETWEEN RISING DISORDER AND COMPLEXITY

Written By Cadell Last

In a new book, The Beginning and the End: The Meaning of Life in Cosmological Perspective, by philosopher Clement Vidal (@clemvidal), the two main trends of the universe – the trends of rising disorder and complexity – are explored. As a result, his investigation takes us to the most extreme conditions possible in our universe.

Continue reading on the site http://kwfoundation.org

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A Step Closer to Human Genome Editing [1665]

de System Administrator - lunes, 15 de febrero de 2016, 16:37
 

UK Will Use CRISPR on Human Embryos — a Step Closer to Human Genome Editing

BY SVETA MCSHANE

"It is human nature and inevitable in my view that we will edit our genomes for enhancements.”
J. Craig Venter

This week, Kathy Niakan, a biologist working at the Francis Crick Institute in London received the green light from the UK’s Human Fertilisation and Embryology Authority to use genome editing technique CRISPR/Cas9 on human embryos.

Niakan hopes to answer important questions about how healthy human embryos develop from a single cell to around 250 cells, in the first seven days after fertilization.

By removing certain genes during this early development phase using CRISPR/Cas9, Niakan and her team hope to understand what causes miscarriages and infertility, and in the future, possibly  improve the effectiveness of in-vitro fertilization and provide better treatments for infertility.

The embryos used in the research will come from patients who have a surplus of embryos in their IVF treatment and give consent for these embryos to be used in research. The embryos would not be allowed to survive beyond 14 days and are not allowed to be implanted in a womb to develop further. The team still needs to have their plans reviewed by an ethics board, but if approved, the research could start in the next few months.

In an op-ed for Time magazine, J. Craig Venter writes that the experiments proposed at the Crick Institute are similar to previous gene knockouts in mice and other species. While some results may be of interest, Venter believes, most will be inconclusive,  as the field has seen in the past.

He continues, “The only reason the announcement is headline-provoking is that it seems to be one more step toward editing our genomes to change life outcomes.”

Venter’s stance on the matter of genome editing echoes that of many other scientists in the field: Proceed with caution. 

In December 2015, The National Academies of Sciences, Engineering and Medicine held an International Summit on Human Genome Editing, and after several days of discussion, released a statement of conclusions.

In a nutshell, the group recommended that basic and preclinical research should continue with the appropriate legal and ethical oversight. If human embryos or germline cells are modified during research, they should not be used to establish a pregnancy.

In cases of clinical use, the group underscored a difference between editing somatic cells (cells whose genomes are not passed on to the next generation) versus germline cells (whose genomes are passed on to the next generation).

Somatic cell editing would include editing genes that cause diseases such as sickle-cell anemia. Because these therapies would only affect the individual, the group recommends these cases should be evaluated based on “existing and evolving” gene-therapy regulations.

It’s worth noting that governments across the world have significantly diverse ways of handling gene-therapy regulations. 

In the US, the National Institutes of Health (NIH) won’t fund genomic editing research involving human embryos. Research like Kathy Niakan’s is not illegal, as long as it is privately funded. In China, the government doesn’t ban any particular type of research, while countries like Italy and Germany are on the other side of the spectrum, where all human embryo research is banned.

The International Summit on Genome Editing concluded that today it would be “irresponsible to proceed with any clinical use of germline editing” until we have more knowledge of the possible risks and outcomes of doing so. 

In spite of that, the group also concluded that as “scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.”  Similarly, Venter writes of the need for the scientific community to gain better understanding of the “software of life before we begin re-writing this code.”

While the “proceed with caution” message from scientists is loud and clear, the age of programmable biology seems to be getting closer and closer.

Between Venter’s statement that it is inevitable that we will edit our genomes for enhancements and the suggestion that human germline editing should be ‘revisited’ as opposed to banned, it seems even the scientific community is assuming a future which includes human genome editing.

So, where do we go from here?

This brave new future seems equal parts exciting, frightening — and inevitable. At this stage, more research is critical — so when the time comes to rewrite the software of life, we do so with wisdom.

Image Credit: Shutterstock.com

Link: http://singularityhub.com/2016/02/07/uk-will-use-crispr-on-human-embryos-a-step-closer-to-human-genome-editing/

RELATED TOPICS: 

Link: http://singularityhub.com

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A step towards gene therapy against intractable epilepsy [1612]

de System Administrator - lunes, 7 de diciembre de 2015, 11:42
 

3D model of DNA double helix. Credit: Peter Artymiuk / Wellcome Images

A step towards gene therapy against intractable epilepsy

by Nikitidou Ledri L et al.

By delivering genes for a certain signal substance and its receptor into the brain of test animals with chronic epilepsy, a research group at Lund University in Sweden with colleagues at University of Copenhagen Denmark has succeeded in considerably reducing the number of epileptic seizures among the animals. The test has been designed to as far as possible mimic a future situation involving treatment of human patients.

Many patients with epilepsy are not experiencing any improvements from existing drugs. Surgery can be an alternative for severe epilepsy, in case it is possible to localize and remove the epileptic focus in the brain where seizures arise.

"There is a period between the detection of this focus and the operation when the gene therapy alternative could be tested. If it works well, the patient can avoid surgery. If it doesn't, surgery will go ahead as initially planned and the affected part will then be removed. With this approach, the experimental treatment will be more secure for the patient", says Professor Merab Kokaia.

He and his group are working on a rat model that mimics temporal lobe epilepsy, the most common type of epilepsy. The test animals are given injections of the epilepsy-inducing substance, kainate, in the temporal lobe of one the cerebral hemispheres. Most of the animals had seizures of varying degrees, whereas some had no seizures, which Merab Kokaia considers a good result, as it is similar to the situation among people. Brain damage resulting from various accidents has very different consequences for different patients, as some develop epilepsy, whereas others do not.

The rats that developed epilepsy were then given gene therapy in the part of the brain in which the kainate had been injected, and where the seizures arose. Genes were delivered for both the signal substance (neuropeptide Y) and one of its receptors. The idea was that the combination would create a larger effect than only delivering the gene for the signal substance itself. Neuropeptide Y can bind to several different receptors and in the worst case it binds to a receptor that promotes increase in the number of seizures instead of decrease.

The study results have so far been positive. The increase in the frequency of seizures that has been seen among the control animals that were treated with inactive genes was halted after the treatment with combination of active genes, and for 80 % of the animals the number of seizures was reduced by almost half.

"The test must be repeated in more animal studies, so that the possible side effects, on memory for example, can be studied. But, we regard this study as promising proof of concept, a demonstration that the method works," states Merab Kokaia.

He expects that the first gene therapy treatments will be carried out on patients who have already been selected for surgical procedures. In the long term, however, gene therapy will be of the greatest benefit to those patients who cannot be operated on. There are patients with severe epilepsy whose epileptic focus is so badly placed that an operation is out of question since it can impair e.g. speech or movement. These patients can therefore never undergo a surgical procedure, but could be helped by gene therapy in the future.

Note: Material may have been edited for length and content. For further information, please contact the cited source.

Publication

Link: http://www.neuroscientistnews.com

 

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A Vaulted Mystery [698]

de System Administrator - martes, 5 de agosto de 2014, 23:12
 

 

©G.E. KIDDLER SMITH/CORBIS

A Vaulted Mystery

Nearly 30 years after the discovery of tiny barrel-shape structures called vaults, their natural functions remain elusive. Nevertheless, researchers are beginning to put these nanoparticles to work in biomedicine.

By Eufemia S. Putortì and Massimo P. Crippa

In the mid-1980s, biochemist Leonard Rome of the University of California, Los Angeles, (UCLA) School of Medicine and his postdoc Nancy Kedersha were developing new ways to separate coated vesicles of different size and charge purified from rat liver cell lysates when they stumbled upon something else entirely. They trained a transmission electron microscope on the lysate to check whether the vesicles were being divvied up correctly, and the resulting image revealed three dark structures: a large protein-coated vesicle, a small protein-coated vesicle, and an even smaller and seemingly less dense object. (See photograph below.) The researchers had no idea what the smallest one was.

“There were many different proteins and membrane-bound vesicles in the various fractions we analyzed,” Kedersha recalls, but this small vesicle was different. And it was “not a contaminant,” she says, as additional micrographs of partially purified vesicles revealed similar strange objects, always found in association with the coated vesicles. The ovoid particles displayed a distinct shape, which reminded the researchers of a raspberry, a hand grenade, or a barrel, and all were smaller than any known organelle. Rome gave his postdoc the green light to investigate further.

 

A MINI MYSTERY: An electron micrograph taken by researchers 30 years ago reveals one of the first looks at the nanoscale structures now known as vaults. Abbreviations: large coated vesicle (LCV), vault (V), small coated vesicle (SCV)

NANCY KEDERSHA AND LEONARD ROME

Kedersha designed a way to purify the mystery particles, based on a procedure previously described in the literature for isolating coated vesicles, then stained and imaged what she’d collected using electron microscopy. The tiny structures had a complex but consistent barrel-shape morphology and measured 35 by 65 nanometers—much smaller than lysosomes, which range in diameter from 100 to more than 1,000 nanometers (1 micrometer), or mitochondria, which are 0.5 to 10 micrometers long. Kedersha also treated the particles with various proteases, as well as enzymes to digest RNA and DNA, to assess their constituent molecules, finding evidence of three major proteins and an RNA component. With a total mass of approximately 13 megadaltons, they appeared to be the largest eukaryotic ribonucleoprotein particles ever discovered. By comparison, ribosomes measure just 20 to 25 nanometers in diameter and weigh in at just over 3 megadaltons.

Kedersha dubbed the structures “vaults,” after the arched shape of the very first particle she and Rome observed, reminiscent of the vaulted ceilings of cathedrals.1 To screen for these new nanostructures in other species, Kedersha developed an antibody against one of the vault proteins she’d discovered, and used it to purify vaults from species across the animal kingdom: the minibarrels were abundant in the cells of rabbits, mice, chickens, cows, bullfrogs, sea urchins, and several human cell lines—varying from 10,000 to 100,000 per cell. Remarkably, they all appeared to be similar in size, shape, and morphology to those Kedersha and Rome isolated from rat livers. Clearly, this was an important cellular structure, and there were no reports of anything like it in the literature.

The broad distribution and strong conservation of vaults in eukaryotic species suggest that their function is essential to cells, but that function remains unclear to this day. In fact, in the three decades that have passed since their discovery, vaults have gone largely unnoticed by the scientific community. But a handful of dedicated groups are making strides in understanding what vaults are and what they do, with clues emerging that hint at their roles in cargo transport, cellular motility, and drug resistance, among other possible functions.

Cracking the vault

Scientists have taken several approaches to deciphering the structure of the nanosize vaults, including cryo-electron and freeze-etch microscopy and three-dimensional image reconstruction. Such work has revealed a symmetrical central barrel with a cinched middle and a cap protruding from the barrel’s top and bottom. (See illustration.) Cross sections reveal a very thin shell surrounding a large, hollow interior. Interestingly, a vault’s interior is spacious enough to enclose molecules as large as ribosomal subunits, but researchers have not confirmed whether vaults ever house cellular cargo.

As Kedersha’s early analyses suggested, vaults are composed of multiple copies of at least four distinct components: three proteins and one RNA molecule. The major vault protein (MVP) accounts for some 75 percent of the particles’ mass, with each vault containing 78 copies of the protein. In fact, the expression of MVP in an insect cell line—insects themselves are one of the few eukaryotic organisms that don’t have vaults—results in the spontaneous formation of particles with morphologic characteristics similar to those of endogenous vaults.2 Another protein typically found in vaults is vault poly(ADP-ribose) polymerase (VPARP). VPARP and MVP mRNA transcripts are expressed in similar patterns in the cell, and subcellular fractionation studies point to a strong binding between the two proteins.

Kedersha dubbed the structures “vaults,” after the arched shape of the very first particle she and Rome observed, reminiscent of the vaulted ceilings of cathedrals.

The third vault protein is TEP1, previously identified as the mammalian telomerase-associated protein 1, which binds RNA in the telomerase complex. TEP1-knockout mice exhibited no alterations in telomerase function, suggesting its role in the nucleus is redundant, but vaults purified from these animals revealed a complete absence of the fourth component of vaults: vault RNA (vRNA), a small untranslated RNA found at the tips of the particles. This work pointed to TEP1’s role in the recruitment and stabilization of vRNA.

The freeze-etching technique—which consists of physically breaking apart a frozen biological sample and then examining it with transmission electron microscopy—has revealed that vaults are not rigid, impermeable structures, but dynamic entities that are able to open and close, with a structure resembling a petaled flower.3 (See photograph below.) The “flowers” are usually seen in pairs, suggesting that an intact vault comprises two folded flowers with eight rectangular petals, each of which is connected to a central ring by a thin, short hook. (See illustration.)

The ability of vaults to open and close points to a possible function in cargo transport. At present, however, a definitive answer about the function of vaults remains elusive. In fact, in addition to cellular transport, more than a dozen roles for vaults have been proposed, including playing a part in multidrug resistance, cellular signaling, neuronal dysfunctions, and apoptosis and autophagy.

In search of function

Vaults are found in the cytoplasm, so far appearing to be completely excluded from the nucleus (except in sea urchins4). Within the cytoplasm, however, they are not randomly dispersed: they colocalize and interact with cytoskeletal elements, such as actin stress fibers and microtubules, and are also abundant in highly motile cells such as macrophages, suggesting the structures may help cells move around.

 

THE STRUCTURE OF VAULTS: Vaults are hollow, barrel-shape structures, measuring 35 x 65 nanometers. They are symmetrical, with a crease along the outside of the barrel’s middle and smaller caps on either end.
See full infographic: JPG | PDF

©LAURIE O'KEEFE

Vaults’ interactions with cytoskeletal elements also lend support to the idea that these particles act as cytoplasmic cargo transporters. Researchers hypothesize that vaults open, encapsulate molecules, then close and travel across the cytoplasm along microtubules or actin fibers before releasing their contents into the desired subcellular compartment.

In addition to the now well-characterized flower pattern of vault opening, Rome and colleagues have proposed two alternative hypotheses for how vaults might open: by separating at the waist, splitting into two completely dissociated halves, or by the raising of opposing petals on the two vault halves, hinging from the caps to open at the waist.5 (See illustration.) The latter may avoid destroying the integrity of the whole particle, potentially allowing vaults to repeatedly transport and release cargos. More recently, researchers have found evidence that the vaults “breathe” in solution, taking up and releasing proteins without ever fully opening.

Vaults also seem to be closely associated with nuclear pore complexes (NPC), protein conglomerations that span the inner and outer membranes of the nuclear envelope. This raises the possibility that vaults shuttle contents between the cytoplasm and nucleus. Interestingly, some structural characteristics of vaults, such as mass, diameter, and shape, are very similar to those of the NPC, although research has not yet conclusively established whether vaults actually form some sort of plug to stop up the NPC.

Researchers have also proposed a role for vaults in cancer cells’ ability to resist the pharmaceuticals doctors throw at them. In 1993, immunologist and experimental pathologist Rik Scheper of VU University in Amsterdam and colleagues found that a non-small-cell lung cancer cell line could be selected for resistance to the chemotherapy drug doxorubicin.6 The resulting cells overexpressed a large protein initially named lung resistance-related protein (LRP). Two years later, the group discovered that LRP was nothing other than human MVP,7 and the literature soon blossomed with papers on the possible role of vaults in chemotherapeutic drug resistance.

Experiments have yielded several observations that exclude a direct participation of MVP in such resistance, however. Knockdown of MVP does not affect cell survival, for instance, and upregulation of MVP does not increase resistance to anticancer drugs.8 Thus, while many clinical studies recognize MVP as a negative prognostic factor for response to chemotherapy, it remains to be seen whether vaults play a direct role in drug resistance or whether they are merely markers of a drug-resistance phenotype.

Putting vaults to work

While many questions about vaults remain, including whether they serve as cargo transporters for the cell, their large, hollow interiors have led some scientists to see the nanobarrels as potential tools for the delivery of biomaterials. A variety of strategies for encapsulating biomaterials already exists, including viruses, liposomes, peptides, hydrogels, and synthetic and natural polymers, but the use of these materials is often limited by insufficient payload, immunogenicity, lack of targeting specificity, and the inability to control packaging and release. Vaults, on the other hand, possess all the features of an ideal delivery vehicle. These naturally occurring cellular nanostructures have a cavity large enough to sequester hundreds of proteins; they are homogeneous, regular, highly stable, and easy to engineer; and, most of all, they are nonimmunogenic and totally biocompatible.

 

BLOOMING VAULTS: Splitting at the midsection, vaults appear to break open into two flower-shape structures (yellow arrows). Partially open vaults (orange arrows) are seen along the top of this electron micrograph image.

JOHN HEUSER

But the actual packaging of foreign materials into vaults remains challenging. In 2005, Rome and long-time UCLA collaborator Valerie Kickhoefer discovered a particular region at the VPARP’s C-terminus, named major vault protein interaction domain (mINT), which is responsible for binding VPARP to MVP. The researchers hypothesized that mINT acts as a kind of zip code directing VPARP to the inside of the vault and speculated that any protein tagged with the mINT sequence at the C-terminus could be packaged into vaults just like VPARP. Fusing the sequence to luciferase, the enzyme that makes fireflies glow, and expressing the construct in an insect cell line, they successfully generated vaults with the engineered protein packaged inside the central barrel in the same two rings typically formed of VPARP.9

Rome and his colleagues have since demonstrated that the technique can successfully incorporate any number of proteins into the tiny cellular particles, and even discovered that they can make changes to vault proteins to alter such packaging. For example, the addition of extra amino acids at the N-terminus of MVP produces vaults with the engineered protein packaged exclusively at the waist. Conversely, the addition of extra amino acids at the MVP C-terminus produces two blobs of densely packed protein at the ends of vaults. Vaults can also be engineered to bind antibodies or express cancer cell ligands on their surface, allowing for the precise delivery of biomaterials to target cells. Researchers believe that, once inside the body, the engineered vaults act as slow-release particles for whatever protein is packaged inside.

Three decades after their chance dis­covery, vaults remain mysterious. But researchers are not waiting for all the questions to be answered.

In collaboration with Rome, pathologist Kathleen Kelly’s group at UCLA is working to create a vault-based nasal spray that acts as a vaccine against Chlamydia infection.10 They engineered vaults to encase the major outer membrane protein (MOMP) of Chlamydia, which possesses highly immunogenic properties, then created a nasal spray to deliver the modified vaults to the nasal mucosa. After the immunization, they challenged female mice with a Chlamydia infection and found that the treatment significantly limited bacterial infection in mucosal tissue.

Vaults may also help fight cancer. The lymphoid chemokine CCL21 binds to the chemokine receptor CCR7 and serves as a chemoattractant for tumor-fighting cells of the immune system. Pulmonologist Steven Dubinett and immunologist Sherven Sharma of UCLA and their colleagues injected CCL21 into mice with a lung carcinoma, but because CCL21 is small, it rapidly dissipated out of the tumor and was relatively ineffective at drawing immune cells to the tumor. In collaboration with Rome’s group, the researchers tagged the chemokine with mINT to package it into vaults prior to injection, causing an increase in the number of leukocytic cells that infiltrated the tumor and, most importantly, leading to a significant decrease in tumor growth.11 Rome and colleagues have since started a company to advance this vault-based therapy through human trials. (See “Opening the Medical Vault” below.)

Three decades after their chance discovery, vaults remain mysterious. But researchers are not waiting for all the questions to be answered. Vault-based therapies show promise in treating a variety of diseases, and the success of such applications could give these nanosize barrels a big dose of recognition.

Eufemia S. Putortì recently completed her bachelor’s degree in medical and pharmaceutical biotechnology at the Vita-Salute San Raffaele University in Milan, Italy, with a thesis on the history and function of vaults. While an undergraduate, she interned in the lab of Massimo P. Crippa, a senior researcher at the institute, and is now working on her master’s degree in molecular and cellular medical biotechnology.

 

Opening the Medical Vault

 

TUMOR-FIGHTING VAULTS: By tagging CCL21 cytokines with the mINT sequence derived from the C-terminus of the VPARP protein, researchers have engineered vaults carrying the immune-activating proteins. These CCL21-loaded vaults have shown promise in a mouse model of lung cancer, and clinical trials testing the therapeutic in patients are anticipated by the end of next year.

© LAURIE O'KEEFE

Fifteen years ago, my postdoc Andy Stephen brought me a result that blew my mind. Because he needed to make large amounts of the major vault protein (MVP) in order to further study its properties, he had expressed the protein in insect cells, which, unlike most animal cells, lack vaults. To our great surprise, MVP was not only expressed at high levels, but it assembled within the insect cell cytoplasm into empty vault-like particles that appeared structurally identical to the naturally occurring vaults we had purified from other eukaryotes.

This discovery changed the direction of my laboratory. My colleague Valerie Kickhoefer and I began to engineer vault particles as nanoscale capsules for a wide range of applications. We identified a section of the vault poly(ADP-ribose) polymerase (VPARP) protein that binds with high affinity to the inside of vaults. Fusion of this sequence, called mINT, to any protein or peptide of interest facilitated its packaging into vaults and, thanks to a tight but reversible binding interaction, its slow release. Moreover, by fusing peptides to the C-terminus of MVP, we are able to engineer vaults with specific markers displayed on their surface, allowing the development of strategies for targeting vaults to cells or tissues.12

To develop such vaults for medical needs, I partnered with entrepreneur Michael Laznicka to form Vault Nano Inc. in the summer of 2013. The first vault-based therapeutic that we are moving forward is a human recombinant vault packaged with the CCL21 chemokine, which is normally produced in lymph nodes, where it attracts and activates T cells and dendritic cells. Injecting the recombinant vaults into a lung tumor model in mice, we observed that the attracted T cells and dendritic cells react with tumor antigens to halt tumor growth.11 Now, in collaboration with Steven Dubinett and Jay Lee here at UCLA, Vault Nano is moving the CCL21-vault into clinical studies, hoping to initiate a Phase 1 trial by the end of next year. If successful, the CCL21-vault therapeutic would be an off-the-shelf reagent that can harness the power of a patient’s own immune system to attack cancer.

With our UCLA collaborators Kathleen Kelly and Otto Yang, we are also pursuing the development of vault vaccines against Chlamydia and HIV. Current studies in animal models have demonstrated that when a pathogen-derived protein or peptide is packaged in vaults, the resulting nanocapsules can stimulate a robust immune response. With the help of Vault Nano, these studies will soon advance to the clinic.  —Leonard H. Rome

Leonard H. Rome is a professor of biological chemistry at UCLA’s David Geffen School of Medicine and chief scientific officer of Vault Nano Inc.

References

  1. N.L. Kedersha, L.H. Rome, “Isolation and characterization of a novel ribonucleoprotein particle: Large structures contain a single species of small RNA,” J Cell Biol, 103:699-709, 1986.
  2. A.G. Stephen et al., “Assembly of vault-like particles in insect cells expressing only the major vault protein,” J Biol Chem, 276:23217-20, 2001.
  3. N.L. Kedersha et al., “Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with octagonal symmetry,” J Cell Biol, 112:225-35, 1991.
  4. D.R. Hamill, K.A. Suprenant, “Characterization of the sea urchin major vault protein: a possible role for vault ribonucleoprotein particles in nucleocytoplasmic transport”, Dev Biol, 190:117-128, 1997.
  5. M.J. Poderycki et al., “The vault exterior shell is a dynamic structure that allows incorporation of vault-associated proteins into its interior,” Biochemistry, 45:12184-93, 2006.
  6. R.J. Scheper et al., “Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance,” Cancer Res, 53:1475-79, 1993.
  7. G.L. Scheffer et al., “The drug resistance-related protein LRP is the human major vault protein,”Nat Med, 1:578-82, 1995.
  8. K.E. Huffman, D.R. Corey, “Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line,” Biochemistry, 44:2253-61, 2005.
  9. V.A. Kickhoefer et al., “Engineering of vault nanocapsules with enzymatic and fluorescent properties,” PNAS, 102:4348-52, 2005.
  10. C.I. Champion et al., “A vault nanoparticle vaccine induces protective mucosal immunity,” PLOS ONE, 4:e5409, 2009.
  11. U.K. Kar et al., “Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth,” PLOS ONE, 6:e18758, 2011.
  12. L.H. Rome, V.A. Kickhoefer, “Development of the vault particle as a platform technology,” ACS Nano, 7:889–902, 2013.

 

 

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ACOSO PSICOLÓGICO EN EL TRABAJO [1146]

de System Administrator - martes, 10 de marzo de 2015, 23:36
 

AVANCES EN EL ESTUDIO DEL ACOSO PSICOLÓGICO EN EL TRABAJO

por Mariano García-Izquierdo, Mariano Meseguer, Mª Isabel Soler y Mª Concepción Sáez

Universidad de Murcia | ENAE. Business School

En las dos últimas décadas, el acoso psicológico en el trabajo o mobbing ha sido uno de los tópicos de investigación en el ámbito de la Psicología del Trabajo y de las Organizaciones. Desde su creación en 2001, el Servicio de Ergonomía y Psicosociología Aplicada (Serpa) de la Universidad de Murcia viene trabajando sobre este problema que tiene un gran protagonismo y repercusión en el ámbito laboral y social. En este trabajo se hace un repaso de los hallazgos más interesantes obtenidos por este grupo de investigación y su comparación con otros resultados que aparecen en la literatura científica. Así, se comienza con cuestiones sobre la delimitación del concepto, las formas de cuantificación, la prevalencia y la procedencia de las conductas de acoso. Posteriormente, se revisan los determinantes y consecuentes, y se hace mención a un recurso personal, la autoeficacia, que puede moderar los efectos de las conductas de acoso en la salud. Por último, se comentan las principales formas de intervención y se realizan algunas consideraciones de cara a una adecuada prevención.

Por favor lea el archivo PDF adjunto.

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ADHD Isn’t a Disorder of Attention [1621]

de System Administrator - domingo, 27 de diciembre de 2015, 14:36
 

ADHD Isn’t a Disorder of Attention

By Margarita Tartakovsky, M.S. 

Many people think of ADHD as a disorder of attention or lack thereof. This is the traditional view of ADHD. But ADHD is much more complex. It involves issues with executive functioning, a set of cognitive skills, which has far-reaching effects.

In his comprehensive and excellent book Mindful Parenting for ADHD: A Guide to Cultivating Calm, Reducing Stress & Helping Children Thrive,developmental behavioral pediatrician Mark Bertin, MD, likens ADHD to an iceberg. 

Above the water, people see poor focus, impulsivity and other noticeable symptoms. However, below the surface are a slew of issues caused by impaired executive function (which Bertin calls “an inefficient, off-task brain manager”).

Understanding the role of executive function in ADHD is critical for parents, so they can find the right tools to address their child’s ADHD. Plus, what may look like deliberate misbehaving may be an issue with ADHD, a symptom that requires a different solution.

And if you’re an adult with ADHD, learning about the underlying issues can help you better understand yourself and find strategies that actually work — versus trying harder, which doesn’t.

It helps to think of executive function as involving six skills. In Mindful Parenting for ADHD, Dr. Bertin models this idea after an outline from ADHD expert Thomas E. Brown. The categories are:

Attention Management

ADHD isn’t an inability to pay attention. ADHD makes it harder to manage your attention. According toBertin, “It leads to trouble focusing when demands rise, being overly focused when intensely engaged, and difficulty shifting attention.”

For instance, in noisy settings, kids with ADHD can lose the details of a conversation, feel overwhelmed and shut down (or act out). It’s also common for kids with ADHD to be so engrossed in an activity that they won’t register anything you say to them during that time.

Action Management

This is the “ability to monitor your own physical activity and behavior,” Bertin writes. Delays in this type of executive function can lead to fidgeting, hyperactivity and impulsiveness.

It also can take longer to learn from mistakes, which requires being aware of the details and consequences of your actions. And it can cause motor delays, poor coordination and problems with handwriting.

Task Management

This includes organizing, planning, prioritizing and managing time. As kids get older, it’s task management (and not attention) that tends to become the most problematic.

Also, “Unlike some ADHD-related difficulties, task management doesn’t respond robustly to medication,” Bertin writes. This means that it’s important to teach your kids strategies for getting organized.

Information Management

People with ADHD can have poor working memory. “Working memory is the capacity to manage the voluminous information we encounter in the world and integrate it with what we know,” Bertin writes. We need to be able to temporarily hold information for everything from conversations to reading to writing.

This explains why your child may not follow through when you give them a series of requests. They simply lose the details. What can help is to write a list for your child, or give them a shorter list of verbal instructions.

Emotion Management

Kids with ADHD tend to be more emotionally reactive. They get upset and frustrated faster than others. But that’s because they may not have the ability to control their emotions and instead react right away.

Effort Management

Individuals with ADHD have difficulty sustaining effort. It isn’t that they don’t value work or aren’t motivated, but they may run out of steam. Some kids with ADHD also may not work as quickly or efficiently.

Trying to push them can backfire. “For many kids with ADHD, external pressure may decrease productivity …Stress decreases cognitive efficiency, making it harder to solve problems and make choices,” Bertin writes. This can include tasks such as leaving the house and taking tests.

Other Issues

Bertin features a list of other signs in Mindful Parenting for ADHD because many ADHD symptoms involve several parts of executive function. For instance, kids with ADHD tend to struggle with maintaining routines, and parents might need to help them manage these routines longer than other kids.

Kids with ADHD also have inconsistent performance. This leads to a common myth: If you just try harder, you’ll do better. However, as Bertin notes, “Their inconsistency is their ADHD. If they could succeed more often, they would.”

Managing time is another issue. For instance, individuals with ADHD may not initially see all the steps that are required for a project, thereby taking a whole lot more time. They may underestimate how long a task will take (“I’ll watch the movie tonight and write my paper before the bus tomorrow”). They may not track their time accurately or prioritize effectively (playing until it’s too late to do homework).

In addition, people with ADHD often have a hard time finishing what they start. Kids may rarely put things away, leaving cabinets open and leaving their toys and clothes all over the house.

ADHD is complex and disruptions in executive functioning affect all areas of a person’s life. But this doesn’t mean that you or your child is doomed. Rather, by learning more about how ADHD really works, you can find specific strategies to address each challenge.

And thankfully there are many tools to pick from. You can start by typing in “strategies for ADHD” in the search bar on Psych Central and checking out Bertin’s valuable book.

Child hearing noise photo available from Shutterstock

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ADHD Isn’t a Disorder of Attention [1678]

de System Administrator - martes, 16 de febrero de 2016, 00:36
 

ADHD Isn’t a Disorder of Attention 

Many people think of ADHD as a disorder of attention or lack thereof. This is the traditional view of ADHD. But ADHD is much more complex. It involves issues with executive functioning, a set of cognitive skills, which has far-reaching effects.

In his comprehensive and excellent book Mindful Parenting for ADHD: A Guide to Cultivating Calm, Reducing Stress & Helping Children Thrive, developmental behavioral pediatrician Mark Bertin, MD, likens ADHD to an iceberg. 

Above the water, people see poor focus, impulsivity and other noticeable symptoms. However, below the surface are a slew of issues caused by impaired executive function (which Bertin calls “an inefficient, off-task brain manager”).

Understanding the role of executive function in ADHD is critical for parents, so they can find the right tools to address their child’s ADHD. Plus, what may look like deliberate misbehaving may be an issue with ADHD, a symptom that requires a different solution.

And if you’re an adult with ADHD, learning about the underlying issues can help you better understand yourself and find strategies that actually work — versus trying harder, which doesn’t.

It helps to think of executive function as involving six skills. In Mindful Parenting for ADHD, Dr. Bertin models this idea after an outline from ADHD expert Thomas E. Brown. The categories are:

Attention Management

ADHD isn’t an inability to pay attention. ADHD makes it harder to manage your attention. According to Bertin, “It leads to trouble focusing when demands rise, being overly focused when intensely engaged, and difficulty shifting attention.”

For instance, in noisy settings, kids with ADHD can lose the details of a conversation, feel overwhelmed and shut down (or act out). It’s also common for kids with ADHD to be so engrossed in an activity that they won’t register anything you say to them during that time.

Action Management

This is the “ability to monitor your own physical activity and behavior,” Bertin writes. Delays in this type of executive function can lead to fidgeting, hyperactivity and impulsiveness.

It also can take longer to learn from mistakes, which requires being aware of the details and consequences of your actions. And it can cause motor delays, poor coordination and problems with handwriting.

Task Management

This includes organizing, planning, prioritizing and managing time. As kids get older, it’s task management (and not attention) that tends to become the most problematic.

Also, “Unlike some ADHD-related difficulties, task management doesn’t respond robustly to medication,” Bertin writes. This means that it’s important to teach your kids strategies for getting organized.

Information Management

People with ADHD can have poor working memory. “Working memory is the capacity to manage the voluminous information we encounter in the world and integrate it with what we know,” Bertin writes. We need to be able to temporarily hold information for everything from conversations to reading to writing.

This explains why your child may not follow through when you give them a series of requests. They simply lose the details. What can help is to write a list for your child, or give them a shorter list of verbal instructions.

Emotion Management

Kids with ADHD tend to be more emotionally reactive. They get upset and frustrated faster than others. But that’s because they may not have the ability to control their emotions and instead react right away.

Effort Management

Individuals with ADHD have difficulty sustaining effort. It isn’t that they don’t value work or aren’t motivated, but they may run out of steam. Some kids with ADHD also may not work as quickly or efficiently.

Trying to push them can backfire. “For many kids with ADHD, external pressure may decrease productivity …Stress decreases cognitive efficiency, making it harder to solve problems and make choices,” Bertin writes. This can include tasks such as leaving the house and taking tests.

Other Issues

Bertin features a list of other signs in Mindful Parenting for ADHD because many ADHD symptoms involve several parts of executive function. For instance, kids with ADHD tend to struggle with maintaining routines, and parents might need to help them manage these routines longer than other kids.

Kids with ADHD also have inconsistent performance. This leads to a common myth: If you just try harder, you’ll do better. However, as Bertin notes, “Their inconsistency is their ADHD. If they could succeed more often, they would.”

Managing time is another issue. For instance, individuals with ADHD may not initially see all the steps that are required for a project, thereby taking a whole lot more time. They may underestimate how long a task will take (“I’ll watch the movie tonight and write my paper before the bus tomorrow”). They may not track their time accurately or prioritize effectively (playing until it’s too late to do homework).

In addition, people with ADHD often have a hard time finishing what they start. Kids may rarely put things away, leaving cabinets open and leaving their toys and clothes all over the house.

ADHD is complex and disruptions in executive functioning affect all areas of a person’s life. But this doesn’t mean that you or your child is doomed. Rather, by learning more about how ADHD really works, you can find specific strategies to address each challenge.

And thankfully there are many tools to pick from. You can start by typing in “strategies for ADHD” in the search bar on Psych Central and checking out Bertin’s valuable book.

Child hearing noise photo available from Shutterstock

About Margarita Tartakovsky, M.S.

 

Margarita Tartakovsky, M.S., is an Associate Editor at Psych Central. She also explores self-image issues on her own blog Weightless and creativity on her blog Make a Mess: Everyday Creativity.

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ADOLESCENCIAS EN LA CONTEMPORANEIDAD [945]

de System Administrator - sábado, 18 de octubre de 2014, 20:23
 

LAS ADOLESCENCIAS EN LA CONTEMPORANEIDAD

Las tribus, los Ni-Ni, las generaciones X, Y y Z

por Hugo Lerner

Por favor lea el whitepaper adjunto.

 

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AI interns: Software already taking jobs from humans [1195]

de System Administrator - sábado, 4 de abril de 2015, 22:55
 

 

AI interns: Software already taking jobs from humans

People have talked about robots taking our jobs for ages. Problem is, they already have – we just didn't notice

FORGET Skynet. Hypothetical world-ending artificial intelligence makes headlines, but the hype ignores what's happening right under our noses. Cheap, fast AI is already taking our jobs, we just haven't noticed.

This isn't dumb automation that can rapidly repeat identical tasks. It's software that can learn about and adapt to its environment, allowing it to do work that used to be the exclusive domain of humans, from customer services to answering legal queries.

These systems don't threaten to enslave humanity, but they do pose a challenge: if software that does the work of humans exists, what work will we do?

In the last three years, UK telecoms firm O2 has replaced 150 workers with a single piece of software. A large portion of O2's customer service is now automatic, says Wayne Butterfield, who works on improving O2's operations. "Sim swaps, porting mobile numbers, migrating from prepaid onto a contract, unlocking a phone from O2" – all are now automated, he says.

Humans used to manually move data between the relevant systems to complete these tasks, copying a phone number from one database to another, for instance. The user still has to call up and speak to a human, but now an AI does the actual work.

To train the AI, it watches and learns while humans do simple, repetitive database tasks. With enough training data, the AIs can then go to work on their own. "They navigate a virtual environment," says Jason Kingdon, chairman of Blue Prism, the start-up which developed O2's artificial workers. "They mimic a human. They do exactly what a human does. If you watch one of these things working it looks a bit mad. You see it typing. Screens pop-up, you see it cutting and pasting."

One of the world's largest banks, Barclays, has also dipped a toe into this specialised AI. It used Blue Prism to deal with the torrent of demands that poured in from its customers after UK regulators demanded that it pay back billions of pounds of mis-sold insurance. It would have been expensive to rely entirely on human labour to field the sudden flood of requests. Having software agents that could take some of the simpler claims meant Barclays could employ fewer people.

The back office work that Blue Prism automates is undeniably dull, but it's not the limit for AI's foray into office space. In January, Canadian start-up ROSS started using IBM's Watson supercomputer to automate a whole chunk of the legal research normally carried out by entry-level paralegals.

Legal research tools already exist, but they don't offer much more than keyword searches. This returns a list of documents that may or may not be relevant. Combing through these for the argument a lawyer needs to make a case can take days.

ROSS returns precise answers to specific legal questions, along with a citation, just like a human researcher would. It also includes its level of confidence in its answer. For now, it is focused on questions about Canadian law, but CEO Andrew Arruda says he plans for ROSS to digest the law around the world.

Since its artificial intelligence is focused narrowly on the law, ROSS's answers can be a little dry. Asked whether it's OK for 20 per cent of the directors present at a directors' meeting to be Canadian, it responds that no, that's not enough. Under Canadian law, no directors' meeting may go ahead with less than 25 per cent of the directors present being Canadian. ROSS's source? The Canada Business Corporations Act, which it scanned and understood in an instant to find the answer.

By eliminating legal drudge work, Arruda says that ROSS's automation will open up the market for lawyers, reducing the time they need to spend on each case. People who need a lawyer but cannot afford one would suddenly find legal help within their means.

ROSS's searches are faster and broader than any human's. Arruda says this means it doesn't just get answers that a human would have had difficulty finding, it can search in places no human would have thought to look. "Lawyers can start crafting very insightful arguments that wouldn't have been achievable before," he says. Eventually, ROSS may become so good at answering specific kinds of legal question that it could handle simple cases on its own.

Where Blue Prism learns and adapts to the various software interfaces designed for humans working within large corporations, ROSS learns and adapts to the legal language that human lawyers use in courts and firms. It repurposes the natural language-processing abilities of IBM's Watson supercomputer to do this, scanning and analysing 10,000 pages of text every second before pulling out its best answers, ranked by confidence.

Lawyers are giving it feedback too, says Jimoh Ovbiagele, ROSS's chief technology officer. "ROSS is learning through experience."

Massachusetts-based Nuance Communications is building AIs that solve some of the same language problems as ROSS, but in a different part of the economy: medicine. In the US, after doctors and nurses type up case notes, another person uses those notes to try to match the description with one of thousands of billing codes for insurance purposes.

Nuance's language-focused AIs can now understand the typed notes, and figure out which billing code is a match. The system is already in use in a handful of US hospitals.

Kingdon doesn't shy away from the implications of his work: "This is aimed at being a replacement for a human, an automated person who knows how to do a task in much the same way that a colleague would."

But what will the world be like as we increasingly find ourselves working alongside AIs? David Autor, an economist at the Massachusetts Institute of Technology, says automation has tended to reduce drudgery in the past, and allowed people to do more interesting work.

"Old assembly line jobs were things like screwing caps on bottles," Autor says. "A lot of that stuff has been eliminated and that's good. Our working lives are safer and more interesting than they used to be."

Deeper inequality?

The potential problem with new kinds of automation like Blue Prism and ROSS is that they are starting to perform the kinds of jobs which can be the first rung on the corporate ladders, which could result in deepening inequality.

Autor remains optimistic about humanity's role in the future it is creating, but cautions that there's nothing to stop us engineering our own obsolescence, or that of a large swathe of workers that further splits rich from poor. "We've not seen widespread technological unemployment, but this time could be different," he says. "There's nothing that says it can't happen."

Kingdon says the changes are just beginning. "How far and fast? My prediction would be that in the next few years everyone will be familiar with this. It will be in every single office."

Once it reaches that scale, narrow, specialised AIs may start to offer something more, as their computation roots allow them to call upon more knowledge than human intelligence could.

"Right now ROSS has a year of experience," says Ovbiagele. "If 10,000 lawyers use ROSS for a year, that's 10,000 years of experience."

This article appeared in print under the headline "You are being replaced"

Which jobs will go next?

Artificial intelligence is already on the brink of handling a number of human jobs (see main story). The next jobs to become human-free might be:

Taxi drivers: Uber, Google and established car companies are all pouring money into machine vision and control research. It will be held back by legal and ethical issues, but once it starts, human drivers are likely to become obsolete.

Transcribers: Every day hospitals all over the world fire off audio files to professional transcribers who understand the medical jargon doctors use. They transcribe the tape and send it back to the hospital as text. Other industries rely on transcription too, and slowly but surely, machine transcription is starting to catch up. A lot of this is driven by data on the human voice gathered in call centres.

Financial analysts: Kensho, based in Cambridge, Massachusetts, is using AI to instantly answer financial questions which can take human analysts hours or even days to answer. By digging into financial databases, the start-up can answer questions like: "Which stocks perform best in the days after a bank fails". Journalists at NBC can already use Kensho to answer questions about breaking news, replacing a human researcher.

Link: http://www.newscientist.com