Monday
Feb182013

No love in the time of cholera.

By Brooke Napier

It’s no secret by now that one of my very favorite topics in science is the idea that many bacterial species have co-evolved with humans to become successful pathogens, aka super ninja killing machines.

Since this is HUGE topic with WAY too many cool avenues, I want to focus on one (very smart) bacterial species that laughs in the face of the human immune system: Vibrio cholerea. Dun dun DUN!

Old school, yo.

Vibrio cholerea is the causative agent of the horribly unpleasant, life threatening diarrheal disease cholera.

Yes, I’ve heard of cholera, but what is cholera?

Cholera is an acute diarrheal disease caused by an infection of the intestines by the bacterium Vibro cholerae. V. cholerae likes to hid out in water or food that have been contaminated by feces, that way it can be ingested by unsuspecting humans and wreak havoc in the intestines (seems like a scary trip from the mouth to the intestines, right? Lots of enzymes, lowered pH, etc… this will be important later).

Fortunately the advancement of water treatment (specifically chlorination and filtering), spearheaded by John Snow in England during the late 1800’s after identifying that contaminated water caused an increase in cholera incident, has allowed the US to evade a serious cholera outbreak within the last 100 years.

However this disease is still rampant throughout developing countries. Specifically, there are around 3-5 million cases an over 100,000 deaths per year due to cholera.

That is why V. cholerae is still a problem, but how is it such a ninja?

One of the way pathogenic bacteria have evolved to be replicating-puss-inducing badasses is by detecting when they’re inside of a human. They can do this by sensing temperature change (inside is warmer than outside), lowered pH (in the stomach), differential concentrations of ions (iron is limiting in the innate immune cells), etc. They sense these environmental changes with the use of highly sophisticated signal transduction systems – or a very tiny form of telephone.

Briefly, bacteria have a sensor on their outer membrane that can detect these environmental changes. In response to changes this sensor protein phosphorylates itself (autophosphorylates). This phosphate group acts as the secret password to inform the inside of the cell things have changed! Next, this phosphorylated sensor protein transfers this phosphate group to its buddy in the cell, good ole’ response regulator. Response regulator then controls the expression of “holy-crap-protect ourselves” genes, or… you know, some genes that contribute to protecting the bacteria in whatever environment it sense. 

Above is a very well described two-component system that responds to influxes in cationic antimicrobial peptides (positively charged antibacterial peptides).

PhoQ (sensor protein) senses environmental changes, which then passes on the message (phosphate – P) to PhoP (response regulator) that now can increase expression of genes that will modify the bacterial membrane to make it more positive (to avoid confrontation with the cationic antimicrobial peptides).

That’s just one of many, but back to our story on V. cholerae!

V. cholerae is well known, and feared, for it’s very-toxic-to-humans: Cholera toxin (CT). CT is what makes V. cholerae so prone to causing disease, specifically it’s to blame for the diarrhea characteristic of cholera.

So wouldn’t it be interesting if V. cholerae could increase expression of CT in response to some type of environmental change indicative of the human body?

 Menghua Yang et al., were asking the same question. You will never believe how they did this…

1)   They created a strain of V. cholerae that lights up (literally) when it is expressing TcpA (response regulator that is incharge of increasing expression of CT).

2)   They took a mouse’s intestines and cut them up in very small chunks and put each of the individual chunks into a test tube with the light-up V. cholerae. Essentially, if the V. cholerae lights up in the presence of specific chunks of the intestines this means that CT is being expressed, and they can trace back the chunk of intestine to the map of the intestine and know what part of the mouse intestine increases expression of CT. BRILLIANT.

3)   They took the small intestine of infant and adult mice and found that something in these pieces of the intestine trigger CT expression. So they took the small intestines of these mice and identified some small molecules that were present within these samples by thin-layer chromatography (for a description of this method follow this link).

4)   BILE SALTS. That is what they found induces the expression of CT. The presence of bile salts influenced the expression of this very potent toxin that causes the worse symptoms of cholera. Amazing.

5)   Not only that, TcpA (the response regulator that is in charge of increasing expression of CT) needs to be dimerized to increase expression of CT, and they show that bile salts from the small intestines can induce the di-sulfide bonds that hold TcpA dimers together.

 I'm pretty sure they have no idea what protein is sensing bile salt, so you can name that protein whatever you'd like.

Essentially, V. cholerae monitors normal host digestive systems to up-regulate it’s virulence, or disease-causing, cascades.

It is highly likely that there are other environmental signals that contribute to the increased expression of CT, but this is a very good first step at understanding this ninja-of-a-bacteria.  

My guess, as well as the author’s, is that other intestinal pathogens can control their virulence cascades by bile salts as well – to the lab!


ResearchBlogging.orgYang M, Liu Z, Hughes C, Stern AM, Wang H, Zhong Z, Kan B, Fenical W, & Zhu J (2013). Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence. Proceedings of the National Academy of Sciences of the United States of America, 110 (6), 2348-53 PMID: 23341592

Friday
Feb082013

Focusing the search for communicative aliens

Though our ability to scientifically and satisfactorily answer the question, "So are we the only ones?" is not assured, the investigation of our biolotical aloneness in the universe is a fundamentally important task. It's a basic question in a series of basic questions--how did the universe get here? how did we get here? did others also get here? how will it all end for all of us?--and has philosophical, social, and scientific implications. If life is abundant, it must spring up pretty easily, and transitions like the one from 'organic molecule' to 'bonobo' must be ones the universe's rules compel it to follow. 

We have now found organic molecules with 10+ atoms in interstellar space. We think tiny organisms might exist in subglacial Antarctic sheets. This stuff is persistent and dedicated to its own existence. 

And while it's exciting to think that little green bacteria are drifting around in alien lakes, a) that's hard to prove, b) isn't it more exciting to think that, somewhere out there, a communicating being is watching Little Green Downton Abbey? Not that that's very much easier to prove. The universe is quite a large place and we would need to be looking in the right place at the right time in the right way to make a detection.

Scientists are looking for several different things when they investigate life in the universe, primarily under the categories of prebiotic compounds; evidence of tiny, stupid life (like certain metabolism-produced chemicals in planetary atmospheres); and smart, talkative life.

This XKCD comic shows the relative sizes of the 786 planets known in June of 2012. In February, 2013, there are 76 more. Click to enlarge.The latter category has received criticism in the past (and in Contact, DAVID DRUMLIN) for just searching the skies without much direction, using telescope time and computing power for a question whose answer we may never know. But in the past few years, the number of exoplanets (planets outside our solar system) has gone crazy. There are 862 confirmed and thousands more candidates.

SETI scientists can now be more picky with their targets, choosing not just stars like the Sun (which is how SETI began) and not just choosing stars that have planets but choosing stars that have rocky planets in habitable zones with temperatures that could support the kind of life with which we're familiar. Because exoplanet-finding technology blew up, exoplanet science blew up, and because exoplanet science blew up, SETI researchers have a better chance of finding something, and they are able to make meaningful statistics out of their data even if they do not find anything. Everybody wins. 

 

A paper forthcoming in the Astrophysical Journal and currently available online describes the work of Siemion, et al., who looked directly at 86 planet candidates discovered using Kepler data

  • have temperatures between -46 and 224 F or
  • are in systems with 5+ planet candidates or
  • are in systems with a SuperEarth in a 50-or-more-day orbit.

The Green Bank Telescope is the world's largest steerable telescope, and it happens to be located in a really pretty spot. Convenient for SETI researchers. (Credit: Pocahontas County Visitors' Bureau)In other words, systems that could support life as we know it. They used the Green Bank Telescope to look for purposeful, synthetic radio waves coming these systems. Radio waves coming from astrophysical processes are "broadened," or spread out over a range of frequencies, even if it is a small range. So one way to create a signal that would make another civilization (us) stand up and say, "Hey, are you people-like?" is to send out a very narrow signal, spread over a very, very small range of frequencies.

Siemion and team looked for such waves. And, as the paper says, "Ultimately, experiments such as the one described here seek to firmly determine the number of other intelligent, communicative civilizations outside of Earth. However, in placing limits on the presence of intelligent life in the galaxy, we must very carefully qualify our limits with respect to the limitations of our experiment. In particular, we can offer no argument that an advanced, intelligent civilization necessarily produces narrow-band radio emission, either intentional or otherwise. Thus we are probing only a potential subset of such civilizations, where the size of the subset is difficult to estimate."

They did not detect any signals from extraterrestrial civilizations.

Combining that data with the paper's statement means that the conclusion is, essentially, "We succeeded in not finding any ETI that likes to broadcast this particular kind of radio wave and happens to have been doing it such that the radio waves would arrive at our telescopes while we were taking data."

It's a specific conclusion. It's a small answer to a small question that is part of a larger question. Small answer + small answer + small answer adds up in SETI work as it does in all science. And, as always, more research is needed.

Thursday
Feb072013

Binge drinking leads to type 2 diabetes, no seriously.

By Brooke Napier

Simple, new evidence provided by Claudia Lindter, et al. in Science Translational Medicine says: Binge drinking leads to type 2 diabetes.

This picture was labeled, "Binge drinking consequences"... I figured this caught the magnitude of my point.Is this one of those correlations that we all kind of figured happened, but no one has described yet? For me it wasn’t. I had never made the connection between binge drinking (>4 drinks/2 hrs for men, >3 drinks/2 hrs for women) and type 2 diabetes, however this correlation has been known for quite some time now… but why?

First, does binge drinking just cause the person to get loosey-goosey with their food preferences due to alterations in central reward pathways? I know that when I was in college I rarely ate McDonald’s sober.

OR is this epidemiological association due to binge drinking inducing insulin resistance?

Let’s slow down here for a second…

Brief (but necessary) background on insulin:

Insulin stimulates glucose uptake and utilization in muscle and fat while suppressing glucose production (carbohydrate) in the liver and stopping utilization of fat as an energy source.

Watch this video to learn a little more about the basics...

Without insulin the body cannot control glucose levels in the blood (type 1 and type 2 diabetes). Additionally, insulin controls autonomic nervous system (or the involuntary nervous system, which affects heart rate, digestion, respiratory rate, salivation, perspiration, urination, sexual arousal) signaling to the liver and fatty tissue through the central nervous system - therefore restraining glucose production and fatty acid release.

So the brain and insulin are related?

Indeed! Insulin acts as a signal in the hypothalamus to stop glucose production and breakdown of fatty acids, or your love handles. It does this because you ate another bag of Skittles and now you have free energy, why make more or use your fat storage (see: beer gut)?

There’s been genetic manipulation of mice that show impaired insulin signaling in the hypothalamus can lead to systemic insulin resistance = diabetes! Meaning manipulation of the brain can lead to diabetes, das crazy yo.

Ok, so back to the story now…

How is this related to binge-drinkers?

Well, it has already been found that binge drinking is related to type 2 diabetes… but there is also previous data that shows that alcohol INCREASES insulin receptor signaling… that means that the alcohol isn’t affecting insulin-related signaling in the liver, then WTF is it affecting?

The Magic Brain! Dun Dun DUNN

Claudia Lindter, et al. found that over-consumption of alcohol in rats leads to impaired hypothalamic insulin action, thus impairing glucose production and fatty acid break-down.

There were two major findings:

1)   Impaired insulin action in fatty tissue increases fatty acid and glycerol flux in the liver = negatively feeds back on insulin action by increasing the supply of sugar substrates, pretty much making insulin really inefficient = insulin resistance.

 

2)   Hypothalamic insulin action were reduced = brain not responding very well to sugars & fats = insulin resistance.

Neurotoxic effects of alcohol have been reported extensively in the last few decades, however this is a new level of alcohol’s neural control of the body.

Unfortunately, these data make a lot of sense when I think about the people I know with type 2 diabetes…

 

ResearchBlogging.org Lindtner, C., Scherer, T., Zielinski, E., Filatova, N., Fasshauer, M., Tonks, N., Puchowicz, M., & Buettner, C. (2013). Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action Science Translational Medicine, 5 (170), 170-170 DOI: 10.1126/scitranslmed.3005123

Thursday
Jan242013

3...2...1...NewSpace

"We can at least afford sleek modern graphics, even if we haven't proven we can afford to actually do what those graphics depict." (Credit: Deep Space Industries)

A few days ago the soon-to-be-or-wannabe-asteroid-mining-company Deep Space Industries (which is, by the way, an entirely male [like 100% male, including advisory board] company) announced that they will begin missions to nearby space-rocks in 2015 and use the material not only for earth-bound goals but also for fuel and parts for spaceships. Parts 3D-printed in space, obviously, because that's how the twenty-first century wants going to roll. DSI joins another company, Planetary Resources (which at least has a singular female employee), in the race to chip away at the leftovers of solar system formation.

These two companies embody the spirit of NewSpace -- the private, entreprenurial, and burgeoning industry of trying to send people to various places in space, ranging in the near-term from suborbital arcs to the International Space Station to Mars. With no realistic human space exploration plans in NASA's near future, and with money like the X Prizes at stake, the industry is, pun intended, taking off.

NewSpace companies' philosophies differ from those of NASA -- formerly the main US entity in charge of sending stuff into space -- primarily because they are companies.

  • They work on faster timelines, because they need to become profitable and because they want to be first and best to beat out competition. Imagine NASA saying today that they planned to launch a new type of ship in 2015. You can't!
  • They are dreamer-corporations, led by visionary types who also happen to have a lot of money and connections. They make grand statements like, "'If you can dream it, you can be it,' is our starting point (DSI)" and, "A passion for achievement and a thirst for exploration have driven humanity to accomplish its most historic advances (Golden Spike).
  • But they are definitely corporations. They are motivated not just by "thirst" for human advancement but also by being the ones to profit from that human advancement.
  • That's not necessarily a bad thing. Government funding, in case you haven't turned on NPR in a really long time, is short. And these companies are in competition with each other -- to do it first, to do it best, to do it differently, to do it for less. Who was competing with NASA? And why would NASA care? The amount of money it has does not depend on how much money it makes.
  • Besides, not only does NASA not have the kind of dough necessary to pull exploratory/human spaceflight off as fast and innovatively as private companies, it also doesn't have motivation. NASA is, above other aspects of its personality, a science-driven organization. And, "Hey, we can scrape platinum off this rock!" is not exactly a Nature cover story.
  • Many of them supply, or plan to supply, NASA and other federal organizations with orbital and suborbital crafts and hardware. But, again, they are in competition with each other for those contracts.

Anyway, there are a lot of these private space explorers. Or would-be explorers. They are all at different stages of development, and some of them will not succeed. But some of them will! And some of them already have. Here is a run-down of NewSpacecadets. It's not an exhaustive list, but it provides a representation of the kinds of corps that are out there.

Click to read more ...

Tuesday
Jan152013

The universe might not be a fair place

by Sarah Scoles

Large Quasar Groups -- also known as LQGs, also known as large groups of quasars, also known as quasars in large groups -- are clottings of active, far-away supermassive black holes (presumed to be in the centers of host galaxies). And on January 11, scientists announced that they'd found the largest one yet.

And it is large.

From the author's paper about the benefits of bubble tea, here is a diagram of the 73 quasars in the HugeLGC, as well as the galaxies in the smaller CCLQG. The axes are in Megaparsecs.U1.27 is 4 billion by 2 billion by 1 billion light-years. Its largest dimension spans nearly 30% of the observable universe. It is made up of 73 quasars that, combined, total 8.8 million times the mass of the Milky Way. That means each quasar has about 120,000 times the mass of the galaxy in which we live.

But let's go back to the idea that this structure runs across 4 billion light-years.

Rules of the universe

The universe appears to have small structures that are grouped into large structures that are grouped into larger structures, etc. Similarly, on Earth, most people have houses, and those houses are arranged into towns, and large groups of towns are counties, and onward and upward to continents. These, however, get a little arbitrary. What, truly, defines a county? Physical laws and the invisible presence of dark matter determine how the universe arranges itself, whereas in 1889 the California Legislature just decided to split Laguna and Orange Counties.

Solar systems are arranged into galaxies; galaxies live in groups; groups reside in clusters; clusters clump into superclusters; superclusters are part of supercluster complexes. A place for everything and everything in its place. For a very cool graphic showing our particular place in that, make this image a lot bigger.

In the paper describing the newest, biggest LQG -- which the authors refer to as the HugeLQG -- the scientists posit that LQGs are the ancestors of supercluster complexes. Until LQGs, supercluster complexes were the largest things we knew of, period. The CfA2 Great Wall was thought to be a whopper 300 million light-years across, and the Sloan Great Wall wowed everybody with its 1.5 billion light-year length ... until this rave-party (also known as "rave") of quasars showed up.

Who sees that little man in the bottom center? (Credit: Gott and Juric).

But an idea called the Cosmological Principle says structures as big as the HugeLQG should not exist.

Which is why the HugeLQG is interesting. If it were merely big, we'd say, "Eh." Because pretty much everything is bigger than we are, and a bunch of densely strung-out galaxies a billion light-years away doesn't really "feel" that much bigger than a supercluster complex.

But the thing is, this violates the universe's sense of fairness. The Cosmological Principle states that the properties of the universe should look the same in all directions no matter where you're viewing from. A hovel in Brooklyn or a skyscraper in Tokyo or a planet in a galaxy far, far away.

In other words, the universe is supposed to be homogeneous if you zoom out enough. But something like the HugeLQG is so big that even if you zoomed way, way out, you would still be able to say, "Hey, what's that huge thing?"

Anything bigger than 1.2 billion light-years is "too big" for the Cosmological Principle's liking, according to the Yadav 2010 model.

The HugeLQG is not the first to violate the CP.

The Sloan Great Wall might have done it. Big empty voids might do it. Large-scale features in the cosmic microwave background might do it.

In short, everybody might be doing it.

When everybody starts violating a principle, maybe it's time to take a look at that principle (works as an argument for all speed limits being 5 mph higher, too). And scientists are doing that, and they're looking at different estimations of "what's too big to be smoothed into homogeneity."

 

But if homogeneity is not real, and there is more dark matter in some directions than others, and the density of galaxies is higher in one direction than other, then we live in a very different universe than we first thought. If the universe is not homogeneous, then what we see is not necessarily a fair representation. Our view -- all views -- would be biased by the location of the viewer, and so the conclusions we made about the universe would be biased by our location. The effects of this bias could be small, or they could be more akin to basing a multinational marketing strategy on a single survey of 150 three-year-old blonde boys. 

 

Yeah, the target market hates it when you directly compare your brand to other brands. Your landing page should be all about your brand image and its unique selling proposition's own merits (Credit: theykid.com)

ResearchBlogging.org

Clowes, R., Harris, K., Raghunathan, S., Campusano, L., Sochting, I., & Graham, M. (2013). A structure in the early Universe at z 1.3 that exceeds the homogeneity scale of the R-W concordance cosmology Monthly Notices of the Royal Astronomical Society DOI: 10.1093/mnras/sts497

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