Monday, September 23, 2013

Image post 9: infection blocks trash removal to cause ulcers, cancer

What's that ... a meteor blazing past a molten planet?  No, it's a self-destructing cell just shed from a gastric gland made up of the tightly packed blue cells running across the bottom.

Gastric glands that secrete digestive juices into the stomach, like all epithelial cells (skin, lining of blood vessels, etc.), constantly shed old cells from their outer layers and replace them with new ones. The turnover keeps tissues viable throughout adult life. When the shed cells sense they have outlived their usefulness, they initiate self-destruct mechanisms.

With some cells always in the process of self-destructing, other nearby cells are charged with swallowing up the dying cells and disposing of them. That explains the red cloud surrounding the yellow dot at the center of the image. An antigen-presenting cell (dyed red) has engulfed a self-destructing cell (yellow) to remove it.

The system works pretty well until a person's stomach gets infected with the bacteria Helicobacter pylori.

The infection causes cells to release TNF-alpha, a signaling chemical that triggers the waves of cell activation and chemical release meant to kill invading bacteria or viruses (inflammation). While the process protects us against infectious disease, it also plays a role in many disease processes when it goes too far.

recent study by a team of UAB researchers found that, along with triggering inflammation, TNF-alpha also blocks the engulfment and removal of dying cells. Cellular debris builds up to drive further inflammation in a vicious cycle.

Why does this matter?  Inflammation caused by Helicobactor pylori is behind the development of nearly all ulcers. Furthermore, the same chronic inflammation damages DNA, creating risk for hard-to-treat gastric cancer.

The image was created by Diane Bimczok, DVM, Ph.D., an instructor in UAB's Division of Gastroenterology and Hepatology, using routine fluorescence microscopy and digital imaging. Phillip Smith, M.D., was senior author of the related study. 

Thursday, September 19, 2013

Alcohol throws off circadian clock to damage liver

Having evolved to keep time with our planet's rhythms – day and night, light and dark – we are wired at the genetic level to sleep at night and to wake and eat during the day. Research in recent years revealed that genetic and protein feedback loops – or clocks – operate in 24-hour cycles in every human cell. The clocks signal to thousands of genes, many of which speed up our ability to make and use energy from food during the day and turn it down at night.

Bucking those patterns – say by working the night shift – has been shown to increase a person’s risk for heart disease, diabetes, cancer, depression, etc.

In a new twist, Shannon Bailey, Ph.D., associate professor in the Division of Molecular and Cellular Pathology within the UAB School of Medicine, just published a study that found chronic alcohol use may interfere with the genetic clocks in liver cells to accelerate liver damage. Dr. Bailey is a longtime liver disease expert with a new research focus on the role of circadian clocks in alcohol-related liver damage.

We thought to ask her whether too many martinis can throw off molecular clocks and, from a circadian point of view, what the healthiest hour is to drink a glass of wine.

Show notes for the podcast:

1:51 Genes are long chains of molecules that encode instructions for the building of the proteins, the workhorse molecules that make up bodily structures and signals. Interestingly, the process of turning genes into proteins proceeds at a certain rate, so it has become the basis of a system that keeps time like a clock. To achieve a biochemical balance necessary for life, many genes are part of pathways that sense when there enough of any given protein, and sends signals to shut down the building process: so-called feedback loops. The twenty or so genes and proteins that make up the human circadian clock happen to perform these loops in a roughly 24-hour cycle, and so evolution favored them. Creatures that happened to align their metabolism to these clocks became one with their environment and were more likely to survive. Thus, the cells making up most life on earth today -- bacteria, plants, animals, etc. -- include genetic clocks.

3:44 In a larger sense, the clocks show the ability of genes to adjust their action in the face of changing environment. Genetic changes in energy use also occur after meals whenever they occur, and during the flight or fight response.

4:35 One of the functions of the circadian clocks in every human cell type is to turn off metabolic pathways that produce cellular energy from food when we don't need them. While obviously vital to life, highly active metabolic pathways create byproducts like free radicals that tear apart sensitive cell components and cause cells to self-destruct as part of many diseases, including major ones related to energetics: diabetes and heart disease. Shutting them down at night may help us to live longer.  

5:33  A major focus of Dr. Bailey's research is the mitochondria, sub-compartments of human cells that convert sugar from food into cellular energy by using oxygen.  She is especially interested in the role of mitochondria in liver disease. Overproduction of free radicals by mitochondria in liver cells damages other parts of the same cells, and shutting down these pathways at night may give cells a chance to repair the damage. A key emerging question is how not circadian clock genes in the nuclei of liver cells signal to mitochondria to control energy production.

6:39  While most studies look at the effect of staying up at night on circadian biology, Dr. Bailey wanted to look at the effect of alcohol on circadian clocks. Some of her interest stems from the fact that neuroscientists have been exploring in recent years whether or not circadian clocks in nerve cells in the brain may contribute to the forming of addictions. Up until the current study, only a few studies had looked at the effect of alcohol consumption on peripheral cells (gut, heart, liver, etc.). It's really starting to take off, says Dr. Gohlke.

8:43 As whole, the body’s circadian clock is regulated by a part of the brain called the suprachiasmatic nucleus, which drives daily physiological and behavioral rhythms. The newest frontier, embodied by Dr. Bailey’s study, is the effort to understand the role of the circadian clock in each cell type, and what happens when the cell-specific clocks are out of sync with the central clock in the brain. The liver is the organ in the body most responsible for regulating system-wide energy needs and is charged with holding steady levels of sugar supplied to cells by the bloodstream. Studies have shown that molecular clocks in the liver help keep the blood sugar level constant as we eat and fast, sleep and wake., largely through adjusting levels of the hormone insulin. If we throw the clocks off, we throw our blood sugar off and contribute to the development of diabetes.

9:54  The liver also plays a prominent role in the amount of cholesterol and fat in the blood, as well as the breakdown of drugs in the bloodstream.  Should the clocks be shown to regulate those pathways and alcohol affects them, then chronic drinking hardens arteries, the leading cause of heart attacks and strokes, and contributes to obesity.

10:32 To study the effect of alcohol on circadian clocks, Dr. Bailey and her team separated mice into two groups, one that received a healthy diet, and a second that had the same diet plus a steady supply of alcohol (ethanol). They then collected brain and liver samples for both mice to look for changes in clock genes patterns. They found that expression of metabolic genes that normally up and down  in 24 hours cycles no longer do so with chronic alcohol use. It also looked like metabolic pathways that normally operate in sync became disjointed.

13:35 In a healthy individual, certain clock genes in liver cells are expressed three hours after the same genes are expressed in the brain. One theory holds that the time lapse is a temporal signal between the systems that monitor how much energy we need, and those that supply the right amount of energy in response.  If alcohol throws off the liver cell clocks, they may no longer proceed in sync with the brain clock. Such a loss of synchrony represents a potential disease mechanism in heart disease, diabetes and obesity.

15:56 Fatty liver disease, which is very common in the United States, is the earliest stage in the progression toward much more serious liver diseases like cirrhosis. It is also seen people in pre-diabetes or obesity. Healthy people store their fat in their fat cells, their adipose tissue, and not their liver cells. Dr. Bailey is interested in whether or not disruption of liver clocks contributes to this build up of fat in liver cells.

17:31 As the understanding of molecular clocks grows, researchers will seek to influences parts of the clock that contribute to disease. Research teams have already shown that some drugs, at least in animal models, can fine-tune clocks to counter weight gain. Dr. Baily is looking forward to testing whether such drugs can counter the contribution of clock genes, under the action of alcohol, to liver damage

18:03 Dr. Bailey's study did look at whether the expression of proteins that break down alcohol fluctuate with time of day, but not at how active those proteins are. She has proposed a series of studies that will seek to determine what time of day is best for that glass of wine. The studies so far at least suggest that there may be times of day when the liver is more or less vulnerable to the toxic effects of alcohol.

Monday, September 2, 2013

Mechatronics: from minivans that predict crashes to unmanned battlefield rovers

Remember the Subaru ad about how its cars "transfer power from the wheels that slip to the wheels that grip"?  Behind and beyond that jingle is an emerging field of engineering described by technical terms like mechatronics and agile vehicle dynamics.

Foxhound Vehicle. Courtesy UK Ministry of Defense.
The field seeks to design intelligent vehicles that adjust power distribution to the wheels, suspension stiffness and traction control with extreme speed in the face of changing road conditions. When perfected, such "agile" vehicles will make proactive decisions to avert crashes as the wheels begin to spin.

Systems that transfer power to the gripping wheels are also a must for vehicles meant to operate on loose soil for farming, construction, emergencies or military operations. Agile, unmanned vehicles, for instance, will soon negotiate the chaotic terrain of battlefields and disaster zones, making their own decisions while climbing out of ravines or driving over downed power poles.

We thought to talk with Vladimir Vantsevich, Ph.D., a specialist in vehicle design, as he gets set to host the UAB “agile vehicle” symposium Sept. 8-11, 2013, at the Hilton Birmingham Perimeter Park Hotel. The event will be the first to assemble experts in the specialty from around the world, and it will explore ground vehicle dynamics, energy efficiency and performance in severe environments.

Show notes for the podcast: 

1:17 Dr. Vantsevich earned his Ph.D. and Sc.D., the highest degree in the former U.S.S.R., from Belarusian National Technical University. Belarus is an independent country and home to several automotive design companies. In 1997, he received an assignment to work the deputy permanent representative from Belarus to as for the United Nations, where for the years he worked on issues related to the protection of intellectual property rights as part of the U.N. Commission on Science and Technology. After three and a half years there, he took a facutly position at Lawrence Technical University in Michigan, where he built automotive engineering programs for 11 years, before coming to UAB a year ago.

2:10  Dr. Vantsevich is a pioneer in the design of systems that distribute power between the wheels. What may seem like a technical detail has everything to with the ability of a passenger car to achieve traction on a wet road, not to mention its fuel efficiency

3:33 Dr. Vantsevich holds 30 certified inventions and is well known in the American Society of Mechanical Engineering, with most of his innovations concerned with slip differentials. A differential is a set of gears that enable wheels to rotate at different speeds as the engine applies power to them and as road conditions vary. When a car turns for instance, the wheel travelling around the outside of the turn must roll farther and faster than its counterpart on the inside. A limited slip differential is a gear arrangement that, in an off-road environment, senses when one wheel if off of the ground or has hit a patch of ice and transfers power to the wheels still in contact with the ground.

6:30 Alabama's reputation is growing internationally as a center for automotive engineering, and now is a great time to gather leaders in Birmingham to decide on next steps for the field. The symposium promises to have a positive impact on UAB and local automotive companies as well, potentially helping them to recruit talent to the area, Dr. Vantsevich said.

8:58 The symposium also focuses on dynamics, the study of what happens when you apply forces to a moving body, say a vehicle. What happens to a car when you combine the forces transmitted by the engine to the wheels with those applied by the wheels to the ground combined with a strong side wind?

12:14 Many ads about luxury cars talk about the "active safety features" available in new cars today.  Your car might issue a warning if you attempt to change lanes into space already occupied by another car.  It might tell you if you're about to back out of parking space into an oncoming car. Despite these wonders, there is still tremendous potential to improve these systems, Dr. Vantsevich said. To realize their potential will require researchers to develop theoretical and analytic foundations, the agile dynamic underpinnings of future systems. The symposium in Birmingham will launch some of those efforts.

14:48 There also may be value in creating unmanned vehicles that are autonomous, with no need for remote control as they go about their mission and stream intel back to headquarters. Such "ground drones" may save many soldiers lives, but only if they are capable of negotiating extreme terrain. If their mission requires them travel long distances, such vehicles must also be fuel efficient, and especially in the case of autonomous rovers deployed to the surface of Mars.

16:52  Furthermore, such unmanned vehicles would often have a "mission-related payload," like a robotic arm on top. Experts in mechatronics would have to consider how the weight and motion of the arm changed the agile vehicle dynamics and a rover drove up a steep slope.

18:54 While cars started out as mechanical systems, like wind up clocks based gears and mechanisms but no electricity, they have become something else, said Dr. Vantsevich. Cars today might have five computers, which is more than the space shuttle had. The interplay between mechanical, computer and electrical systems of any device, from a smart phone to a car, is the province of mechatronics. It's not just a combination of separate mechanical, electronic and computer systems, but an approach where different sets of physics become one.

23:55 In recent years, car designers have added many electronic devices to cars in seeking to improve their performance and fuel efficiency. An unintended result is that today's car has two kilometers of wires running though it that together weigh 30 kilograms. That weight that costs the car in fuel efficiency and handling, and mechatronics-minded engineers are seeking to reduce that burden.

28:02 Dr. Vantsevich seeks to develop a world class program in mechatronics at UAB, which will include courses at the bachelor's, master's and Ph.D. level. Newly offered courses include "introduction to mechatronics, design of robots and design of hybrid vehicles, the latter in partnership with The Southern Company. As electricity producers, power companies like The Southern Company have taken an interest in charging stations for electric cars and in the cars themselves.

29:07  The symposium starts on Sept. 8 and is formally titled The Agile Ground Vehicle Dynamics Energy Efficiency and Performance in Severe Environments International Engineering Symposium. It will be hosted by the UAB School of Engineering and Department of Mechanical Engineering, Barber Motorsports, Southern Company, the Birmingham Chapter of American Society of Mechanical Engineers and the International Society for Terrain Vehicle Systems.
Speakers will include:
Other symposium participants will include Ford Motor Company, General Motors, John Deere and Volvo.
Conference registration is $250 for students and professionals from developing countries, $550 for professionals and $750 for exhibitors. Registration discounts are available to local companies and academic institutions. UAB students, faculty and staff may attend workshops at no cost, but must pay to attend the banquet. For more information, contact Dr. Vantsevich at or 205-975-5855.