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Monday, September 24, 2007

Resveratrol, of course, is somewhat famous as the substance in red wine that is widely believed to be able to retard aging and promote longevity. There are various hypotheses as to how it might do this, and several may turn out to be correct, as they are not mutually exclusive. There is experimental evidence supporting several of these hypotheses.

Ironically, however, it may be that the amount of resveratrol available in red wine is not sufficient to account for the experimentally supported effects, and there may be other substances in red wine that account for whatever anti-aging properties red wine may have.

Among the properties of resveratrol that might explain an ability to promote longevity are its antioxidant characteristics or other abilities to impede cancer. Resveratrol also has anti-inflammatory properties. Yet another hypothesis is that resveratrol is able to stimulate sirtuin proteins. These proteins are hypothesized to promote longevity, and they may also explain the known longevity-enhancing effects of calorie restriction.

I plan to write about both sirtuins and calorie restriction soon, but right now let's just focus on resveratrol. The most recent news about resveratrol concerns its anti-cancer properties:

Red Wine Compound Shown To Prevent Prostate Cancer
Researchers at the University of Alabama at Birmingham (UAB) have found that nutrients in red wine may help reduce the risk of developing prostate cancer.

The study involved male mice that were fed a plant compound found in red wine called resveratrol, which has shown anti-oxidant and anti-cancer properties. Other sources of resveratrol in the diet include grapes, raspberries, peanuts and blueberries.

The magnitude of the observed effect was substantial:
In the study resveratrol-fed mice showed an 87 percent reduction in their risk of developing prostate tumors that contained the worst kind of cancer-staging diagnosis. The mice that proved to have the highest cancer-protection effect earned it after seven months of consuming resveratrol in a powdered formula mixed with their food.

Other mice in the study, those fed resveratrol but still developed a less-serious form of prostate cancer, were 48 percent more likely to have their tumor growth halted or slowed when compared to mice who did not consume the compound, the UAB research team said.

Unfortunately, the amount of resveratrol (in proportion to body weight) the mice received to achieve these effects would not be very practical for humans to get from wine:
The amounts used in the UAB mice studies were the equivalent of one person consuming one bottle of red wine per day, which is not advisable. Since drinking alcohol in excessive amounts can have harmful health effects, doctors generally recommend moderate red wine consumption, which is an average of two drinks a day for men and one drink a day for women.

Actually, the amounts used are the equivalent of far more than one bottle of wine per day – see further discussion on this below.

Unfortunately, too, this research doesn't address various questions we'd really like answers to. Does resveratrol have a similar effect with other cancers? What is the mechanism by which resveratrol affects cancer?

Here's a blog post at Futurepundit with more on this research, and in particular some suggestions about connection with sirtuins: Resveratrol Reduces Prostate Cancer In Mice

Let's now go back a little way in time, to November 2006, when resveratrol made a big splash with apparent longevity-enhancing effects of a different kind.

Red Wine Molecule Extends Lifespan Of Fat Mice Lives By Reversing Obesity-Related Gene Pathways (11/2/06)
Researchers have used a single compound to increase the lifespan of obese mice, and found that the drug reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets--some of which are associated with diabetes, heart disease, and other significant diseases related to obesity. The research, led by investigators at Harvard Medical School and the National Institute on Aging, is the first time that the small molecule resveratrol has been shown to offer survival benefits in a mammal.

Importantly, one of the other principal investigators in this research is David Sinclair, who has been one of the main researchers studying sirtuins (see references in the Futurepundit post mentioned above), has done previous work with resveratrol (in non-mammals), and whose research has also been somewhat controversial. Some relevant background:
Resveratrol is found in red wines and produced by a variety of plants when put under stress. It was first discovered to have an anti-aging properties by Sinclair, other HMS researchers, and their colleagues in 2003 and reported in Nature. The 2003 study showed that yeast treated with resveratrol lived 60 percent longer. Since 2003, resveratrol has been shown to extend the lifespan of worms and flies by nearly 30 percent, and fish by almost 60 percent. It has also been shown to protect against Huntington's disease in two different animal models (worms and mice).

Here's what the researchers say about the sirtuin connection:
Investigators identified resveratrol while looking for compounds that activate Sir2, an enzyme linked to lifespan extension in yeast and other lower organisms. For the last 70 years, scientists have been able to increase the lifespan of a variety of species by reducing their normal food consumption by 30 to 40 percent - a diet known as calorie restriction. Through this research, scientists identified Sir2 as a key contributor to life extension. Without Sir2, for example, fruit flies see none of the benefits from either calorie restriction or treatment by resveratrol. The mammalian version of the Sir2 gene is SIRT1, which has the same enzymatic activity as Sir2, but modifies a wider variety of molecules throughout cells. Indicators in this study show that resveratrol might also be activating SIRT1 in mice, as well as other known longevity pathways.

The experiments divided their mice into three categories: standard diet (SD), high-calorie diet (HC), and high-calorie diet with resveratrol (HCR). Among other findings, there were some which looked specifically at standard indicators of diabetes.
In humans, high calorie diets can increase glucose and insulin levels leading to diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. In the HC fed mice, researchers found biomarkers that might predict diabetes, including increased levels of insulin, glucose and insulin-like growth factor-1 (IGF-1). Conversely, the HCR fed group had significantly lower levels of these markers, paralleling the SD group. For example, a standard diabetes glucose test on the HCR fed group found considerably higher insulin sensitivity, meaning the HCR group had a lower disposition toward diabetes than the HC fed group. Lower insulin levels also predict increased lifespan in mice.

All-in-all, this appears to be a pretty comprehensive piece of research. However, there are a couple of flies in the ointment. Most importantly, as with the prostate cancer research reported above, the mice received rather high doses of resveratrol – much higher, even, in Sinclair's study. The following article by Nicholas Wade explains it pretty well:

Yes, Red Wine Holds Answer. Check Dosage. (11/2/06)
The mice were fed a hefty dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-lb person would need to drink 750 to 1,500 bottles of red wine a day to get such a dose.

Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, also said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses, Dr. Hodes said.

One person who is not following this prudent advice, however, is Dr. Sinclair, the chief author of the study. He has long been taking resveratrol, though at a dose of only five milligrams per kilogram. Mice given that amount in a second feeding trial have shown similar, but less pronounced, results as those on the 24-milligram-a-day dose, he said.

So Sinclair is taking about one fifth the dose as his mice – still something like the equivalent of 150 to 300 bottles of wine per day. It's probably a good idea not to expect that drinking even a bottle a day will provide any significant protection against diabetes. The recognized fact that there does appear to be some health benefit to people who consume moderate amounts of wine must therefore be due either to other effects of resveratrol (anti-oxidant, anti-inflammatory, for example), or else to other substances in wine.

It is possible that dietary supplements containing more concentrated resveratrol might help, but probably not any currently on the market, as Wade notes:
Many companies sell the substance, along with claims that rivals’ preparations are inactive. One such company, Longevinex, sells an extract of red wine and knotweed that contains an unspecified amount of resveratrol. But each capsule is equivalent to “5 to 15 5-ounce glasses of the best red wine,” the company’s Web site asserts.

A couple of other problems are that the longevity-enhancing effects of resveratrol – or even calorie restriction, for that matter – have not yet been demonstrated in human trials, and that the lack of human trials also leaves open the question of possible harmful side-effects at high dosage, given the other properties of resveratrol (anti-oxidant, anti-inflammatory).

And if all that weren't enough to worry about, the connection between resveratrol and sirtuins is still not clearly demonstrated to general scientific satisfaction. As Wade writes,
“It hasn’t really been clearly shown, the way a biochemist would want to see it, that resveratrol can activate sirtuin,” said Matt Kaeberlein, a former student of Dr. Guarente’s who does research at the University of Washington in Seattle. Sirtuin is the protein produced by the SIRT-1 gene.

Dr. Sinclair said experiments at Sirtris had essentially wrapped up this point. But they have not yet been published, so under the rules of scientific debate he cannot use them to support his position. In his Nature article he therefore has to concede that “Whether resveratrol acts directly or indirectly through Sir-2 in vivo is currently a subject of debate.

Sinclair is working with a start-up biotech company (Sirtris Pharmaceuticals) that is developing pills containing resveratrol and similar molecules for eventual use in humans. But it almost always takes 5 to 10 years to guide a new drug – which must show measurable beneficial effects for specific diseases as well as safety – through clinical trials in humans, in order to gain approval from the FDA.

Other reports on this research: here, here, here, here, here, and here.

Results of this study were followed closely by those of another study, which apparently was funded by Sirtris:

Red wine compound boosts athletic endurance (11/16/06)
High doses of a compound found naturally in grape skins and red wine can improve muscle endurance in mice, and the compound also keeps them slim, a new study shows. ...

Johan Auwerx at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France, and colleagues placed mice on a high-fat diet. Half of those mice received daily amounts of up to 400 milligrams of resveratrol per kilogram of body weight. ...

After three weeks, the mice on the resveratrol supplements weighed only about 20% more than mice on a standard diet. But those on the high-fat diet that did not receive the supplement weighed 60% more than the control mice. The resveratrol also improved the rodents endurance in fitness tests, and seemed to have no toxic side effects.

Mice on the high-fat diet that also took resveratrol were able to run twice as far on a treadmill as those on the same diet but without the supplement, even after the animals’ weight differences were taken into account.

Note that the dose of 400 mg per kg of body weight is about 17 times as much as was used in Sinclair's study. One has to wonder whether these dosage levels have been reported correctly. It would seem to make more sense to use similar dosages so that similar studies of this sort would be more comparable to each other.

Another report on this research suggests a possible explanation for the results:

A Second Pour of Good News About Substance in Red Wine (11/17/06)
Additional experiments on the animals' cells indicate the substance works by increasing the activity of an enzyme known as SIRT1, boosting the number and activity of structures inside cells called mitochondria, the researchers said. Mitochondria are like power plants inside cells, burning fat and providing energy. They tend to get revved up by exercise, and deteriorate with age.

Mice fed resveratrol had more muscle tissue resembling that of a trained athlete, sharply increasing their endurance. They could run twice as far before collapsing as mice that did not receive the substance.

The researchers in this study also had something to say about the connection with sirtuins in humans:
In addition to the mouse experiments, the researchers also produced evidence supporting the theory that SIRT1 plays a key role in longevity in humans in an accompanying analysis of 123 Finnish adults. The subjects born with certain variations of the SIRT1 gene had faster metabolisms, naturally burning energy more efficiently, indicating the same pathway works in humans, too.

According to a third report, Sirtris has actually (as of last November) begun phase 1 clinical trials in humans of their more potent formulation of resveratrol:

Red Wine Compound Could Boost Endurance (11/17/06)
But if you think that drinking more wine or taking resveratrol supplements might turn you into a super-athlete, think again, said Sirtris CEO Dr. Christoph Westphal.

"Native resveratrol from red wine or nutraceuticals cannot reach therapeutic levels in man," he said. "You would need to drink hundreds of glasses of red wine or take hundreds of nutraceutical pills in a day to get a therapeutic dose."

According to Westphal, the company has completed two phase 1 studies with 85 human volunteers of an improved formulation of resveratrol which reaches therapeutic levels in man and is safe.

In addition, Sirtris has started giving diabetic patients its resveratrol compound in a 28-day phase 1 trial to test the safety of the drug and to see how it affects glucose levels.

Another report on this study: here.

Just about 10 days later additional cold water was thrown on the notion that resveratrol in red wine is responsible for the apparent benefits of wine drinking for cardiovascular health. Whatever virtues resveratrol may actually have, there simply isn't enough of it in wine to make a difference. Instead, other substances in wine are more likely to deserve the credit:

Forget Resveratrol, Tannins Key to Heart Health from Wine (11/29/06)
Resveratrol, a molecule found in the skin of red grapes, among other places, has been found to have a host of health effects, most recently prolonging the life spans of obese mice. But the natural wonder drug does not play a role in the beneficial effects of wine drinking, according to research published in the November 28 issue of Nature. "There are some fascinating effects of resveratrol in animal systems," notes plant biochemist Alan Crozier of the University of Glasgow. "To get similar doses into humans through red wine, you would have to consume more than 1,000 liters of red wine a day."

... Using the endothelial cells that line human artery walls, the researchers tested which compounds in wine had the greatest effect. The tests showed that flavonoids called oligomeric procyanidins--essentially condensed tannins, the compounds that impart bitterness to young reds--suppressed production of the peptide responsible for hardening arteries. Such procyanidins can make up as much as 50 percent of the bioactive compounds in a given wine, the researchers observed. "Resveratrol," Crozier notes, "is available at one one-hundredth or one one-thousandth of the levels of procyanidin." Corder adds: "The role of resveratrol in the health benefits of wine has been popularized without any scientific evidence to support it, given the amounts needed for these actions are approximately 1,000-fold greater than could be achieved by wine consumption."

Other reports of this research: here, here.

Unfortunately, some people have perhaps gone off the deep end where resveratrol is concerned. In spite of the tiny amount of it that's actually in red wine, some folks have actually invested their time in charting that amount in different wines and spinning fantasies about adding information on resveratrol content to wine labels:

Resveratrol Content Varies Among Red Wines (4/20/07)
“The long-term aim is for people to be able to go along to the supermarket and to be able to know at a glance the levels of resveratrol contained in the wines they are choosing,” said Dr Hoffman.

Such information, if ever provided, will serve no other purpose than (wine merchants hope) sell more wine, but otherwise be next to useless.

However, one should not conclude that resveratrol has been over-hyped and is nothing but one of the latest "neutraceutical" scams. The problem is that it's a natural substance that hasn't been specifically optimized as a therapeutic drug – especially while in the form of just one biologically active trace ingredient in wine.

Many researchers, including David Sinclair, are hard at work to find a better form or chemical analogue of resveratrol. Sirtris Pharmaceuticals is also working hard to that end. The following article from January of this year profiles the company and its CEO. The profile is mostly from a business perspective, but there's a lot about resveratrol itself in it, so it's worth reading, despite its length:

Can red wine help you live forever? (1/19/07)
[I]f [Sirtris] succeeds, its medicines may retard the onset or progression of a whole slew of age-related diseases, from diabetes to Alzheimer's to cancer. The drugs may also have an extremely provocative side effect: They might extend life span. You have to go back to the advent of antibiotics in the first half of the 20th century to find such broad therapeutic potential.

There's much more to say about Sirtris and about the related scientific issues of calorie restriction and sirtuin proteins. But that will have to wait for later.


Further information:

Via Eye on DNA I see some new research by David Sinclair and others has just been reported, dealing with calorie restriction: New Clue To Why Eating Fewer Calories Can Help You Live Longer.

There's a lot of information on resveratrol, as well as the related topic of sirtuins, at the Ouroboros blog. In fact, the whole blog is about the biology of aging. For resveratrol see here, and for sirtuins see here.

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Friday, September 21, 2007

As we noted in this article back in July, there are several hormones and neurotransmitters that have noteworthy effects on appetite and eating behavior, and as a result are of much interest with respect to weight gain (or loss) and obesity. The two mentioned in that article were NPY and PYY. The protein leptin is another hormone of this sort. It is often discussed in connection with obesity, because it is believed to increase metabolism and decrease appetite (as a signal of satiety). Another hormone, ghrelin, is produced in the stomach as a signal of hunger, and so it increases appetite.

A lot of research is currently appearing that deals with these substances and others, and how they are related to fat metabolism and obesity. I intend to discuss some of this research, and will begin with yet another hormone – adiponectin, which is produced exclusively in adipose tissue, i. e. fat, and hence the name. (Leptin is also produced in adipose tissue.) Unsurprisingly, adiponectin is involved in a number of metabolic processes, such as glucose regulation and the metabolism of fat for energy production.

Levels of adiponectin are inversely correlated with body mass index (BMI), and it seems to play a role in helping to stave off or ameliorate disorders such as obesity, diabetes, and atherosclerosis.

Let's begin with some older research first.

Fat Cell Hormone Causes Weight Loss (4/23/04)
Researchers at the University of Pennsylvania School of Medicine have established in an animal model that the hormone adiponectin secreted by fat tissue acts in the brain to reduce body weight. In contrast to leptin, a related hormone, adiponectin can cause weight loss by raising metabolic rate while not affecting appetite. ...

When adiponectin, which is involved in glucose and lipid metabolism, was introduced into the cerebrospinal fluid of normal mice, they showed no changes in food intake, but their metabolism rose. "The animal burns off more calories, so over time loses weight, which was very fascinating because we knew that leptin caused weight loss by suppressing appetite and increasing metabolic rate," explains [lead author Rexford] Ahima. "Here we have another fat hormone that can cause weight loss but without affecting intake."

To summarize, both leptin and adiponectin are produced in fat tissue, and both lead to increased metabolic rate. Leptin is known to be a satiety signal that also acts on the brain to decrease appetite. Although this older research suggests adiponectin has little effect on the central nervous system, we shall see that later research contradicts this.

From just about the same time we have the following, which found high levels of adiponectin in human milk, and therefore might explain the known association between breastfeeding and reduced risk of obesity later in life:

Study Detects Protein In Human Milk Linked To Reduced Risk Of Obesity (5/3/04)
The protein is adiponectin, which is secreted by fat cells and affects how the body processes sugars and lipids -- fatty substances in the blood. It's been suggested that adiponectin is involved in the metabolic syndrome, which includes insulin resistance, obesity, type 2 diabetes and coronary artery disease and occurs in 20-25 percent of adults. Higher levels of adiponectin have been associated with less disease.

If adiponectin is present in human milk, the Cincinnati Children's researchers theorized, the protein could have an influence over the metabolic "programming" of infants. That is, it could affect adiposity, or "fatness," later in life.

High levels of adiponectin were found in samples of human milk.
The researchers also confirmed the presence of leptin in human milk. Leptin is another protein produced by fat that appears to play an important role in the regulation of body fat. Leptin is a satiety hormone, involved in the state of being "full."

Adiponectin levels, however, are substantially greater than leptin in human milk, according to [lead author] Dr. [Lisa] Martin

Before we get to the latest research, here's some additional, earlier research involving adiponectin. In most of these studies, the main focus was on something else, but adiponectin was recognized as playing an important role:

Metabolic 'Footprint' May Be New Measure Of Obesity Risk In Kids (3/8/04)
Levels of a fat protein, called adiponectin, is significantly lower in overweight children and young adults. ... Adiponectin adheres to blood vessel walls, possibly protecting them by fighting inflammation at a cellular level.
Scientists Discover Obesity Disrupts Appetite Hormone, May Sabotage Body's Cues For Hunger, Fullness (7/1/04)
In addition to lower levels of ghrelin overall, the obese men showed higher levels of leptin and lower levels of adiponectin than the lean men.
Fat May Promote Inflammation, New Study Suggests (4/6/05)
In 15 study participants without diabetes, higher levels of the "bad" proteins, interleukin 6 and tumor necrosis factor alpha, were associated with a lower ability to respond to insulin and use glucose. On the other hand, higher levels of the "good" protein adiponectin were associated with an increased ability to use glucose. ... "This suggests that low production of adiponectin in subcutaneous fat is linked with an elevated risk of heart disease."
Researchers Consider Possible Mechanistic Links Between Obesity And Asthma (5/12/05)
There are also changes in the blood levels of hormones derived from fat tissue in the obese that may affect the airways. One of these hormones, leptin, is pro-inflammatory and obese individuals have higher leptin levels than lean individuals. Leptin is found at higher levels among asthmatics regardless of the extent of obesity. In contrast, blood levels of another hormone, adiponectin, which has anti-inflammatory properties, are actually lower among obese individuals.
Researchers Find Lack Of Protein In Obese People Is Risk Factor For Kidney, Heart Disease (11/28/05)
Researchers have found that mice with low levels of the protein hormone adiponectin may also have high levels of a protein called albumin which, in humans, may be a sign of kidney disease. ... To prove the relationship, they also studied mice without adiponectin (“adiponectin knockout”) compared to wild-type mice whose levels were normal. The team found that the knockout mice had three times the level of urine albumin than the wild-type mice. ... In a separate study ... researchers measured the adiponectin levels of a group of obese African American adolescents. They found similar results—subjects who had a low level of adiponectin also had the condition known as albuminuria—as indicated by high levels of the protein albumin in their urine. Albuminuria is an indicator for kidney disease.
Fat-generated Hormone Drives Energetic Capacity Of Muscle (7/6/06)
The fat-generated hormone adiponectin plays an important role in the energetic capacity of skeletal muscle, according to a new study. ... Adiponectin is unusual among fat hormones in that its levels generally decline in those who are obese. The researchers report evidence in people and mice, linking low adiponectin levels to insulin resistance and reductions in the number of "cellular power plants" called mitochondria in skeletal muscle. The findings suggest that therapies designed to boost the adiponectin signal might prove beneficial for the treatment of insulin resistance and diabetes.
New Research Could Help Women Facing High Risk Of Stillbirth (9/17/06)
They particularly looked at a key signalling molecule, mainly produced by fat cells, called adiponectin. This is known to have anti-diabetic properties as well as anti-inflammatory and anti-atherogenic actions (it prevents blood clotting which can block arteries). ... Observations showed that adiponectin levels were higher in pregnant women with type 1 diabetes at all stages of the study compared with the non-diabetic patients. Leptin levels were not different. Furthermore, they have identified adiponectin receptors on the human placenta and detected that the placenta also produces adiponectin. The researchers believe that the fetus produces adiponectin to protect itself from an adverse environment.
Weight-loss Supplement Shows Good And Bad Traits (2/1/07)
The researchers monitored insulin sensitivity in all mice throughout the study. They also monitored levels of adiponectin, a hormone secreted by fat tissue and thought to play a role in insulin resistance. “Adiponectin helps regulate insulin levels,” Belury said. “Lowered levels are associated with obesity and type 2 diabetes.” The researchers found that CLA [conjugated linoleic acid] supplementation significantly decreased body fat in the first group of mice, but at the same time excessive amounts of fat accumulated in the animals' livers. Belury and her colleagues linked this accumulation of fat in the liver to increased insulin resistance. ... But the group of mice given [insulin-sensitizer] rosiglitazone injections while on a CLA-rich diet neither lost weight nor became insulin resistant. “The drug kept adiponectin levels steady during the weeks the mice consumed CLA,” Belury said. “We think that's what kept the animals from becoming resistant to insulin.
Anti-obesity Drug May Prevent And Treat Obesity-related Liver Disease (7/4/07)
Treatment with rimonabant also normalized levels of adiponectin, a hormone that plays a key role in metabolic disorders. It is noteworthy that these results were not (or were only slightly observed) in the control animals eating the same diet but not given rimonabant, which demonstrates the beneficial effects of the drug compared to diet alone. "Our hypothesis is that the multi-protective effects of rimonabant may be mediated for a large part by both the reduction in pro-inflammatory cytokines such as TNFa and the increase in anti-inflammatory and protective cytokines or hormones such as adiponectin," the authors conclude.

In most of these earlier studies, something other than adiponectin was the main focus, yet adiponectin was recognized to have several beneficial effects, such as counteracting inflammation and insulin resistance. These effects in turn help control disorders such as diabetes, atherosclerosis, and fatty liver disease.

But let's look now at recent studies aimed at examining adiponectin itself. First off, concerning adiponectin and inflammation:

Fat Protein Cuts Blood Vessel Inflammation, May Help Heart, Scientists Find (6/24/07)
A natural substance secreted by fat cells can protect blood vessels from the damaging effects of inflammation, one of the factors that contribute to heart disease. Researchers at Jefferson Medical College have shown for the first time in an animal model that the substance – a protein called adiponectin – helps prevent immune system white blood cells from binding to the inside of blood vessel walls.

Importantly, adiponectin acted not only on leukocytes adhering to blood vessel walls, but also on inflammatory cytokines:
The scientists also looked at the effects of adiponectin on inflammation in normal mice. They gave mice a substance, TNF-alpha, which caused the release of inflammatory substances called cytokines. Injecting the mice with the active adiponectin-fragment reversed the effects of the cytokines and the resulting inflammation.

Inflammation is common in cardiovascular disease.

The next research takes a closer look at how adiponectin acts in the central nervous system:

Insulin Sensitizer Also Serves As Energy-conserving Signal To The Brain (7/12/07)
A fat-derived protein known for its effects on the liver and skeletal muscle might also serve as an energy-conserving signal to the brain during periods of starvation, suggests a new study in the July issue of Cell Metabolism, a publication of Cell Press. The substance, known as adiponectin, acts on the brain to boost appetite and slow energy expenditure in an effort to maintain adequate fat stores during lean times, the researchers report.

First off, there is the question of whether adiponectin even reaches the central nervous system.
The researchers now report evidence in mice that adiponectin receptors are present in the hypothalamic region of the brain and that some forms of the chemical enter the cerebrospinal fluid from the blood.

Then, supposing adiponectin reaches the central nervous system, there is the question of what effect, if any, it has there.
Once in the brain, adiponectin enhances the activity of a metabolic enzyme called AMP-activated protein kinase (AMPK) to stimulate greater food consumption.

Moreover, the researchers found that adiponectin decreased energy expenditure. They also showed that blood and spinal fluid adiponectin levels in the brain normally increase during fasting and decrease after refeeding, suggesting that adiponectin acts mainly during food shortages.

So this research claims that adiponectin increases appetite, unlike leptin, which has the opposite effect. Further, adiponectin leads to lower activity and energy expenditure, thus conserving available energy supplies. But such effects are reversed if adiponectin is absent:
In adiponectin-deficient mice, AMPK activity in the brain slowed, causing the animals to eat less and expend more energy. That action, in turn, made the animals resistant to becoming obese even on a high-fat diet. Moreover, animals lacking adiponectin lost more fat after 12 hours of fasting than normal mice did.

If indeed adiponectin tends to lead to lower activity levels and energy expenditure, one has to ask whether it promotes fat storage or even obesity. The next, and latest, research – which received a lot more attention outside specialist literature than research mentioned above – dramatically suggests that is the case.

The research began with mice genetically engineered to lack leptin. Without this satiety hormone, the mice overate and became quite obese. However, when a subgroup of these mice were engineered to overproduce adiponectin, they ate even more, and became almost twice as obese:

‘World's fattest mouse’ appears immune to diabetes (8/23/07)
The “world’s fattest mice”, genetically engineered to overproduce a key hormone, weigh five times as much as normal mice do – but bizarrely do not develop diabetes, reveals a new study. The findings shed light on how current diabetes medications work and point to new drug targets to treat the disease, say the study's researchers.

Philipp Scherer at the University of Texas Southwestern Medical Center in Dallas, Texas, US, and his colleagues studied mice that had been genetically engineered to overeat. The mice gorged on food because they lacked the ability to produce an important appetite-suppressing hormone called leptin.

The researchers then bred a subgroup of these leptin-deficient mice to overproduce another key hormone that gets released by fat cells, called adiponectin, by about threefold. Under normal circumstances, an increase in adiponectin levels signals that an animal has entered "starvation mode" because it has not eaten for some time.

All of the leptin-deficient mice ate non-stop, but those bred to overproduce adiponectin packed on almost twice as much weight by the end of the 20-week experiment.

Incidentally (or maybe not) it was Dr. Scherer who discovered adiponectin, in 1994.

Obviously, the most interesting outcome of this research is that the mice that overproduced adiponectin did not develop diabetes, in spite of their obesity.
Interestingly, none of the rodents that made extra adiponectin developed symptoms of diabetes, such as high blood sugar. By comparison, all of the other leptin-deficient mice developed this disease during the course of the experiment.

So why might that be?
When Scherer and his team examined the distribution of body fat within the mice, they found that the obese rodents with an abundance of adiponectin had a great deal of fat stored under the skin, but very little fat within organs such as the liver.

This unusual allocation of fat might explain why the animals remained in good health – extra fat in the liver can make the organ less sensitive to insulin, thereby leading to diabetes.

Scherer firmly believes that the distribution of fat can make all the difference in terms of whether obesity will lead to diabetes. "It's a little bit like real estate; it's location, location, location."

But wait, isn't ("type 2") diabetes mostly due to an inability to use insulin – insulin resistance? The original press release on the research ties insulin resistance directly to storage of fat in the wrong places:

Key Hormone Protects Obese Mice From Diabetes (8/28/07)
"The continual firing of adiponectin generated a 'starvation signal' from fat that says it is ready to store more energy," he said. "The mice became what may be the world's fattest mice, but they have normal fasting glucose levels and glucose tolerance.

"This indicates that the inability to appropriately expand fat mass in times of overeating may be an underlying cause of insulin resistance, diabetes and cardiovascular disease."

This discovery also suggests that in people who have low adiponectin levels fat cells don't send the signal that they're ready to accept fat, Dr. Scherer said. Instead, the fat is stored in dangerous places -- liver, heart and muscle tissues -- where it can cause inflammation and pave the way for disease.

There's at least one question left to which I don't see an obvious answer: If adiponectin is produced in fat cells ("white adipose cells", to be exact), why is it negatively correlated with obesity? That is, at least in humans, we've seen that lower levels of adiponectin go along with obesity.

That's odd. Is there some mechanism that turns off adiponectin production? Evidently so, if adiponectin normally acts as a signal of food deprivation. But exactly what is the mechanism? Would interfering with the mechanism, to keep adiponectin levels high, be worthwhile for preventing insulin resistance, inflammation, and other problems? Even if weight gain, due to increased appetite, also resulted? Needs further research, I guess.

Additional references on this research:

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Beyond Einstein redux

Sunday, September 16, 2007

You may recall a rather detailed discussion last November of NASA's Beyond Einstein program back here. In a nutshell, NASA was looking at a number of very interesting space missions related to astrophysics and cosmology. But because of the foolish emphasis being placed on manned missions to the moon and (eventually) Mars and the multi-billion-$ cost of such missions, it remained to be determined whether enough money would be left over for even a few of the science missions.

Among the proposed science missions, there were two that were well along in the planning stage – LISA (to detect and study gravitational waves), and Constellation-X (a powerful X-ray observatory to be used for studying black holes and hot gas in galaxy clusters).

In addition, there were three other projects less far along in planning: a dark energy probe, an inflation probe, and a black hole finder.

In order to prioritize and choose among these missions, the Powers That Be decided to ask the National Research Council to evaluate the various missions and report back. In April Steinn Sigurðsson at Dynamics of Cats provided an interim report on the occasion of a meeting of the committee given the assessment task.

On September 5 an answer came back from the NRC:

'Beyond Einstein' Research Should Begin with Mission to Study Dark Energy
NASA and the U.S. Department of Energy should pursue the Joint Dark Energy Mission (JDEM) as the first mission in the "Beyond Einstein" program, according to a new report from the National Research Council. Beyond Einstein is NASA's research roadmap for five proposed mission areas to study the most compelling questions at the intersection of physics and astronomy. The committee that wrote the report added that another proposed mission to detect gravitational waves using the Laser Interferometer Space Antenna (LISA) should eventually become the flagship mission of Beyond Einstein, given that it is likely to provide an entirely new way to observe the universe. However, LISA needs more testing before a launch can be planned, whereas the Joint Dark Energy Mission is ready now for a competitive selection of mission concept proposals.

So it appears that LISA and JDEM are at least still getting serious consideration for eventual mission funding. But don't forget that this is merely a recommendation to NASA and the Department of Energy (the agencies that must actually fund the projects). The projects could easily be blocked or delayed by the agencies themselves, the Executive Office of the President (especially by budget officials), or Congress.

Note that JDEM, the dark energy mission, is actually three competing proposals, among which it will still be necessary to settle on one:
So far, three specific mission plans have been studied in this area: the Supernova Acceleration Probe (SNAP), the Dark Energy Space Telescope (DESTINY), and the Advanced Dark Energy Physics Telescope (ADEPT), but the eventual JDEM could be any one of the three or be based on a different option altogether. The committee found that the underlying technology for a dark energy mission is, for the most part, in the prototype phase, and will require less development than most of the other missions. The potential gains for JDEM also outweigh its scientific risks, such as the possibility that the mission may not provide substantial insight beyond that provided by telescopes on the ground. The report recommends that NASA and DOE proceed immediately with a competition for mission proposals that will investigate the nature of dark energy with high precision.

LISA is also recommended for continued development. It's status is somewhat different in that the project is being funded jointly between NASA and the European Space Agency (ESA). And further, future plans depend on what is learned about the technology (an ambitions space-based interferometer) from a preliminary project called LISA Pathfinder, which is to be launched in 2009.

The NRC recommendation leaves the three remaining projects in limbo:
[T]he three elements of Beyond Einstein that are not being recommended for immediate implementation are still important endeavors that should receive continued support. The committee found that because the Constellation-X mission is a general-purpose x-ray observatory capable of broad contributions to astrophysics, it should be funded and assessed in a broader context than the Beyond Einstein program. The Black Hole Finder Probe and Inflation Probe missions will also make important scientific contributions; however, because of scope and technical readiness issues, they fell behind JDEM and LISA. The committee recommended that Constellation-X, Black Hole Finder Probe, and Inflation Probe receive continued support to prepare them for the next decadal survey of astronomy and astrophysics.

Additional news reports have focused mainly on the dark energy mission, for example here, here, here.

Steinn, of course, has some enlightening commentary here, here, and especially here.

The next shoe to drop is a reply from NASA, which could come at any time. It should be noted that there are possible ways and means to squeeze in some of the scientific missions which did not get recommended at this time, but that will require continued lobbying and can only be speculated on now. And everything goes up for grabs again, after January 20, 2009. One step at a time.

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Study Lights Up The Political Brain

Since we've been looking at political science a bit recently (here and here), perhaps a little more might not be out of order. One interesting thing about the studies discussed so far is that they rely largely on experimental techniques of classical psychology – subjects pushing buttons when presented with various stimuli, for example.

One wonders whether more modern techniques have been used, such as fMRI. The answer: a little, but not very much, apparently. The following seems to be part of what may be the most noteworthy effort:

Emory Study Lights Up The Political Brain
When it comes to forming opinions and making judgments on hot political issues, partisans of both parties don't let facts get in the way of their decision-making, according to a new Emory University study. The research sheds light on why staunch Democrats and Republicans can hear the same information, but walk away with opposite conclusions.

The investigators used functional neuroimaging (fMRI) to study a sample of committed Democrats and Republicans during the three months prior to the U.S. Presidential election of 2004. The Democrats and Republicans were given a reasoning task in which they had to evaluate threatening information about their own candidate. During the task, the subjects underwent fMRI to see what parts of their brain were active. What the researchers found was striking.

"We did not see any increased activation of the parts of the brain normally engaged during reasoning," says Drew Westen, director of clinical psychology at Emory who led the study. "What we saw instead was a network of emotion circuits lighting up, including circuits hypothesized to be involved in regulating emotion, and circuits known to be involved in resolving conflicts."

There probably isn't going to be much disagreement that political appeals in democracies (or most other governmental arrangements) are based a lot more on emotion than on reason and logic. It's hardly a new idea. However, what is intriguing is the possibility that fMRI and similar brain-scanning techniques can eventually reveal, for example, what kinds of emotional appeals work best with different personality types, when (if ever) rational mechanisms in the cortex become involved, and so forth.

Further information:

Neural Bases of Motivated Reasoning: An fMRI Study of Emotional Constraints on Partisan Political Judgment in the 2004 U.S. Presidential Election – abstract of the research paper (sub. rqd. for full access)

Drew Westen – The Political Brain: The Role of Emotion in Deciding the Fate of the Nation – recent (6/2007) book


Petascale computing and beyond

Friday, September 14, 2007

National Science Board Approves Funds For Petascale Computing Systems
Today [Aug. 14, 2007] the National Science Board (NSB) approved a resolution authorizing the National Science Foundation (NSF) to fund the acquisition and deployment of the world's most powerful "leadership-class" supercomputer, proposed in response to NSF's "Track 1" supercomputing solicitation. This "petascale" system is expected to be able to make arithmetic calculations at a sustained rate in excess of a sizzling 1,000-trillion operations per second (a "petaflop" per second) to help investigators solve some of the world's most challenging science and engineering research problems.

This would be a significant milestone – "petascale" supercomputers that can process 1000 trillion floating point operations per second.

But there's something puzzling about this announcement. A little further on it describes the "Track 1" system:
In the first award, the University of Illinois at Urbana-Champaign (UIUC) will receive $208 million over 4.5 years to acquire and make available a petascale computer it calls "Blue Waters," which is 500 times more powerful than today's typical supercomputers. The system is expected to go online in 2011.

This system is described as being 500 times as powerful as a "typical" supercomputer today. It's not clear what is being assumed as "typical", but according to the Wikipedia article, as of August 2007 the fastest supercomputer currently installed and operational is an IBM Blue Gene/L at Lawrence Livermore National Laboratory, which is rated at 280 teraflops, or .28 petaflop. Of course, that's not a "typical" supercomputer, but one wonders exactly what is expected for this proposed "Track 1" system.

However, it appears that an actual petaflop supercomputer will be available this year, not 2011, if IBM meets the objectives with "Blue Gene/P" described here:

IBM Triples Performance of World's Fastest, Most Energy-Efficient Supercomputer
ARMONK, NY - 26 Jun 2007: IBM (NYSE: IBM) today announced Blue Gene/P, the second generation of the world's most powerful supercomputer. Blue Gene/P nearly triples the performance of its predecessor, Blue Gene/L -- currently the world's fastest computer. ...

The IBM® System Blue Gene®/P Solution scales to operate continuously at speeds exceeding one "petaflop" -- or one-quadrillion operations per second. ...

The U.S. Dept. of Energy's Argonne National Laboratory, Argonne, Ill., will deploy the first Blue Gene/P supercomputer in the U.S. beginning later this year. In Germany, the Max Planck Society and Forschungszentrum Julich also plan to begin installing Blue Gene/P systems in late 2007.

If the schedule and performance objectives are met, then the petascale threshold will be crossed little more than 10 years after the terascale threshold was crossed in 1997 – by ASCI Red. So there would be a factor of 1000 top speed growth in a little over 10 years – which represents nearly a doubling of top speed every year.

It will be interesting to observe whether this keeps up. That would mean we could see exascale computing (an exaflop, which is one million teraflops) in 2017. This will depend to a large extent on whether Moore's Law holds up 10 more years, and that's not by any means a done deal.

Between 1997 and 2007, smallest silicon integrated circuit feature sizes decreased from about 500nm to 45nm, so a 100-fold improvement in areal density was achieved together with 1000-fold improvement in top computer speed. The 100-fold increase in circuit density translates to a similar increase in speed, assuming that results from being able to fit 100 times as many instruction processors in roughly the same size package. The additional factor of 10 in performance presumably results from some combination of faster processor "clock speed", internal parallelism, and larger total system size.

Somehow I don't see general purpose quantum computers available within 10 years, yet some technology beyond current silicon chips will most likely be needed to keep speed doubling going until 2017. State of the art feature sizes this year are at 45nm. Even a 10-fold improvement to 4.5nm – which may not be feasible – would yield only 100-fold improvement in number of circuits per unit area. As in the previous decade, additional performance improvements will be required to add a further factor of 10 in total performance. What techniques might allow this? For example, will it be possible to fabricate practicable 3D multilayer devices by 2017?

Here are just some of the engineering challenges that must be overcome in order to push feature sizes towards 5nm with anything like current silicon chip designs:

  • Preventing current leakage between adjacent features
  • Dissipation of heat from more densely packed circuit elements
  • Development of new fabrication technologies if current lithographic techniques don't scale down as far as necessary
  • Testing and error detection in nanoscale circuits, and achieving acceptable manufacturing "yield"

Perhaps exascale computing power will be within reach by 2017. But it won't be easy. To be accomplished with anything like current silicon technology assumes that trends of the past 10 years continue in both decreasing feature size and the ability to squeeze another factor of 10 in speed from additional parallelism, clock speed, or other means.

Or perhaps it will be necessary to successfully implement radical new technologies, such as circuits fabricated with carbon nanotubes.

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Readings, 12 September 2007

Wednesday, September 12, 2007

Today's edition deals with psychology and neuroscience

The text following each item is quoted material, except for editorial comments, which are in color.

Lobes of Steel
Scientists have suspected for decades that exercise, particularly regular aerobic exercise, can affect the brain. But they could only speculate as to how. Now an expanding body of research shows that exercise can improve the performance of the brain by boosting memory and cognitive processing speed. Exercise can, in fact, create a stronger, faster brain.

Researchers: New understanding of autism is near
While many parents of autistic children - Murdock included - suspect thimerosal, a mercury-based preservative used in routine childhood vaccines as the disorder's cause, most scientists suspect it lurks in the human genome, etched unmistakably in the DNA. ...

As Gould and Murdock worry about their sons, molecular geneticist Michael Wigler, a few miles away at Cold Spring Harbor Laboratory, believes he and his colleagues are on the cusp of understanding why autism occurs and how some families can be affected more than once. Wigler and his team have discovered how certain spontaneous genetic mutations are relatively common and how they can be passed on by very healthy parents to their offspring.

It's unfortunate, as the article points out, that parents of autistic children misconstrue the idea that autism is a consequence of genetic errors to be "blaming the parents". Perhaps this is partly a holdover from earlier hypotheses, which now seem very mistaken, that autism is a consequence of bad parenting. An example of this idea, sometimes called the "refigerator mother" theory of autism, was promulgated by the once-influential but now mostly discredited Freudian psychoanalyst Bruno Bettelheim. As some people who have had him as a teacher can testify, Bruno had serious psychological issues of his own.

For a press release that describes Wigler's research, see here. Another article on the research: here. Additional but different research on neurological aspects of autism: here.

This is your brain on love
All animals mate: The most primitive system in the brain, one that even reptiles have, knows it needs to reproduce. Turtles do it but then lay their eggs in the sand and head back to sea, never seeing their mate again.

Human brains are considerably more complicated, with additional neural systems that seek romance, others that want comfort and companionship, and others that are just out for a roll in the hay.

"Love makes the world go 'round" has served as an epigram to inspire a number of popular songs over the years. A more cynical point of view would suggest that it's the mating instinct that makes the world go 'round. Or even more crudely, it's sex that makes the world go 'round. Whatever. In any case, in humans this impulse manifests itself within their brains in a variety of elaborate and complicated ways.

Study Finds Men Go for Good Looks
Science is confirming what most women know: When given the choice for a mate, men go for good looks.

And guys won't be surprised to learn that women are much choosier about partners than they are.

"Just because people say they're looking for a particular set of characteristics in a mate, someone like themselves, doesn't mean that is what they'll end up choosing," Peter M. Todd, of the cognitive science program at Indiana University, Bloomington, said in a telephone interview.

Researchers led by Todd report in Tuesday's edition of Proceedings of the National Academy of Sciences that their study found humans were similar to most other mammals, "following Darwin's principle of choosy females and competitive males, even if humans say something different."

If these findings aren't obvious to you, perhaps you're still a little wet behind the ears... More on this research: here, here, here.

The Whys of Mating: 237 Reasons and Counting
Perhaps you thought that the motivations for sex were pretty obvious. Or maybe you never really wanted to know what was going on inside other people’s minds, in which case you should stop reading immediately.

For now, thanks to psychologists at the University of Texas at Austin, we can at last count the whys. After asking nearly 2,000 people why they’d had sex, the researchers have assembled and categorized a total of 237 reasons — everything from “I wanted to feel closer to God” to “I was drunk.” They even found a few people who claimed to have been motivated by the desire to have a child.

This is so quintessentially human – the need for novelty and variety is so great that humans need to think of so many rationalizations for what essentially boils down to: reproduction. More on this research: here, here.

Who’s Minding the Mind?
In a recent experiment, psychologists at Yale altered people’s judgments of a stranger by handing them a cup of coffee.

The study participants, college students, had no idea that their social instincts were being deliberately manipulated. On the way to the laboratory, they had bumped into a laboratory assistant, who was holding textbooks, a clipboard, papers and a cup of hot or iced coffee — and asked for a hand with the cup.

That was all it took: The students who held a cup of iced coffee rated a hypothetical person they later read about as being much colder, less social and more selfish than did their fellow students, who had momentarily held a cup of hot java. ...

Psychologists say that “priming” people in this way is not some form of hypnotism, or even subliminal seduction; rather, it’s a demonstration of how everyday sights, smells and sounds can selectively activate goals or motives that people already have.

Gee, you don't suppose, do you, that this sort of mechanism is at work when somebody notices a person of the opposite sex wearing clothing that has connotations of, say, power, affluence, or allure – and decides that it might be advantageous to become better acquainted with that person... and can think of 237 reasons for that....

But aside from that, this idea of "priming" also reminds me of the following:

A New Study Suggests A Relationship Between Fear Of Death And Political Preferences
This research is based on the idea that reminders of death increase the need for psychological security and therefore the appeal of leaders who emphasize the greatness of the nation and a heroic victory over evil. ...

For their current research, the scientists asked students to think about their own death or a control topic and then read campaign statements of three hypothetical political candidates, each with a different leadership style: "charismatic" (i.e. those emphasizing greatness of the nation and a heroic victory over evil, as described above), task-oriented or relationship-oriented. Following a reminder of death, there was almost an 800 percent increase in votes for the charismatic leader, but no increase for the two other candidates.

This research came out in 2004. But it seems appropriate to remember any time one observes would-be "leaders" who seem to talk a lot about "9/11" or "War on Terror" or "Al Qaeda". There's a very recent and prescient article on this connection here.

Sleights of Mind
In his opening address, Michael Gazzaniga, the president of the consciousness association, had described another form of prestidigitation — a virtual reality experiment in which he had put on a pair of electronic goggles that projected the illusion of a deep hole opening in what he knew to be a solid concrete floor. Jolted by the adrenaline rush, his heart beat faster and his muscles tensed, a reminder that even without goggles the brain cobbles together a world from whatever it can.

Here's a delightful article on many other ways that our brains/minds can play tricks on us, by the versatile writer George Johnson, whom I recently had the pleasure of meeting. It shows, once again, how easily we can be misled by others who are motivated to do so (including, sometimes, our unconscious selves).

Ironically, and very sadly, the parrot mentioned in the article, named Alex, has just died. Obituaries: here, here, here, here, here, here.

Out-of-body experiences are 'all in the mind'
By deliberately scrambling a person's visual and tactile senses, it is now possible to give them an "out-of-body" experience.

Two procedures – which are the first to imitate an out-of-body experience artificially – use cameras to fool people into thinking they are standing or sitting somewhere else in a room. They provide the strongest proof yet that people only imagine floating out of their bodies during surgery or near-death experiences.

"The brain can trick itself, and when it is trying to interpret sensory information, the image it produces doesn't have to be a real representation," says Henrik Ehrsson, of the Institute of Neurology, University College London, UK, who designed the first experiment.

Accidental or deliberate deceptions of the mind, like this one (perpetrated by oneself or others) – besides simply chemical influences such as alcohol or other drugs – show how convincingly the mind can be fooled given the right conditions. Such findings seem able to account for experiences that people describe as "religious" or "spirtual" or "numinous" or the like.

Other reports on this research: here, here, here, here, here, here, here.

Political affiliation could be all in the brain

Sunday, September 9, 2007

For a long time I've felt that political science is just a branch of psychopathology. Now it appears that technology is approaching the point that political science can be studied by techniques of neuroscience:

Political affiliation could be all in the brain
A brain scan might one day predict your voting patterns. That is the implication of a study that found different brain activity among liberals and conservatives asked to carry out a simple button-pushing test. The study implies that our political diversity may be the result of neurological differences.

More: here (updated here), here, here, here, here, here, here, here

Related: here


Readings, 8 September 2007

Saturday, September 8, 2007

Today's edition deals with physics and mathematics.

The text following each item is quoted material, except for editorial comments, which are in color.

In its near 40-year history, string theory has gone from a theory of hadrons to a theory of everything to, possibly, a theory of nothing. Indeed, modern string theory is not even a theory of strings but one of higher-dimensional objects called branes. Matthew Chalmers attempts to disentangle the immense theoretical framework that is string theory, and reveals a world of mind-bending ideas, tangible successes and daunting challenges – most of which, perhaps surprisingly, are rooted in experimental data.

Quite a substantial article. You might prefer to read it in the PDF form. You are probably aware – because it has been splashed all over the popular media – that many physicists and philosophers of science are skeptical of string theory. They have many good points to make. But string theorists have good points of their own to make, and this article makes a lot of them. And even prominent critics of string theory, such as Sheldon Glashow and Gerard 't Hooft, are quoted acknowledging some of these points.

Are Planetary Systems Filled to Capacity?
Computer simulations suggest that the answer may be yes. But observations of extrasolar systems will provide the ultimate test.

This is a more interesting topic than it might at first seem. For one thing, there have long been questions about the stability of many-body systems such as the solar system – especially since we now understand more about the fact and implications of "chaotic" behavior. But also the fact we can now observe distant extrasolar planetary systems opens the possibility of comparing theory to reality. One consequence of the ideas described here is that planets in a "habitable zone" around their star may not be all that unlikely.

Higher Games
It's been 10 years since IBM's Deep Blue beat Garry Kasparov in chess. A prominent philosopher asks what the match meant.

Some philosophers, who understood neither chess nor computers all that well, used to predict that a computer could never beat the best human players. Daniel Dennett was not one such philosopher.

Chasing down zeros at math camp
In sessions at the American Institute of Math, geniuses munch food and crunch numbers, contemplating labyrinthine ideas.

Although this article disses modern mathematics in the customary way of those who equate math with the ability to balance a checkbook, it does manage to convey some flavor of what the American Institute of Mathematics is about.

Math Plus Cryptography Equals Drama And Conflict
Cryptography is just about as old as written communication itself, and mathematics has long supplied methods for the cryptographic toolbox.

Starting in the 1970s, increasingly sophisticated mathematics began to make inroads into cryptography, changing the nature of the field and bringing new perspectives on what it means to keep communications secure.

Neal Koblitz has written textbooks with titles like p-adic Numbers, p-adic Analysis, and Zeta-Functions. Nevertheless, his article The Uneasy Relationship Between Mathematics and Cryptography, described in the above press release, is accessible and discusses a practical side of very abstract mathematics.

Toiling in the Fields of Physics
The huge warehouse seems out of place in the French countryside, surrounded by pastures and cornfields. And if the farmers who work those fields were to take a look inside the structure, they might be forgiven if they thought space aliens had dropped a flying-saucer factory in their midst. Sticking up from the warehouse floor are massive disks of metal, lined up in a row and rising more than four stories into the air.

These are pieces of the Compact Muon Solenoid, one of the four major detectors being built for the world's most powerful particle collider.

For the next year or two there will be tons of articles appearing on the Large Hadron Collider. Get used to it.

Putting electronics in a spin
When engineers flick the switch to turn on the world's fastest supercomputer later this year it will be capable of chewing its way through 1,000 trillion calculations every second.

About the technology of spintronics, which is already affecting consumer electronics, and may eventually make quantum computing possible.

The Gedanken Experimenter
In putting teleportation, entanglement and other quantum oddities to the test, physicist Anton Zeilinger hopes to find out just how unreal quantum reality can get.

Zeilinger works in the fields of quantum information (pertinent to quantum computers) and the question of "quantum reality".

What Visions in the Dark of Light
Lene Vestergaard Hau made headlines by slowing light to below highway speed. Now the ringmaster of light can stop it, extinguish it and revive it—and thereby give quantum information a new look.

Hau's field is quantum optics, another area of possible relevance to quantum computing.

Memory and long-term potentiation

Tuesday, September 4, 2007

To begin with, we have an in-depth series of four recent articles by Terry McDermott of the Los Angeles Times on Gary Lynch and his work on the neurobiology of memory. In spite of some minor criticisms, it's as heroic a piece of exposition as one will find in the mass media. You can learn a lot about the current "story" of how memory works by reading these articles.

You can learn a lot more, besides – namely, how science really works. This particular story is quite amazing actually. Lynch's career has had more ups and downs than a roller coaster. I wouldn't be surprised to see the story made into a Hollywood drama before too long.

Except for one thing: it's not over yet. The tight connection between long-term potentiation has been for the last 30 years or so just a hypothesis. Only about a year ago was the paper published that seems to be accepted as the long-awaited verification of the hypothesis. And it's merely one of the ironies of this Byzantine story that this confirmatory paper came out of a laboratory at the other end of the country from Lynch's. Unfortunately, McDermott does not even mention this part of the story. To make up for that, you will find at the end of this note some references to work that has appeared in the past year on long-term potentiation. One of them is about Gary Lynch and his associates and the goal they managed to (finally) achieve.

The most exciting thing about it all is that the accomplishment is just the beginning, not the end of the story. What seems to have been achieved is a technique for actually visualizing memory traces. This should make it possible eventually to map out how memories are laid down in the brain, in a manner that could become as routine as the technique of staining cells for microscopy was 100 years ago.

Unfortunately, I can't quickly summarize the story that McDermott tells in his series of articles. Even though it could take you several hours to read through the whole thing, it's worth it. I wouldn't be surprised to see this turned into a book (and then into the movie) – but you'll learn the story much sooner if you just read the articles.

The text following each item is quoted material, except for editorial comments, which are in color.

One man's epic quest for understanding
Lynch is a neuroscientist at UC Irvine, where he has spent 37 years trying to uncover the biochemical mechanisms of memory.

He has, for almost the length of his career, been trying to answer essentially a single pair of questions: What happens in the brain when a human being encounters a new experience so that he or she can recall it at will tonight, tomorrow, in 2025? And what goes wrong when we can't remember?

Trials, and a series of errors, in the brain lab
Yanagihara one day, finally, working with the brains of young rats, got his experiment to work right, and found the result he was expecting to find. "If we get it tomorrow in middle-aged rats, it's great," he said.

"If you see a garbage can flying out of the lab onto the hedge, you'll know we didn't," Kramar said.

The next day, the trash cans remained inside, but only because nobody had the energy to throw them out the window. The experiment had failed again.

Unfortunately, one can't rely on the technical accuracy of everything written in this series. An example in this part is the confusion of nitric oxide with nitrous oxide. The former is the molecule of greater interest in biology, while the latter is "laughing gas". At least the error is acknowledged in a note within the article. But it makes one wonder just how many other details not so readily checked can be relied upon. Like, for instance, the reference to antibodies as just "chemicals" – well, yes, but...

Breakthroughs, and new crises, in the lab
After weeks of repeated failures on almost every other front, Lynch was ecstatic. "You mean this crap actually works?" he said. "You don't expect to see a result this black-and-white. You expect ambiguity. Aging does not occur uniformly even across a single neuron. It's an instant default explanation for memory loss. It's getting to the point where we might have to start believing we were right."

Another bit of sloppy writing in this installment of the series. In one place it says, correctly, that a neuron has just one axon. Then in the same paragraph it talks about the "axons" of one neuron.

Success and rejection
It seemed fitting, somehow. There he sat at the end of the great, long chase, often sick as a dog, the entry locked, the clamorous tribes of the neurosciences a low hum in the distance; no phone, no e-mail, not even a name on the door to betray his presence. The only way you would know he was there at all was the blue Corvette out front. And, of course, the science, which, no matter the circumstance, difficulty or hour, had poured out for 30 years like water from the well. And poured still.

Memory: a glossary of terms
You might want to keep this glossary open in a separate window if you need help with some of the terminology.

Further references

And now we have some pointers to the additional details, as promised early on.

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Stellar Siblings in Serpens South

Sunday, September 2, 2007

Stellar Siblings in Serpens South (8/8/07)
This Spitzer Space Telescope photograph shows the Serpens South star cluster – a relatively dense group of 50 young stars, 35 of which are protostars just beginning to form. Tints of green in the image represent hot hydrogen gas excited when high-speed jets of gas ejected by infant stars collide with the cool gas in the surrounding cloud. Wisps of red in the background are organic molecules called polycyclic aromatic hydrocarbons (PAHs).

Serpens South star cluster – click for 630×900 image

More information: here, here

Inflammation, IL-6, NF-κB, and disease

Saturday, September 1, 2007

Inflammation is a part of the body's immune response that has been implicated in a number of disease conditions, such as atherosclerosis, diabetes, osteoporosis, and cancer. Previous posts on the subject can be found here, here, here, and here.

Much of the research discussed in those posts reports on some correlation found between markers of inflammation and occurrence of disease. What we really want, however, is to understand the underlying mechanisms that might explain the correlation. Here we'll take a look at one of the hypothesized mechanisms.

This article: The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases is a fascinating but technical and difficult review article that makes the daring claim that
Inhibition of the signal transduction pathway for Interleukin 6 mediated inflammation is key to the prevention and treatment of aging and age-related disorders including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, type 2 diabetes, dementia, Alzheimer's disease and some forms of arthritis and cancer.

Be forewarned, if you undertake to read the article, that it presumes at least a passing knowledge of biochemistry, the mammalian immune system, and the physiology behind diseases such as diabetes and cardiovascular disorders. In addition, it could be better written, with clearer development of its central arguments. Finally, its contention as quoted above is a sweeping, far-reaching hypotheses that will require much additional research to establish securely.

It is also possible that there is some element of hype in the claims made. One should always adopt a skeptical attitude towards a declaration that anything like a potential "fountain of youth" has been discovered.

This hypothesis may well be too broad. Nevertheless, the paper provides an excellent means of focusing discussion on a number of important topics that seem to be linked inevitably to strategies for preventing or delaying the onset of the aging and age-related diseases listed above. Who could fail to find that prospect interesting?

So we'll begin with some setting of the stage. Inflammation is a major feature of the mammalian immune system, which employs the vascular system (among other things) to mount a response to infections, damaged cells, and other harmful stimuli. For example, signaling proteins, known as cytokines, are dumped into the blood stream to attract the attention of other components of the immune system, such as white blood cells (leukocytes), which then migrate through the blood stream to the site of the problem.

Several cytokines play an important role in the inflammatory process. The list includes Interleukin-1 (IL-1), Tumor Necrosis Factor α (TNF-α), and Interleukin-6 (IL-6). Of these, the last, IL-6, is singled out for special attention, because it appears to be especially important in the inflammatory process itself. Control of the process is important, because research implicates an excessive or overactive inflammatory response as a significant factor in the diseases of aging listed above.

Control of IL-6, in turn, may depend on control of the protein NF-κB (Nuclear Factor κB), which is a transcription factor that is thought to be necessary for the expression of the gene for IL-6. NF-κB is an essential part of the signaling pathway through which IL-6 is produced. Without activated NF-κB there may be no IL-6. However, NF-κB is also implicated in a number of other physiological processes as seemingly independent from the inflammatory response as synaptic plasticity and memory. This poses a challenge to any attempt to regulate the inflammatory response by regulating NF-κB.

As we shall see in subsequent postings, there's a lot of very interesting research going on related to the role of inflammation in disease in general, and with the involvement of NF-κB in particular.

We'll describe here just a couple of the recent examples.

Key To Out-of-control Immune Response In Lung Injury Found
Acute Respiratory Distress Syndrome, or ARDS, is an often fatal complication of severe traumatic injury, bacterial infections, blood transfusions and overdoses of some medications. In ARDS, the lungs become swollen with fluid and breathing becomes impossible. ...

Sepsis, an overwhelming bacterial infection of the blood and organs, is the most common cause of ARDS. When the immune system responds to the infection, molecules called inflammatory cytokines and chemokines are released. These molecules attract inflammatory white blood cells and destroy bacteria, but also lead to fever, swelling and other symptoms of shock and can wreak havoc on the patient in the course of fighting off the infection.

The researchers worked with a strain of mice that lacked a gene called Cblb. This gene codes for a protein that disables a cell surface receptor. Unless this receptor is disabled it will keep NF-κB activated, and therefore leads to the overproduction of inflammatory cytokines. The result is a "cytokine storm" that leads to ARDS-like symptoms and greater likelihood of fatal results for the Cblb-deficient mice:
When sepsis was induced in mice with and without the Cblb gene, there was a marked difference in the level of the inflammatory response and survival. Mice lacking the Cblb gene were much less likely to survive than control mice.

It shouldn't be concluded, however, that NF-κB (or IL-6 for that matter) is intrinsically harmful. If that were the case, it would not be so widely conserved in evolution, as it is. NF-κB is found even in the simplest of animals, such as corals, sea anemones, and sponges.

As noted, NF-κB is a transcription factor for a number of genes besides IL-6. Some of these genes code for proteins that promote cell survival and proliferation. This, too, can be a double-edged sword, as with inflammatory cytokines. In particular, it appears that NF-κB plays a non-trivial role in various types of cancer. We'll write about that in another article. However, the following research seems to demonstrate a case where the cell survival role of NF-κB predominates:

Researchers Identify Molecular Basis Of Inflammatory Bowel Disease
[Researchers] generated a mouse model that does not express NEMO, a protein needed to activate NF-κB, in intestinal epithelial cells. As a result, these mice developed severe chronic intestinal inflammation very similar to Colitis in humans.

"A close look at the mice revealed that their gut epithelium was damaged," says Manolis Pasparakis, who recently moved from heading a lab at EMBL to becoming a professor at the University of Cologne. "NF-κB acts as a survival signal for cells. Without the molecule cells are much more likely to die and this is what happened in the intestines of our mice; individual epithelial cells died disrupting the gut lining."

Through these gaps bacteria could penetrate the intestinal wall. Right behind the gut epithelium lie cells of the intestinal immune system, the biggest immune system of our body. It detects the invading bacteria and generates a strong immune response to fight off the invaders. In the process of combating the bacteria, the immune cells secrete a cocktail of signals that bring about the symptoms of inflammation.

"This is where the vicious cycle closes," explains Markus Neurath, professor at the University of Mainz. "Inflammatory signals also reach the epithelial cells that due to the lack of NF-κB are very sensitive to them and die. The death of more epithelial cells creates bigger gaps in the gut lining so that more bacteria enter. The result is a constant immune response leading to chronic inflammation as we know it from inflammatory bowel diseases in humans."

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