Describing humor with an equation

A new theory suggests an equation for identifying the cause and level of our responses to any humorous stimuli: h = m x s

A new theory suggests an equation for identifying the cause and level of our responses to any humorous stimuli: h = m x s

The theory argues that human beings are more reliant for their behavioural instruction on culturally inherited information than any other species, and that the accuracy of that information is therefore of unparalleled importance. Yet the individual is exposed to the continual threats of error and deception, which can seriously affect their chances of survival and success.

To compensate, humour rewards us for seeing through misinformation that has come close to taking us in. The pleasure we get (h) is calculated by multiplying the degree of misinformation perceived (m) by the extent to which the individual is susceptible to taking it seriously (s).

Humour therefore exists to encourage us to take information apart and to reject that which is unsound and could potentially harm our prospects. Every time we laugh, we have successfully achieved this, resolving inconsistencies in the fabric of our knowledge as we do so.

"I am not attempting to claim that we each engage in an algebraic equation before we find something funny," says the author, Alastair Clarke, "but that this schematic description reflects the instantaneous reactions of the brain to potentially dangerous misinformation."

One of two contrasting theories of humour by Clarke, 'Information Normalization Theory' is due for publication in the spring. In the meantime, further information and downloadable introductory essays are available at www.alastairclarke.net.

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Immune molecule regulates brain connections

The number of connections between nerve cells in the brain can be regulated by an immune system molecule, according to a new study from UC Davis. The research, published Feb. 27 in the journal Nature Neuroscience, reveals a potential link between immunity, infectious disease and conditions such as schizophrenia or autism.

Schizophrenia, autism and other disorders are associated with changes in connectivity in the brain, said Kimberley McAllister, associate professor in the Center for Neuroscience and Departments of Neurology and Neurobiology, Physiology and Behavior at UC Davis. Those changes affect the ability of the brain to process information correctly.

"Certain immune genes and immune dysregulation have also been associated with autism and schizophrenia, and the immune molecules that we study in brain development could be a pathway that contributes to that altered connectivity," McAllister said.

The study does not show a direct link between immune responses and autism, but rather reveals a molecular pathway through which a peripheral immune response or particular genetic profile could alter early brain development, McAllister said.

The researchers looked at a protein called Major Histocompatibility Complex type 1 (MHC type I). In both rodents and humans, these proteins vary between individuals, and allow the immune system to distinguish between 'self' and 'non-self.' They play a role, for example, in rejecting transplanted organs and in defending against cancer and virus infections.

In this and another recently published study, McAllister's group found that MHC type I molecules are present on young brain cells during early postnatal development. To test their function, they studied mice lacking MHC type I on the surface of neurons, as well as isolated neurons from mice and rats with altered levels of MHC type I. They found that when the density of these molecules on the surface of a brain cell goes up, the number of connections, or synapses, it has with neighboring brain cells goes down. The reverse was also true: decreased MHC expression increased synaptic connections.

"The effect on synapse density was mediated through MHC type I proteins," McAllister said.

"But these immune proteins don't just regulate synapse density, they also determine the balance of excitation and inhibition on young neurons -- a property critical for information processing and plasticity in young brains."

Expression of MHCI on neurons was itself regulated by neural activity, the team found, and MHCI mediated the ability of neural activity to alter synaptic connections.

About 10 years ago, other researchers discovered that MHC type I is involved in elimination of connections during a critical period of late postnatal brain development.

"We have now found that there is another role for MHC type I in establishing connections during early postnatal development of the brain," McAllister said.

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HIV makes protein that may help virus's resurgence

Children's Hospital of Philadelphia study sheds light on how HIV takes over cell cycle

New research enhances the current knowledge of how human immunodeficiency virus type-1 (HIV-1), which causes AIDS, controls the cell cycle of cells that it infects. The new findings may shed light on how the virus reactivates after entering a dormant state, called latency.

"As we better understand the biological events that revive HIV from latency, we hope to devise ways to eventually intervene in this process with better treatments for people with HIV infection," said study leader Terri H. Finkel, M.D., Ph.D., chief of Rheumatology at The Children's Hospital of Philadelphia.

Finkel is the senior author of a study published in the Jan. 27 issue of the journal Blood. The first author, also from Children's Hospital, is Jiangfang Wang, M.D., Ph.D.

Viral latency is one of the persistent problems in treating HIV infection. Current combinations of anti-HIV drugs can reduce HIV to undetectable levels, but the virus hides in latently infected cells in a sort of hibernation. If a patient stops taking medication, or is weakened by a different infection, HIV can make a resurgence out of its viral reservoirs, often becoming resistant to previously effective drugs.

The current study focused on a protein, Vif (for viral infectivity factor), that HIV-1 produces. Finkel and colleagues previously discovered that Vif causes HIV-infected cells to stop growing at one phase of the cell cycle, the G2 phase. The study team has now found that Vif also acts at an earlier stage in the cell cycle, driving cells out of the G1 phase and into the more active S phase.

This activity may be important, said Finkel, because G1 is a resting phase, and a biological interaction that "wakes up" a latent infected cell may reactivate the infection. Other viruses that have a latent infectious state, such as the herpes virus and the Epstein-Barr virus, also express proteins that drive a transition from G1 to S phase. "By regulating the cell cycle, viruses control their infectivity," said Finkel.

The researchers carried out their work in HeLa cells, a human cell line long used in cell studies, as well as in human T cells, immune cells found in the blood. They identified two proteins, Brd4 and Cdk9, which interact with Vif. This interaction was a new discovery, although the proteins were already known to regulate the progression of the cell cycle.

Identifying Vif's cellular partners may also implicate them as potential targets for therapy. "If we can interrupt the activity of Brd4 or Cdk9, we may be able to prevent latent infection from becoming active," said Finkel. "Alternatively, by harnessing Brd4 or Cdk9, we may be able to drive cells out of latency and make the virus susceptible to anti-HIV drugs." She added that early preclinical testing of inhibitors is getting under way for other conditions, but cautioned that it is too early to foresee whether, or how soon, her research findings will lead to clinical treatments for HIV.

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Researchers looking at a rare disease make breakthrough that could benefit everyone

Geneticists unveil workings of 3 genes that control cell development and growth

By working with Canadians of French ancestry who suffer a rare genetic disease, researchers have discovered how three genes contribute to abnormal growth, making a breakthrough that will improve our understanding of many disorders such as foetal and childhood growth retardation, abnormal development of body parts and cancer. "As a result of the Human Genome Project, we know the basic identity of essentially all the genes in the human body, but we don't automatically know what they do in detail," explained lead researcher Dr. Mark Samuels of the University of Montreal's Department of Medicine and the Sainte-Justine University Hospital Research Centre. "It's like opening your car and seeing the parts, but not knowing what each one does. When a part breaks however, you learn how it fits with the rest of the machine. Working with people who have specific health or development problems linked to specific genes enables us to see how those genes contribute to our bodies' development and functioning."

In this case, the team of researchers characterized the molecular basis in patients who suffer from Meier-Gorlin Syndrome (MGS), a rare disorder that is characterized by short stature, small ears, and absent or underdeveloped knee-caps. The patients were mostly francophonic, coming from the Maritimes, Quebec, British Columbia as well as the Louisiana Cajun community. MGS is a classic "single gene disorder," meaning it is related to mutations in individual genes, although in the case of MGS different patients surprisingly seem to carry mutations in any of three different genes.

The genes are called ORC1L, ORC4L and CDT1, and are known to play a critical role in correct copying of DNA. Cells reproduce by dividing in two. All the chromosomes must also be duplicated. This process is tightly controlled to prevent having too many or two few copies of large segments of the genome. "This seems to be the first example of any naturally occurring, inherited mutations identified in this set of important regulatory genes in any mammal. Finding the genes is a great example of the value of this type of research," Samuels said. "We learn the cause of the disease, and discover new things about our cellular function. However we still have a lot to learn about why mutations in these genes lead to the specific consequences in Meier-Gorlin patients."

There are 20-25,000 genes in the human genetic sequence, and it's important to note that they don't necessarily each correspond to a specific function or group of functions, or indeed to a single disease. The same gene can have subtle effects on a number of bodily functions. Moreover, in complex genetic diseases – diabetes, for example – environment and lifestyle have as much or more of an impact on health than a person's genetic background.

"Understanding rare genetic conditions like MGS is important to the general public for two reasons," Samuels stressed. "Firstly, they provide insight into how our genes, and therefore our bodies, work. Secondly, although there are few people concerned for each particular disorder, in sum all patients with genetic conditions consume substantial amounts of health resources, and by diagnosing them more quickly, we can improve patient management and reduce the strain on the health care system." Research suggests that up to 70% of admissions to paediatric hospitals may be related to some kind of genetic disorder. "It's also important to note that behind the science and the statistics, there are real people suffering. It's an immense relief for patients and their families to finally have a clear diagnosis," Samuels added.

In an unusual coincidence, a competing team of researchers obtained similar findings on Meier-Gorlin Syndrome in a different set of patients. These findings were published in the same issue of Nature Genetics. Samuels notes, "Neither team can claim absolute priority in the discovery. However this is the way science works best: when important results are quickly verified by multiple teams independently."

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Research opens door to vaccines that can circumvent maternal antibodies

New research that reveals how maternal antibodies block an immune response to the measles virus is a first step toward improving current childhood vaccination practices, scientists say.

Maternal antibodies are passed to fetuses during pregnancy and to newborns in their mothers' milk. The antibodies protect infants against disease in the first months of life, but that protection comes at a cost: Their presence also interferes with the generation of a natural immune response to vaccination. As a result, most babies receive measles immunizations at the age of 12 to 15 months, when maternal antibodies are gone.

Years of studies have advanced the theory that maternal antibodies shield the measles virus so that cells that generate an immune response can't see the pathogen. If that were the case, little could be done to intervene.

But Ohio State University researchers have demonstrated an entirely different mechanism in an animal model, showing that maternal antibodies bind to a specific receptor that sends a message to stop activation of an immune response to vaccination. The scientists also determined that signals to the immune response can be manipulated, and they are already devising ways that vaccines could be designed to circumvent this natural process.

"In effect, we have found how maternal antibodies affect the off-switch in the immune response, and we have found a potential on-switch," said Stefan Niewiesk, associate professor of veterinary biosciences at Ohio State University and senior author of the study.

The research is published in the online First Edition of the journal Blood.

Under current pediatric practices, children receive measles vaccinations at age 12 to 15 months, and again when they are 5 years old. Maternal antibodies can be active in babies for up to nine months; this schedule is designed to offer protection after the decline of maternal antibodies.

"The maternal antibodies are high at birth, and go down over time. By age 1 year, the maternal antibodies are gone. So this vaccine schedule works quite well if protection is not so urgent. But there is a window of opportunity for measles to come in and infect. So we would like to be able to immunize earlier," said Niewiesk, also an investigator in Ohio State's Center for Microbial Interface Biology.

Niewiesk has been a leader in developing the cotton rat as an animal model for infectious diseases. The animal is susceptible to common human pathogens that affect the respiratory system, and Niewiesk's lab has developed antibodies and other substances that help to evaluate the immune response, which is similar to that found in humans.

As a result, researchers around the world have consulted with Niewiesk for years, using the animals to test vaccine candidates. Often, the experimental vaccines do not work in the presence of maternal antibodies. And even for the one vaccine that did work, the researchers couldn't explain why at the time.

So Niewiesk changed direction, setting aside vaccine testing and instead studying how the maternal antibodies influence the immune response to an antigen – in this case, the measles virus. With this new information, he and colleagues now have better information to guide the design of a measles vaccine that will be effective even while maternal antibodies are present.

In a normal immune response, white blood cells known as B cells grow and release antibodies that are prepared to fight a specific invader, known as an antigen. The B cells are called to action by B cell receptors on their surface; when the antigen binds to these B cell receptors, the cells get the message to proliferate and then secrete antibodies that are made strictly for the task of fending off the attacking virus.
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How long do stem cells live?

When patients receive a bone marrow transplant, they are getting a new population of hematopoietic stem cells. Fresh stem cells are needed when a patient is low on red blood cells, as in anemia, or white blood cells, which can be caused by cancer or even cancer treatments such as irradiation or chemotherapy. The problem is that a bone marrow transplant might not succeed because the transplanted stem cells don't live long enough or because they proliferate too well, leading to leukemia.

To help determine how long a bone marrow (stem cell) graft will last, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have developed a mathematical model that predicts how long a stem cell will live and tested those predictions in a mouse model. The study, led by Christa Muller-Sieburg, Dr. rer. nat., was published online the week of February 28, in the journal Proceedings of the National Academy of Sciences.

"It has long been assumed that stem cells are immortal – they continue to self-renew, thus generating more stem cells that collectively can outlast an individual's life," said Dr. Muller-Sieburg, professor in Sanford-Burnham's Stem Cells and Regenerative Biology Program. "But now we have found that each stem cell is pre-programmed to self-renew only for a set amount of time that, in mice, ranges from a few months to several years. So we created a computer program that predicts that lifespan."

Researchers drew blood from transplant recipients, took a few initial measurements of the mature white blood cells generated from the transplant, and entered those parameters into a computer program that predicts their lifespan. This information was then compared to the stem cells' true lifespan. Some stem cells lasted five months and others more than three years, but again and again the computer program predicted survival time with surprising accuracy.

Dr. Muller-Sieburg and her colleagues found that stem cell self-renewal is strictly regulated to successfully negotiate a precarious balance: too much self-renewal results in leukemia, while too little leads to bone marrow failure. This new understanding now allows them to better predict the conditions that lead to normal stem cell proliferation.

Not only are these findings relevant to bone marrow transplants, they could also have implications for regenerative medicine. The safety and efficacy of using embryonic and other stem cells for tissue regeneration will depend on harnessing and precisely controlling their proliferative capacity. By providing a better understanding of how stem cells proliferate, and when they die, this lifespan prediction program could help improve their therapeutic potential for diabetes, Alzheimer's disease and other conditions.

Mathematical modeling has other benefits, too. According to lead author Hans Sieburg, Dr. rer. nat, "Computer simulation allows us to generate a hypothesis, make predictions about what should be true, and then better plan our experiments in a way that requires fewer animal experiments."
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Scientists reveal new insights into tendon injury

Scientists have discovered how tendons – the fibrous tissue that connects muscle to bone – become damaged through injury or the ageing process in what could lead to new treatments for people with tendon problems.

The University of Manchester team, working with colleagues at Glasgow University, have been investigating 'adhesions', which are a build up of unwanted fibrous tissue on internal organs that have been damaged as a result of surgery or injury.

Adhesions cause organs to stick together and are extremely painful and distressing for patients, who often have to undergo surgery and rehabilitation. The estimated cost of adhesions to the NHS is £100 million each year.

In this study, published in the journal PLoS One, the researchers wanted to understand how tendon adhesions form, so examined the surface of healthy tendons and discovered that they are covered by a thin layer of skin.

"Tendons attach our muscles to bone and are essential for movement," said lead researcher Professor Karl Kadler, from the Wellcome Trust Centre for Cell Matrix Research in Manchester's Faculty of Life Sciences.

"In order to do this, tendons need to glide freely but when an adhesion forms the tendon can no longer travel over the bone, which causes pain, stiffness and reduced movement.

"We reasoned that the surface of tendons must contain a special cell that stops adhesions from forming in healthy people. We discovered that the tendon is actually covered by a thin layer of epithelial cells, which are usually found in skin.

"Undamaged tendons do not form adhesions but when the tendon 'skin' is damaged, the cells inside the tendon form an unwanted adhesion which begins to stick to nearby tissues."

The team were able to show that mice with defective cells at the surface of their tendons appeared to have difficulty walking and spontaneously develop tendon adhesions, even without surgery or injury.
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UCSF researchers uncover hormone pathway to fatty liver disease

Scientists at the UCSF Cardiovascular Research Institute have discovered how a change in growth hormone activity in mice leads to fatty liver disease, a condition whose human counterpart is of rising concern worldwide.

Disruption of a key protein in the pathway that responds to growth hormone could explain how fatty liver disease develops, the researchers said, but may also offer insights into how our bodies regulate fat in general.

The team's findings and the first reports of a mouse model to study the pathway will appear in the April issue of the Journal of Clinical Investigation and online March 1 at www.jci.org.

Until recently, the growth of fat deposits in the liver that characterizes fatty-liver disease was mainly considered a result of alcoholism. Over the last decade, though, scientists have been baffled by the rising incidence of the non-alcoholic version of the disease, which now affects as many as one in four people worldwide, according to UCSF cardiologist Ethan Weiss, MD, senior author of the paper.

Known risk factors for the condition include obesity, diabetes and malnutrition, among many others, but its precise mechanism had eluded researchers.

"Fatty liver disease is an increasingly prevalent condition that is poorly understood," Weiss said. "We knew that growth hormone had been linked to fatty liver, but previous reports showed that it both causes and cures the condition. We set out to figure out why that happens."

The team focused on a protein in the liver known as JAK2. While better known as being linked to cancers such as blood cancers, this protein is also a key player in an important chemical pathway in the liver.

Normally, the pituitary gland secretes growth hormone, which communicates with JAK2 and sets off a series of steps to produce insulin-like growth factor 1 (IGF-1), an important mediator of growth and other effects. It was common knowledge that disrupting this pathway would halt IGF-1 production, but in their analysis, Weiss and his team found that disrupting the pathway also caused fatty liver disease.

The team engineered a mouse model in which the gene producing JAK2 had been removed solely in the liver, disrupting the pathway that produces the insulin-like growth factor. As expected, the levels of growth factor in these mice were low or nonexistent and the mice developed early and severe fatty-liver disease. Further analysis showed that another protein, called CD36, was working in the liver to draw in the fat in the JAK2-deficient mice.

The amount of growth hormone secreted by the pituitary gland also was dramatically elevated. The team realized that low IGF-1 levels were sending the pituitary gland into overdrive, secreting more growth hormone in order to jumpstart the growth factor's production. But without JAK2, the signaling pathway was broken and IGF-1 production was at a standstill.

That explained the low growth factor levels, but not the fatty livers. The team then took advantage of a second set of mice with no capability of producing growth hormone, which is known to activate energy from fat stores. When crossing the JAK2-deficient mice with the growth hormone-deficient "little" mice, the researchers noticed a huge difference in the offspring.
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Signaling path in brain may prevent that 'I'm full' message, UT Southwestern scientists discover

Researchers at UT Southwestern Medical Center have identified a signaling pathway in the brain that's sufficient to induce cellular leptin resistance, a problem that decreases the body's ability to "hear" that it is full and should stop eating.

"Leptin resistance is a significant factor, yet the mechanisms that underlie the problem remain unclear," said Dr. Joel Elmquist, professor of internal medicine and pharmacology at UT Southwestern and senior author of the study appearing in the March issue of Cell Metabolism. "The fact that this cellular pathway may be involved is a novel observation."

Leptin is a hormone released by fat cells that is known to indicate fullness, or satiety, in the brain. If the body is exposed to too much leptin, however, it will become resistant to the hormone. Once that occurs, the body can't "hear" the hormonal messages telling the body to stop eating and burn fat. Instead, a person remains hungry, craves sweets and stores more fat instead of burning it.

Leptin resistance also causes an increase in visceral, or belly, fat, which has been shown to predispose people to an increased risk of heart disease, diabetes and metabolic syndrome.

For the current study, the researchers induced leptin resistance in organotypic brain slices from mice. This research technique, used commonly in neuroscience, enabled the researchers to maintain the cellular and anatomical relationships and some of the network connections that normally exist within the brain.

"We're not dispersing cells. We're leaving them in a microenvironment that simulates what's going on in the brain," Dr. Elmquist said.

When the researchers began manipulating the network – known as cAMP-EPAC pathway – they found that activating this previously unexplored signaling avenue is enough to induce leptin resistance within hypothalamic neurons, a critical site of leptin action. They also found that when the pathway was blocked, the cells were no longer resistant to leptin.

"In the follow-up experiments, which we conducted in mice, we were able to induce leptin resistance simply by infusing activators of this pathway, further supporting our theory that this signaling pathway may contribute to leptin resistance in obesity," said Dr. Makoto Fukuda, instructor of internal medicine at UT Southwestern and the study's lead author.

Dr. Elmquist said that while the EPAC signaling pathway itself is not novel, this is the first time it has been studied in the hypothalamus and in the context of energy balance and leptin signaling.

The next step, Dr. Elmquist said, is to investigate how critical the EPAC pathway actually is in leptin responsive neurons and to determine its role in maintaining energy balance and leptin sensitivity.

"These results are potentially interesting and provocative, but the physiological importance remains to be seen," Dr. Elmquist said. "If, however, this pathway is indeed important, it will offer new insights into the mechanisms that high levels of leptin cause in leptin resistance."
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