Scientists at the Salk Institute for Biological Studies have identified a gene that regulates sleep and wake rhythms.

The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travellers adjust to time differences more quickly. The results can point to treatment strategies for sleep problems caused by a variety of disorders.

“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”

Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.

More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.

In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.

“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.

By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren’t in sync with one another, despite appearing rhythmic individually.

“It was all about communication–the neurons were not talking to each other without this molecule,” says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.

Studying a mouse version of jet lag–an 8-hour shift in their day-night cycle–the scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.

These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.

“This approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN,” Panda says. “It can compensate for the loss of Lhx1.”

On the other hand, cutting back on Vip could be another way to treat jet lag. Vip could be an even easier drug target compared with Lhx1 because Vip is secreted from cells rather than inside cells, Panda says. “If we find a drug that will block the Vip receptor or somehow break down Vip, then maybe that will help us reset the clock much faster,” he adds. Salk Institute for Biological Studies

Babies suffering from bacterial infections like sepsis could benefit from better treatment, thanks to a ground-breaking study.

For the first time Edinburgh researchers have been able to detect and decode a signal generated from a baby’s DNA that can tell doctors whether or not a bacterial infection is present in the bloodstream.  The findings could help develop a test for bacterial infection in newborns, using a single drop of blood.

Immediate detection of such infections, which are a major cause of death among young children, is currently impossible as no simple test exists.

The Edinburgh team identified a signal consisting of 52 molecular characters – like a biological tweet – that is specific to bacterial infection.

The researchers have spent the past decade trying to unravel the complexities of blood poisoning and its treatment among premature and full-term babies.

They say that the genome’s signal provides critical, immediate information on the infection.

Using blood samples from newborn babies in Edinburgh, the study investigated thousands of signals written in biological code known as messenger RNAs.  Through meticulous code-breaking the scientists were able to decipher with close to 100 per cent accuracy the signals generated by an infant’s genome that specifically tell if they are suffering from sepsis.

Diagnosing sepsis in newborns is extremely difficult, as signs of infection, such as a high temperature, may not occur – or if they do, they may not be due to an infection.  Currently the most reliable way to detect infection is by detecting the bacteria in the blood but require a large volume of blood.

Just as a Twitter user can send a 140 character message so a baby’s genome produces short messages or signals that produce code information to communicate with the infant’s immune and metabolic systems so that it can fight the infection. The 52-character ‘tweet’ or message that we have identified appears to be specific for bacterial but not viral infection. This type of signal could also be used to detect infection in children and adults. We are now working on ways of using a single drop of blood to detect this vital signal. This work is also leading us onto a response to tackling antibiotics resistance. University of Edinburgh

Scientists at the Max Planck Institute for Biology of Ageing in Cologne and University College London have now unearthed the way in which a specific genetic mutation leads to neuronal damage in two serious afflictions. In rare cases, patients may even suffer from these two diseases, amyotrophic lateral sclerosis and frontotemporal dementia, at the same time.

Amyotrophic lateral sclerosis is a devastating type of motor neuron disease that causes rapid weakening of muscles and death. Frontotemporal dementia is the second most common cause of dementia in people under 65. It causes distressing symptoms, including changes in personality and behaviour and problems with language and thinking.  The DNA of affected patients contains a mutation of the gene C9orf72: There are thousands of repeats of a specific short segment of genetic material, whereas in unaffected persons, there are only up to thirty copies of this segment. This specific genetic alteration is the cause of illness in around eight percent of patients with this type of motor neuron disease or dementia. Eight percent is a relatively high proportion. For instance, less than one percent of the causes in Alzheimer’s disease are genetic.

Researchers at the Max Planck Institute for Biology of Ageing, the Institute of Neurology and Institute for Healthy Ageing at University College London have now discovered that the repeats in the mutant gene cause neurodegeneration by making toxic proteins.
Fruitflies can undergo neurodegeneration in a similar way to humans

Previously it was thought that the problem could be a consequence of disruption of the gene by the inserted repeats. Another theory was that the repeats produce a different type of toxic RNA molecule. It now turns out that the repeats in the mutant gene can produce a variety of proteins and that two of these are extremely toxic to nerve cells. Both are highly enriched in arginine, an amino acid.

To pinpoint the role of the toxic proteins, the researchers produced artificial repeat segments that could produce potentially toxic RNA and protein or only toxic RNA or only protein. They then introduced them into the nerve cells of fruit flies, which can undergo neurodegeneration in a similar way to humans. Repeat segments that made both RNA and protein caused striking neurodegeneration and reduced the lifespan of the flies, showing that they are a good organism in which to study these diseases. Interestingly, the protein-only repeat segments caused just as bad a neurodegeneration. In contrast, the RNA-only segments were harmless, pinpointing the role of toxic proteins in these diseases. The proteins that contained arginine were the most toxic. Max Planck Society

In a new study, research scientists from Uppsala University present for the first time a large-scale study of the significance of genetic, clinical and lifestyle factors for protein levels in the bloodstream. The results of the study show that genetics and lifestyle are determining factors for protein levels, a discovery which greatly influences the possibilities for using more biomarkers to identify disease.

Biomarkers used for diagnosing disease should preferably indicate variations in protein levels only for those individuals who are suffering from a particular disease. Nor should they vary for reasons that have nothing to do with the disease. By analysing 92 protein biomarkers for cancer and inflammation in a clinical study of 1,000 healthy individuals, researchers at Uppsala University have for the first time surveyed the significance of genetic, clinical and lifestyle factors for protein levels in the bloodstream. The results of the study show that hereditary factors play a significant role for more than 75 per cent of the proteins, and a detailed genetic analysis demonstrates 16 genes with a strong effect on protein levels.

“These results are important, as they show which variables are significant for variations in the measurable values. If these factors are known, we have a greater possibility of seeing variations and we get clearer breakpoints between elevated values and normal values. By extension this may lead to the possibility of using more biomarkers clinically,” explains Stefan Enroth, researcher at the Department of Immunology, Genetics and Pathology at Uppsala University.

According to the study, genetics and lifestyle together account in some cases for more than 50 per cent of variations in protein levels among healthy individuals. This means that information about both genetic and lifestyle factors must be taken into account in order for protein biomarkers to be used effectively. Uppsala University

A Finnish-Swedish research group at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, and Karolinska institutet, Stockholm, has developed a novel “man and machine” decision support system for diagnosing malaria infection. The method is based on computer vision algorithms similar to those used in facial recognition systems combined with visualization of only the diagnostically most relevant areas. Tablet computers can be utilized in viewing the images.
In this newly developed method, a thin layer of blood smeared on a microscope slide is first digitized. The algorithm analyses more than 50,000 red blood cells per sample and ranks them according to the probability of infection. Then the program creates a panel containing images of more than a hundred most likely infected cells and presents that panel to the user. The final diagnosis is done by a health-care professional based on the visualized images.
By utilizing a set of existing, already diagnosed samples, the researchers were able to show that the accuracy of this method was comparable to the quality criteria defined by the World Health Organization. In the test setting, more than 90% of the infected samples were accurately diagnosed based on the panel. The few problematic samples were of low quality and in a true diagnostic setting would have led to further analyses.

 “We are not suggesting that the whole malaria diagnostic process could or should be automated. Rather, our aim is to develop methods that are significantly less labour intensive than the traditional ones and have a potential to considerably increase the throughput in malaria diagnostics”, said Research Director Johan Lundin (MD, PhD) from the Institute for Molecular Medicine Finland, FIMM.

“The equipment needed for digitization of the samples is a challenge in developed countries. In the next phase of our project we will test the system in combination with inexpensive mobile microscopy devices that our group has also developed”, told the shared first author of the article Nina Linder (MD, PhD) from FIMM.

The developed support system can be applied in various other fields of medicine. In addition to other infectious diseases such as tuberculosis, the research group is planning to test the system fro cancer diagnostics in tissue samples. Institue for Molecular Medicine Finland