A recent breakthrough in understanding the cause of a rare, hard-to-treat allergic disorder has been made by a group of research institutions that include the University of Arkansas for Medical Sciences (UAMS) and the Arkansas Children’s Hospital Research Institute (ACHRI).

The discovery could lead to new targeted therapies for eosinophilic eophagitis (EoE). The allergic/immune condition causes inflammation of the oesophagus, usually from consuming foods such as dairy products, eggs, soy and wheat.

The condition can cause infants and toddlers to refuse food and hinder their development. Older children may have recurring abdominal pain, vomiting and trouble swallowing, while teenagers and adults typically have difficulty swallowing. Food may also become stuck in the inflamed oesophagus, creating a medical emergency.

Existing treatments for EoE are limited to prescribing long-term restrictive diets and steroid sprays to swallow.

“We hope this discovery will open the door to some additional treatment options,” said Stacie Jones, M.D., a professor in the departments of Pediatrics and Physiology & Biophysics in the UAMS College of Medicine. She is also section chief of Allergy & Immunology and leads the allergy research team ACHRI.

The study found that EoE is triggered by the interaction between epithelial cells, which help form the lining of the oesophagus, and a gene called CAPN14. It also identified a marker that can be used to measure the activity of the disease, said UAMS’ Robert Pesek, M.D., an author on the study and an assistant professor in the Department of Pediatrics in the UAMS College of Medicine. 

“Currently, the only tool we have for measuring that is endoscopy, and that becomes impractical for repeated use on children,” Pesek said.

Although new treatments have yet to be realized, UAMS’ participation in EoE and other food allergy research gives Arkansas patients access to cutting-edge research and treatment expertise not available anywhere else in the state. University of Arkansas for Medical Sciences

In a new study, scientists at the National Institutes of Health took a molecular-level journey into microtubules, the hollow cylinders inside brain cells that act as skeletons and internal highways. They watched how a protein called tubulin acetyltransferase (TAT) labels the inside of microtubules. The results answer long-standing questions about how TAT tagging works and offer clues as to why it is important for brain health.
Microtubules are constantly tagged by proteins in the cell to designate them for specialized functions, in the same way that roads are labelled for fast or slow traffic or for maintenance. TAT coats specific locations inside the microtubules with a chemical called an acetyl group. How the various labels are added to the cellular microtubule network remains a mystery. Recent findings suggested that problems with tagging microtubules may lead to some forms of cancer and nervous system disorders, including Alzheimer’s disease, and have been linked to a rare blinding disorder and Joubert Syndrome, an uncommon brain development disorder.
‘This is the first time anyone has been able to peer inside microtubules and catch TAT in action,’ said Antonina Roll-Mecak, Ph.D., an investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and the leader of the study.
Microtubules are found in all of the body’s cells. They are assembled like building blocks, using a protein called tubulin. Microtubules are constructed first by aligning tubulin building blocks into long strings. Then the strings align themselves side by side to form a sheet. Eventually the sheet grows wide enough that it closes up into a cylinder. TAT then bonds an acetyl group to alpha tubulin, a subunit of the tubulin protein.
Some microtubules are short-lived and can rapidly change lengths by adding or removing tubulin pieces along one end, whereas others remain unchanged for longer times. Recognising the difference may help cells function properly. For example, cells may send cargo along stable microtubules and avoid ones that are being rebuilt. Cells appear to use a variety of chemical labels to describe the stability of microtubules.
‘Our study uncovers how TAT may help cells distinguish between stable microtubules and ones that are under construction,’ said Dr. Roll-Mecak. According to Dr. Roll-Mecak, high levels of microtubule tagging are unique to nerve cells and may be the reason that they have complex shapes allowing them to make elaborate connections in the brain.
For decades scientists knew that the insides of long-lived microtubules were often tagged with acetyl groups by TAT. Changes in acetylation may influence the health of nerve cells. Some studies have shown that blocking this form of microtubule tagging leads to nerve defects, brain abnormalities or degeneration of nerve fibres. Since the discovery of microtubule acetylation, scientists have been puzzled about how TAT accesses the inside of the microtubules and how the tagging reaction happens.
To watch TAT at work, Dr. Roll-Mecak and her colleagues took high resolution movies of individual TAT molecules interacting with microtubules in real time. They saw that TAT surfs through the inside of microtubules and although it can find acetylation sites quickly, the process of adding the tag occurs very slowly.
In general, tagging reactions work like keys fitting into locks: the better the key fits, the faster the lock can open. Similarly, the rate of the reactions is determined by how well TAT molecules fit around tagging sites.
Dr. Roll-Mecak’s team investigated this idea by using a technique called X-ray crystallography to look at how atoms on TAT molecules interact with acetylation sites on tubulin molecules. Their results suggested that TAT fit poorly around the sites.
‘It looks as though TAT can easily journey through microtubules spotting acetylation sites but may only label those that are stable for longer periods of time,’ said Dr. Roll-Mecak.
This may help cells identify the microtubules they need to rapidly change shapes or send cargo to other places. Further studies may help researchers understand how microtubule tagging influences nerve cells in health and disease. National Institute of Neurological Disorders and Stroke

Genetics could be the key to explaining nation’s levels of happiness, according to research from the University of Warwick.

Economists at the University’s Centre for Competitive Advantage in the Global Economy (CAGE) have looked at why certain countries top the world happiness rankings. In particular they have found the closer a nation is to the genetic makeup of Denmark, the happier that country is. The research could help to solve the puzzle of why a country like Denmark so regularly tops the world happiness rankings.

Dr Eugenio Proto and Professor Andrew Oswald found three forms of evidence for a link between genetic makeup and a nation’s happiness.

Firstly they used data on 131 countries from a number of international surveys including the Gallup World Poll, World Value Survey and the European Quality of Life Surveys. The researchers linked cross-national data on genetic distance and well-being.

Dr Proto said: “The results were surprising, we found that the greater a nation’s genetic distance from Denmark, the lower the reported wellbeing of that nation. Our research adjusts for many other influences including Gross Domestic Product, culture, religion and the strength of the welfare state and geography.

The second form of evidence looked at existing research suggesting an association between mental wellbeing and a mutation of the gene that influences the reuptake of serotonin, which is believed to be linked to human mood.

Dr Proto added: “We looked at existing research which suggested that the long and short variants of this gene are correlated with different probabilities of clinical depression, although this link is still highly debated. The short version has been associated with higher scores on neuroticism and lower life satisfaction. Intriguingly, among the 30 nations included in the study, it is Denmark and the Netherlands that appear to have the lowest percentage of people with this short version.”

The final form of evidence looked at whether the link between genetics and happiness also held true across generations, continents and the Atlantic Ocean.

Professor Oswald said: “We used data on the reported wellbeing of Americans and then looked at which part of the world their ancestors had come from. The evidence revealed that there is an unexplained positive correlation between the happiness today of some nations and the observed happiness of Americans whose ancestors came from these nations, even after controlling for personal income and religion.” University of Warwick

A computer science and engineering associate professor and her doctoral student graduate are using a genetic computer network inference model that eventually could predict whether a person will suffer from bipolar disorder, schizophrenia or another mental illness.

The findings are detailed in the paper “Inference of SNP-Gene Regulatory Networks by Integrating Gene Expressions and Genetic Perturbations,” which was recently published. The principal investigators were Jean Gao, an associate professor of computer science and engineering, and Dong-Chul Kim, who recently earned his doctorate in computer science and engineering from UT Arlington.

“We looked for the differences between our genetic computer network and the brain patterns of 130 patients from the University of Illinois,” Gao said. “This work could lead to earlier diagnosis in the future and treatment for those patients suffering from bipolar disorder or schizophrenia. Early diagnosis allows doctors to provide timely treatments that may speed up aid to help affected patients.”

The UT Arlington researchers teamed with Jiao Wang of the Beijing Genomics Institute at Wuhan, China; and Chunyu Liu, visiting associate professor at the University of Illinois Department of Psychiatry, on the project.

Gao said the findings also could lead to more individualized drug therapies for those patients in the early stages of mental illnesses.

“Our work will allow doctors to analyse a patient’s genetic pattern and apply the appropriate levels of personalized therapy based on patient-specific data,” Gao said.

One key to the research is designing single nucleotide polymorphism or SNP networks, researchers said.

“SNPs are regulators of genes,” said Kim, who joins the University of Texas-Pan American this fall as an assistant professor. “Those SNPs visualize how individual genes will act. It gives us more of a complete picture.” UT Arlington

During breast-tissue development, a transcription factor called SLUG plays a role in regulating stem cell function and determines whether breast cells will mature into luminal or basal cells.

Studying factors, such as SLUG, that regulate stem-cell activity and breast-cell identity are important for understanding how breast tumours arise and develop into different subtypes. Ultimately, this knowledge may help the development of novel therapies targeted to specific breast-tumour subtypes.

Background: Stem cells are immature cells that can differentiate, or develop, into different cell types. Stem cells are important for replenishing cells in many tissues throughout the body. Defects that affect stem-cell activity can lead to cancer because mutations in these cells can cause uncontrollable growth. Some transcription factors regulate the differentiation or ‘programming’ of breast stem cells into the more mature cells of the breast tissue. Abnormal expression of these transcription factors can change the normal programming of cells, which can lead to imbalances in cell types and the over-production of cells with enhanced properties of stem cells.

Breast tissue has two main types of cells: luminal cells and basal cells. Transcription factors, like SLUG, help control whether cells are programmed to become luminal cells or basal cells during normal breast development. In cancer, transcription factors can become deregulated, influencing what type of breast tumour will form. In aggressive basal-type breast tumours, SLUG is often over-expressed.

Previous work led by Charlotte Kuperwasser, principal investigator and senior author, determined that some common forms of breast cancer originate from luminal cells, whereas rare forms of breast cancer originate from basal cells. This difference in origins suggests that genes that affect the ability of a cell to become luminal or basal may also affect the formation of breast tumours. Because SLUG can regulate breast-cell differentiation, Kuperwasser’s team investigated SLUG’s role in breast-cell differentiation and tumor growth.

The research team reduced the expression of the SLUG gene in human-derived breast cells and then used cell-sorting techniques to separate the cells into groups of luminal, basal, and stem cells. Next, they used mathematical modelling to measure the rate and frequency that each of the three cell types changed into another cell type. By comparing the rates between control cells and cells in which SLUG was reduced, the team was able to determine the role of SLUG in luminal-, basal-, and stem-cell transitions.

To test the result of their mathematical model, the research team examined and compared breast-tissue samples from mice in two groups: a control group with normal SLUG and an experimental group that did not express SLUG. Mammary glands from the experimental and control groups were analyzed for changes in structure, the amount and distribution of luminal and basal cells in the gland, and whether these cells had stem-cell activity.

The SLUG-deficient mice exhibited defects in breast-cell differentiation. The mammary glands of these mice had too many luminal cells and defective basal cells that had luminal-cell characteristics. The control group of normal mice had a normal ratio of luminal to basal cells.

The SLUG-deficient mice showed defects in stem-cell function: Specifically, tumour formation and tissue regeneration was inhibited, an indication of defective stem cells, suggesting that SLUG was necessary to maintain normal luminal and basal cells within the mammary gland.

Additionally, SLUG-deficient cells when transplanted could not regenerate the mammary gland of the mouse, suggesting that SLUG is necessary for mammary stem-cell function. Tumour formation was also inhibited in SLUG-deficient mice, suggesting that SLUG may affect stem-cell activity necessary for tumour formation. Tufts University