Mutations in the gene encoding the enzyme protein tyrosine phosphatase N2 (PTPN2) have been associated with the development of autoimmune disease including Type 1 diabetes, Crohn’s Disease and rheumatoid arthritis.
In important fundamental research, Monash University researchers have identified a crucial part of the enzyme’s role in early T-cell development, and have shown that decreased levels of this enzyme can lead to the type of T-cells that can contribute to the development of autoimmune disease.
Autoimmune diseases represent a broad spectrum of diseases, which arise when immune responses are directed against, and damage, the body’s own tissues. Collectively their incidence exceeds that of cancer and heart disease and they are a leading cause of death and disability, in particular in the Western world.
The Monash Biomedicine Discovery Institute researchers had already shown in studies over the years that decreased levels of PTPN2 result in T-cells attacking the body’s own cells and tissues. 
In a paper they drilled deeper, exploring roles for the enzyme in early T-cell development and the development of particular T-cell subsets (αβ and γδ) implicated in the development of different autoimmune and inflammatory diseases.
By removing the gene coding for PTPN2 in laboratory trials, the scientists found that the developmental process for T-cells was skewed towards the generation of γδ T cells with pro-inflammatory properties that are known to contribute to the development of different diseases including Irritable Bowel Disease, Crohn’s Disease and rheumatoid arthritis.
“This is an important advance in our understanding of critical checkpoints in T-cell development,” lead researcher Professor Tony Tiganis said.
“It helps decide whether the progenitors go on to become T-cells or something else; if they become one type of T-cell or another type,” he said.
As part of the study, the researchers looked at the pathways that PTPN2 regulates.
“There are drugs that target some of these pathways – potentially we might be able to use existing drugs to target these pathways in the context of autoimmune and inflammatory diseases to help a subset of patients with a deficiency in this gene, although that is a long way off,” Professor Tiganis said. 
First author Dr Florian Wiede said, “Understanding the mechanisms that govern early T-cell development and how these are altered in human disease may ultimately afford opportunities for novel treatments. This is very exciting.”

Monash Biomedicine Discovery Institute
www.monash.edu/news/articles/monash-university-scientists-make-critical-insights-into-t-cell-development

A recent study has confirmed that EKF’s  Quo-Test^® A1c point-of-care testing (POCT) analyser shows comparable performance to a lab-based HPLC system for the measurement of glycated hemoglobin (HbA1c). Published in Practical Laboratory Medicine, the study undertaken by the Diabetes Research Unit Cymru, Swansea University, UK, also observed that under the correct circumstances using WHO guidelines Quo-Test is appropriate for the diagnosis of Type 2 diabetes.
HbA1c is routinely used as a measure for the assessment of long-term diabetes control and, more recently, it has also been recommended for diabetes diagnosis. With the increasing use of POCT devices for the measurement of HbA1c without the waiting time associated with laboratory testing, it is crucial to determine how their performance compares. The Swansea University study aimed to compare the Quo-Test POCT analyser using boronate fluorescence quenching technology with an established HPLC laboratory method.
Using whole blood EDTA samples (n=100) from subjects with and without diabetes, the study found good overall agreement between the Quo-Test and reference HPLC method (R2=0.9691; p<0.0001). A diagnostic comparison was also made in line with WHO diagnostic ranges for HbA1c. Use of the Quo-Test as a diagnostic tool, showed 97% (n=79) agreement with the HPLC analyser for glucose intolerance and 100% (n=72) agreement for Type 2 diabetes.
Gareth Dunseath, Diabetes Research Unit Cymru Laboratory Manager, commented, “Device validation and testing is an important part of the research work that the Diabetes Research Unit Cymru laboratory undertakes, especially where the findings can expand on the services that we are able to provide. In this study, our findings showed very good reproducibility and agreement between the Quo-Test and an established laboratory HPLC method across a spectrum of glucose tolerance. This gives the reassurance that the Quo-Test can be used in situations where the immediate result afforded by a POCT method is of benefit, such as screening for eligibility for clinical trials.”
The Diabetes Research Unit Cymru study follows another by scientists from the European Reference Laboratory for Glycohemoglobin. This demonstrated that Quo-Test A1c easily met International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) performance criteria for HbA1c measurement. Meeting the IFCC accepted quality targets (>2 sigma at 10% total allowable error (TAE) at 48 mmol/mol HbA1c) is essential for the effective monitoring of glycemic control in diabetes patients.
EKF’s Quo-Test^® analyser has been designed for easy and reliable HbA1c measurement in a point-of-care setting, such as diabetes clinics and doctors’ surgeries. It is fully automated, measuring glycated hemoglobin from a 4 μL sample taken from a finger prick or venous whole blood. Sample results are available within four minutes and reported in IFCC and DCCT standard units. It is also unaffected by most hemoglobin variants. www.ekfdiagnostics.com

Scientists investigating the genetic causes and altered functioning of nerve cells in motor neurone disease (MND) have discovered a new mechanism that could lead to fresh treatment approaches for one of the most common forms of the disease.
The team, based in the Sheffield Institute for Translational Neuroscience (SITraN), investigated a mutation in one particular gene, which causes sections of DNA to replicate themselves inexplicably within cells. They found a way to prevent RNA, carrying these replicated sequences, from leaving the cell’s nucleus and travelling into the surrounding cytoplasm where they cause cell death.
Patients with MND suffer progressive paralysis as the nerves supplying muscles degenerate. Although there are several different types of MND, this mutation, in a gene called C9ORF72, is responsible for the most common type of MND, called Amyotrophic Lateral Sclerosis (ALS). This accounts for about 40-50 per cent of inherited cases and 10 per cent of all MND cases. The mutations or environmental factors causing the vast majority of MND cases remain unknown.
DNA is produced in the cell’s nucleus and contains the instructions which cells use to carry out their functions. Messenger RNA, called mRNA, transcribes this information and carries it out of the cell to ‘protein factories’ in the cytoplasm surrounding the nucleus. It is quite common for some sections of repeated DNA stretches to replicate themselves for reasons that are poorly understood. These repetitions are ‘non-coding’ sections that are not responsible for building proteins and are edited out before they leave the nucleus to serve as templates for the production of proteins.
In this particular type of motor neurone disease, however, the RNA not only contains the unnecessary replicated sequences, it is able to take them out of nucleus and into the cell’s cytoplasm. Once in the cytoplasm, the RNA is used to make up repeated proteins that clump together and block the normal function of the cell, causing it to die.
In an early stage study the researchers have been able to pinpoint why the repeated RNA sequences are able to leave the cell’s nucleus to cause cell death. The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door.
Working in partnership with researchers at the MRC Mitochondrial Biology Unit at the University of Cambridge, the team have shown that by targeting the SRSF1 protein, it is possible to reduce the amount of rogue RNA escaping into the cell’s cytoplasm.
“This is a completely new approach to tackling the most common type of motor neurone disease. No one has yet attempted to prevent these repeated sequences of RNA from leaving the cell’s nucleus and it opens up new areas of investigation for gene therapy,” explains University of Sheffield’s Dr Guillaume Hautbergue, who conceived the study and led the research jointly with Dr Alexander Whitworth, of the University of Cambridge, and SITraN Director, Professor Dame Pamela Shaw.

The University of Sheffield
www.sheffield.ac.uk/news/nr/motor-neurone-disease-1.716303

A DNA variant—located in the DNMT3B gene and commonly found in people of European and African descent—increases the likelihood of developing nicotine dependence, smoking heavily, and developing lung cancer, according to a new study led by RTI International.
Nearly 1 billion people smoke and 6 million premature deaths occur worldwide each year from cigarette smoking, according to the World Health Organization. Smoking is the leading cause of preventable death and one person dies approximately every 6 seconds from smoking-related causes, according to the WHO.
The new study is the largest genome-wide association study of nicotine dependence. Researchers studied more than 38,600 former and current smokers from the United States, Iceland, Finland, and the Netherlands.
“This new finding widens the scope of how genetic factors are known to influence nicotine dependence,” said Dana Hancock, Ph.D., genetic epidemiologist at RTI and lead author of the study. “The variant that we identified is common, occurring in 44 percent of Europeans or European Americans and 77 percent of African Americans, and it exerts important effects on gene regulation in human brain, specifically in the cerebellum, which has long been overlooked in the study of addiction.”
The genetic variant was linked to an increased risk of nicotine dependence by testing nearly 18 million variants across the genome for association with nicotine dependence. The variant was also tested in independent studies and found to associate with heavier smoking and with increased risk of lung cancer. 

RTI International
www.rti.org/news/researchers-identify-gene-influences-nicotine-dependence