Researchers have found evidence that genetic factors may contribute to the development of language during infancy.

Scientists from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol worked with colleagues around the world to discover a significant link between genetic changes near the ROBO2 gene and the number of words spoken by children in the early stages of language development.

Children produce words at about 10 to 15 months of age and our range of vocabulary expands as we grow – from around 50 words at 15 to 18 months, 200 words at 18 to 30 months, 14,000 words at six-years-old and then over 50,000 words by the time we leave secondary school.

The researchers found the genetic link during the ages of 15 to 18 months when toddlers typically communicate with single words only before their linguistic skills advance to two-word combinations and more complex grammatical structures.

The results shed further light on a specific genetic region on chromosome 3, which has been previously implicated in dyslexia and speech-related disorders.

The ROBO2 gene contains the instructions for making the ROBO2 protein. This protein directs chemicals in brain cells and other neuronal cell formations that may help infants to develop language but also to produce sounds.

The ROBO2 protein also closely interacts with other ROBO proteins that have previously been linked to problems with reading and the storage of speech sounds.

Dr Beate St Pourcain, who jointly led the research with Professor Davey Smith at the MRC Integrative Epidemiology Unit, said: ‘This research helps us to better understand the genetic factors which may be involved in the early language development in healthy children, particularly at a time when children speak with single words only, and strengthens the link between ROBO proteins and a variety of linguistic skills in humans.”

Dr Claire Haworth, one of the lead authors, based at the University of Warwick, commented: “In this study we found that results using DNA confirm those we get from twin studies about the importance of genetic influences for language development. This is good news as it means that current DNA-based investigations can be used to detect most of the genetic factors that contribute to these early language skills.’ University of Bristol

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a professor of biology and the Verne M. Willaman Chair in Life Sciences at Penn State. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found.

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. ‘Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,’ Chen said.

The research behind those drugs had targeted the long-recognised feature of Alzheimer’s patients’ brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die.

‘The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,’ Chen explained.

‘We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients,’ Chen said.

He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called ‘reactive astrocytes’ in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.

Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped ‘astrocyte’ cells which, in a healthy individual, surround and support individual neurons in the brain. ‘Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,’ Chen said.

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice).

‘Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,’ Chen said.

His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Importantly, Chen said, ‘After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.’ Penn State University

A new blood test provides a fast and accurate tool to diagnose tuberculosis in children, a new proof-of-concept study shows. The newly developed test (TAM-TB assay) is the first reliable immunodiagnostic assay to detect active tuberculosis in children. The test features excellent specificity, a similar sensitivity as culture tests in combination with speed of a blood test. The promising findings are a major advance for the diagnosis of tuberculosis in children, particularly in tuberculosis-endemic regions.

Tuberculosis (TB) in children is a serious public health problem especially in low-resource countries. About one million children per year develop tuberculosis worldwide. Unfortunately, the diagnosis of paediatric TB poses a major challenge. TB symptoms in children are often non-specific and similar to those of common paediatric illnesses, including pneumonia and malnutrition. Further, obtaining adequate respiratory specimens for direct mycobacterial confirmation is problematic. Consequently, there is an urgent need for a more precise, rapid and affordable diagnostic test for childhood tuberculosis.

The new so-called TAM-TB assay is a sputum-independent blood test. It makes use of an immunological phenomenon during tuberculosis disease: During an active infection, the expression of CD27 – a surface marker expressed on mycobacteria specific CD4+ T cells – is lost. Using standard intracellular cytokine staining procedures and polychromatic flow cytometry, the test result is available within 24 hours after blood sampling.

New blood test assessed in tuberculosis endemic regions in Tanzania
The new test was assessed in tuberculosis endemic regions in Tanzania at the Ifakara Health Institute and the NIMR Mbeya Medical Research Center. Sputum and blood samples were obtained from children with tuberculosis symptoms to compare the performance of the new assay with culture tests. For the assessment of the diagnostic performance of the new test, the children were assigned to standardized clinical case classifications based on microbiological and clinical findings. The test proved to have a good sensitivity and excellent specificity.

“This rapid and reliable test has the great potential to significantly improve the diagnosis of active tuberculosis in children ” says TB CHILD Program Manager Klaus Reither from the Swiss Tropical and Public Health Institute (Swiss TPH), who coordinated the study.

In a collaborative effort between Swiss TPH and Ludwigs-Maximilians-Universität München (LMU Munich), the test will now be further refined to optimise performance, particularly in HIV-infected children, and to reduce costs. The goal is to finally validate and implement a rapid, robust and accurate diagnostic test for active paediatric tuberculosis that can be used on the district level in resource-poor, tuberculosis-endemic countries. Swiss Tropical and Public Health Institute

Researchers at Karolinska Institutet in Sweden have for the first time identified a gene driving the development of pernicious adipose tissue in humans. The findings imply that the gene may constitute a risk factor promoting the development of insulin resistance and type 2 diabetes.

Adipose tissue can expand in two ways: by increasing the size and/or the number of the fat cells. It is well established that subjects with few but large fat cells, so-called hypertrophy, display an increased risk of developing type 2-diabetes. In the current study, researchers identified a gene, EBF1, which according to these new findings drive the development of the unhealthy adipose tissue. This gene encodes a protein that controls a set of other genes, a so-called transcription factor, and regulates the formation of new fat cells as well as their metabolic function.

The investigators compared adipose tissue from subjects with small or large fat cells and found that EBF1 was closely linked to hypertrophy. Individuals with large fat cells had markedly lower EBF1 expression in their adipose tissue, displayed altered lipid mobilisation and were insulin resistant. Insulin resistance – a condition characterised by reduced cellular response to the hormone insulin that is released when the blood glucose levels rise after a meal – is an important causal factor underlying the increased risk of diabetes in individuals with hypertrophic adipose tissue. Insulin resistance leads to increased circulating levels of glucose and lipids in the blood.

In collaboration with Professor Mark C. Horowitz at Yale School of Medicine, U.S. the researchers also investigated genetically modified mice expressing lower levels of the murine variant of the human EBF1-gene. It turned out that these mice developed adipose hypertrophy and displayed increased lipid mobilisation from fat cells. When the mice were put on high-fat diet they became insulin resistant.

‘Our findings represent an important step forward in the understanding of how adipose tissue links to the development of metabolic disease’, comments Professor Peter Arner, one of the principal investigators at Karolinska Institutet along with Hui Gao, Niklas Mejhert and Mikael Rydén. ‘This is the first time someone has identified a gene which may cause malfunctioning adipose tissue in man. In the future, it might be possible to develop drugs that improve EBF1 function in adipose tissue, which could be used to treat type 2-diabetes.’ Karolinska Institute

Researchers from IMIM (Hospital del Mar Medical Research Institute) have identified a new protein, galectin-1, as a possible therapeutic target for pancreatic cancer. For the first time they have demonstrated the effects of the inhibition of this protein in mice suffering this type of cancer and the results showed an increase in survival of 20%. The work further suggests that it could be a therapeutic target with no adverse effects.

Until now, the strategies for treating this tumour were aimed at attacking the tumour cells and had little success. The latest studies indicate that trying to destroy what surrounds the tumour is possibly a better strategy. “Our contribution is directed toward this, as the reduction of galectin-1 mainly affects the immune system and the cells and structure that surrounds the tumour cells, which is called the stroma. Therefore, galectin-1 as a therapeutic target has great potential”, explains Dr. Pilar Navarro, co-ordinator of the research group on molecular mechanisms of tumorigenesis of IMIM and director of the research.

It was known that galectin-1 was not found in the normal pancreas despite being strongly expressed in pancreatic tumours. Furthermore, some clear functions were known which demonstrate the relationship between galectin-1 and tumour progression in other contexts. In fact, some preclinical studies for other diseases use inhibitor molecules and antibodies against this protein. “We are aiming at its possible use in pancreatic cancer” states Dr. Neus Martínez, researcher of the group on molecular mechanisms and tumorigenesis of IMIM and first author of this article. “We have also observed that the elimination of galectin-1 in mice has no harmful consequences, indicating that it could be a safe therapeutic target with no adverse effects”, she adds.

In collaboration with the Hospital del Mar Anatomical Pathology Service, which has analysed some samples, pancreatic tumours were studied in mice with high levels of galectin-1 and after its depletion. They observed that tumours without this protein showed less proliferation, fewer blood vessels, less inflammation and an increase in the immune response. All these changes are associated with less aggressive tumours. IMIM