Wednesday, April 26, 2017

Cortisol and Parkinson's Disease

Research team from Daegu Gyeongbuk Institute Of Science And Technology (DGIST) has performed a high-throughput screening method to identify drug candidates that promote dopaminergic neuronal cell activation by inducing the expression of the parkin protein, the cell protection gene which can inhibit the death of dopaminergic neurons. The results of study are published in Scientific Reports.

Results of the study identified that cortisol induces the expression of the parkin protein and prevents dopaminergic neuronal death by eliminating the accumulation of cell death factors through ubiquitin proteasome system.

Hydrocortisone binds to glucocorticoid receptor which in turn leads to expression of CREB. CREB increases parkin expression via binding to CREB binding motifs of parkin promoter region. Hydrocortisone-stimulated parkin expression results in the downregulation of the toxic parkin substrate AIMP2, which is beneficial for dopaminergic neuronal survival.
In addition, the team has demonstrated the mechanism by which cortisol induces the expression of the parkin protein and CREB (cAMP response element-binding protein) transcriptional regulator through the hormone receptor regulates the expression of the parkin protein through the cell and animal model experiments.

Citation: Ham, Sangwoo, Yun-Il Lee, Minkyung Jo, Hyojung Kim, Hojin Kang, Areum Jo, Gum Hwa Lee, Yun Jeong Mo, Sang Chul Park, Yun Song Lee, Joo-Ho Shin, and Yunjong Lee. "Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson’s disease model." Scientific Reports 7, no. 1 (2017).
doi:10.1038/s41598-017-00614-w.
Adapted from press release by Daegu Gyeongbuk Institute Of Science And Technology.

Monday, April 24, 2017

Researchers create heat stable vaccines using silica

Researchers at the University of Bath, working with colleagues at the University of Newcastle, have created a technique which can keep vaccines intact at high temperatures by encasing them in silica cages. When a protein in solution is mixed with silica, silicon dioxide binds closely around the protein to match its shape and encases the protein. A major advantage of this method is that it doesn't require freeze-drying, something that around half of all vaccines won't survive intact. A powder of ensilicated proteins and the silica cage enveloping the protein means it can be heated to 100°C or stored at 22°C for at least six months with no loss of function.

Once the protein has been encased in silica it can be stored or transported without refrigeration before the silica coat can be removed chemically, leaving the proteins unaffected.

The discovery means that vaccines and other important medicines could be transported much more easily, cheaply and safely, especially to remote areas or places lacking infrastructure where the need is often greatest.

The teams call their method ensilication and hope it will solve the costly and often impractical need for a cold chain to protect protein-based products including vaccines, antibodies and enzymes. The research is published in the journal Scientific Reports. The research team tested the method on three proteins; one from a tetanus vaccine, horse haemoglobin and an enzyme from egg white.

Citation: Chen, Yun-Chu, Tristan Smith, Robert H. Hicks, Aswin Doekhie, Francoise Koumanov, Stephen A. Wells, Karen J. Edler, Jean Van Den Elsen, Geoffrey D. Holman, Kevin J. Marchbank, and Asel Sartbaeva. "Thermal stability, storage and release of proteins with tailored fit in silica." Scientific Reports 7 (2017): 46568.
doi:10.1038/srep46568.
Research funding: Royal Society, The Annett Trust
Adapted from press release by the University of Bath.

Wednesday, April 12, 2017

Gut microbiome shown to protect against type 2 diabetes

New study form the University of Eastern Finland showed that a high concentration of indolepropionic acid in the serum protects against type 2 diabetes. Indolepropionic acid is a metabolite produced by intestinal bacteria, and its production is boosted by a whole grain products and fibre-rich diet. According to the researchers, the discovery provides additional insight into the role of intestinal bacteria in the interplay between diet, metabolism and health.

The findings were published in Scientific Reports. The study was carried out in the LC-MS Metabolomics Centre of the University of Eastern Finland together with a large number of partners from Finnish and Swedish research institutes.

The study compared two groups participating in the Finnish Diabetes Prevention Study, DPS. At the onset of the study, all participants were overweight and had impaired glucose tolerance. The researchers investigated the serum metabolite profile of 200 participants with impaired glucose tolerance, who either developed type 2 diabetes within the first 5 years, or did not convert to type 2 diabetes within a 15-year follow-up. The differences between the groups were analysed by non-targeted metabolomics analysis. The greatest differences in the metabolic profiles of those who developed type 2 diabetes and those who didn't were observed in the concentrations of indolepropionic acid and certain lipid metabolites. A higher concentration of indolepropionic acid seemed to promote insulin secretion by pancreatic beta cells, which might explain the protective effect.

In addition to the DPS data, the association of indolepropionic acid with the risk of diabetes was also studied in two other population-based datasets: in the Finnish Metabolic Syndrome In Men Study, METSIM, and in the Swedish Västerbotten Intervention Project, VIP. In these datasets too, indolepropionic acid was discovered to protect against diabetes.

The study also identified several new lipid metabolites whose high concentrations were associated with improved insulin resistance and reduced risk of diabetes. The concentrations of these metabolites were also associated with dietary fat: the lower the amount of saturated fat in the diet, the higher the concentrations of these metabolites. Similarly to indolepropionic acid, high concentrations of these lipid metabolites also seemed to protect against low-grade inflammation.

The Finnish Diabetes Prevention Study was the first randomised, controlled lifestyle intervention study to show that in persons with impaired glucose tolerance, type 2 diabetes can be prevented by lifestyle changes. The most important lifestyle changes included weight loss, more exercise and dietary adjustments to include more whole grain products, fruits and vegetables.

Citation: Mello, Vanessa D. De, Jussi Paananen, Jaana Lindström, Maria A. Lankinen, Lin Shi, Johanna Kuusisto, Jussi Pihlajamäki, Seppo Auriola, Marko Lehtonen, Olov Rolandsson, Ingvar A. Bergdahl, Elise Nordin, Pirjo Ilanne-Parikka, Sirkka Keinänen-Kiukaanniemi, Rikard Landberg, Johan G. Eriksson, Jaakko Tuomilehto, Kati Hanhineva, and Matti Uusitupa. "Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study." Scientific Reports 7 (2017): 46337.
doi:10.1038/srep46337.
Adapted from press release by University of Eastern Finland.

Tuesday, April 11, 2017

Research finds new genes behind Intellectual disability

Researchers at the Centre for Addiction and Mental Health (CAMH) and Queen's University have identified 26 new genes linked to intellectual disability. The study, published online today in Molecular Psychiatry, has implications for the diagnosis and clinical care of those affected, and also adds to our growing knowledge of brain development and functioning. It may eventually lead to personalized treatments for affected individuals. Interestingly, some of the genes identified are thought to be connected with autism spectrum disorders.

More than one in 100 children worldwide are affected by intellectual disability, which is characterized by significant limitations in learning that also affect their day-to-day lives. Frequently, intellectual disability also accompanies symptoms of autism spectrum disorders, and many genes have been found to be shared by the two illnesses.

Intellectual disability is frequently caused by recessive genes, meaning that an affected child gets a defective copy of the gene from each parent. Studying families with this background, and multiple affected individuals, can enable researchers to identify disease genes that would otherwise remain hidden.

The study involved 192 families from Pakistan and Iran with more than one affected family member. This strategy involves various genetic techniques, including microarray genotyping and whole exome sequencing, and studying families with a history of marriage among relatives. The Canadian research team pinpointed mutations related to intellectual disability in half of these 192 families, in 72 different genes. The identification of 26 new genes adds to 11 new genes that the team had previously linked to intellectual disability.

One immediate implication of the study is to prevent future cases of intellectual disability, the researchers note. Unaffected family members and relatives could be genetically screened to see if they carry these mutations, and provided with counselling on the risks of "within family" marriages. A broader goal is to develop diagnostic screening tools that are also relevant to populations in which "within family" marriages are rare, such as Canada, USA, Japan, China and Europe. Ultimately, this information would be used to plan more personalized treatment.

Citation: Harripaul, R., N. Vasli, A. Mikhailov, M. A. Rafiq, K. Mittal, C. Windpassinger, T. I. Sheikh, A. Noor, H. Mahmood, S. Downey, M. Johnson, K. Vleuten, L. Bell, M. Ilyas, F. S. Khan, V. Khan, M. Moradi, M. Ayaz, F. Naeem, A. Heidari, I. Ahmed, S. Ghadami, Z. Agha, S. Zeinali, R. Qamar, H. Mozhdehipanah, P. John, A. Mir, M. Ansar, L. French, M. Ayub, and J. B. Vincent. "Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families." Molecular Psychiatry, 2017. doi:10.1038/mp.2017.60.
Research funding: Canadian Institutes of Health Research
Adapted from press release by Centre for Addiction and Mental Health (CAMH).

Monday, April 10, 2017

New technique of cellular vaccination against HIV

Scientists at The Scripps Research Institute have found a way to tether HIV-fighting antibodies to immune cells, creating a cell population resistant to the virus. Researchers have used membrane-tethered, receptor blocking antibodies to achieve this outcome.

Here, cells protected from rhinovirus by membrane-tethered,
receptor-blocking antibodies survive well and form colonies.
Credit: Jia Xie, Lerner lab, The Scripps Research Institute.
Their experiments under lab conditions show that these resistant cells can quickly replace diseased cells, potentially curing the disease in a person with HIV. "This protection would be long term," said Jia Xie, senior staff scientist at TSRI and first author of the study published today in the journal Proceedings of the National Academy of Sciences.

The new TSRI technique offers a significant advantage over therapies where antibodies float freely in the bloodstream at a relatively low concentration. Instead, antibodies in the new study hang on to a cell's surface, blocking HIV from accessing a crucial cell receptor  called CD4, and thereby preventing spreading of infection. With the antibodies monopolizing that site, the virus cannot enter the cell to spread infection. "This is really a form of cellular vaccination," said study senior author Richard Lerner, M.D.

The scientists further confirmed that these tethered antibodies blocked HIV more effectively than free-floating, soluble antibodies in experiments led by study co-authors Devin Sok of the International AIDS Vaccine Initiative (IAVI) and TSRI Professor Dennis R. Burton.

Citation: Xie, Jia, Devin Sok, Nicholas C. Wu, Tianqing Zheng, Wei Zhang, Dennis R. Burton, and Richard A. Lerner. "Immunochemical engineering of cell surfaces to generate virus resistance." Proceedings of the National Academy of Sciences, 2017, 201702764.
doi:10.1073/pnas.1702764114.
Adapted from press release by The Scripps Research Institute.

Thursday, March 16, 2017

Digital PCR found effective and reproducible in a research study

21 independent labs quantified a rare single nucleotide variant using digital PCR (dPCR) with high reproducibility between labs, demonstrating the method's potential for routine clinical testing, according to a study published in Analytical Chemistry.

The research study is the first to examine the reproducibility of digital PCR between such a large number of laboratories at different geographic locations. The findings illustrate the inherent potential advantages of dPCR in measuring clinically important mutations, including greater reproducibility and less variability than real-time quantitative PCR (qPCR). In addition, the findings highlight the ability of dPCR to detect relevant rare sequence variants, according to the authors.

"Digital PCR lends itself to clinical testing where precise and reproducible results are critical not only for interlab data comparability, but also for dynamic testing in the same lab to track disease progression," said George Karlin-Neumann, co-author and Director of Scientific Affairs at Bio-Rad's Digital Biology Group.

The method permits precise and accurate quantification of nucleic acid concentration by minimizing the variability from common sources of error that can influence qPCR results. These sources include PCR inhibitors that can alter assay efficiency and skew standard curves. Digital PCR also provides absolute quantification of target nucleic acids without the need to establish standard curves, a major source of variability in qPCR.

The blinded study was part of the BioSITrace project, coordinated by the Laboratory of the Government Chemist (LGC), a private life sciences measurement and testing company and the UK's designated National Measurement Laboratory for chemical and biomeasurement. Researchers in 21 laboratories across North America and Europe were asked to use dPCR to quantify copy number concentrations and fractional abundance of a KRAS mutant DNA with a single nucleotide variation (G12D) in the presence of excess wild-type DNA (down to ~0.2% minor allele frequency). The laboratories performed the experiments using Bio-Rad's Droplet Digital™ PCR (ddPCR™) technology, on either a QX100™ or a QX200™ Droplet Digital PCR System from Bio-Rad. Droplet Digital PCR is Bio-Rad's proprietary method for performing digital PCR in which a sample is divided into 20,000 water-oil emulsion droplets.

Cancer-derived mutations that differ only slightly from a wild-type sequence present in a sample in large excess are particularly difficult to detect and quantify using qPCR, especially when fractional abundance of the mutant is less than 5%.

The results of all 21 laboratories agreed with each other within a rigorously defined margin of error. Though three laboratories initially reported differing results, further analysis revealed methodological error attributed to misclassification of positive and negative droplets rather than measurement error. When the data were reanalyzed according to the recommended guidelines, they generated results consistent with the other 18 labs, validating the potential of dPCR for clinical testing applications.

Citation: Whale, Alexandra S., Alison S. Devonshire, George Karlin-Neumann, Jack Regan, Leanne Javier, Simon Cowen, Ana Fernandez-Gonzalez, Gerwyn M. Jones, Nicholas Redshaw, Julia Beck, Andreas W. Berger, Valérie Combaret, Nina Dahl Kjersgaard, Lisa Davis, Frederic Fina, Tim Forshew, Rikke Fredslund Andersen, Silvia Galbiati, Álvaro González Hernández, Charles A. Haynes, Filip Janku, Roger Lacave, Justin Lee, Vilas Mistry, Alexandra Pender, Anne Pradines, Charlotte Proudhon, Lao H. Saal, Elliot Stieglitz, Bryan Ulrich, Carole A. Foy, Helen Parkes, Svilen Tzonev, and Jim F. Huggett. "International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant." Analytical Chemistry 89, no. 3 (2017): 1724-733.
doi:10.1021/acs.analchem.6b03980.
Adapted from press release by Bio-Rad.

Friday, March 10, 2017

Research on Allulose, a rare naturally occuring sugar show promise as healthy alternative to Sucrose

Animal research have shown that low calorie natural sugars like allulose could help regulate glucose levels. Researchers are now trying to find out how it works, and their findings are reported in Journal of Agricultural and Food Chemistry.

Sucrose is the natural sweetener what everyone refer to when sugar is on the ingredient list. Allulose, which is 70 percent as sweet as sucrose, and other rare sugars also can be found in fruits and vegetables in very small amounts. Recently researchers discovered an industrial way to produce allulose in large quantities from high-fructose corn syrup. Past studies have suggested that allulose can help control weight gain and control glucose levels. Tomoya Shintani and colleagues wanted to confirm these results and understand how it works.

To find out researchers gave three groups of rats plain water, water with high-fructose corn syrup and water with rare-sugar syrup containing glucose, fructose, allulose and other rare sugars for 10 weeks. The rats drinking rare-sugar syrup infused water gained less weight, had less abdominal fat, and had lower blood glucose and insulin levels compared to the high-fructose corn syrup group. The research showed that rats fed with rare-sugar syrup infused water had increased levels of glucokinase in liver cells. Glucokinase is an enzyme that reduces blood-sugar levels by helping convert glucose to its stored form, glycogen.

Although more research is needed, the scientists say, the findings suggest that rare sugars could be a good alternative sweetener.

Citation: Shintani, Tomoya, Takako Yamada, Noriko Hayashi, Tetsuo Iida, Yasuo Nagata, Nobuaki Ozaki, and Yukiyasu Toyoda. "Rare Sugar Syrup Containing d-Allulose but Not High-Fructose Corn Syrup Maintains Glucose Tolerance and Insulin Sensitivity Partly via Hepatic Glucokinase Translocation in Wistar Rats." Journal of Agricultural and Food Chemistry, 2017. doi:10.1021/acs.jafc.6b05627.
Adapted from press release by American Chemical Society.