Showing posts with label Research. Show all posts
Showing posts with label Research. Show all posts

Tuesday, June 28, 2016

Myanmar - Health Ministry considers adding research procedures, medical ethics to curriculum

The Ministry of Health is considering the inclusion of research procedures and medical ethics in medical curriculum and is planning projects to serve physicians and other medical professionals.

The ministry plans to increase its budget to fund research at medical universities since current levels are not sufficient.

Since the 2012-2013 academic year, the matriculation score for entry to medical universities had been being high, and the number of medical students countrywide has been reduced in order to favour quality over quantity.

Also, post graduate diploma courses in medicine will admit not only the civil servants but also private sector physicians who have practiced since 2015. For the 2015-2016 academic year, the University of Medicine-1 has opened diplomas in obstetrics and gynaecology, child health education, pathology, anaesthetics, radiology and first aid.

According to data released by the Health Ministry, a total of 12,866 physicians, 674 dentists, 407 dental nurses and 30,793 medical nurses have already appointed in the public sector as of 2015.

Thmon


Sunday, May 1, 2016

Singapore - $7.5 million to be pumped into liver cancer research

SINGAPORE - A Singapore-based team researching the most common type of liver cancer has been awarded a $7.5 million grant to continue its studies, it was announced on Wednesday.

Professor Pierce Chow, a senior consultant surgeon with National Cancer Centre Singapore (NCCS) is leading a multi-disciplinary team comprising clinicians and researchers from several institutions to carry out in-depth studies on the genomics and immunology of liver cancer.

A pilot study into the most common type of liver cancer, Hepatocellular Carcinoma or HCC, has found significant heterogeneity within tumours.This means different parts of the same cancer may have different genetic mutations or produce different immune response.

It explains why current approaches to drug development in HCC have not been fruitful, according to Professor Pierce Chow.

The team has been awarded a $7.5 million grant under the TCR Flagship Programme grant by Singapore's National Medical Research Council (NMRC).

Its research will involve five centres from Singapore and the region and start in the third quarter of this year. The study will be conducted using tumour samples from 100 patients.

The effort could enable doctors to predict the outcome of therapies and help them select appropriate treatments, said Prof Chow.

"Through this translational clinical research, we hope to find an answer to the shortage of efficacious therapies and the challenges of bringing precision medicine to patients with HCC," said Prof Chow.

The team aims to create customised therapies for individual liver cancer patients within the next five years.

In Singapore, 500 new liver cancer patients are diagnosed each year.

It is the fourth most common cancer among men in Singapore. Between 2010 and 2014, 2,254 men were diagnosed with it. It is less common in women and is not within the top 10 cancers in women.

Between 2010 and 2014, 2,516 people died from this form of cancer.



Sunday, June 29, 2014

Singapore - The fat source makes the difference

Stem cells derived from distinct sources of fat display different cell-surface markers — with implications for their roles in metabolism and disease.

Stem cells derived from different types of fat express different cell-surface markers

Mesenchymal stem cells (MSCs) have a natural ability to differentiate into various cell types, such as muscle, cartilage and bone. They can be classified according to their source and include adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMSCs). ASCs, in particular, hold tremendous potential for tissue engineering and regenerative medicine because of their relatively high abundance and ease of isolation.

Shigeki Sugii at the A*STAR Singapore Bioimaging Consortium and co-workers have now isolated ASCs from two different sources of fat: subcutaneous fat found underneath the skin and visceral fat from inside the abdominal cavity1. The team showed that ASCs derived from subcutaneous fat express cell-surface markers that differ from those derived from visceral fat. The finding has implications for determining the origins of ASCs and the roles of their different subtypes in metabolism-related conditions, such as obesity, and diseases such as soft tissue tumors.

Stem cells, like all other cells, express molecules at their surface that are recognized by the body’s immune system. Like a fingerprint, the expression profile of these cell-surface markers is unique to each stem cell type. Scientists already know that MSCs express the cell-surface markers CD73, CD90 and CD105 but not CD14, CD19, CD34 and CD45. Recent studies have also shown that while ASCs express CD36 but not CD106, the opposite is true for BMSCs. Thus, MSCs derived from different tissues express different cell-surface markers, providing a valuable tool for determining the origins of MSCs.

Sugii and co-workers therefore proposed that ASCs derived from different types of fat may also express different cell-surface markers. To investigate this, they extracted subcutaneous and visceral fat from 12 obese patients, as well as normal and obese mice. After isolating ASCs from the fat, the team analyzed the expression profiles of over 240 cell surface markers for each sample. Their analysis revealed a high level of CD10 expression in ASCs derived from subcutaneous fat compared to ASCs derived from visceral fat. In addition, they detected a high level of CD200 expression in ASCs derived from visceral fat compared to those derived from subcutaneous fat.

The researchers also discovered that while CD10-rich ASCs from subcutaneous fat differentiate better than their CD10-deficient counterparts, CD200-deficient ASCs from visceral fat differentiate better than their CD200-rich counterparts.

“Our results suggest that CD10 and CD200 are markers of high and low adipogenic capacities,” says Sugii. “Therefore CD10 and CD200 are biomarkers as well as indicators of adipogenic potentials for use in high-throughput drug-screening systems.”

The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium and the Institute of Molecular and Cell Biology

Reference


  1. Ong, W. K., Tan, C. S., Chan, K. L., Goesantoso, G. G., Chan, X. H. D. et al. Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots. Stem Cell Reports 2, 172–179 (2014). | article

Singapore - The secretions of stem cells

Exosomes secreted from mesenchymal stem cells help to increase the number of regulatory T cells and prevent skin graft rejection in mice.

Tiny vesicles secreted by mesenchymal stem cells can modulate the immune system and prevent the rejection of grafted tissue

Mesenchymal stem cells (MSCs) can be extracted from many different types of tissues and are currently used in clinical trials for a range of conditions, including autoimmune diseases. Now, a team of researchers led by Sai Kiang Lim at the A*STAR Institute of Medical Biology in Singapore has demonstrated that small vesicles secreted by MSCs, called exosomes, can exert anti-inflammatory effects on immune cells in tissue culture and also in mice that have received skin transplants1.

Exosomes contain a variety of proteins and other factors from their originating cells. Previous studies have shown that MSC-derived exosomes protect heart tissue, prompting Lim and colleagues to investigate whether MSC exosomes could have an effect on immune cell function. The researchers isolated MSC exosomes but found that they did not have a direct effect on the proliferation of lymphocytes — a type of white blood cell — taken from the spleen. However, because lymphocyte function is steered by monocytes, another type of white blood cell, the researchers decided to further investigate whether MSC exosomes could activate monocytes instead. They discovered that MSC exosomes reduced the expression of pro-inflammatory factors and increased the expression of anti-inflammatory factors in monocytes.

Toll-like receptors on immune cells are proteins that initiate the immune response following activation by many different factors, including one found in MSC exosomes called fibronectic 1 (FN1). By blocking FN1 with an antibody, the researchers were able to reduce the ability of MSC exosomes to activate monocytes.

When Lim and colleagues exposed the exosome-treated monocytes to developing T cells, a type of lymphocyte, the cells matured into regulatory T (Treg) cells — a cell type that suppresses the immune system. The findings suggest that MSC exosomes probably act directly on monocytes, which can then modulate lymphocyte maturation and function.

As a result of their immunosuppressive properties, Treg cells can help to prevent the rejection of skin grafts by the immune system. To test whether MSC exosomes could facilitate the process, the researchers grafted skin onto mice, and then treated some of the grafted mice with MSC exosomes. Rejection of the grafted skin was delayed by a few days in the exosome-treated mice compared to normal mice, probably due to the higher levels of Treg cells in the exosome-treated mice.

“Our findings suggest that MSC exosomes could be used to alleviate diseases that have a dysfunctional immune component, such as lupus, psoriasis and sepsis,” explains Lim. “A*STAR is currently funding the clinical development of MSC exosomes,” he says.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Bioprocessing Technology Institute

Reference


  1. Zhang, B., Yin, Y., Lai, R. C., Tan, S. S., Choo, A. B. H. & Lim, S. K. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells and Development 23, 1233–1244 (2014). | article

Singapore - Genetic Landscape Of ‘Cantonese Cancer’ Mapped

A study of over 100 nasopharyngeal cancer patients has uncovered the genetic basis of the disease and identified possible drug targets.

AsianScientist (Jun 27, 2014) – A team of scientists from Singapore has identified a distinct mutational signature and nine mutated genes associated with nasopharyngeal cancer, paving the way to developing novel therapies for this deadly disease. The research has been published in the journal Nature Genetics.

The study, led by Professor H. Phillip Koeffler, Senior Principal Investigator at the Cancer Science Institute of Singapore and Deputy Director of National University Cancer Institute of Singapore, is the first comprehensive genomic study of nasopharyngeal carcinoma; a disease with such an usually high prevalence in Southern China that it is sometimes known as “Cantonese cancer”. The findings provide an enhanced road map for the study of the molecular basis of this form of cancer.

Nasopharyngeal carcinoma arises from the epithelial lining of the nasopharynx, the upper part of the throat behind the nose. Unlike cancers that have been extensively studied, such as breast and colon cancers, there is currently a limited understanding of the molecular biology of nasopharyngeal cancer. To date, no targeted therapy has been established and there is an urgent need for a comprehensive genomic landscape of this disease to guide the development of novel therapies.

In this study, the researchers analysed the DNA and proteins of over 100 nasopharyngeal cancer patients in Singapore. The research revealed that many genes are mutated and dysfunctional in the nasopharyngeal tumour cells, some of which cause and exacerbate the disease. Furthermore, the study uncovered a number of novel druggable candidates, proteins that are suitable drug targets due to their ability to bind with high affinity.

Dr. Lin Dechen, research fellow at CSI Singapore and first author of the paper, said, “This malignancy has been somewhat neglected because nasopharyngeal cancer is very rare in the US and Europe. However, the disease is particularly common in Southeast Asia, especially Singapore. Our current study offers immediate translational significance for nasopharyngeal cancer research, specifically, for identifying tailored targeted therapies for the patients, who continue to suffer because to date, no such regimens have been established.”

Prof. Koeffler said, “We wanted to boost the understanding of the etiology as well biology of nasopharyngeal cancer with the hope for improvements in diagnostics, prognostics and therapy, which will promote the well-being of Singaporeans. By completely deciphering all human genes at the single nucleotide level, our current findings provide an important foundation for the study of the molecular basis underlying this malignancy.

“More importantly, many potential therapeutic drugs have surfaced from our analysis, with some of them already in use for treating other types of tumours. Therefore, the results have the potential to rapidly facilitate the development of novel treatment strategies for nasopharyngeal cancer patients.”

With the discovery of these previously unrecognised genetic defects in nasopharyngeal cancer, Prof. Koeffler and his team will explore the detailed molecular mechanisms of these defects in the next phase of research. Associate Professor Loh Kwok Seng from NUH and NCIS, as well as Associate Professor Goh Boon Cher and Associate Professor Lee Soo Chin, from CSI Singapore and NCIS, who are authors of the paper and doctors to many of the patients involved in the study, will evaluate whether some of the genetic defects can be explored in the clinic to effectively treat this disease.



Source: National University of Singapore; Photo: Libertas Academica/Flickr/CC.

Tuesday, December 31, 2013

Asia - Asian Countries among Leaders in Fast-Growing Stem Cell Field

Singapore, Japan and China are among the leaders in stem cell research, a field growing twice as fast as the average growth in research.

Stem cell research is growing twice as fast as the world average growth in research, according to a study of the growth and development of the field. The study also found that Singapore and Japan have some of the highest activity in stem cell research while China is a top contributor in terms of volume.

The report, released at the World Stem Cell Summit, is based on a comprehensive analysis of publications in the stem cell field which includes research on embryonic stem (ES) cells, human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells.

In order to provide a broad and transparent data driven view of the field, the study reviewed leading nations’ research output, citation impact and collaboration behavior, as well as assessing international differences in focus and growth.

The report combines a comprehensive publication analysis from Elsevier’s Scopus, a scientific abstract and citation database, together with scientists’ and other stakeholders’ views on current progress and future expectations of the field.

“This report gives us a bird’s eye view of the international stem cell field, drawing on advanced bibliometric techniques to identify national and international trends – where is stem cell research strongest, where is the sector developing fastest, are the results of individual funding initiatives translating into high impact publications, and so on,” said Professor Clare Blackburn, the Project Coordinator of EuroStemCell.

“It has been extremely interesting to analyze these data, they contain a lot of provocative information. We hope readers will gain a new understanding of the shape of the field that will stimulate future policy discussions.”

According to the report, Singapore, Italy, the USA, Japan, and Israel show the highest level of activity in stem cell research while the US and China show the highest volume.

In addition to the finding that stem cell research is growing twice as fast (7%) as the world average growth in research (2.9%), the study also found that area of induced pluripotent stem cells (awarded the Nobel Prize in Physiology or Medicine in 2012) has grown at an astonishing rate of 77% annually since 2008.
The analysis also found that stem cell publications are 50% more cited than the world average for all related subject areas and that around half of all stem cell papers use keywords related to “drug development” or “regenerative medicine”, reflecting the field’s clinical promise.

While the field has attracted priority status in many countries, it has also been the focus of continuous discussion around ethics and regulation with each nation taking its own policy position, some of which have had a clear effect on the dynamics of the field.

“The challenge for the coming decade is to expand on multi-disciplinary and multi-sector collaboration aimed at large-scale production of high-quality human pluripotent stem cells, and also, robust and reliable production of high-quality differentiated cells”, said Professor Norio Nakatsuji, Founding Director of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS).

“In order to provide adequate support to accelerate such research, a nation should take an evidence-based approach with an understanding of the global trend from a multitude of perspectives.”



Singapore - Keeping the dengue virus unmasked

Mosquitoes spread four different strains of dengue virus, each of which causes dengue fever. For a vaccine to be effective, it needs to prevent infection by all four strains.

A method that stops the dengue virus from resembling a host’s RNA could yield an effective and affordable vaccine

Cases of dengue fever — a potentially life-threatening disease spread by the Aedesmosquito — are increasing worldwide, thanks to expanding mosquito habitats. According to the World Health Organization, the dengue virus infects 50 to 100 million people annually, with Southeast Asia and South America most affected.

An effective and affordable vaccine has eluded scientists, largely because the dengue virus can be one of four types. Each serotype, or any combination of the types, can prevail in a single location. Thus, an effective inoculation needs to confer protection against all of the serotypes.

Katja Fink and co-workers at the A*STAR Singapore Immunology Network, together with scientists across Singapore, China and the United States, have developed a novel strategy for producing a live dengue fever vaccine1. The vaccine currently protects against two of the serotypes, and the team is working to expand this to all four strains.

“We used a mutated form of the dengue virus to create the vaccine,” says Fink. “The mutated virus replicates slowly in the body but does no harm, creating an immune memory response, which is triggered if the host encounters the wild-type virus.”

Usually, RNA molecules in the dengue virus are modified by an enzyme called MTase that adds a methyl group to the viral RNA. This methylation makes the viral RNA resemble the host cell’s RNA and consequently, the body’s immune system does not attack it. Fink and co-workers created mutations in MTase so that the RNA remained unmodified by methylation. The mutations led to a form of the dengue virus that cannot spread quickly yet triggers an effective immune response.

“Our virus is the first live dengue vaccine that contains defined mutations to block a viral enzyme,” explains Fink. “These mutations could be equally introduced to all four serotypes, meaning that no serotype would have an advantage over the others — a situation that otherwise creates an imbalanced immunity.”

The new vaccine gave full protection against wild-type virus infection when tested in mice and monkeys. The researchers found that the mutations remained stable over time and did not revert to the wild type, a potential complication in vaccine development. Furthermore, mosquitoes feeding on blood containing the mutant dengue virus did not become infected.

Live vaccines are relatively cheap and easy to produce. “The enzyme mutation can also be introduced into new strains if dengue virus evolves over time,” says Fink. “Our next challenge is to see whether we can achieve full protection against all four serotypes.”


Reference
  1. Züst, R., Dong, H., Li, X.-F., Chang, D. C., Zhang, B. et al. Rational design of a live attenuated dengue vaccine: 2’-O-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques. PLoS Pathogens 9, e1003521 (2013). | article


Saturday, June 15, 2013

Singapore - Development: When fate hinges on cell–cell contact

Pulling pipettes apart to gently separate early embryonic cells.

Proper cell–cell interactions are required for the cells of early embryos to develop normally

Some 50 years have passed since scientists first proposed the so-called ‘inside–outside model’ of development, which holds that the inner cells of the early embryo eventually form all the definitive structures of the fetus, whereas the outer cells give rise to the placenta. Yet, the determinants of this developmental duality have remained elusive: are lineage decisions predetermined in the egg or is cell–cell contact needed to determine cell fate?

By physically separating cells in young mouse embryos, a team led by Barbara Knowles and Davor Solter from the A*STAR Institute of Medical Biology has definitively shown that extensive cell–cell interactions are required for proper lineage commitment1.

After five rounds of cell division, a fertilized egg reaches the 32-cell stage. Chanchao Lorthongpanich, a postdoctoral fellow in the Knowles–Solter laboratory, mechanically separated cells at this and prior stages and then cultured the cells individually (see image). With her colleagues, she then measured the gene expression profiles of the separated cells. They showed that the pattern was out of sync with normal development, owing to the lack of proper cell–cell contact and the associated positional information that it confers.

Each of the cells, known as blastomeres, failed to display gene markers characteristic of either the inner cell mass — the part of the embryo that gives rise to the fetus proper — or the nourishing trophectoderm, the precursor to the placenta. However, the researchers observed a tendency toward ‘trophectoderm-like’ expression consistent with cells receiving an ‘outside’ signal. Furthermore, when the researchers reassembled the cells, they could not organize themselves into the multiple tissue layers needed for proper development.

“In the absence of structure and the clues provided by it, haphazard and incoherent gene expression is coupled with loss of lineage determination,” says Solter, who is now working to determine the exact cues by which cell–cell interactions lead to proper development. This process is reversible for a short time, but the subsequent loss of proper signals results in permanent damage to the blastomeres, according to Solter.

In addition to providing insights into the basic biology of mammalian development, the results could have important implications for human reproductive medicine. Currently, embryo screening techniques to test for genetic diseases require destroying one or two cells from the embryo at the eight-cell stage. Since the fate of blastomeres is determined by positional cues, rather than any predetermined fate, such diagnostic testing is unlikely to result in fetal malformation, Solter notes.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Bioinformatics Institute

References

  1. Lorthongpanich, C., Doris, T. P. Y., Limviphuvadh, V., Knowles, B. B. & Solter, D. Developmental fate and lineage commitment of singled mouse blastomeres. Development 139, 3722–3731 (2012). | article

Sunday, March 17, 2013

USA - Clinical research shows mouth device as possible treatment for TBI


The tongue is an amazing organ.

Thousands of nerve fibers in it help us eat, drink and swallow. Without them, we would not taste. The tongue helps us speak. Quietly, its surface defends our bodies from germs.

Yet for everything the tongue can do, perhaps one of its most exciting roles is to serve as a direct “gateway” to the brain through thousands of nerve endings.

Now researchers at the U.S. Army Medical Research and Materiel Command in collaboration with the University of Wisconsin-Madison and NeuroHabilitation Corporation are leveraging the power of those tiny nerves. They are aiming to restore lost physical and mental function for service members and civilians who suffered traumatic brain injury or stroke, or who have Parkinson’s or multiple sclerosis.

The treatment involves sending specially patterned nerve impulses to a patient’s brain through an electrode-covered oral device called a “PoNS,” a battery-operated appliance placed on the tongue. The 20-30 minute stimulation therapy, called cranial nerve non-invasive neuromodulation, or CN-NiNM, is accompanied with a custom set of physical, occupational, and cognitive exercises, based on the patient’s deficits. The idea is to improve the brain’s organizational ability and allow the patient to regain neural control.

NeuroHabilitation Corporation is funding the commercial development of the device, and has more than just financial investments in PoNS. The company was created with support by Montel Williams, a celebrity and military veteran who was diagnosed with multiple sclerosis in 1999.

Williams was originally introduced to the research through an American Way magazine an attendant gave to him while he was on an American Airlines flight. The magazine included an article about work being done at the University of Wisconsin-Madison. Shortly after reading the article, Williams joined a study at the University of Wisconsin-Madison’s Tactile Communication & Neurorehabilitation Lab, which is in the Department of Biomedical Engineering.

“The third day there I said we need this in the mouths of our Soldiers,” recalled Williams, stating that he has always kept his ties with the military after serving in the Marine Corps and graduating from the U.S. Naval Academy.

The PoNS prototype and associated therapeutic use were developed by University of Wisconsin-Madison scientists Yuri Danilov, Ph.D., Mitchell Tyler, M.S., P.E., and Kurt Kaczmarek, Ph.D. Their research is driven by the principle that brain function is not hardwired or fixed, but can be reorganized in response to new experiences, sensory input and functional demands. This area of research is called neuroplasticity and is a promising and rapidly growing area of brain research.

Preliminary data from University of Wisconsin showed CN-NiNM to have great potential for a wide variety of neurological issues. Remarkably, the therapy doesn’t only slow functional loss, but also has the potential to restore lost function. That’s why researchers are saying that it “breaks the rules.”

“When we talk about a brain changing itself, this is what we mean,” Danilov said.

Because of its possible application for service members, especially those returning from combat with blast-related traumatic brain injuries, the USAMRMC signed a Cooperative Research and Development Agreement with NeuroHabilitation Corporation (founded by Williams and his colleagues, including the University of Wisconsin scientists), Feb. 8, that allows the Army to further evaluate the device.

“This exciting agreement leverages a unique private-public partnership,” said Col. Dallas Hack, director of the USAMRMC Combat Casualty Care Research Program. “By collaborating with University of Wisconsin-Madison and NeuroHabilitation Corporation, we maximize our resources to explore a potential real-world treatment for injured service members and civilians with a variety of health conditions.”

Testing will include a collaborative study with researchers and clinicians at the Blanchfield Army Community Hospital in Fort Campbell, Ky., due to start this month as the result of a yearlong coordination effort led by Capt. Ian Dews, deputy director of CCCRP. The hospital is home to the Warrior Resiliency and Recovery Center, which is dedicated to the treatment of Soldiers with physical and neuropsychological problems due to service-related trauma.

Additional patient testing will be conducted at other veteran facilities and civilian medical institutions. Concurrently, the USAMRMC, in collaboration with its subcommands the U.S. Army Medical Materiel Agency and the U.S. Army Medical Materiel Development Activity, will conduct environmental testing, such as temperature and humidity limitations for the device, to better understand potential constraints. At the conclusion, the USAMRMC hopes to seek U.S. Food and Drug Administration clearance for PoNS.


Singapore - Scientists Discover Genes That Cause Cornea Blindness


Scientists in Singapore have identified genes for central corneal thickness that may cause potentially blinding eye conditions such as glaucoma.

Scientists in Singapore have identified genes for central corneal thickness (CCT) that may cause potentially blinding eye conditions such as glaucoma.

The multi-center study, led by researchers at the Singapore Eye Research Institute (SERI) and the Agency for Science, Technology and Research (A*STAR) Genome Institute of Singapore (GIS), involved 55 hospitals and research centers around the world, and more than 20,000 individuals of European and Asian descent.

Their findings were published this month in the journal Nature Genetics.

CCT is associated with potentially blinding eye conditions such as keratoconus, a condition where the cornea progressively thins and takes on a more conical shape that may eventually require transplantation. CCT has an estimated heritability up to 95 percent and may determine the severity of one’s glaucoma and assist eye doctors in identifying patients with high risk for progression. CCT is also one of the leading causes of corneal transplantation worldwide.

Prior to this study, the Singapore team had identified six distinct CCT-associated loci via samples from Singaporean Chinese, Indians, and Malays, as well as Beijing Chinese.

However, none of these loci was found to be associated with common eye diseases like this study has now shown. Overall, this new study identified a total of 27 associated loci, including six for keratoconus.

“Yet again, this paper underscores the power of modern genetic approaches studied in very large sample sizes in revealing the hereditable basis of normal human traits, and how the extremes of which may give rise to common diseases,” said Assistant Professor Khor Chiea Chuen, Principal Investigator, Division of Human Genetics at GIS, who was the co-lead author on this study.


Source: A*STAR;


Australia - Genetic Risk Factor For Deadly Parasitic Disease Raises Hopes Of Vaccine

Scientists have uncovered a major genetic risk factor for visceral leishmaniasis which is caused by the Leishmania parasite.

Scientists have uncovered a major genetic risk factor for visceral leishmaniasis which is caused by the Leishmania parasite. The discovery paves the way for the development of a vaccine against the fatally infectious parasite which is carried in the bite of sandflies.

Visceral leishmaniasis, also known as kala-azar or black fever, is the second-largest parasitic killer in the world after malaria. Leishmaniasis affects 12 million people and there are an estimated 1.5 million new cases annually mainly in India, Bangladesh, Nepal, Sudan, South Sudan, Ethiopia. and Brazil.

The parasite can cause fever, weight loss, mucosal ulcers, fatigue, anemia, and substantial swelling of the liver and spleen. If left untreated, the disease is almost always fatal.

To identify genetic risk factors for visceral leishmaniasis, scientists from India, Australia, Brazil, the UK, and the USA conducted a large-scale genome-wide association study of over 2,000 visceral leishmaniasis patients and more than 3,000 healthy subjects in India and Brazil.

In their study, published online in Nature Genetics, they found that variation in a specific region of the major immune response locus, known to immunologists as the major histocompatibility complex (MHC), is the single most important genetic risk factor for the disease.

Teams in Australia, the UK, and the USA are using the results in vaccine research to study the way the immune system interacts with the disease in mice.

“Earlier genetic studies of visceral leishmaniasis in inbred mice allowed us to clearly demonstrate the importance of the MHC in regulating this disease,” said Professor Jenefer Blackwell, who led the LeishGEN Consortium that carried out all of the field work and sample collection.

“Now, major advances in human genetics and the ability to compare the genomes of large numbers of people with and without the disease have allowed us to identify the precise molecular basis to this MHC control in humans.”

“This will have a major impact on refining research towards the ultimate goal of a vaccine.”

The first vaccine against fatal visceral leishmaniasis entered phase I clinical trials last year.




Sunday, January 27, 2013

Singapore - Cerebral malaria: Pinpointing a potential therapeutic target


Dendritic cells from human blood are integral parts of the immune system.

Identification of the subtype of immune cells that is crucial to the onset of cerebral malaria provides a therapeutic starting point

An excessive response of the immune system to malarial infection can lead to serious complications, such as cerebral malaria. While the mechanism causing the onset of cerebral malaria is unclear, immunologists think that contributing factors include cells of the immune system and the inflammation that they cause. Laurent Renia and co-workers at the A*STAR Singapore Immunology Network and collaborators from Nanyang Technological University, Singapore, have now singled out one subtype of immune cells that is key to the onset of this often fatal disease1.

The researchers used an established mouse model of the disease, called experimental cerebral malaria (ECM). Accumulation of CD8+ T cells, immune cells that destroy infected or damaged cells, is one known contributing factor in this model. Dendritic cells (see image), another type of immune cell, are important in activating certain types of T cells and are also known to be involved in experimental cerebral malaria.

“Dendritic cells are essential for the development of the immune response in particular T cells,” explains Renia. “These cells express different markers and are present in many tissues like the spleen. It was previously shown that splenic dendritic cells are important for ECM to develop.”

In the earlier work, dendritic cells were modified so that they could be selectively destroyed. A marker that all dendritic cells express, called CD11c, was targeted with a diphtheria toxin receptor, allowing them to be killed using this toxin. The targeted destruction of dendritic cells prevented experimental cerebral malaria. However, this method did not discriminate between the several subtypes of dendritic cells that express CD11c, so the exact dendritic cell type responsible remained elusive.

Renia and his co-workers used a similar approach in this study, but targeted a marker called Clec9A with the diphtheria toxin receptor. Clec9A is expressed by one subtype of dendritic cells only. The subtype, called CD11chighCD8+, is a candidate in experimental cerebral malaria because its cells are involved in activating CD8+ T cells.

Destroying the CD11chighCD8+ cells provided mice with complete protection from experimental cerebral malaria. Renia and co-workers also showed that without these cells, fewer CD8+ T cells were activated in the spleen and fewer were found in the brain. “Our findings show that these dendritic cells are essential to CD8+ T cell development and thus to experimental cerebral malaria,” says Renia.

Although this work was done in an artificial model of the disease in mice, Renia notes that it provides a starting point in overcoming the disease in people.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network

References
  1. Piva, L., Tetlak, P., Claser, C., Karjalainen, K., Renia, L. et al. Clec9A+ dendritic cells mediate the development of experimental cerebral malaria. The Journal of Immunology 189, 1128–1132 (2012). |  article

Singapore - Biomaterials: Shining light on hair composition


When the molecules that comprise human hair’s outer surface (blue) are packed together tightly (top), they are forced to stand erect, resulting in a thicker layer than when they are less tightly packed (bottom).

A computational study of human hair provides insights into the structure of its poorly understood outer surface

Human hair is a complex, multi-layered material, the composition of which is only partly established. Hair fibers are sheathed in a thin protective coating called the epicuticle, but despite its industrial importance — the epicuticle is the first surface with which hair products interact — the exact structure of this layer is unknown. Now, a theoretical model of epicuticle structure developed at the A*STAR Institute of High Performance Computing (IHPC) has revealed the likely composition and properties of hair’s outer surface1. The model, developed by Daniel Cheong and his co-workers at IHPC, is already helping to resolve apparent discrepancies over epicuticle structure.

Previous experimental research has shown that hair’s outermost surface consists of a thin monolayer of fatty acid molecules called 18-MEA, which stand on end like the bristles on a brush. According to Cheong, one study suggested that these molecules attach to the surface around 1 nanometer apart. “Although this distance is frequently cited, it has never been corroborated, as it is very difficult to measure this value experimentally,” says Cheong.

To examine the 18-MEA separation distance further, Cheong and his co-workers constructed simplified computational models of the hair surface. They then looked for the separation distance that gave the most energetically stable structure. “Surprisingly, our simulation results indicated that the separation distance between the fatty acids should be around 0.5–0.65 nanometers,” says Cheong.

One possible explanation for this apparent disagreement with earlier work could be that bound 18-MEA molecules are indeed spaced 1 nanometer apart; but extra, unbound lipids may pack the space in between to generate the more stable structure, Cheong suggests.

This theory could also resolve apparently conflicting results regarding experimental measurements of the fatty acid layer’s thickness, which have ranged from 1.3 nanometers to 2.6 nanometers. The team’s model shows that the more tightly the fatty acids are packed, the more upright they stand, which makes the epicuticle appear thicker (see image). Cheong suggests that, in studies where this layer was found to be only 1.3 nanometers thick, the free lipids may have been lost, partly collapsing the fatty acid structure. Tellingly, his model predicts that for fatty acids spaced 1 nanometer apart, the layer would appear 1.3 nanometers deep.

“With this simple model, we can also study the interactions between small molecules and the hair surface," Cheong explains. “This would be important in understanding how potential active ingredients in hair products will behave at the hair surface.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of High Performance Computing

References
  1. Cheong, D. W., Lim, F. C. H. & Zhang, L. Insights into the structure of covalently bound fatty acid monolayers on a simplified model of the hair epicuticle from molecular dynamics simulations. Langmuir 28, 13008–13017 (2012). | article

Singapore - Imaging: A sharp look beneath the surface


An optical-coherence tomogram of onion skin, reconstructed with the new method developed by Seck and his co-workers (left), shows sharper details than the original image (right).

A new image-reconstruction method yields clear images of subsurface features in biological specimens and technological components

Optical coherence tomography (OCT) is a popular imaging modality for obtaining three-dimensional, micrometer-resolution pictures of structures that lie beneath the surface of, for example, the human eye or silicon wafers used in the computer industry. The technique could now become even more powerful, thanks to work led by Hon Luen Seck from the Singapore Institute of Manufacturing Technology at A*STAR. The team has found a way to eliminate one of the main noise sources that otherwise blur these images1.

The OCT method works by splitting a light beam into two separate rays. One ray penetrates the sample and partially scatters from features beneath its surface. A fraction of the incident light therefore returns to its origin. This reflected light then interferes with the other ray — known as the ‘reference beam’ — that travelled entirely outside the sample and was reflected from a mirror. The position of the mirror determines which layer of the sample is imaged. By moving the mirror, researchers can obtain information about different parts of the sample.

The method has proved very successful for biological and technological applications. It is, however, plagued by one problem: light returning from the sample not only interferes with the reference beam, but also with other light fields reflected by the sample. “This adds ambiguities when interpreting the image,” says Seck. The method developed by the researchers reliably removes this so-called ‘autocorrelation noise’.

Seck and co-workers liken the process of light scattering from the sample to the passage of light through a particular kind of filter. There are physical constraints on how this filter may look. By putting this additional information into the reconstruction process, the researchers demonstrated that they could almost entirely delete autocorrelation noise from the images (see image). The technique has been developed for OCT, but is not limited to it. “The approach can be adapted to other image-formation processes,” explains Seck.

The team’s method works particularly well with sparse samples, which sport relatively few features. This is the case, for instance, in biological specimens and in layered electronics. “We plan to explore now the application of the technique to the imaging of printed electronics devices and micro-fluidics devices,” says Seck. Moreover, the researchers are working to make the reconstruction algorithm faster: “At the moment, our method is not able to achieve instantaneous reconstruction as required for real-time applications where an area scan is required, but we expect that with ongoing research the computational demand will decrease.”

The A*STAR-affiliated researchers contributing to this research are from the Singapore Institute of Manufacturing Technology
 
References
  1. Seck, H. L., Zhang, Y. & Soh, Y. C. Autocorrelation noise removal for optical coherence tomography by sparse filter design. Journal of Biomedical Optics 17, 076029 (2012). | article

Singapore - Cell biology: Accelerating cellular assembly lines


By selecting antibodies (blue and yellow) with strong affinity for particular targets, scientists can label or isolate proteins of interest, or even modulate the function of those proteins in living cells.

Insights into cellular productivity could boost generation of proteins with valuable research and medical applications

The immune system generates antibodies to mark threats that need to be eliminated, and these protein complexes bind their targets with remarkable strength and selectivity. Scientists have learned how to generate cell lines that can produce large quantities of specific ‘monoclonal’ antibodies (mAbs) with desirable properties; these mAbs are powerful tools for diagnostics, medicine and biological research.

The selection of suitable cell lines is an important aspect of large-scale production, as these can vary considerably in their individual mAb output. To assist manufacturing facilities in maximizing the generation of these precious molecules, Ying Swan Ho’s team at the A*STAR Bioprocessing Technology Institute in Singapore has identified key features of top-performing cells in mAb-producing cultures1.

Previous efforts have sought genetic differences that might affect production, but Ho and co-workers instead devised a strategy that allowed them to directly compare levels of metabolically active molecules present in Chinese hamster ovary (CHO) cells that secrete large or small amounts of a given mAb. “This approach enabled us to gain a deeper insight into the metabolic milieu that supports recombinant protein production in mammalian cell cultures,” explains Ho.

The researchers cultivated CHO clones that were either high or low mAb producers, where productivity differed by up to 28-fold. They observed clear differences between the two groups in levels of molecules associated with several key metabolic pathways. For example, high-producer clones contained elevated levels of compounds associated with the electron transport chain, a mechanism that generates the adenosine triphosphate (ATP) molecules that power virtually every cellular process.

As energy and mAb production ramp up, cells also generate large quantities of molecules known as reactive oxygen species, which can inflict serious damage on the cell. This threat can be neutralized by molecules such as reduced glutathione (GSH). Ho and co-workers determined that high producers of mAbs also generated greater amounts of GSH than their low-production counterparts.

These findings offer a more global view into how CHO cells might brace themselves to handle the rigors of large-scale protein synthesis. The researchers now intend to explore the individual contributions of these various metabolic pathways. “This will be done by evaluating the effects of increasing the cellular pools of these metabolites on mAb productivity in different cell lines,” says Ho. With a deeper understanding of the key pathways, scientists should be able to either improve the selection of mAb-producing clones or modify culture conditions to ensure that the cells can work as hard as possible.

The A*STAR-affiliated researchers contributing to this research are from the Bioprocessing Technology Institute

References
  1. Chong, W. P. K., Thng, S. H., Hiu, A. P., Lee, D.-Y., Chan, E. C. Y. & Ho, Y. S. LC-MS-based metabolic characterization of high monoclonal antibody-producing Chinese hamster ovary cells. Biotechnology and Bioengineering 109, 3103–3111 (2012). | article