Over the past several decades, malaria diagnosis has changed very little. After taking a blood sample from a patient, a technician smears the blood across a glass slide, stains it with a special dye, and looks under a microscope for the Plasmodium parasite, which causes the disease. This approach gives an accurate count of how many parasites are in the blood — an important measure of disease severity — but is not ideal because there is potential for human error.
A research team from the Singapore-MIT Alliance for Research and Technology (SMART) has now come up with a possible alternative. The researchers have devised a way to use magnetic resonance relaxometry (MRR), a close cousin of magnetic resonance imaging (MRI), to detect a parasitic waste product in the blood of infected patients. This technique could offer a more reliable way to detect malaria, says Jongyoon Han, a professor of electrical engineering and biological engineering at MIT.

“There is real potential to make this into a field-deployable system, especially since you don’t need any kind of labels or dye. It’s based on a naturally occurring biomarker that does not require any biochemical processing of samples” says Han, one of the senior authors of a paper describing the technique.

With the traditional blood-smear technique, a technician stains the blood with a reagent that dyes cell nuclei. Red blood cells don’t have nuclei, so any that show up are presumed to belong to parasite cells. However, the technology and expertise needed to identify the parasite are not always available in some of the regions most affected by malaria, and technicians don’t always agree in their interpretations of the smears, Han says.

“There’s a lot of human-to-human variation regarding what counts as infected red blood cells versus some dust particles stuck on the plate. It really takes a lot of practice,” he says.
The new SMART system detects a parasitic waste product called haemozoin. When the parasites infect red blood cells, they feed on the nutrient-rich haemoglobin carried by the cells. As haemoglobin breaks down, it releases iron, which can be toxic, so the parasite converts the iron into hemozoin — a weakly paramagnetic crystallite.
Those crystals interfere with the normal magnetic spins of hydrogen atoms. When exposed to a powerful magnetic field, hydrogen atoms align their spins in the same direction. When a second, smaller field perturbs the atoms, they should all change their spins in synchrony — but if another magnetic particle, such as hemozoin, is present, this synchrony is disrupted through a process called relaxation. The more magnetic particles are present, the more quickly the synchrony is disrupted.

“What we are trying to really measure is how the hydrogen’s nuclear magnetic resonance is affected by the proximity of other magnetic particles,” Han says.
For this study, the researchers used a 0.5-tesla magnet, much less expensive and powerful than the 2- or 3-tesla magnets typically required for MRI diagnostic imaging, which can cost up to $2 million. The current device prototype is small enough to sit on a table or lab bench, but the team is also working on a portable version that is about the size of a small electronic tablet.
After taking a blood sample and spinning it down to concentrate the red blood cells, the sample analysis takes less than a minute. Only about 10 microliters of blood is required, which can be obtained with a finger prick, making the procedure minimally invasive and much easier for health care workers than drawing blood intravenously.

“This system can be built at a very low cost, relative to the million-dollar MRI machines used in a hospital,” Peng says. “Furthermore, since this technique does not rely on expensive labelling with chemical reagents, we are able to get each diagnostic test done at a cost of less than 10 cents.” MIT

In a breakthrough discovery at the Children’s Medical Center Research Institute at UT Southwestern (CRI), a research team led by Ralph DeBerardinis, M.D., Ph.D., has taken a significant step in cracking the code of an atypical metabolic pathway that allows certain cancerous tumours to thrive, providing a possible roadmap for defeating such cancers.
Following up on Dr. DeBerardinis’ landmark finding in 2011, this most recent discovery identifies the triggering mechanism that plays a key role in causing a series of energy-generating chemical reactions known as the Krebs cycle to run in reverse.

‘With this finding, we have learned there are particular enzymes that work together to enable the reverse pathway to function, much like the tiny gears that turn in opposite directions to power a mechanical clock,’ said Dr. DeBerardinis, director of CRI’s Genetic and Metabolic Disease Program and associate professor in the Department of Pediatrics and the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center.

The identification of the mechanism could provide a future target for drugs that would attack tumours relying upon the reverse pathway for sustenance and growth. Tumours of this type, often found in the brain, lungs and kidneys, tend to be difficult for oncologists to treat because cells using the atypical pathway seem to resist existing treatments like chemotherapy.

‘Prior to this discovery, we didn’t have enough information about how to tap into the reverse metabolic pathway without disrupting the pathways that were operating in the typical, forward manner,’ said Dr. DeBerardinis, senior author of the study. ‘We now believe there is a specific enzyme critical to the reverse pathway that can be deleted without impairing normal function. If we can eliminate that enzyme, we may be able to starve tumours of their supply of building blocks for growth.’ UT Southwestern

A genomic analysis of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, from 72 patients has uncovered 31 genes that are key to development, growth and spread of the cancer, say researchers from Mayo Clinic in Florida. Eight of these genes had not been previously linked to kidney cancer, and six other genes were never known to be involved in any form of cancer.

Their stud is the most extensive analysis to date of gene expression’s role in ccRCC tumor growth and metastasis. The ccRCC subtype accounts for 80 percent of all kidney cancer cases.
This study is a thorough analysis, because overexpressed genes were functionally tested in kidney cancer cells to ensure they were important to some aspect of the cancer process, says the study’s senior investigator, molecular biologist, John A. Copland, Ph.D.

“The power of this study is that we looked at genes discovered to be over-expressed in patients’ tumours and determined their function in kidney cancer, which has not been done on a large scale before,” he says. “This is a seminal step in identifying key pathways and molecules involved in kidney cancer so that specific therapies that target these new genes can be developed to treat this cancer.” Mayo Clinic

Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.

The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark. Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease.

Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.

“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal.  Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.

Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.

“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.” University of Copenhagen

This spring has brought rare but tangible moments of progress against the devastating lung disease idiopathic pulmonary fibrosis (IPF), which afflicts millions of people worldwide. Two drugs recently showed promise in clinical trials, and now a study offers both an unprecedentedly deep explanation of how the disease progresses and introduces another potential therapeutic avenue.
The new study features a central figure: an evolutionarily ancient protein called ‘chitinase 3-like-1’ (CHI3L1). The authors implicate it as the ‘master regulator’ of what appears to be a tragically errant repair response to the mysterious lung injuries that give rise to the disease. In describing how CHI3L1 works in IPF, the research also points to a strategy for treatment.
The report demonstrates that CHI3L1 is produced to help in response to the injury. It feeds back to protect injured cells from dying and simultaneously stimulates tissue repair to patch the damage that has occurred. But the study also shows how this dual role contributes to the ultimate problem. If IPF resulted from a single injury, like a paper cut, CHI3L1 would decrease the injury and cause local scarring while it restored tissue integrity. In that case, the amount of scarring would not be excessive and tissue function would not be significantly altered. But in IPF lungs, cells undergo ongoing injury, so CHI3L1 is chronically elevated and scar tissue accumulates. As CHI3L1 rescues cell after cell, the scarring builds up, eventually compromising the lung’s ability to breathe. In IPF, 70 percent of patients die within five years.
‘The CHI3L1 is doing exactly what it is supposed to do — it is designed to shut off cell death and decrease injury,’ said Dr. Jack A. Elias, a co-senior author of the study and dean of medicine and biological sciences at Brown University. He is joined on the paper by a host of his former colleagues and students at Yale University where the research occurred. ‘But at the same time it is decreasing cell death it is driving the fibrosis. You’ve got this ongoing injury so you’ve got these ongoing attempts to shut off injury which stimulate scarring.’
　
　
They compared tissues and serum from normal patients, outpatients with IPF, and patients with an acute exacerbation (AE) of IPF. In AE, widespread lung injury is superimposed on the pulmonary fibrosis, which frequently occurs before patients die. In lung biopsies and serum, they found that CHI3L1 levels are elevated in both tissue compartments in the outpatients with IPF and that the levels of CHI3L1 correlated with their disease progression. In the patients with AE, elevated levels of CHI3L1 were not noted, showing that the levels of CHI3L1 decrease right before the patients die.
‘This demonstrates that the CHI3L1 plays a key role in controlling lung injury in this setting,’ Elias said.
After documenting that elevated levels of CHI3L1 correlate with ongoing fibrosis and scarring and that a lack of the protein associates with widespread cell death, the team engaged in several manipulations of CHI3L1 in mice to see how levels and the clinical outcomes might be related. (In mice, CHI3L1 is also called BRP-39.)
Scientists can induce an IPF-like response in mice using a drug called bleomycin. In mice given bleomycin, the researchers found that the levels of CHI3L1 declined at first and then surged. At the times when the protein levels were low, cell damage occurred, and when the protein surged, the excessive scarring set in.
In previous research the team had engineered several lines of genetically modified mice. Some were transgenic and can produce CHI3l1 on chemically delivered command. Other mice were engineered to never produce BRP-39 — the mouse version of CHI3L1 — at all.
Using these mice, the researchers found that if they triggered CHI3L1 production early after administering bleomycin, the mice fared well, experiencing less injury, less damage and less scarring than controls. If they waited several days after bleomycin to trigger CHI3L1, the mice fared very poorly and scarring and mortality went up.
Mice who couldn’t produce CHI3L1/BRP-39, had acute lung cell damage, somewhat like AE patients who have a relative deficiency of CHI3L1. However, without CHI3L1 they did not generate much scarring.
All of these findings were supplemented with several other experiments that were designed to learn how CHI3L1 interacts with other cells involved in the tissue repair response in both human and mouse lungs. The experiments, including studies conducted in a bioengineered 3-D model of lung tissue seeded with relevant cells, showed that CHI3L1 regulates a pathway that recruits cells such as macrophages and fibroblasts that produce the scarring, or fibrosis.
In all, the results show that CHI3L1 plays a fundamental role in the course, if not the origin, of IPF. An ongoing buildup of it results in excessive scarring. Too little and cells die much more frequently.
‘To my knowledge this is the first comprehensive paper that’s been able to explain the many facets and presentations of IPF,’ Elias said. ‘It explains and links the injury and the repair responses that are critical in the disease. It also provides an explanation for the slowly progressing patients and the patients that experience acute exacerbations.’ Brown University