Chipmaker Races to Save Stephen Hawking’s Speech as His Condition Deteriorates

Intel is developing communication technology that can quickly process and respond to signals Hawking sends from the few muscles in his body that he can still control

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Four-stranded ‘quadruple helix’ DNA structure proven to exist in human cells

In 1953, Cambridge researchers Watson and Crick published a paper describing the interweaving ‘double helix’ DNA structure – the chemical code for all life.

Now, in the year of that scientific landmark’s 60^th Anniversary, Cambridge researchers have published a paper proving that four-stranded ‘quadruple helix’ DNA structures – known as G-quadruplexes – also exist within the human genome. They form in regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’.

The findings mark the culmination of over 10 years investigation by scientists to show these complex structures in vivo – in living human cells – working from the hypothetical, through computational modelling to synthetic lab experiments and finally the identification in human cancer cells using fluorescent biomarkers.

The research, published in Nature Chemistry and funded by Cancer Research UK, goes on to show clear links between concentrations of four-stranded quadruplexes and the process of DNA replication, which is pivotal to cell division and production.

Leprosy Bacteria Turn Nerve System Cells into Stem Cells

The study, carried out in mice, found that in the early stages of infection, M. leprae were able to protect themselves from the body’s immune system by hiding in the Schwann cells. Once the infection was fully established, the bacteria were able to convert the Schwann cells to become like stem cells.

Like typical stem cells, these cells were pluripotent, meaning they could then become other cell types, for instance muscle cells. This enabled M. leprae to spread to tissues in the body.

The study, published in the journal Cell, also shows that the bacteria-generated stem cells have unexpected characteristic. They can secrete specialized proteins – called chemokines – that attract immune cells, which in turn pick up the bacteria and spread the infection.

“We have found a new weapon in a bacteria’s armory that enables them to spread effectively in the body by converting infected cells to stem cells. Greater understanding of how this occurs could help research to diagnose bacterial infectious diseases, such as leprosy, much earlier,” said study lead author Prof Anura Rambukkana, Medical Research Council Center for Regenerative Medicine at the University of Edinburgh.

“This is very intriguing as it is the first time that we have seen that functional adult tissue cells can be reprogrammed into stem cells by natural bacterial infection, which also does not carry the risk of creating tumorous cells. Potentially you could use the bacteria to change the flexibility of cells, turning them into stem cells and then use the standard antibiotics to kill the bacteria completely so that the cells could then be transplanted safely to tissue that has been damaged by degenerative disease.”

Dr Rob Buckle, Head of Regenerative Medicine at the Medical Research Council Center for Regenerative Medicine at the University of Edinburgh, said: “this ground-breaking new research shows that bacteria are able to sneak under the radar of the immune system by hijacking a naturally occurring mechanism to ‘reprogramme’ cells to make them look and behave like stem cells. This discovery is important not just for our understanding and treatment of bacterial disease, but for the rapidly progressing field of regenerative medicine. In future, this knowledge may help scientists to improve the safety and utility of lab-produced pluripotent stem cells and help drive the development of new regenerative therapies for a range of human diseases, which are currently impossible to treat.”

The scientists believe mechanisms used by leprosy bacteria could exist in other infectious diseases. Knowledge of this newly discovered tactic used by bacteria to spread infection could help research to improve treatments and earlier diagnosis of infectious diseases.

Researchers turn one form of neuron into another in the brain

A new finding by Harvard stem cell biologists turns one of the basics of neurobiology on its head – demonstrating that it is possible to turn one type of already differentiated neuron into another within the brain.

The discovery by Paola Arlotta and Caroline Rouaux “tells you that maybe the brain is not as immutable as we always thought, because at least during an early window of time one can reprogram the identity of one neuronal class into another,” said Arlotta, an Associate Professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB).

The principle of direct lineage reprogramming of differentiated cells within the body was first proven by SCRB co-chair and Harvard Stem Cell Institute (HSCI) co-director Doug Melton and colleagues five years ago, when they reprogrammed exocrine pancreatic cells directly into insulin producing beta cells.

Arlotta and Rouaux now have proven that neurons too can change their mind. The work is being published on-line by the journal Nature Cell Biology.

In their experiments, Arlotta targeted callosal projection neurons, which connect the two hemispheres of the brain, and turned them into neurons similar to corticospinal motor neurons, one of two populations of neurons destroyed in Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. To achieve such reprogramming of neuronal identity, the researchers used a transcription factor called Fezf2, which long as been known for playing a central role in the development of corticospinal neurons in the embryo.

What makes the finding even more significant is that the work was done in the brains of living mice, rather than in collections of cells in laboratory dishes. The mice were young, so researchers still do not know if neuronal reprogramming will be possible in older laboratory animals – and humans. If it is possible, this has enormous implications for the treatment of neurodegenerative diseases.

"Neurodegenerative diseases typically effect a specific population of neurons, leaving many others untouched. For example, in ALS it is corticospinal motor neurons in the brain and motor neurons in the spinal cord, among the many neurons of the nervous system, that selectively die," Arlotta said. "What if one could take neurons that are spared in a given disease and turn them directly into the neurons that die off? In ALS, if you could generate even a small percentage of corticospinal motor neurons, it would likely be sufficient to recover basic functioning," she said.

The experiments that led to the new finding began five years ago, when “we wondered: in nature you never seen a neuron change identity; are we just not seeing it, or is this the reality? Can we take one type of neuron and turn it into another?” Arlotta and Rouaux asked themselves.

Over the course of the five years, the researchers analyzed “thousands and thousands of neurons, looking for many molecular markers as well as new connectivity that would indicate that reprogramming was occurring,” Arlotta said. “We could have had this two years ago, but while this was a conceptually very simple set of experiments, it was technically difficult. The work was meant to test important dogmas on the irreversible nature of neurons in vivo. We had to prove, without a shadow of a doubt, that this was happening.”

The work in Arlotta’s lab is focused on the cerebral cortex, but “it opens the door to reprogramming in other areas of the central nervous system,” she said.

Arlotta, an HSCI principal faculty member, is now working with colleague Takao Hensch, of Harvard’s Department of Molecular and Cellular Biology, to explicate the physiology of the reprogrammed neurons, and learn how they communicate within pre-existing neuronal networks.

"My hope is that this will facilitate work in a new field of neurobiology that explores the boundaries and power of neuronal reprogramming to re-engineer circuits relevant to disease," said Paola Arlotta.

(Image courtesy Tulane University)

Blood-Based Biomarkers May Lead to Earlier Diagnosis of Parkinson’s Disease

Pilot Study Published in the Journal of Parkinson’s Disease

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"The ideal biomarker should be minimally-invasive, cost efficient, quantifiable, reproducible, specific, and sensitive," explains lead investigator Sok Kean Khoo, PhD, of the Center for Neurodegenerative Science and Genomic Microarray Core Facility at the Van Andel Institute, Grand Rapids, Michigan. "Biofluids such as plasma could provide an ideal resource for development of such desirable biomarkers. However, clinical diagnostic tests based on biochemical analysis of biofluids from PD patients have yet to be established," she continues.

Investigators hypothesized that specific miRNAs related to PD can be detected in plasma. It is known that miRNAs detected in various cells and tissues can also be found in biofluids such as blood plasma and serum. A preliminary study using miRNA microarrays showed that approximately 4% (35/866) of miRNAs from healthy brain tissues could also be detected in the plasma of healthy controls.

In an initial study they obtained the global miRNA expressions in plasma of an initial discovery set of 32 PD patients and 32 normal controls and identified nine pairs of PD-predictive classifiers and 13 most-differentially expressed miRNAs as potential biomarkers to discriminate PD patients from normal controls. They then used a quantitative real-time Polymerase Chain Reaction technique (qRT-PCR) to validate and evaluate the performance of these biomarkers in a new replication set of 42 PD patients and 30 controls from the same clinical site.

They then identified a combination of biomarkers that achieved the highest predictive performance and applied this panel of biomarkers to a new, independent validation set of samples from 30 PD patients from a different clinical site, which showed lower biomarker performance.

The investigators acknowledge that there are still challenges to be overcome in validating biomarker candidates due to clinical and sample variability and factors that influence miRNA expression such as comorbidities and other medication the patient is taking. However, explains Dr Khoo, “This is a proof-of-concept study to demonstrate the feasibility of using plasma-based circulating miRNAs, and the hypothesis that miRNA expression changes are associated with the neurodegenerative disease process, either directly or as part of positive feedback loops, is emerging rapidly. This study opens new opportunities to the exploration of circulating miRNAs for diagnostic, prognostic, and therapeutic interventions for PD and possibly other neurodegenerative diseases.”

"A diagnostic test to determine the status of a patient’s disease onset would provide crucial data for more timely, efficient, and successful therapeutic interventions," said Patrik Brundin, MD, PhD, Director of Van Andel Institute’s Center for Neurodegenerative Science. "There is an urgent need to develop objective, measureable biomarkers to improve PD diagnostics and help define its subtypes, and Dr. Khoo’s interesting study is an important step in that direction."

(Image: Wikipedia)

Robot Allows ‘Remote Presence’ in Programming Brain and Spine Stimulators

With the rapidly expanding use of brain and spinal cord stimulation therapy (neuromodulation), new “remote presence” technologies may help to meet the demand for experts to perform stimulator programming, reports a study in the January issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The preliminary study by Dr. Ivar Mendez of Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada, supports the feasibility and safety of using a remote presence robot—called the “RP-7”—to increase access to specialists qualified to program the brain and spine stimulators used in neuromodulation.

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Light Switch Inside Brain: Laser Controls Individual Nerve Cells in Mouse

Activating and deactivating individual nerve cells in the brain is something many neuroscientists wish they could do, as it would help them to better understand how the brain works.

Scientists in Freiburg and Basel, Switzerland, have developed an implant that is able to genetically modify specific nerve cells, control them with light stimuli, and measure their electrical activity all at the same time. This novel 3-in-1 tool paves the way for completely new experiments in neurobiology, also at Freiburg’s new Cluster of Excellence BrainLinks-BrainTools.

Birthe Rubehn and her colleagues from the Department of Microsystems Engineering (IMTEK) and the Bernstein Center of the University of Freiburg as well as the Friedrich Miescher Institute for Biomedical Research in Basel describe the prototype of their implant in the journal Lab on a Chip. They report that initial experiments in which they implanted prototypes into mice were successful: The team was able to influence the activity of nerve cells in the brain in a controlled manner by means of laser light pulses.

The team used an innovative genetic technique that makes nerve cells change their activity by shining different colored lights on them. In optogenetics, genes from certain species of algae are inserted into the genome of another organism, for instance a mouse. The genes lead to the inclusion of light-sensitive pores for electrically charged particles into a nerve cell’s membrane. These additional openings allow neuroscientists to control the cells’ electrical activity.

However, only the new implant from Freiburg and Basel makes this principle actually practicable. The device, at its tip only a quarter of a millimeter wide and a tenth of a millimeter thick, was constructed on the basis of polymers, special plastics whose safety for implantation into the nervous system has been proven.

Unlike probes developed so far, it is capable of injecting substances necessary for genetic modification, emitting light for the stimulation of the nerve cells, and measuring the effect through various electrical contacts all at once. Besides optimizing the technique for production, the scientists want to develop a second version whose injection channel dissolves over time, reducing the implant’s size even further.

Study findings have potential to prevent, reverse serious disabilities affecting children born prematurely

Physician-scientists at Oregon Health & Science University Doernbecher Children’s Hospital are challenging the way pediatric neurologists think about brain injury in the pre-term infant. In a study published online in the Jan. 16 issue of Science Translational Medicine, the OHSU Doernbecher researchers report for the first time that low blood and oxygen flow to the developing brain does not, as previously thought, cause an irreversible loss of brain cells, but rather disrupts the cells’ ability to fully mature. This discovery opens up new avenues for potential therapies to promote regeneration and repair of the premature brain.

“As neurologists, we thought ischemia killed the neurons and that they were irreversibly lost from the brain. But this new data challenges that notion by showing that ischemia, or low blood flow to the brain, can alter the maturation of the neurons without causing the death of these cells. As a result, we can focus greater attention on developing the right interventions, at the right time early in development, to promote neurons to more fully mature and reduce the often serious impact of preterm birth. We now have a much more hopeful scenario,” said Stephen Back, M.D., Ph.D., lead investigator and professor of pediatrics and neurology in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital.

Researchers at OHSU Doernbecher have conducted a number of studies in preterm fetal sheep to define how disturbances in brain blood flow lead to injury in the developing brain. Their findings have led to important advances in the care of critically ill newborn infants.

For this study, Back and colleagues used pioneering new MRI studies that allow injury to the developing brain to be identified much earlier than previously feasible. They looked at the cerebral cortex, or “thinking” part of the brain, which controls the complex tasks involved with learning, attention and social behaviors that are frequently impaired in children who survive preterm birth. Specifically, they observed how brain injury in the cerebral cortex of fetal sheep evolved over one month and found no evidence that cells were dying or being lost. They did notice, however, that more brain cells were packed into a smaller volume of brain tissue, which led to, upon further examination, the discovery that the brain cells weren’t fully mature.

In a related study published in the same online issue of Science Translational Medicine, investigators at The Hospital for Sick Children and the University of Toronto studied 95 premature infants using MRI and found that impaired growth of the infants was the strongest predictor of the MRI abnormalities, suggesting that interventions to improve infant nutrition and growth may lead to improved cortical development.

“I believe these studies provide hope for the future for preterm babies with brain injury, because our findings suggest that neurons are not being permanently lost from the human cerebral cortex due to ischemia. This raises the possibility that neurodevelopmental enrichment — or perhaps improved early infant nutrition — as suggested by the companion paper, might make a difference in terms of improved cognitive outcome,” Back said.

“Together, these studies challenge the conventional wisdom that preterm birth is associated with a loss of cortical neurons. This finding may change the way neurologists think about diagnosing and treating children born prematurely,” said Jill Morris, Ph.D., a program director at the National Institute’s of Health’s National Institute Neurological Disorders and Stroke.