Insulin can increase mosquitoes' immunity to West Nile virus

A discovery by a Washington State University-led research team has the potential to inhibit the spread of West Nile virus as well as Zika and dengue viruses.

In a study published today in the journal Cell Reports, researchers demonstrated that mammalian insulin activated an antiviral immunity pathway in mosquitoes, increasing the insects' ability to suppress the viruses.

Mosquito (stock image).

Credit: © anatchant / Adobe Stock

Mosquito bites are the most common way humans are infected with flaviviruses, a virus family that includes West Nile, dengue and Zika. In humans, both West Nile and dengue can result in severe illness, even death. Zika has been linked to birth defects when pregnant women are infected.
"It's really important that we have some sort of protection against these diseases because currently, we don't have any treatments. If we're able to stop the infection at the level of the mosquito, then humans wouldn't get the virus," said Laura Ahlers, the study's lead author and a recent Ph.D. graduate from WSU. Ahlers is now a post-doctoral fellow with the National Institutes of Health in Bethesda, Maryland.
Working first with fruit flies, which have similar immune responses to mosquitoes, Ahlers and her colleagues identified an insulin-like receptor in the insects that, when activated, inhibits the replication of the West Nile virus in the flies. The researchers then elicited this same response in mosquitoes by feeding them blood containing elevated insulin. Subsequent tests showed activating this receptor was also effective in suppressing dengue and Zika in insect cells.
While it was already known that insulin boosts immune responses in mosquitoes, this is the first time insulin's connection to a particular immune response pathway, called JAK/STAT, has been identified. It is a significant step toward the long-term goal of creating an intervention, said Alan Goodman, WSU assistant professor and the corresponding author on the paper.
"If we can activate this arm of immunity through the insulin receptor in the mosquito, we can reduce the overall viral load in the mosquito population," Goodman said. "If the mosquitoes are carrying less virus when they bite you, they will transmit less of the virus, and there's a better chance you won't acquire the disease."
 

Journal Reference:

1. Laura R.H. Ahlers, Chasity E. Trammell, Grace F. Carrell, Sophie Mackinnon, Brandi K. Torrevillas, Clement Y. Chow, Shirley Luckhart, Alan G. Goodman. Insulin Potentiates JAK/STAT Signaling to Broadly Inhibit Flavivirus Replication in Insect Vectors. Cell Reports, 2019; 29 (7): 1946 DOI: 10.1016/j.celrep.2019.10.029 

Courtesy: ScienceDaily
 

Specific neurons that map memories now identified in the human brain

An important aspect of human memory is our ability to conjure specific moments from the vast array of experiences that have occurred in any given setting. For example, if asked to recommend a tourist itinerary for a city you have visited many times, your brain somehow enables you to selectively recall and distinguish specific memories from your different trips to provide an answer.

Brain-map overlay concept illustration (stock image).

Credit: © alswart / Adobe Stock

Studies have shown that declarative memory -- the kind of memory you can consciously recall like your home address or your mother's name -- relies on healthy medial temporal lobe structures in the brain, including the hippocampus and entorhinal cortex (EC). These regions are also important for spatial cognition, demonstrated? by the Nobel-Prize-winning discovery of "place cells" and "grid cells" in these regions -- neurons that activate to represent specific locations in the environment during navigation (akin to a GPS). However, it has not been clear if or how this "spatial map" in the brain relates to a person's memory of events at those locations, and how neuronal activity in these regions enables us to target a particular memory for retrieval among related experiences.
A team led by neuroengineers at Columbia Engineering has found the first evidence that individual neurons in the human brain target specific memories during recall. They studied recordings in neurosurgical patients who had electrodes implanted in their brains and examined how the patients' brain signals corresponded to their behavior while performing a virtual-reality (VR) object-location memory task. The researchers identified "memory-trace cells" whose activity was spatially tuned to the location where subjects remembered encountering specific objects. The study is published today in Nature Neuroscience.
"We found these memory-trace neurons primarily in the entorhinal cortex (EC), which is one of the first regions of the brain affected by the onset of Alzheimer 's disease," says Joshua Jacobs, associate professor of biomedical engineering, who directed the study. "Because the activity of these neurons is closely related to what a person is trying to remember, it is possible that their activity is disrupted by diseases like Alzheimer's, leading to memory deficits. Our findings should open up new lines of investigation into how neural activity in the entorhinal cortex and medial temporal lobe helps us target past events for recall, and more generally how space and memory overlap in the brain."
The team was able to measure the activity of single neurons by taking advantage of a rare opportunity: invasively recording from the brains of 19 neurosurgical patients at several hospitals, including the Columbia University Irving Medical Center. The patients had drug-resistant epilepsy and so had already had recording electrodes implanted in their brains for their clinical treatment. The researchers designed experiments as engaging and immersive VR computer games and the bedridden patients used laptops and handheld controllers to move through virtual environments. In performing the task, subjects first navigated through the environment to learn the locations of four unique objects. Then the researchers removed the objects and asked patients to move through the environment and mark the location of one specific object on each trial.
The team measured the activity of neurons as the patients moved through the environment and marked their memory targets. Initially, they identified purely spatially tuned neurons similar to "place cells" that always activated when patients moved through specific locations, regardless of the subjects' memory target. "These neurons seemed only to care about the person's spatial location, like a pure GPS," says Salman E. Qasim, Jacobs' PhD student and lead author of the study.
But the researchers also noticed that other neurons only activated in locations relevant to the memory the patient was recalling on that trial -- whenever patients were instructed to target a different memory for recall, these neurons changed their activity to match the new target's remembered location. What especially excited Jacobs and Qasim is that they could actually decode the specific memory a patient was targeting based on the activity of these neurons.
"Our study demonstrates that neurons in the human brain track the experiences we are willfully recalling, and can change their activity patterns to differentiate between memories. They're just like the pins on your Google map that mark the locations you remember for important events," Qasim says. "This discovery might provide a potential mechanism for our ability to selectively call upon different experiences from the past and highlights how these memories may influence our brain's spatial map."
Jacobs and Qasim plan next to look for evidence that these neurons represent memories in non-spatial contexts to better characterize their role in memory function. "We know now that neurons care about where our memories occur and now we want to see if these neurons care about other features of those memories, like when they occurred, what occurred, and so on," Qasim notes.
 

Journal Reference:

1. Salman E. Qasim, Jonathan Miller, Cory S. Inman, Robert E. Gross, Jon T. Willie, Bradley Lega, Jui-Jui Lin, Ashwini Sharan, Chengyuan Wu, Michael R. Sperling, Sameer A. Sheth, Guy M. McKhann, Elliot H. Smith, Catherine Schevon, Joel M. Stein, Joshua Jacobs. Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex. Nature Neuroscience, 2019; DOI: 10.1038/s41593-019-0523-z 

Courtesy: ScienceDaily
 

Drinking tea improves brain health, study suggests

A recent study led by researchers from the National University of Singapore (NUS) revealed that regular tea drinkers have better organised brain regions -- and this is associated with healthy cognitive function -- compared to non-tea drinkers. The research team made this discovery after examining neuroimaging data of 36 older adults.

"Our results offer the first evidence of positive contribution of tea drinking to brain structure, and suggest that drinking tea regularly has a protective effect against age-related decline in brain organisation," explained team leader Assistant Professor Feng Lei, who is from the Department of Psychological Medicine at the NUS Yong Loo Lin School of Medicine.
The research was carried out together with collaborators from the University of Essex and University of Cambridge, and the findings were published in scientific journal Aging on 14 June 2019.
Benefits of regular intake of tea
Past studies have demonstrated that tea intake is beneficial to human health, and the positive effects include mood improvement and cardiovascular disease prevention. In fact, results of a longitudinal study led by Asst Prof Feng which was published in 2017 showed that daily consumption of tea can reduce the risk of cognitive decline in older persons by 50 per cent.
Following this discovery, Asst Prof Feng and his team further explored the direct effect of tea on brain networks.
The research team recruited 36 adults aged 60 and above, and gathered data about their health, lifestyle, and psychological well-being. The elderly participants also had to undergo neuropsychological tests and magnetic resonance imaging (MRI). The study was carried out from 2015 to 2018.
Upon analysing the participants' cognitive performance and imaging results, the research team found that individuals who consumed either green tea, oolong tea, or black tea at least four times a week for about 25 years had brain regions that were interconnected in a more efficient way.
"Take the analogy of road traffic as an example -- consider brain regions as destinations, while the connections between brain regions are roads. When a road system is better organised, the movement of vehicles and passengers is more efficient and uses less resources. Similarly, when the connections between brain regions are more structured, information processing can be performed more efficiently," explained Asst Prof Feng.
He added, "We have shown in our previous studies that tea drinkers had better cognitive function as compared to non-tea drinkers. Our current results relating to brain network indirectly support our previous findings by showing that the positive effects of regular tea drinking are the result of improved brain organisation brought about by preventing disruption to interregional connections."
Next step in research
As cognitive performance and brain organisation are intricately related, more research is needed to better understand how functions like memory emerge from brain circuits, and the possible interventions to better preserve cognition during the ageing process. Asst Prof Feng and his team plan to examine the effects of tea as well as the bioactive compounds in tea can have on cognitive decline.

Journal Reference:

1. Junhua Li, Rafael Romero-Garcia, John Suckling, Lei Feng. Habitual tea drinking modulates brain efficiency: evidence from brain connectivity evaluation. Aging, 2019; 11 (11): 3876 DOI: 10.18632/aging.102023 

Courtesy: ScienceDaily

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Stressed to the max? Deep sleep can rewire the anxious brain

When it comes to managing anxiety disorders, William Shakespeare's Macbeth had it right when he referred to sleep as the "balm of hurt minds." While a full night of slumber stabilizes emotions, a sleepless night can trigger up to a 30% rise in anxiety levels, according to new research from the University of California, Berkeley.

Deep sleep concept (stock image).

Credit: © stokkete / Adobe Stock

 

UC Berkeley researchers have found that the type of sleep most apt to calm and reset the anxious brain is deep sleep, also known as non-rapid eye movement (NREM) slow-wave sleep, a state in which neural oscillations become highly synchronized, and heart rates and blood pressure drop.
"We have identified a new function of deep sleep, one that decreases anxiety overnight by reorganizing connections in the brain," said study senior author Matthew Walker, a UC Berkeley professor of neuroscience and psychology. "Deep sleep seems to be a natural anxiolytic (anxiety inhibitor), so long as we get it each and every night."
The findings, published today, Nov. 4, in the journal Nature Human Behaviour, provide one of the strongest neural links between sleep and anxiety to date. They also point to sleep as a natural, non-pharmaceutical remedy for anxiety disorders, which have been diagnosed in some 40 million American adults and are rising among children and teens.
"Our study strongly suggests that insufficient sleep amplifies levels of anxiety and, conversely, that deep sleep helps reduce such stress," said study lead author Eti Ben Simon, a postdoctoral fellow in the Center for Human Sleep Science at UC Berkeley.
In a series of experiments using functional MRI and polysomnography, among other measures, Simon and fellow researchers scanned the brains of 18 young adults as they viewed emotionally stirring video clips after a full night of sleep, and again after a sleepless night. Anxiety levels were measured following each session via a questionnaire known as the state-trait anxiety inventory.
After a night of no sleep, brain scans showed a shutdown of the medial prefrontal cortex, which normally helps keep our anxiety in check, while the brain's deeper emotional centers were overactive.
"Without sleep, it's almost as if the brain is too heavy on the emotional accelerator pedal, without enough brake," Walker said.
After a full night of sleep, during which participants' brain waves were measured via electrodes placed on their heads, the results showed their anxiety levels declined significantly, especially for those who experienced more slow-wave NREM sleep.
"Deep sleep had restored the brain's prefrontal mechanism that regulates our emotions, lowering emotional and physiological reactivity and preventing the escalation of anxiety," Simon said.
Beyond gauging the sleep-anxiety connection in the 18 original study participants, the researchers replicated the results in a study of another 30 participants. Across all the participants, the results again showed that those who got more nighttime deep sleep experienced the lowest levels of anxiety the next day.
Moreover, in addition to the lab experiments, the researchers conducted an online study in which they tracked 280 people of all ages about how both their sleep and anxiety levels changed over four consecutive days.
The results showed that the amount and quality of sleep the participants got from one night to the next predicted how anxious they would feel the next day. Even subtle nightly changes in sleep affected their anxiety levels.
"People with anxiety disorders routinely report having disturbed sleep, but rarely is sleep improvement considered as a clinical recommendation for lowering anxiety," Simon said. "Our study not only establishes a causal connection between sleep and anxiety, but it identifies the kind of deep NREM sleep we need to calm the overanxious brain."
On a societal level, "the findings suggest that the decimation of sleep throughout most industrialized nations and the marked escalation in anxiety disorders in these same countries is perhaps not coincidental, but causally related," Walker said. "The best bridge between despair and hope is a good night of sleep."
Co-authors of the study are Aubrey Rossi and Allison Harvey, both at UC Berkeley.
 

Journal Reference:

1. Eti Ben Simon, Aubrey Rossi, Allison G. Harvey, Matthew P. Walker. Overanxious and underslept. Nature Human Behaviour, 2019; DOI: 10.1038/s41562-019-0754-8 

Courtesy: ScienceDaily
 

Carbon dioxide capture and use could become big business

Capturing carbon dioxide and turning it into commercial products, such as fuels or construction materials, could become a new global industry, according to a study by researchers from UCLA, the University of Oxford and five other institutions.

Should that happen, the phenomenon would help the environment by reducing greenhouse gas emissions.
The research, published in Nature, is the most comprehensive study to date investigating the potential future scale and cost of 10 different ways to use carbon dioxide, including in fuels and chemicals, plastics, building materials, soil management and forestry. The study considered processes using carbon dioxide captured from waste gases that are produced by burning fossil fuels or from the atmosphere by an industrial process.
And in a step beyond most previous research on the subject, the authors also considered processes that use carbon dioxide captured biologically by photosynthesis.
The research found that on average each utilization pathway could use around 0.5 gigatonnes of carbon dioxide per year that would otherwise escape into the atmosphere. (A tonne, or metric ton, is equivalent to 1,000 kilograms, and a gigatonne is 1 billion tonnes, or about 1.1 billion U.S. tons.)
A top-end scenario could see more than 10 gigatonnes of carbon dioxide a year used, at a theoretical cost of under $100 per tonne of carbon dioxide. The researchers noted, however, that the potential scales and costs of using carbon dioxide varied substantially across sectors.
"The analysis we presented makes clear that carbon dioxide utilization can be part of the solution to combat climate change, but only if those with the power to make decisions at every level of government and finance commit to changing policies and providing market incentives across multiple sectors," said Emily Carter, a distinguished professor of chemical and biomolecular engineering at the UCLA Samueli School of Engineering and a co-author of the paper. "The urgency is huge and we have little time left to effect change."
According to the Intergovernmental Panel on Climate Change, keeping global warming to 1.5 degrees Celsius over the rest of the 21st century will require the removal of carbon dioxide from the atmosphere on the order of 100 to 1,000 gigatonnes of carbon dioxide. Currently, fossil carbon dioxide emissions are increasing by over 1% annually, reaching a record high of 37 gigatonnes of carbon dioxide in 2018.
"Greenhouse gas removal is essential to achieve net zero carbon emissions and stabilise the climate," said Cameron Hepburn, one of the study's lead authors, director of Oxford's Smith School of Enterprise and Environment. "We haven't reduced our emissions fast enough, so now we also need to start pulling carbon dioxide out of the atmosphere. Governments and corporations are moving on this, but not quickly enough.
"The promise of carbon dioxide utilization is that it could act as an incentive for carbon dioxide removal and could reduce emissions by displacing fossil fuels."
Critical to the success of these new technologies as mitigation strategies will be a careful analysis of their overall impact on the climate. Some are likely to be adopted quickly simply because of their attractive business models. For example, in certain kinds of plastic production, using carbon dioxide as a feedstock is a more profitable and environmentally cleaner production process than using conventional hydrocarbons, and it can displace up to three times as much carbon dioxide as it uses.
Biological uses might also present opportunities to reap co-benefits. In other areas, utilization could provide a "better choice" alternative during the global decarbonization process. One example might be the use of fuels derived from carbon dioxide, which could find a role in sectors that are harder to decarbonize, such as aviation.
The authors stressed that there is no "magic bullet" approach.
"I would start by incentivizing the most obvious solutions -- most of which already exist -- that can act at the gigatonne scale in agriculture, forestry and construction," said Carter, who also is UCLA's executive vice chancellor and provost, and the Gerhard R. Andlinger Professor in Energy and Environment Emeritus at Princeton University. "At the same time, I would aggressively invest in R&D across academia, industry and government labs -- much more so than is being done in the U.S., especially compared to China -- in higher-tech solutions to capture and convert carbon dioxide to useful products that can be developed alongside solutions that already exist in agriculture, forestry and construction."
 

Journal Reference:

1. Cameron Hepburn, Ella Adlen, John Beddington, Emily A. Carter, Sabine Fuss, Niall Mac Dowell, Jan C. Minx, Pete Smith, Charlotte K. Williams. The technological and economic prospects for CO2 utilization and removal. Nature, 2019; 575 (7781): 87 DOI: 10.1038/s41586-019-1681-6 

Courtesy: ScienceDaily
 

Study vaccine protects monkeys against four types of hemorrhagic fever viruses

Scientists funded by the National Institutes of Health have developed an investigational vaccine that protected cynomolgus macaques against four types of hemorrhagic fever viruses endemic to overlapping regions in Africa. The University of Texas Medical Branch in Galveston and Profectus BioSciences of New York are developing and testing the candidate quadrivalent VesiculoVax vaccine, with support from NIH's National Institute of Allergy and Infectious Diseases (NIAID) and Redeemer's University in Nigeria.

The newly published study in the Journal of Clinical Investigation describes how the vaccine was created using a live-attenuated (weakened) vesicular stomatitis virus to deliver proteins that elicit protective immune responses. The proteins are from Ebola virus (Kikwit strain), Sudan virus (Boniface strain, which also causes Ebola virus disease), Marburg virus (Angola strain) and Lassa virus (Josiah strain). There are no licensed vaccines to provide protection from any of those viruses -- all of which can cause severe disease and death -- although the European Medicines Agency has recommended licensing a VSV-Ebola vaccine.

Importantly, the monkeys infected in the study were exposed to different strains of Sudan virus (Gulu) and Lassa virus (0043/LV/14) than those in the candidate vaccine to help the researchers determine whether the vaccine would be cross-protective. Lassa 0043/LV/14 is circulating in an outbreak in Nigeria that began in 2018. Previous studies indicate that the investigational Ebola virus (Kikwit) vaccine will protect against other strains of Ebola virus.

The scientists inoculated 20 macaques with a primary and booster dose of quadrivalent VesiculoVax. The animals had five blood draws to check for an immune response, including on the day of initial vaccination and on days 10 and 28, then on day 56 when they received a booster inoculation, and again on day 66. On day 84 scientists infected the macaques with the four different hemorrhagic fever viruses and monitored them to day 112.

Twelve additional macaques in the study who were infected with the four viruses but not vaccinated all became sick, but none of the vaccinated animals did. Only one of the 20 vaccinated animals had any of the four hemorrhagic fever viruses detectible (Lassa) following the study.

The scientists state that the addition of the Lassa virus component to their multivalent vaccine is an exciting research advance as they already had developed an investigational trivalent vaccine that provided protection against Ebola, Sudan and Marburg viruses. The researchers now plan further vaccine tests against other strains of Lassa virus, and they want to further evaluate whether a single-dose quadrivalent vaccine appears safe and effective.

Journal Reference:

1. Robert W. Cross, Rong Xu, Demetrius Matassov, Stefan Hamm, Theresa E. Latham, Cheryl S. Gerardi, Rebecca M. Nowak, Joan B. Geisbert, Ayuko Ota-Setlik, Krystle N. Agans, Amara Luckay, Susan E. Witko, Lena Soukieh, Daniel J. Deer, Chad E. Mire, Heinz Feldmann, Christian Happi, Karla A. Fenton, John H. Eldridge, Thomas W. Geisbert. Quadrivalent Vesiculovax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and death. Journal of Clinical Investigation, 2019; DOI: 10.1172/JCI131958 

Courtesy: ScienceDaily

In a first, scientists pinpoint neural activity's role in human longevity

The brain's neural activity -- long implicated in disorders ranging from dementia to epilepsy -- also plays a role in human aging and life span, according to research led by scientists in the Blavatnik Institute at Harvard Medical School.

Roundworm Caenorhabditis elegans (stock image).

Credit: © heitipaves / Adobe Stock

 

The study, published Oct. 16 in Nature, is based on findings from human brains, mice and worms and suggests that excessive activity in the brain is linked to shorter life spans, while suppressing such overactivity extends life.

The findings offer the first evidence that the activity of the nervous system affects human longevity. Although previous studies had suggested that parts of the nervous system influence aging in animals, the role of neural activity in aging, especially in humans, remained murky.

"An intriguing aspect of our findings is that something as transient as the activity state of neural circuits could have such far-ranging consequences for physiology and life span," said study senior author Bruce Yankner, professor of genetics at HMS and co-director of the Paul F. Glenn Center for the Biology of Aging.

Neural excitation appears to act along a chain of molecular events famously known to influence longevity: the insulin and insulin-like growth factor (IGF) signaling pathway.

The key in this signaling cascade appears to be a protein called REST, previously shown by the Yankner Lab to protect aging brains from dementia and other stresses.

Neural activity refers to the constant flicker of electrical currents and transmissions in the brain. Excessive activity, or excitation, could manifest in numerous ways, from a muscle twitch to a change in mood or thought, the authors said.

It's not yet clear from the study whether or how a person's thoughts, personality or behavior affect their longevity.

"An exciting future area of research will be to determine how these findings relate to such higher-order human brain functions," said Yankner.

The study could inform the design of new therapies for conditions that involve neural overactivity, such as Alzheimer's disease and bipolar disorder, the researchers said.

The findings raise the possibility that certain medicines, such as drugs that target REST, or certain behaviors, such as meditation, could extend life span by modulating neural activity.

Human variation in neural activity might have both genetic and environmental causes, which would open future avenues for therapeutic intervention, Yankner said.

All roads lead to REST

Yankner and colleagues began their investigation by analyzing gene expression patterns -- the extent to which various genes are turned on and off -- in donated brain tissue from hundreds of people who died at ages ranging from 60 to over 100.

The information had been collected through three separate research studies of older adults. Those analyzed in the current study were cognitively intact, meaning they had no dementia.

Immediately, a striking difference appeared between the older and younger study participants, said Yankner: The longest-lived people -- those over 85 -- had lower expression of genes related to neural excitation than those who died between the ages of 60 and 80.

Next came the question that all scientists confront: correlation or causation? Was this disparity in neural excitation merely occurring alongside more important factors determining life span, or were excitation levels directly affecting longevity? If so, how?

The team conducted a barrage of experiments, including genetic, cell and molecular biology tests in the model organism Caenorhabditis elegans; analyses of genetically altered mice; and additional brain tissue analyses of people who lived for more than a century.

These experiments revealed that altering neural excitation does indeed affect life span -- and illuminated what might be happening on a molecular level.

All signs pointed to the protein REST.

REST, which is known to regulate genes, also suppresses neural excitation, the researchers found. Blocking REST or its equivalent in the animal models led to higher neural activity and earlier deaths, while boosting REST did the opposite. And human centenarians had significantly more REST in the nuclei of their brain cells than people who died in their 70s or 80s.

"It was extremely exciting to see how all these different lines of evidence converged," said study co-author Monica Colaiácovo, professor of genetics at HMS, whose lab collaborated on the C. elegans work.

The researchers found that from worms to mammals, REST suppresses the expression of genes that are centrally involved in neural excitation, such as ion channels, neurotransmitter receptors and structural components of synapses.

Lower excitation in turn activates a family of proteins known as forkhead transcription factors. These proteins have been shown to mediate a "longevity pathway" via insulin/IGF signaling in many animals. It's the same pathway that scientists believe can be activated by caloric restriction.

In addition to its emerging role in staving off neurodegeneration, discovery of REST's role in longevity provides additional motivation to develop drugs that target the protein.

Although it will take time and many tests to determine whether such treatments reduce neural excitation, promote healthy aging or extend life span, the concept has captivated some researchers.

"The possibility that being able to activate REST would reduce excitatory neural activity and slow aging in humans is extremely exciting," said Colaiácovo.

The authors emphasize that the work would not have been possible without large research cohorts of aging people.

"We now have enough people enrolled in these studies to partition the aging population into genetic subgroups," said Yankner. "This information is invaluable and shows why it's so important to support the future of human genetics."

Funding and authorship

Postdoctoral fellows Joseph Zullo and Derek Drake of the Yankner Lab are co-first authors. Additional HMS co-authors are Liviu Aron, Patrick O'Hern, Noah Davidsohn, Sameer Dhamne, Alexander Rotenberg and George Church, the Robert Winthrop Professor of Genetics. Davidsohn and Church are also affiliated with the Wyss Institute for Biologically Inspired Engineering at Harvard University.

Other co-authors are affiliated with the University of Texas McGovern Medical School, the University of Texas MD Anderson Cancer Center and Rush University Medical Center.

This work was supported by an NIH Director's Pioneer Award (DP1OD006849) and National Institutes of Health grants R01AG046174, R01AG26651, R01GM072551, P30AG10161, R01AG15819, R01AG17917, R01AG36836, U01AG46152, EY024376, EY011930 and K99AG050830, as well as the Glenn Foundation for Medical Research and the Ludwig Family Foundation.

Journal Reference:

1. Joseph M. Zullo, Derek Drake, Liviu Aron, Patrick O’Hern, Sameer C. Dhamne, Noah Davidsohn, Chai-An Mao, William H. Klein, Alexander Rotenberg, David A. Bennett, George M. Church, Monica P. Colaiácovo & Bruce A. Yankner. Regulation of lifespan by neural excitation and REST. Nature, 2019 DOI: 10.1038/s41586-019-1647-8 

Courtesy: ScienceDaily

New cancer-driving mutation in 'dark matter' of the cancer genome

An Ontario-led research group has discovered a novel cancer-driving mutation in the vast non-coding regions of the human cancer genome, also known as the "dark matter" of human cancer DNA.

The mutation, as described in two related studies published in Nature on October 9, 2019, represents a new potential therapeutic target for several types of cancer including brain, liver and blood cancer. This target could be used to develop novel treatments for patients with these difficult-to-treat diseases.

"Non-coding DNA, which makes up 98 per cent of the genome, is notoriously difficult to study and is often overlooked since it does not code for proteins," says Dr. Lincoln Stein, co-lead of the studies and Head of Adaptive Oncology at the Ontario Institute for Cancer Research (OICR). "By carefully analyzing these regions, we have discovered a change in one letter of the DNA code that can drive multiple types of cancer. In turn, we've found a new cancer mechanism that we can target to tackle the disease."

The research group discovered that the mutation, termed the U1-snRNA mutation, could disrupt normal RNA splicing and thereby alter the transcription of cancer-driving genes. These molecular mechanisms represent new ways to treat cancers carrying the mutation. One of the potential treatment approaches includes repurposing existing drugs, which, by bypassing early drug development stages, could be brought into the clinic at an accelerated rate.

"Our unexpected discovery uncovered an entirely new way to target these cancers that are tremendously difficult to treat and have high mortality rates," says Dr. Michael Taylor, Paediatric Neurosurgeon, Senior Scientist in Developmental and Stem Cell Biology and Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children (SickKids) and co-lead of the studies. "We've found that with one 'typo' in the DNA code, the resultant cancers have hundreds of mutant proteins that we might be able to target using currently available immunotherapies."

The U1-snRNA mutation was found in patient tumours with certain subtypes of brain cancer, including nearly all of the studied samples from adult patients with sonic hedgehog medulloblastoma. The mutation was also found in samples of chronic lymphocytic leukemia (CLL) -- the most common type of adult leukemia -- and hepatocellular carcinoma -- the most common type of liver cancer.

"This discovery is an example of how OICR is working together with partners in Ontario and across the world to support cutting-edge research that can be used in the development of precision therapies for cancer patients worldwide," says Dr. Laszlo Radvanyi, President and Scientific Director of OICR.

The two related publications -- one which focused on brain cancer and the other on CLL and liver cancer -- were both led by researchers in Ontario, including Dr. Michael Taylor, who is also a Professor in the Departments of Surgery and Laboratory Medicine and Pathobiology at the University of Toronto, and Dr. Lincoln Stein at OICR. Both of the studies involved international collaborators including Dr. Xose Puente at the University of Oviedo, Dr. Elias Campo at the Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) and the Universitat de Barcelona and others.

The studies were powered in part by data from the OICR-led Pan-Cancer Analysis of Whole Genomes (PCAWG) project, one of the largest coordinated cancer research endeavors to date that analyzed more than 2,800 cancer whole genomes from the International Cancer Genome Consortium (ICGC).

This research was supported in part by a Translational Research Initiative grant from OICR through funding provided by the Government of Ontario. This work was also funded in part by Genome Canada and SickKids Foundation.

Journal References:

1. Hiromichi Suzuki, Sachin A. Kumar, Shimin Shuai, Ander Diaz-Navarro, Ana Gutierrez-Fernandez, Pasqualino De Antonellis, Florence M. G. Cavalli, Kyle Juraschka, Hamza Farooq, Ichiyo Shibahara, Maria C. Vladoiu, Jiao Zhang, Namal Abeysundara, David Przelicki, Patryk Skowron, Nicole Gauer, Betty Luu, Craig Daniels, Xiaochong Wu, Antoine Forget, Ali Momin, Jun Wang, Weifan Dong, Seung-Ki Kim, Wieslawa A. Grajkowska, Anne Jouvet, Michelle Fèvre-Montange, Maria Luisa Garrè, Amulya A. Nageswara Rao, Caterina Giannini, Johan M. Kros, Pim J. French, Nada Jabado, Ho-Keung Ng, Wai Sang Poon, Charles G. Eberhart, Ian F. Pollack, James M. Olson, William A. Weiss, Toshihiro Kumabe, Enrique López-Aguilar, Boleslaw Lach, Maura Massimino, Erwin G. Van Meir, Joshua B. Rubin, Rajeev Vibhakar, Lola B. Chambless, Noriyuki Kijima, Almos Klekner, László Bognár, Jennifer A. Chan, Claudia C. Faria, Jiannis Ragoussis, Stefan M. Pfister, Anna Goldenberg, Robert J. Wechsler-Reya, Swneke D. Bailey, Livia Garzia, A. Sorana Morrissy, Marco A. Marra, Xi Huang, David Malkin, Olivier Ayrault, Vijay Ramaswamy, Xose S. Puente, John A. Calarco, Lincoln Stein, Michael D. Taylor. Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma. Nature, 2019; DOI: 10.1038/s41586-019-1650-0
2. Shimin Shuai, Hiromichi Suzuki, Ander Diaz-Navarro, Ferran Nadeu, Sachin A. Kumar, Ana Gutierrez-Fernandez, Julio Delgado, Magda Pinyol, Carlos López-Otín, Xose S. Puente, Michael D. Taylor, Elías Campo, Lincoln D. Stein. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature, 2019; DOI: 10.1038/s41586-019-1651-z 

Courtesy: ScienceDaily

'Artificial leaf' successfully produces clean gas

A widely-used gas that is currently produced from fossil fuels can instead be made by an 'artificial leaf' that uses only sunlight, carbon dioxide and water, and which could eventually be used to develop a sustainable liquid fuel alternative to petrol.

The carbon-neutral device sets a new benchmark in the field of solar fuels, after researchers at the University of Cambridge demonstrated that it can directly produce the gas -- called syngas -- in a sustainable and simple way.

Rather than running on fossil fuels, the artificial leaf is powered by sunlight, although it still works efficiently on cloudy and overcast days. And unlike the current industrial processes for producing syngas, the leaf does not release any additional carbon dioxide into the atmosphere. The results are reported in the journal Nature Materials.

Syngas is currently made from a mixture of hydrogen and carbon monoxide, and is used to produce a range of commodities, such as fuels, pharmaceuticals, plastics and fertilisers.

"You may not have heard of syngas itself but every day, you consume products that were created using it. Being able to produce it sustainably would be a critical step in closing the global carbon cycle and establishing a sustainable chemical and fuel industry," said senior author Professor Erwin Reisner from Cambridge's Department of Chemistry, who has spent seven years working towards this goal.

The device Reisner and his colleagues produced is inspired by photosynthesis -- the natural process by which plants use the energy from sunlight to turn carbon dioxide into food.

On the artificial leaf, two light absorbers, similar to the molecules in plants that harvest sunlight, are combined with a catalyst made from the naturally abundant element cobalt.

When the device is immersed in water, one light absorber uses the catalyst to produce oxygen. The other carries out the chemical reaction that reduces carbon dioxide and water into carbon monoxide and hydrogen, forming the syngas mixture.

As an added bonus, the researchers discovered that their light absorbers work even under the low levels of sunlight on a rainy or overcast day.

"This means you are not limited to using this technology just in warm countries, or only operating the process during the summer months," said PhD student Virgil Andrei, first author of the paper. "You could use it from dawn until dusk, anywhere in the world."

The research was carried out in the Christian Doppler Laboratory for Sustainable SynGas Chemistry in the University's Department of Chemistry. It was co-funded by the Austrian government and the Austrian petrochemical company OMV, which is looking for ways to make its business more sustainable.

"OMV has been an avid supporter of the Christian Doppler Laboratory for the past seven years. The team's fundamental research to produce syngas as the basis for liquid fuel in a carbon neutral way is ground-breaking," said Michael-Dieter Ulbrich, Senior Advisor at OMV.

Other 'artificial leaf' devices have also been developed, but these usually only produce hydrogen. The Cambridge researchers say the reason they have been able to make theirs produce syngas sustainably is thanks the combination of materials and catalysts they used.

These include state-of-the-art perovskite light absorbers, which provide a high photovoltage and electrical current to power the chemical reaction by which carbon dioxide is reduced to carbon monoxide, in comparison to light absorbers made from silicon or dye-sensitised materials. The researchers also used cobalt as their molecular catalyst, instead of platinum or silver. Cobalt is not only lower-cost, but it is better at producing carbon monoxide than other catalysts.

The team is now looking at ways to use their technology to produce a sustainable liquid fuel alternative to petrol.

Syngas is already used as a building block in the production of liquid fuels. "What we'd like to do next, instead of first making syngas and then converting it into liquid fuel, is to make the liquid fuel in one step from carbon dioxide and water," said Reisner, who is also a Fellow of St John's College.

Although great advances are being made in generating electricity from renewable energy sources such as wind power and photovoltaics, Reisner says the development of synthetic petrol is vital, as electricity can currently only satisfy about 25% of our total global energy demand. "There is a major demand for liquid fuels to power heavy transport, shipping and aviation sustainably," he said.

"We are aiming at sustainably creating products such as ethanol, which can readily be used as a fuel," said Andrei. "It's challenging to produce it in one step from sunlight using the carbon dioxide reduction reaction. But we are confident that we are going in the right direction, and that we have the right catalysts, so we believe we will be able to produce a device that can demonstrate this process in the near future."

The research was also funded by the Winton Programme for the Physics of Sustainability, the Biotechnology and Biological Sciences Research Council, and the Engineering and Physical Sciences Research Council.

Journal Reference:

1. Virgil Andrei, Bertrand Reuillard & Erwin Reisner. Bias-free solar syngas production by integrating a molecular cobalt catalyst with perovskite–BiVO₄ tandems. Nature Materials, 2019 DOI: 10.1038/s41563-019-0501-6

Courtesy: ScienceDaily

1 in 300 thrives on very-early-to-bed, very-early-to-rise routine

A quirk of the body clock that lures some people to sleep at 8 p.m., enabling them to greet the new day as early as 4 a.m., may be significantly more common than previously believed.

So-called advanced sleep phase -- previously believed to be very rare -- may affect at least one in 300 adults, according to a study led by UC San Francisco and publishing in the journal SLEEP on Aug. 6, 2019.

Sunrise, rooster weathervane (stock image).

Credit: © pimmimemom / Adobe Stock

Advanced sleep phase means that the body's clock, or circadian rhythm, operates on a schedule hours earlier than most people's, with a premature release of the sleep hormone melatonin and shift in body temperature. The condition is distinct from the early rising that develops with normal aging, as well as the waking in the wee hours experienced by people with depression.
"While most people struggle with getting out of bed at 4 or 5 a.m., people with advanced sleep phase wake up naturally at this time, rested and ready to take on the day," said the study's senior author, Louis Ptacek, MD, professor of neurology at the UCSF School of Medicine. "These extreme early birds tend to function well in the daytime but may have trouble staying awake for social commitments in the evening."
Advanced Sleepers 'Up and at 'Em' on Weekends too
Additionally, "advanced sleepers" rouse more easily than others, he said, and are satisfied with an average of an extra five-to-10 minutes of sleep on non-work days, versus the 30-to-38 minutes' more sleep of their non-advanced sleeper family members.
Ptacek and his colleagues at the University of Utah and the University of Wisconsin calculated the estimated prevalence of advanced sleepers by evaluating data from patients at a sleep disorder clinic over a nine-year period. In total, 2,422 patients were followed, of which 1,748 presented with symptoms of obstructive sleep apnea, a condition that the authors found was not related to sleep-cycle hours.
Among this group, 12 people met initial screening criteria for advanced sleep phase. Four of the 12 declined enrollment in the study and the remaining eight comprised the 0.3 percent of the total number of patients -- or one out of 300 -- that was extrapolated for the general population.
This is a conservative figure, the researchers noted, since it excluded the four patients who did not want to participate in the study and may have met the criteria for advanced sleep phase, as well as those advanced sleepers who had no need to visit a sleep clinic.
Night Owls More Likely to Struggle with Sleep Deficits
"Generally, we find that it's the people with delayed sleep phase -- those night owls that can't sleep until as late as 7 a.m. -- who are more likely to visit a sleep clinic. They have trouble getting up for work and frequently deal with chronic sleep deprivation," said Ptacek.
Criteria for advanced sleep phase include the ability to fall asleep before 8:30 p.m. and wake before 5:30 a.m. regardless of any occupational or social obligations, and having only one sleep period per day. Other criteria include the establishment of this sleep-wake pattern by the age of 30, no use of stimulants or sedatives, no bright lights to aid early rising and no medical conditions that may impact sleep.
All study participants were personally seen by Christopher R. Jones, MD, a former neurologist at the University of Utah and co-author of the paper. Patients were asked about their medical histories and both past and present sleep habits on work days and work-free days. Researchers also looked at sleep logs and level of melatonin in the participants' saliva, as well as sleep studies, or polysomnography, that record brainwaves, oxygen levels in the blood, heart rate and breathing.
Of note, all eight of the advanced sleepers claimed that they had at least one first-degree relative with the same sleep-wake schedule, indicating so-called familial advanced sleep phase. Of the eight relatives tested, three did not meet the full criteria for advanced sleep phase and the authors calculated that the remaining five represented 0.21 percent of the general population.
The authors believe that the percentage of advanced sleepers who have the familial variant may approach 100 percent. However, some participants may have de novo mutations that may be found in their children, but not in parents or siblings, and some may have family members with "nonpenetrant" carrier mutations. Two of the remaining five were found to have genetic mutations that have been identified with familial advanced sleep phase. Conditions associated with these genes include migraine and seasonal affective disorder.
"We hope the results of this study will not only raise awareness of advanced sleep phase and familial advanced sleep phase," said Ptacek, "but also help identify the circadian clock genes and any medical conditions that they may influence."
Funding: The study is supported by grants from the National Institutes of Health and by the William Bowes Neurogenics Fund.
 

Journal Reference:

1. Brian John Curtis, Liza H Ashbrook, Terry Young, Laurel A Finn, Ying-Hui Fu, Louis J Ptáček, Christopher R Jones. Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep–wake phase disorder in a sleep clinic population. Sleep, 2019; DOI: 10.1093/sleep/zsz148 

Courtesy: ScienceDaily
 

Scientists can now manipulate brain cells using smartphone

A team of scientists in Korea and the United States have invented a device that can control neural circuits using a tiny brain implant controlled by a smartphone.

Researchers, publishing in Nature Biomedical Engineering, believe the device can speed up efforts to uncover brain diseases such as Parkinson's, Alzheimer's, addiction, depression, and pain.
The device, using Lego-like replaceable drug cartridges and powerful bluetooth low-energy, can target specific neurons of interest using drug and light for prolonged periods.
"The wireless neural device enables chronic chemical and optical neuromodulation that has never been achieved before," said lead author Raza Qazi, a researcher with the Korea Advanced Institute of Science and Technology (KAIST) and University of Colorado Boulder.
Qazi said this technology significantly overshadows conventional methods used by neuroscientists, which usually involve rigid metal tubes and optical fibers to deliver drugs and light. Apart from limiting the subject's movement due to the physical connections with bulky equipment, their relatively rigid structure causes lesion in soft brain tissue over time, therefore making them not suitable for long-term implantation. Though some efforts have been put to partly mitigate adverse tissue response by incorporating soft probes and wireless platforms, the previous solutions were limited by their inability to deliver drugs for long periods of time as well as their bulky and complex control setups.
To achieve chronic wireless drug delivery, scientists had to solve the critical challenge of exhaustion and evaporation of drugs. Researchers from the Korea Advanced Institute of Science and Technology and the University of Washington in Seattle collaborated to invent a neural device with a replaceable drug cartridge, which could allow neuroscientists to study the same brain circuits for several months without worrying about running out of drugs.
These 'plug-n-play' drug cartridges were assembled into a brain implant for mice with a soft and ultrathin probe (thickness of a human hair), which consisted of microfluidic channels and tiny LEDs (smaller than a grain of salt), for unlimited drug doses and light delivery.
Controlled with an elegant and simple user interface on a smartphone, neuroscientists can easily trigger any specific combination or precise sequencing of light and drug deliveries in any implanted target animal without need to be physically inside the laboratory. Using these wireless neural devices, researchers could also easily setup fully automated animal studies where behaviour of one animal could positively or negatively affect behaviour in other animals by conditional triggering of light and/or drug delivery.
"This revolutionary device is the fruit of advanced electronics design and powerful micro and nanoscale engineering," said Jae-Woong Jeong, a professor of electrical engineering at KAIST. "We are interested in further developing this technology to make a brain implant for clinical applications."
Michael Bruchas, a professor of anesthesiology and pain medicine and pharmacology at the University of Washington School of Medicine, said this technology will help researchers in many ways.
"It allows us to better dissect the neural circuit basis of behaviour, and how specific neuromodulators in the brain tune behaviour in various ways," he said. "We are also eager to use the device for complex pharmacological studies, which could help us develop new therapeutics for pain, addiction, and emotional disorders."
The researchers at the Jeong group at KAIST develop soft electronics for wearable and implantable devices, and the neuroscientists at the Bruchas lab at the University of Washington study brain circuits that control stress, depression, addiction, pain and other neuropsychiatric disorders. This global collaborative effort among engineers and neuroscientists over a period of three consecutive years and tens of design iterations led to the successful validation of this powerful brain implant in freely moving mice, which researchers believe can truly speed up the uncovering of brain and its diseases.
This work was supported by grants from the National Research Foundation of Korea, U.S. National Institute of Health, National Institute on Drug Abuse, and Mallinckrodt Professorship.
 

Journal Reference:

1. Raza Qazi, Adrian M. Gomez, Daniel C. Castro, Zhanan Zou, Joo Yong Sim, Yanyu Xiong, Jonas Abdo, Choong Yeon Kim, Avery Anderson, Frederik Lohner, Sang-Hyuk Byun, Byung Chul Lee, Kyung-In Jang, Jianliang Xiao, Michael R. Bruchas, Jae-Woong Jeong. Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation. Nature Biomedical Engineering, 2019; DOI: 10.1038/s41551-019-0432-1 

Courtesy: ScienceDaily
 

Pupil dilation and heart rate, analyzed by AI, may help spot autism early

Autism and other neurodevelopmental disorders often aren't diagnosed until a child is a few years of age, when behavioral interventions and speech/occupational therapy become less effective. But new research this week in PNAS suggests that two simple, quantifiable measures -- spontaneous fluctuations in pupil dilation or heart rate -- could enable much earlier diagnosis of Rett syndrome and possibly other disorders with autism-like features.

Child's eye (stock image).

Credit: © Anton / Adobe Stock

 

The study, led by Boston Children's Hospital neuroscientist Michela Fagiolini, PhD, and postdoctoral fellow Pietro Artoni, PhD, unveils a machine-learning algorithm that can spot abnormalities in pupil dilation that are predictive of autism spectrum disorder (ASD) in mouse models. It further shows that the algorithm can accurately detect if a girl has Rett syndrome, a genetic disorder that impairs cognitive, sensory, motor, and autonomic function starting at 6 to 18 months of age, as well as autism-like behaviors.
Fagiolini and colleagues hope this system could provide an early warning signal not just for Rett syndrome but for ASD in general. In the future, they believe it could also be used to monitor patients' responses to treatments; currently, a clinical trial is testing the drug ketamine for Rett syndrome, and a gene therapy trial is planned.
"We want to have some readout of what's going on in the brain that is quantitative, objective, and sensitive to subtle changes," says Fagiolini. "More broadly, we are lacking biomarkers that are reflective of brain activity, easy to quantify, and not biased. A machine could measure a biomarker and not be affected by subjective interpretations of how a patient is doing."
Altered arousal in autism
Fagiolini and Artoni, in close collaboration with Takao Hensch, PhD, and Charles Nelson, PhD, at Boston Children's, began with the idea that people on the autism spectrum have altered behavioral states. Prior evidence indicates that the brain's cholinergic circuits, which are involved in arousal, are especially perturbed, and that altered arousal affects both spontaneous pupil dilation/constriction and heart rate.
Fagiolini's team, supported by the IRCN at Boston Children's F.M. Kirby Neurobiology Center, set out to measure pupil fluctuations in several mouse models of ASD, including mice with the mutations causing Rett syndrome or CDKL5 disorder, as well as BTBR mice. Spontaneous pupil dilation and constriction were altered even before the animals began showing ASD-like symptoms, the team found.
Moreover, in mice lacking MeCP2, the gene mutated in Rett syndrome, restoring a normal copy of the gene, in cholinergic brain circuits only, prevented the onset of pupillary abnormalities as well as behavioral symptoms.
Predicting Rett syndrome in girls
To systematically link the observed arousal changes to the cholinergic system, the team took advantage of an earlier discovery by Hensch: mice lacking the LYNX1 protein exhibit enhanced cholinergic signaling. Based on about 60 hours of observation of these mice, the investigators "trained" a deep learning algorithm to recognize abnormal pupillary patterns. The same algorithm accurately estimated cholinergic dysfunction in the BTBR, CDKL5, and MeCP2-deficient mice.
The team then brought this algorithm to 35 young girls with Rett syndrome and 40 typically developing controls. Instead of measuring the girls' pupils (as patients may fidget), they used heart rate fluctuations as the measure of arousal. The algorithm nonetheless successfully identified the girls with Rett, with an accuracy of 80 percent in the first and second year of life.
"These two biomarkers fluctuate in a similar way because they are proxies of the activity of autonomic arousal," says Artoni. "It is the so-called 'fight or flight response."
Autonomic arousal, a property of the brain that is strongly preserved across different species, is a robust indicator of an altered developmental trajectory, Fagiolini and Artoni found.
Biomarkers for babies?
In a previous study with Nelson, Fagiolini showed that visual evoked potentials, an EEG measure of visual processing in the brain, could also serve as a potential biomarker for Rett syndrome. She believes that together, such biomarkers could offer robust yet affordable screening tools for infants and toddlers, warning of impending neurodevelopmental problems and helping to follow the progression of their development or treatment.
"If we have biomarkers that are non-invasive and easily evaluated, even a newborn baby or non-verbal patient could be monitored across multiple timepoints," Fagiolini says.
 

Journal Reference:

1. Pietro Artoni, Arianna Piffer, Viviana Vinci, Jocelyn LeBlanc, Charles A. Nelson, Takao K. Hensch, Michela Fagiolini. Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients. Proceedings of the National Academy of Sciences, 2019; 201820847 DOI: 10.1073/pnas.1820847116 

Courtesy: ScienceDaily
 

'Tickle' therapy could help slow aging, research suggests

'Tickling' the ear with a small electrical current appears to rebalance the autonomic nervous system for over-55s, potentially slowing down one of the effects of ageing, according to new research.

Scientists found that a short daily therapy delivered for two weeks led to both physiological and wellbeing improvements, including a better quality of life, mood and sleep.

The therapy, called transcutaneous vagus nerve stimulation, delivers a small, painless electrical current to the ear, which sends signals to the body's nervous system through the vagus nerve.

The new research, conducted at the University of Leeds, suggests the therapy may slow down an important effect associated with ageing.

This could help protect people from chronic diseases which we become more prone to as we get older, such as high blood pressure, heart disease and atrial fibrillation. The researchers, who published their findings today in the journal Aging, suggest that the 'tickle' therapy has the potential to help people age more healthily, by recalibrating the body's internal control system.

Lead author Dr Beatrice Bretherton, from the School of Biomedical Sciences at the University of Leeds, said: "The ear is like a gateway through which we can tinker with the body's metabolic balance, without the need for medication or invasive procedures. We believe these results are just the tip of the iceberg.

"We are excited to investigate further into the effects and potential long-term benefits of daily ear stimulation, as we have seen a great response to the treatment so far."

The study was conducted by scientists from the University of Leeds and funded by the Dunhill Medical Trust.

What is the autonomic nervous system?

The autonomic nervous system controls many of the body's functions which don't require conscious thought, such as digestion, breathing, heart rate and blood pressure.

It contains two branches, the sympathetic and the parasympathetic, which work against each other to maintain a healthy balance of activity.

The sympathetic branch helps the body prepare for high intensity 'fight or flight' activity, whilst the parasympathetic is crucial to low intensity 'rest and digest' activity.

As we age, and when we are fighting diseases, the body's balance changes such that the sympathetic branch begins to dominate. This imbalance makes us more susceptible to new diseases and leads to the breakdown of healthy bodily function as we get older.

Clinicians have long been interested in the potential for using electrical currents to influence the nervous system. The vagus nerve, the major nerve of the parasympathetic system, has often been used for electrical stimulation and past research has looked at the possibility of using vagus nerve stimulation to tackle depression, epilepsy, obesity, stroke, tinnitus and heart conditions.

However, this kind of stimulation needs surgery to implant electrodes in the neck region, with associated expense and a small risks of side effects.

Fortunately, there is one small branch of the vagus nerve that can be stimulated without surgery, located in the skin of specific parts of the outer ear.

In Leeds, previous research has shown that applying a small electrical stimulus to the vagus nerve at the ear, which some people perceive as a tickling sensation, improves the balance of the autonomic nervous system in healthy 30-year-olds.

Other researchers worldwide are now investigating if this transcutaneous vagus nerve stimulation (tVNS) could provide a therapy for conditions ranging from heart problems to mental health.

Diane Crossley, aged 70, from Leeds, took part in the study and received the tVNS therapy for two weeks. She said: "I was happy to be a participant in this really interesting study, it helped me with my awareness of my own health.

"It was a fascinating project and I was proud to be part of it."

In their new study, scientists at the University of Leeds wanted to see whether tVNS could benefit over 55-year-olds, who are more likely to have out-of-balance autonomic systems that could contribute to health issues associated with ageing.

They recruited 29 healthy volunteers, aged 55 or above, and gave each of them the tVNS therapy for 15 minutes per day, over a two week period. Participants were taught to self-administer the therapy at home during the study.

The therapy led to an increase in parasympathetic activity and a decrease in sympathetic activity, rebalancing the autonomic function towards that associated with healthy function. In addition, some people reported improvements in measures of mental health and sleeping patterns.

Being able to correct this balance of activity could help us age more healthily, as well as having the potential to help people with a variety of disorders such as heart disease and some mental health issues.

Additionally, improving the balance of the autonomic nervous system lowers an individual's risk of death, as well as the need for medication or hospital visits.

Researchers found that individuals who displayed the greatest imbalance at the start of the study experienced the most pronounced improvements after receiving the therapy.

They suggest that in future it may be possible to identify who is most likely to benefit from the therapy, so it can be offered through a targeted approach.

tVNS therapy has previously been shown to have positive psychological effects for patients with depression, and this study shows it could also have significant physiological benefits.

Dr Susan Deuchars, one of the senior authors on the study, said: "We believe this stimulation can make a big difference to people's lives, and we're now hoping to conduct further studies to see if tVNS can benefit multiple disorders."

Further studies are now needed to understand what the long-term health effects of tVNS might be, as this study involved a small number of participants over a short time period.

Journal Reference:

1. Beatrice Bretherton, Lucy Atkinson, Aaron Murray, Jennifer Clancy, Susan Deuchars, Jim Deuchars. Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation. Aging, 2019; DOI: 10.18632/aging.102074 

Courtesy: ScienceDaily

3D printing the human heart

A team of researchers from Carnegie Mellon University has published a paper in Science that details a new technique allowing anyone to 3D bioprint tissue scaffolds out of collagen, the major structural protein in the human body. This first-of-its-kind method brings the field of tissue engineering one step closer to being able to 3D print a full-sized, adult human heart.

The technique, known as Freeform Reversible Embedding of Suspended Hydrogels (FRESH), has allowed the researchers to overcome many challenges associated with existing 3D bioprinting methods, and to achieve unprecedented resolution and fidelity using soft and living materials.
Each of the organs in the human body, such as the heart, is built from specialized cells that are held together by a biological scaffold called the extracellular matrix (ECM). This network of ECM proteins provides the structure and biochemical signals that cells need to carry out their normal function. However, until now it has not been possible to rebuild this complex ECM architecture using traditional biofabrication methods.
"What we've shown is that we can print pieces of the heart out of cells and collagen into parts that truly function, like a heart valve or a small beating ventricle," says Adam Feinberg, a professor of biomedical engineering (BME) and materials science & engineering at Carnegie Mellon, whose lab performed this work. "By using MRI data of a human heart, we were able to accurately reproduce patient-specific anatomical structure and 3D bioprint collagen and human heart cells."
Over 4000 patients in the United States are waiting for a heart transplant, while millions of others worldwide need hearts but are ineligible for the waitlist. The need for replacement organs is immense, and new approaches are needed to engineer artificial organs that are capable of repairing, supplementing, or replacing long-term organ function. Feinberg, who is a member of Carnegie Mellon's Bioengineered Organs Initiative, is working to solve these challenges with a new generation of bioengineered organs that more closely replicate natural organ structures.
"Collagen is an extremely desirable biomaterial to 3D print with because it makes up literally every single tissue in your body," explains Andrew Hudson, a BME Ph.D. student in Feinberg's lab and co-first author on the paper. "What makes it so hard to 3D print, however, is that it starts out as a fluid -- so if you try to print this in air it just forms a puddle on your build platform. So we've developed a technique that prevents it from deforming."
The FRESH 3D bioprinting method developed in Feinberg's lab allows collagen to be deposited layer-by-layer within a support bath of gel, giving the collagen a chance to solidify in place before it is removed from the support bath. With FRESH, the support gel can be easily melted away by heating the gel from room temperature to body temperature after the print is complete. This way, the researchers can remove the support gel without damaging the printed structure made of collagen or cells.
This method is truly exciting for the field of 3D bioprinting because it allows collagen scaffolds to be printed at the large scale of human organs. And it is not limited to collagen, as a wide range of other soft gels including fibrin, alginate, and hyaluronic acid can be 3D bioprinted using the FRESH technique, providing a robust and adaptable tissue engineering platform. Importantly, the researchers also developed open-source designs so that nearly anyone, from medical labs to high school science classes, can build and have access to low-cost, high-performance 3D bioprinters.
Looking forward, FRESH has applications in many aspects of regenerative medicine, from wound repair to organ bioengineering, but it is just one piece of a growing biofabrication field. "Really what we're talking about is the convergence of technologies," says Feinberg. "Not just what my lab does in bioprinting, but also from other labs and small companies in the areas of stem cell science, machine learning, and computer simulation, as well as new 3D bioprinting hardware and software."
"It is important to understand that there are many years of research yet to be done," adds Feinberg, "but there should still be excitement that we're making real progress towards engineering functional human tissues and organs, and this paper is one step along that path."
Other collaborators on the paper include co-first author Andrew Lee, a BME Ph.D. student in Feinberg's lab; BME postdoctoral researcher Dan Shiwarski; BME Ph.D. students Joshua Tashman, TJ Hinton, Sai Yerneni, and Jacqueline Bliley; and BME Research Professor Phil Campbell.
 

Journal Reference:

1. A. Lee, A. R. Hudson, D. J. Shiwarski, J. W. Tashman, T. J. Hinton, S. Yerneni, J. M. Bliley, P. G. Campbell, A. W. Feinberg. 3D bioprinting of collagen to rebuild components of the human heart. Science, 2019; 365 (6452): 482 DOI: 10.1126/science.aav9051

Courtesy: ScienceDaily

 

 

 

Illustration of tick, inset of Lyme disease bacteria (stock image). Credit: © Kateryna_Kon / Adobe Stock As Lyme disease increases, researchers have taken a significant step toward finding new ways to prevent its transmission. The experts, who include a pioneer in Lyme disease discovery, have sequenced the genome of the animal carrying the bacteria that causes the illness. The advance by researchers at the University of California, Irvine and colleagues provides a launching pad for fresh approaches to stopping Lyme disease from infecting people. Results of their study appear today in Science Advances. The scientists dedicated four years to decoding the genetic makeup of the white-footed mouse Peromyscus leucopus, which harbors the Lyme disease-causing bacteria. Unlike mice that scurry into human homes, these rodents inhabit forests, shrubbery and wetlands. People become infected when a tick bites them after feeding on a white-footed mouse carrying the bacteria. "Many efforts to combat Lyme disease have focused on trying to control those ticks, but they have been difficult to put in practice," said Lyme disease pioneer Alan Barbour, M.D. "So we decided that instead we should look at the animal carrying it." Barbour co-discovered Borreliella burgdorferi, the bacteria causing the illness. He is a professor of medicine and microbiology & molecular genetics for the UCI School of Medicine. As a next step in examining the white-footed mouse's role in Lyme disease's spread, Anthony Long, Ph.D., professor of ecology & evolutionary biology in the UCI School of Biological Sciences, worked with Barbour and other researchers on the complex task of determining the DNA letter sequence that makes up the animal's genome. With 2.45 billion of those letters, representing nucleotides that form DNA's basic structural unit, its genome is similar in size to that of humans. "If you want to understand a species, knowing its genetic blueprint is invaluable," said Long, a geneticist and genomicist. "It provides a road map that makes new research approaches much faster and more efficient." While these rodents are called mice, they are more closely related to hamsters than to the house mouse and the researchers' new data emphasized this fact. With the genome in hand, the scientists are interested in pursuing several potential avenues for preventing Lyme disease transmission. Among them are developing an environmentally-safe, humane vaccination method for white-footed mice in the wild, a process already used to prevent rabies transmission in other kinds of animals. They also would like to find out why the rodents don't develop Lyme disease even though they carry the bacteria. "Understanding what shields them from getting sick could guide us in protecting humans from it," Barbour said. He noted that besides harboring Lyme disease, the rodents carry other emerging infections, including a form of viral encephalitis and illnesses similar to malaria and Rocky Mountain spotted fever. The white-footed mouse genome is now available for free download to all who are interested in Lyme or in the additional disease-causing microorganisms that can be transferred from the rodent carrier to humans. The scientists say they hope the information will help others in the quest to fight this transmission. As they move forward with their investigations, the researchers say it remains very important for the public to continue safeguarding against Lyme disease by preventing tick bites. Information on how to protect people, pets and yards from the insects is available on the Centers for Disease Control and Prevention website. The reported number of confirmed and probable Lyme disease cases in the United States rose more than 17 percent between 2016 and 2017, increasing from 36,429 to 42,743, according to the CDC. Noting that those figures likely represent only a fraction of the actual amount, it also says reported cases have tripled since the late 1990s. The CDC cites several factors as contributing to Lyme's rise, including the growth of forests in what were once agricultural fields, the development of suburbs in those areas, and changes in ecological patterns due to climate change

Illustration of tick, inset of Lyme disease bacteria (stock image).

Credit: © Kateryna_Kon / Adobe Stock

As Lyme disease increases, researchers have taken a significant step toward finding new ways to prevent its transmission. The experts, who include a pioneer in Lyme disease discovery, have sequenced the genome of the animal carrying the bacteria that causes the illness. The advance by researchers at the University of California, Irvine and colleagues provides a launching pad for fresh approaches to stopping Lyme disease from infecting people.

Results of their study appear today in Science Advances.

The scientists dedicated four years to decoding the genetic makeup of the white-footed mouse Peromyscus leucopus, which harbors the Lyme disease-causing bacteria. Unlike mice that scurry into human homes, these rodents inhabit forests, shrubbery and wetlands. People become infected when a tick bites them after feeding on a white-footed mouse carrying the bacteria.

"Many efforts to combat Lyme disease have focused on trying to control those ticks, but they have been difficult to put in practice," said Lyme disease pioneer Alan Barbour, M.D. "So we decided that instead we should look at the animal carrying it."

Barbour co-discovered Borreliella burgdorferi, the bacteria causing the illness. He is a professor of medicine and microbiology & molecular genetics for the UCI School of Medicine.

As a next step in examining the white-footed mouse's role in Lyme disease's spread, Anthony Long, Ph.D., professor of ecology & evolutionary biology in the UCI School of Biological Sciences, worked with Barbour and other researchers on the complex task of determining the DNA letter sequence that makes up the animal's genome. With 2.45 billion of those letters, representing nucleotides that form DNA's basic structural unit, its genome is similar in size to that of humans.

"If you want to understand a species, knowing its genetic blueprint is invaluable," said Long, a geneticist and genomicist. "It provides a road map that makes new research approaches much faster and more efficient." While these rodents are called mice, they are more closely related to hamsters than to the house mouse and the researchers' new data emphasized this fact.

With the genome in hand, the scientists are interested in pursuing several potential avenues for preventing Lyme disease transmission. Among them are developing an environmentally-safe, humane vaccination method for white-footed mice in the wild, a process already used to prevent rabies transmission in other kinds of animals.

They also would like to find out why the rodents don't develop Lyme disease even though they carry the bacteria. "Understanding what shields them from getting sick could guide us in protecting humans from it," Barbour said. He noted that besides harboring Lyme disease, the rodents carry other emerging infections, including a form of viral encephalitis and illnesses similar to malaria and Rocky Mountain spotted fever.

The white-footed mouse genome is now available for free download to all who are interested in Lyme or in the additional disease-causing microorganisms that can be transferred from the rodent carrier to humans. The scientists say they hope the information will help others in the quest to fight this transmission.

As they move forward with their investigations, the researchers say it remains very important for the public to continue safeguarding against Lyme disease by preventing tick bites. Information on how to protect people, pets and yards from the insects is available on the Centers for Disease Control and Prevention website.

The reported number of confirmed and probable Lyme disease cases in the United States rose more than 17 percent between 2016 and 2017, increasing from 36,429 to 42,743, according to the CDC. Noting that those figures likely represent only a fraction of the actual amount, it also says reported cases have tripled since the late 1990s.

The CDC cites several factors as contributing to Lyme's rise, including the growth of forests in what were once agricultural fields, the development of suburbs in those areas, and changes in ecological patterns due to climate change.

Journal Reference:

1. Anthony D. Long, James Baldwin-Brown, Yuan Tao, Vanessa J. Cook, Gabriela Balderrama-Gutierrez, Russell Corbett-Detig, Ali Mortazavi, Alan G. Barbour. The genome of Peromyscus leucopus, natural host for Lyme disease and other emerging infections. Science Advances, 2019; 5 (7): eaaw6441 DOI: 10.1126/sciadv.aaw6441 

Courtesy: ScienceDaily

New cause of cell aging discovered

New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works. The findings potentially pave the way for better cancer treatments and revolutionary new drugs that could vastly improve human health in the twilight years.

Cells illustration (stock image).

Credit: © Anusorn / Adobe Stock

 The work, from Assistant Professor of Chemical Engineering and Materials Science Nick Graham and his team in collaboration with Scott Fraser, Provost Professor of Biological Sciences and Biomedical Engineering, and Pin Wang, Zohrab A. Kaprielian Fellow in Engineering, was recently published in the Journal of Biological Chemistry.

"To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing," Graham said. "We're doing the opposite; we're trying to study the reasons cells age, so that we might be able to design treatments for better aging."

What causes cells to age?

To achieve this, lead author Alireza Delfarah, a graduate student in the Graham lab, focused on senescence, a natural process in which cells permanently stop creating new cells. This process is one of the key causes of age-related decline, manifesting in diseases such as arthritis, osteoporosis and heart disease.

"Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division," Delfarah said. "Senescent cells can never divide again. It's an irreversible state of cell cycle arrest."

The research team discovered that the aging, senescent cells stopped producing a class of chemicals called nucleotides, which are the building blocks of DNA. When they took young cells and forced them to stop producing nucleotides, they became senescent, or aged.

"This means that the production of nucleotides is essential to keep cells young," Delfarah said. "It also means that if we could prevent cells from losing nucleotide synthesis, the cells might age more slowly."

Graham's team examined young cells that were proliferating robustly and fed them molecules labeled with stable isotopes of carbon, in order to trace how the nutrients consumed by a cell were processed into different biochemical pathways.

Scott Fraser and his lab worked with the research team to develop 3D imagery of the results. The images unexpectedly revealed that senescent cells often have two nuclei, and that they do not synthesize DNA.

Before now, senescence has primarily been studied in cells known as fibroblasts, the most common cells that comprised the connective tissue in animals. Graham's team is instead focusing on how senescence occurs in epithelial cells, the cells that line the surfaces of the organs and structures in the body and the type of cells in which most cancers arise.

Graham said that senescence is most widely known as the body's protective barrier against cancer: When cells sustain damage that could be at risk of developing into cancer, they enter into senescence and stop proliferating so that the cancer does not develop and spread.

"Sometimes people talk about senescence as a double-edged sword, that it protects against cancer, and that's a good thing," Graham said. "But then it also promotes aging and diseases like diabetes, cardiac dysfunction or atherosclerosis and general tissue dysfunction," he said.

Graham said the goal was not to completely prevent senescence, because that might unleash cancer cells.

"But then on the other hand, we would like to find a way to remove senescent cells to promote healthy aging and better function," he said.

Graham said that the team's research has applications in the emerging field of senolytics, the development of drugs that may be able to eliminate aging cells. He said that human clinical trials are still in early stages, but studies with mice have shown that by eliminating senescent cells, mice age better, with a more productive life span.

"They can take a mouse that's aging and diminishing in function, treat it with senolytic drugs to eliminate the senescent cells, and the mouse is rejuvenated. If anything, it's these senolytic drugs that are the fountain of youth," Graham said.

He added that in order for successful senolytic drugs to be designed, it was important to identify what is unique about senescent cells, so that drugs won't affect the normal, non-senescent cells.

"That's where we're coming in -- studying senescent cell metabolism and trying to figure out how the senescent cells are unique, so that you could design targeted therapeutics around these metabolic pathways," Graham said.

Journal Reference:

1. Alireza Delfarah, Sydney Parrish, Jason A. Junge, Jesse Yang, Frances Seo, Si Li, John Mac, Pin Wang, Scott E. Fraser, Nicholas A. Graham. Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells. Journal of Biological Chemistry, 2019; 294 (27): 10564 DOI: 10.1074/jbc.RA118.005806 

Courtesy: ScienceDaily