Tag: science

Identification of genes that are involved in age-related brain deterioration

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A group of genes and genetic switches involved in age-related brain deterioration have been identified by scientists at the Babraham Institute, Cambridge and Sapienza University, Rome. The research, published online today (5th March) in Aging Cell, found that changes to one of these genes, called Dbx2, could prematurely age brain stem cells, causing them to grow more slowly. The study was led jointly by Giuseppe Lupo and Emanuele Cacci in Italy and Peter Rugg-Gunn in the UK.

Cells in the brain are constantly dying and being replaced with new ones produced by brain stem cells. As we age, it becomes harder for these stem cells to produce new brain cells and so the brain slowly deteriorates. By comparing the genetic activity in brain cells from old and young mice, the scientists identified over 250 genes that changed their level of activity with age. Older cells turn some genes, including Dbx2, on and they turn other genes off.

By increasing the activity of Dbx2 in young brain stem cells, the team were able to make them behave more like older cells. Changes to the activity of this one gene slowed the growth of brain stem cells. These prematurely aged stem cells are not the same as old stem cells but have many key similarities. This means that many of the genes identified in this study are likely to have important roles in brain ageing.

The research also identified changes in several epigenetic marks – a type of genetic switch – in the older stem cells that might contribute to their deterioration with age. Epigenetic marks are chemical tags attached to the genome that affect the activity of certain genes. The placement of these marks in the genome change as we age and this alters how the cells behave. The researchers think that some of these changes that happen in the brain may alter causing brain stem cells to grow more slowly.

First author on the paper, Dr Giuseppe Lupo, Assistant Professor at Sapienza University said: “The genes and gene regulators that we identified are corrupted in neural stem cells from older mice. By studying the Dbx2 gene we have shown that these changes may contribute to ageing in the brain by slowing the growth of brain stem cells and by switching on the activity of other age-associated genes.”

Co-lead scientist Dr Peter Rugg-Gunn at the Babraham Institute said: “Ageing ultimately affects all of us and the societal and healthcare burden of neurodegenerative diseases is enormous. By understanding how ageing affects the brain, at least in mice, we hope to identify ways to spot neural stem cell decline. Eventually, we may find ways to slow or even reverse brain deterioration – potentially by resetting the epigenetic switches – helping more of us to stay mentally agile for longer into old age.”

Co-lead scientist Dr Emanuele Cacci at Sapienza University said: “We hope this research will lead to benefits for human health. We have succeeded in accelerating parts of the ageing process in neural stem cells. By studying these genes more closely, we now plan to try turning back the clock for older cells. If we can do this in mice, then the same thing could also be possible for humans.”

This article has been republished from materials provided by the Babraham Institute. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference: Lupo, G., Nisi, P. S., Esteve, P., Paul, Y.-L., Novo, C. L., Sidders, B., … Rugg-Gunn, P. J. (n.d.). Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. Aging Cell, n/a-n/a. https://doi.org/10.1111/acel.12745

https://www.technologynetworks.com/genomics/news/these-genes-are-involved-in-age-linked-brain-deterioration-298221?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=61138279&_hsenc=p2ANqtz-_FeiFbqi-SP5EqlFOOosvK1dViRCt4fG_ztTzGnpct1WLd4sY0BUbdkcuE7-2clIdZwQsKU1fdtv-8HDaJoh76WD9KwA&_hsmi=61138279

A simple score may be able to determine the personal risk of developing Alzheimer’s disease

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For the first time, an international team of scientists, led by researchers at University of California San Diego School of Medicine, have determined that an Alzheimer’s disease (AD) polygenic risk score can be used to correctly identify adults with mild cognitive impairment (MCI) who were only in their 50s. MCI is considered a precursor to AD.

Findings were published in the February 27 online edition of Molecular Psychiatry.

The AD polygenic risk score was created from genome-wide association studies of AD with a combination of genes weighted according to the association of single nucleotide polymorphisms (SNPs) with AD. SNPs are variations of a single nucleotide or DNA-building block that occur at a specific position in the genome. There is some SNP variation in genomic information in all humans, which affects individual susceptibility to disease.

“Current studies of the AD polygenic risk score typically occur in adults in their 70s, but the AD pathological process begins decades before the onset of dementia,” said William S. Kremen, PhD, professor of psychiatry and co-director of the Center for Behavior Genetics of Aging at UC San Diego School of Medicine. “By focusing on a younger population with cognitive impairment, we may be better able to identify patients for critical early interventions and clinical trials.”

Kremen and team found that someone with an AD polygenic risk score in the upper quartile was 2.5 to 3 times more likely to have MCI than someone with a score in the lowest quartile. Signs of MCI may include difficulty with word recall, forgetting appointments, or often losing personal belongings. The type of MCI most associated with memory loss is called amnestic MCI.

According to the National Institute on Aging, more people with MCI than those without it go on to develop Alzheimer’s. Approximately eight of every 10 persons who fit the definition of amnestic MCI develop Alzheimer’s disease within seven years.

“Our research team found that the polygenic score could differentiate individuals with mild cognitive impairment from those who were cognitively normal,” said Kremen. “We also noticed that for study participants who had cognitive deficits other than memory problems, diabetes was three-fold more likely.”

Kremen added that while this test is not yet available to primary care physicians, it may be an important tool to aid researchers in predicting MCI and AD, and, eventually, reducing the number of future cases.

“The Alzheimer’s Association and others have modeled how the impact of delaying the onset of AD by five years could reduce the number of cases by nearly 50 percent by 2050. We want to do what we can to make this projection a reality,” said Kremen.

Data for this study were collected from 1,329 men who participated in the Vietnam Era Twin Study of Aging (VESTA.). VESTA constitutes a national sample comparable to U.S. men in their age range with respect to health and lifestyle characteristics. Approximately 90 percent of subjects in this analysis were in their 50s. Diagnosis of AD was based on the Jak-Bondi actuarial/neuropsychological approach.

This article has been republished from materials provided by UCSD. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference: Logue, M. W., Panizzon, M. S., Elman, J. A., Gillespie, N. A., Hatton, S. N., Gustavson, D. E., … Kremen, W. S. (2018). Use of an Alzheimer’s disease polygenic risk score to identify mild cognitive impairment in adults in their 50s. Molecular Psychiatry, 1. https://doi.org/10.1038/s41380-018-0030-8

Case Western Reserve University Scientists generate first microscopic image of full length serotonin receptor

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3D reconstruction of a serotonin receptor generated by cryo-electron microscopy

by Rebecca Pool

Claiming a world first and using cryo-electron microscopy, researchers from Case Western Reserve University School of Medicine, US, have observed full-length serotonin receptors. The proteins are common drug targets, and the new images provide details about molecular binding sites that could lead to more precise drug design. Serotonin receptors, which reside in cell membranes throughout the body, are highly dynamic and difficult to image. In the past, the receptors have been sectioned into pieces to study, but by capturing full-length samples, researchers have revealed how different portions interact.

Dr Sandip Basak from Physiology and Biophysics, and colleagues, describe ‘a finely tuned orchestration of three domain movements’ that allows the receptors to elegantly control passageways across cell membranes. “The serotonin receptor acts as a gateway, or channel, from outside the cell to inside,” he says. “When serotonin binds onto the receptor, the channel switches conformation from closed to open. It eventually twists into a ‘desensitized’ state, where the channel closes but serotonin remains attached,” he adds. “This prevents it from being reactivated.”

For this study, the researchers used a FEI Titan Krios microscope, operating at 300 kV, and equipped with a Gatan K2-Summit direct detector camera, at the National Cryo-Electron Microscopy Facility in Frederick, Maryland.

“Successful design of safer therapeutics [for cancer therapies and gastrointestinal diseases] has slowed because there is currently a limited understanding of the structure of the serotonin receptor itself, and what happens after serotonin binds,” says research leader, Professor Sudha Chakrapani. “Our new structure of the serotonin receptor in the resting state has the potential to serve as a structural blueprint to drive targeted drug design and better therapeutic strategies.”

This research is published in Nature Communications.

https://microscopy-analysis.com/editorials/editorial-listings/first-images-full-length-receptor-structure

How flashing lights and pink noise might banish Alzheimer’s, improve memory and more

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Illustration by Paweł Jońca

by Helen Thomson

In March 2015, Li-Huei Tsai set up a tiny disco for some of the mice in her laboratory. For an hour each day, she placed them in a box lit only by a flickering strobe. The mice — which had been engineered to produce plaques of the peptide amyloid-β in the brain, a hallmark of Alzheimer’s disease — crawled about curiously. When Tsai later dissected them, those that had been to the mini dance parties had significantly lower levels of plaque than mice that had spent the same time in the dark.

Tsai, a neuroscientist at Massachusetts Institute of Technology (MIT) in Cambridge, says she checked the result; then checked it again. “For the longest time, I didn’t believe it,” she says. Her team had managed to clear amyloid from part of the brain with a flickering light. The strobe was tuned to 40 hertz and was designed to manipulate the rodents’ brainwaves, triggering a host of biological effects that eliminated the plaque-forming proteins. Although promising findings in mouse models of Alzheimer’s disease have been notoriously difficult to replicate in humans, the experiment offered some tantalizing possibilities. “The result was so mind-boggling and so robust, it took a while for the idea to sink in, but we knew we needed to work out a way of trying out the same thing in humans,” Tsai says.

Scientists identified the waves of electrical activity that constantly ripple through the brain almost 100 years ago, but they have struggled to assign these oscillations a definitive role in behaviour or brain function. Studies have strongly linked brainwaves to memory consolidation during sleep, and implicated them in processing sensory inputs and even coordinating consciousness. Yet not everyone is convinced that brainwaves are all that meaningful. “Right now we really don’t know what they do,” says Michael Shadlen, a neuroscientist at Columbia University in New York City.

Now, a growing body of evidence, including Tsai’s findings, hint at a meaningful connection to neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug. More than two dozen clinical trials are aiming to modulate brainwaves in some way — some with flickering lights or rhythmic sounds, but most through the direct application of electrical currents to the brain or scalp. They aim to treat everything from insomnia to schizophrenia and premenstrual dysphoric disorder.

Tsai’s study was the first glimpse of a cellular response to brainwave manipulation. “Her results were a really big surprise,” says Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It’s a novel observation that would be really interesting to pursue.”


A powerful wave

Brainwaves were first noticed by German psychiatrist Hans Berger. In 1929, he published a paper describing the repeating waves of current he observed when he placed electrodes on people’s scalps. It was the world’s first electroencephalogram (EEG) recording — but nobody took much notice. Berger was a controversial figure who had spent much of his career trying to identify the physiological basis of psychic phenomena. It was only after his colleagues began to confirm the results several years later that Berger’s invention was recognized as a window into brain activity.

Neurons communicate using electrical impulses created by the flow of ions into and out of each cell. Although a single firing neuron cannot be picked up through the electrodes of an EEG, when a group of neurons fires again and again in synchrony, it shows up as oscillating electrical ripples that sweep through the brain.

Those of the highest frequency are gamma waves, which range from 25 to 140 hertz. People often show a lot of this kind of activity when they are at peak concentration. At the other end of the scale are delta waves, which have the lowest frequency — around 0.5 to 4 hertz. These tend to occur in deep sleep (see ‘Rhythms of the mind’).

At any point in time, one type of brainwave tends to dominate, although other bands are always present to some extent. Scientists have long wondered what purpose, if any, this hum of activity serves, and some clues have emerged over the past three decades. For instance, in 1994, discoveries in mice indicated that the distinct patterns of oscillatory activity during sleep mirrored those during a previous learning exercise. Scientists suggested that these waves could be helping to solidify memories.

Brainwaves also seem to influence conscious perception. Randolph Helfrich at the University of California, Berkeley, and his colleagues devised a way to enhance or reduce gamma oscillations of around 40 hertz using a non-invasive technique called transcranial alternating current stimulation (tACS). By tweaking these oscillations, they were able to influence whether a person perceived a video of moving dots as travelling vertically or horizontally.

The oscillations also provide a potential mechanism for how the brain creates a coherent experience from the chaotic symphony of stimuli hitting the senses at any one time, a puzzle known as the ‘binding problem’. By synchronizing the firing rates of neurons responding to the same event, brainwaves might ensure that the all of the relevant information relating to one object arrives at the correct area of the brain at exactly the right time. Coordinating these signals is the key to perception, says Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, “You can’t just pray that they will self-organize.”


Healthy oscillations

But these oscillations can become disrupted in certain disorders. In Parkinson’s disease, for example, the brain generally starts to show an increase in beta waves in the motor regions as body movement becomes impaired. In a healthy brain, beta waves are suppressed just before a body movement. But in Parkinson’s disease, neurons seem to get stuck in a synchronized pattern of activity. This leads to rigidity and movement difficulties. Peter Brown, who studies Parkinson’s disease at the University of Oxford, UK, says that current treatments for the symptoms of the disease — deep-brain stimulation and the drug levodopa — might work by reducing beta waves.

People with Alzheimer’s disease show a reduction in gamma oscillations5. So Tsai and others wondered whether gamma-wave activity could be restored, and whether this would have any effect on the disease.

They started by using optogenetics, in which brain cells are engineered to respond directly to a flash of light. In 2009, Tsai’s team, in collaboration with Christopher Moore, also at MIT at the time, demonstrated for the first time that it is possible to use the technique to drive gamma oscillations in a specific part of the mouse brain6.

Tsai and her colleagues subsequently found that tinkering with the oscillations sets in motion a host of biological events. It initiates changes in gene expression that cause microglia — immune cells in the brain — to change shape. The cells essentially go into scavenger mode, enabling them to better dispose of harmful clutter in the brain, such as amyloid-β. Koroshetz says that the link to neuroimmunity is new and striking. “The role of immune cells like microglia in the brain is incredibly important and poorly understood, and is one of the hottest areas for research now,” he says.

If the technique was to have any therapeutic relevance, however, Tsai and her colleagues had to find a less-invasive way of manipulating brainwaves. Flashing lights at specific frequencies has been shown to influence oscillations in some parts of the brain, so the researchers turned to strobe lights. They started by exposing young mice with a propensity for amyloid build-up to flickering LED lights for one hour. This created a drop in free-floating amyloid, but it was temporary, lasting less than 24 hours, and restricted to the visual cortex.

To achieve a longer-lasting effect on animals with amyloid plaques, they repeated the experiment for an hour a day over the course of a week, this time using older mice in which plaques had begun to form. Twenty-four hours after the end of the experiment, these animals showed a 67% reduction in plaque in the visual cortex compared with controls. The team also found that the technique reduced tau protein, another hallmark of Alzheimer’s disease.

Alzheimer’s plaques tend to have their earliest negative impacts on the hippocampus, however, not the visual cortex. To elicit oscillations where they are needed, Tsai and her colleagues are investigating other techniques. Playing rodents a 40-hertz noise, for example, seems to cause a decrease in amyloid in the hippocampus — perhaps because the hippo-campus sits closer to the auditory cortex than to the visual cortex.

Tsai and her colleague Ed Boyden, a neuro-scientist at MIT, have now formed a company, Cognito Therapeutics in Cambridge, to test similar treatments in humans. Last year, they started a safety trial, which involves testing a flickering light device, worn like a pair of glasses, on 12 people with Alzheimer’s.

Caveats abound. The mouse model of Alzheimer’s disease is not a perfect reflection of the disorder, and many therapies that have shown promise in rodents have failed in humans. “I used to tell people — if you’re going to get Alzheimer’s, first become a mouse,” says Thomas Insel, a neuroscientist and psychiatrist who led the US National Institute of Mental Health in Bethesda, Maryland, from 2002 until 2015.

Others are also looking to test how manipulating brainwaves might help people with Alzheimer’s disease. “We thought Tsai’s study was outstanding,” says Emiliano Santarnecchi at Harvard Medical School in Boston, Massachusetts. His team had already been using tACS to stimulate the brain, and he wondered whether it might elicit stronger effects than a flashing strobe. “This kind of stimulation can target areas of the brain more specifically than sensory stimulation can — after seeing Tsai’s results, it was a no-brainer that we should try it in Alzheimer’s patients.”

His team has begun an early clinical trial in which ten people with Alzheimer’s disease receive tACS for one hour daily for two weeks. A second trial, in collaboration with Boyden and Tsai, will look for signals of activated microglia and levels of tau protein. Results are expected from both trials by the end of the year.

Knight says that Tsai’s animal studies clearly show that oscillations have an effect on cellular metabolism — but whether the same effect will be seen in humans is another matter. “In the end, it’s data that will win out,” he says.

The studies may reveal risks, too. Gamma oscillations are the type most likely to induce seizures in people with photosensitive epilepsy, says Dora Hermes, a neuroscientist at Stanford University in California. She recalls a famous episode of a Japanese cartoon that featured flickering red and blue lights, which induced seizures in some viewers. “So many people watched that episode that there were almost 700 extra visits to the emergency department that day.”

A brain boost

Nevertheless, there is clearly a growing excitement around treating neurological diseases using neuromodulation, rather than pharmaceuticals. “There’s pretty good evidence that by changing neural-circuit activity we can get improvements in Parkinson’s, chronic pain, obsessive–compulsive disorder and depression,” says Insel. This is important, he says, because so far, pharmaceutical treatments for neurological disease have suffered from a lack of specificity. Koroshetz adds that funding institutes are eager for treatments that are innovative, non-invasive and quickly translatable to people.

Since publishing their mouse paper, Boyden says, he has had a deluge of requests from researchers wanting to use the same technique to treat other conditions. But there are a lot of details to work out. “We need to figure out what is the most effective, non-invasive way of manipulating oscillations in different parts of the brain,” he says. “Perhaps it is using light, but maybe it’s a smart pillow or a headband that could target these oscillations using electricity or sound.” One of the simplest methods that scientists have found is neurofeedback, which has shown some success in treating a range of conditions, including anxiety, depression and attention-deficit hyperactivity disorder. People who use this technique are taught to control their brainwaves by measuring them with an EEG and getting feedback in the form of visual or audio cues.

Phyllis Zee, a neurologist at Northwestern University in Chicago, Illinois, and her colleagues delivered pulses of ‘pink noise’ — audio frequencies that together sound a bit like a waterfall — to healthy older adults while they slept. They were particularly interested in eliciting the delta oscillations that characterize deep sleep. This aspect of sleep decreases with age, and is associated with a decreased ability to consolidate memories.

So far, her team has found that stimulation increased the amplitude of the slow waves, and was associated with a 25–30% improvement in recall of word pairs learnt the night before, compared with a fake treatment7. Her team is midway through a clinical trial to see whether longer-term acoustic stimulation might help people with mild cognitive impairment.

Although relatively safe, these kinds of technologies do have limitations. Neurofeedback is easy to learn, for instance, but it can take time to have an effect, and the results are often short-lived. In experiments that use magnetic or acoustic stimulation, it is difficult to know precisely what area of the brain is being affected. “The field of external brain stimulation is a little weak at the moment,” says Knight. Many approaches, he says, are open loop, meaning that they don’t track the effect of the modulation using an EEG. Closed loop, he says, would be more practical. Some experiments, such as Zee’s and those involving neuro-feedback, already do this. “I think the field is turning a corner,” Knight says. “It’s attracting some serious research.”

In addition to potentially leading to treatments, these studies could break open the field of neural oscillations in general, helping to link them more firmly to behaviour and how the brain works as a whole.

Shadlen says he is open to the idea that oscillations play a part in human behaviour and consciousness. But for now, he remains unconvinced that they are directly responsible for these phenomena — referring to the many roles people ascribe to them as “magical incantations”. He says he fully accepts that these brain rhythms are signatures of important brain processes, “but to posit the idea that synchronous spikes of activity are meaningful, that by suddenly wiggling inputs at a specific frequency, it suddenly elevates activity onto our conscious awareness? That requires more explanation.”

Whatever their role, Tsai mostly wants to discipline brainwaves and harness them against disease. Cognito Therapeutics has just received approval for a second, larger trial, which will look at whether the therapy has any effect on Alzheimer’s disease symptoms. Meanwhile, Tsai’s team is focusing on understanding more about the downstream biological effects and how to better target the hippocampus with non-invasive technologies.

For Tsai, the work is personal. Her grandmother, who raised her, was affected by dementia. “Her confused face made a deep imprint in my mind,” Tsai says. “This is the biggest challenge of our lifetime, and I will give it all I have.”

https://www.nature.com/articles/d41586-018-02391-6

Heavy drinking leads to early-onset dementia

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Research published in The Lancet Public Health indicated that alcohol use disorder is a major risk factor for dementia, especially early-onset dementia.

“The relationships between alcohol use and cognitive health in general, and dementia in particular, are complex,” Michaël Schwarzinger, MD, of the Translational Health Economics Network, France, and colleagues wrote. “Moderate drinking has been consistently associated with detrimental effects on brain structure, and nearly every review describes methodological problems of underlying studies, such as inconsistent measurement of alcohol use or dementia, or both, and insufficient control of potential confounders. By contrast, heavy drinking seems detrimentally related to dementia risk, whatever the dementia type.”

To determine how alcohol use disorders effect dementia risk, especially among those aged younger than 65 years, researchers conducted a nationwide retrospective cohort of hospitalized adults in France discharged with alcohol-related brain damage, vascular dementia or other dementias between 2008 and 2013. Alcohol use disorder was the primary exposure, and dementia was the main outcome. Using the French National Hospital Discharge database, they studied the prevalence of early-onset dementia and determined whether alcohol use disorders or other risk factors were associated with dementia onset.

In total, 1,109,343 adults discharged from hospital in France were diagnosed with dementia and included in the study. Of those, 35,034 cases of dementia were attributable to alcohol-related brain damage, and 52,625 cases had other alcohol use disorders. Among the 57,353 early-onset dementia cases, 22,338 (38.9%) were attributable to alcohol-related brain damage and 10,115 (17.6%) had an additional diagnosis of alcohol use disorders.

Analysis revealed that alcohol use disorders were linked to a threefold increased risk for all types of dementia and “were the strongest modifiable risk factor for dementia onset” (adjusted HR = 3.34 [95% CI, 3.28–3.41] for women; HR = 3.36 [95% CI, 3.31–3.41] for men). Alcohol use disorders remained associated with an increased risk for vascular and other dementias even after excluding alcohol-related brain damage, according to the findings. Furthermore, chronic heavy drinking was also linked to all other independent risk factors for dementia onset, including tobacco smoking, high blood pressure, diabetes, lower education, depression and hearing loss.

“Our findings suggest that the burden of dementia attributable to alcohol use disorders is much larger than previously thought, suggesting that heavy drinking should be recognized as a major risk factor for all types of dementia,” Schwarzinger said in a press release. “A variety of measures are needed, such as reducing availability, increasing taxation and banning advertising and marketing of alcohol, alongside early detection and treatment of alcohol use disorders.”

Previous research has largely focused on modest alcohol use, and its possible beneficial effect, thus overlooking the effect of heavy alcohol use as a modifiable risk factor for dementia, according to a related comment written by Clive Ballard, MBChB, MRCPsych, and Iain Lang, PhD, of the University of Exeter Medical School, U.K.

“Although many questions remain, several can be answered using existing data, which would provide an opportunity to refine our understanding of the pathways of modifiable risk and develop optimal prevention strategies,” Ballard and Lang wrote. “In our view, this evidence is robust, and we should move forward with clear public health messages about the relationship between both alcohol use disorders and alcohol consumption, respectively, and dementia.” – by Savannah Demko

https://www.healio.com/psychiatry/alzheimers-disease-dementia/news/online/%7B90f5e375-9dd3-4715-9206-7c148d563d80%7D/heavy-drinking-may-increase-risk-for-dementia?utm_source=selligent&utm_medium=email&utm_campaign=psychiatry%20news&m_bt=1162769038120

New heroin vaccine offers promise for treatment

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Scientists at The Scripps Research Institute (TSRI) have achieved a major milestone toward designing a safe and effective vaccine to both treat heroin addiction and block lethal overdose of the drug. Their research, published today in the journal Molecular Pharmaceutics, shows how a new anti-heroin formulation that is safe in animal models remains stable at room temperature for at least 30 days. As a result, the vaccine is close to being ready for human testing.

“The heroin vaccine is one step closer to clinical evaluation,” says Candy S. Hwang, PhD, first author of the study and a research associate at TSRI.

According to the National Institute on Drug Abuse, 15,446 Americans died from heroin overdose between 2000 and 2016, and the mortality rates are increasing. Heroin abuse has been further fueled by a rise in prescription opioid abuse—studies show that opioid pain reliever users are 40 times more likely to abuse heroin.

The first formulation of the heroin vaccine was developed in 2013 by a team led by Kim D. Janda, PhD, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. It has been shown to be effective—and safe—in both mouse and non-human primate models.

The vaccine works by training the immune system antibodies to recognize and bind to heroin molecules, blocking the drug from reaching the brain to cause a “high.” Researchers believe that blocking the high of heroin will help eliminate the motivation for many recovering addicts to relapse into drug use.

The heroin molecule does not naturally prompt an antibody response, so researchers attach it to a carrier protein that alerts the immune system to start making antibodies. Scientists also add an ingredient called an adjuvant to the vaccine, which boosts the immune response and makes the vaccine more effective.

Hwang says, “Our goal was to prepare a vaccine that could be advanced to clinical trials. As such, we were looking for the best combination of ‘hapten’ (the heroin molecule), carrier protein and adjuvant to keep the vaccine both stable for transport and storage but still efficacious.”

For the new study, the researchers investigated how 20 different carrier protein/adjuvant combinations worked, including shelf stability based on temperature and storage time and whether the formulation was a liquid or powder.

Their experiments in rodent models showed that the best vaccine formulation contained a carrier protein called tetanus toxoid (TT) and adjuvants called alum and CpG ODN. The discovery that alum worked best as an adjuvant was especially significant since alum is one of the few adjuvants used in vaccines already approved by the U.S. Food and Drug Administration. The researchers also found that there was no difference in how well it worked between the liquid and powder versions of this formulation.

Hwang notes that the best vaccine formulation showed protection against lethal doses of heroin. This is particularly important as many heroin addicts have succumb to overdose and death during their attempts to quit the drug.

With this new study, the researchers have shown that the vaccine is safe and effective in animal models, stable under clinical conditions and reliant on an already-approved adjuvant. The next step is to find a producer to make the vaccine on a large scale.

“We believe that a heroin vaccine would be tremendously beneficial for people who have a heroin substance use disorder but have found difficulty in trying to quit,” says Hwang.

In addition to Hwang and Janda, authors of the study, “Enhancing Efficacy and Stability of an Anti-Heroin Vaccine: Examination of Antinociception, Opioid Binding Profile, and Lethality,” were Paul T. Bremer, Cody J. Wenthur, Beverly Ellis and Bin Zhou of The Scripps Research Institute; and Sam On Ho, SuMing Chiang and Gary Fujii of Molecular Express, Inc.

The study was supported by the National Institutes of Health (grants UH3DA041146, F32AI126628, F32DA043323, R42DA040422 and R44AI094770).

https://www.scripps.edu/news/press/2018/20180213janda.html

Temperature-resistant crops are being developed in anticipation of coping with climate change

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Pod shatter in oilseed rape – problem for farmers worldwide.

Breeding temperature-resilient crops is an “achievable dream” in one of the most important species of commercially-cultivated plants, according to a new study.

The vision of crop improvement in the face of climate change is outlined in research by the John Innes Centre which establishes a genetic link between increased temperature and the problem of “pod shatter” (premature seed dispersal) in oilseed rape.

Research by the team led by Dr Vinod Kumar and Professor Lars Østergaard, reveals that pod shatter is enhanced at higher temperature across diverse species in the Brassicaceae family which also includes cauliflower, broccoli and kale.

This new understanding brings a step closer the prospect of creating crops that are better adapted to warmer temperatures a step closer.

Dr Vinod Kumar, a co-author of the paper explained the significance of the findings:

“It’s almost as if there is a thermostat that controls seed dispersal, or pod shatter. As we learn how it works, we could in the future ‘rewire’ it so seed dispersal does not happen at the same pace at higher temperatures

“This piece of the puzzle, coupled with the use of advanced genetic tools means that developing temperature-resilient crops becomes an achievable dream.”

Controlling seed dispersal, or “pod shatter” is a major issue for farmers of oilseed rape worldwide, who lose between 15-20% of yield on average per year due to prematurely dispersed seeds lost in the field.

The study set out to find out if temperature increases had a direct influence on pod shatter in oilseed rape, and how this is controlled by genetics.

“Over the last two decades, scientists have identified the genes that control pod shatter. However, it is not until now that we begin to understand how their activity is affected by the environment, and in this case temperature,” explained Professor Lars Østergaard.

To study the effects of temperature on seed dispersal, Dr Xinran Li, a postdoctoral researcher, monitored fruit development in Arabidopsis, a model plant related to the important Brassicaceae crops, at three different temperatures 17, 22 and 27 degrees centigrade.

This showed that stiffening of the cell wall at the tissue where pod shatter takes place is enhanced by increasing temperature leading to accelerated seed dispersal.

Dr. Li demonstrated that this was true not only for Arabidopsis, but across the Brassicaceae family, including oilseed rape.

The team went on to establish the genetic mechanism which organises the plant response to higher temperatures. Previous studies have shown that pod shatter is controlled by a gene called INDEHISCENT (IND). This study reveals that IND is under the control of a thermo-sensory mechanism in which a histone called H2A.Z is a key player.

The report concludes: “Our findings introduce an environmental factor to the current knowledge, which provide alternative avenues for crop improvement in the face of climate change.”

The paper Temperature modulates tissue-specification programme to control fruit dehiscence in Brassicaceae which appears in the journal Molecular Plant also identifies the genetic pathways behind the temperature sensing mechanism which coordinates the crop’s response to rises in temperature.

Temperature modulates tissue-specification program to control fruit dehiscence in Brassicaceae: authors Xin-Ran Li, Joyita Deb, S. Vinod Kumar and Lars Østergaard.

Read the full report and paper here: http://www.cell.com/molecular-plant/fulltext/S1674-2052(18)30023-6

https://www.jic.ac.uk/news-and-events/news/2018/02/temperature-resilient-crops/#

Praying mantises wearing tiny glasses help researchers discover new type of 3D vision

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by Lacy Cook

This praying mantis isn’t just wearing minuscule 3D glasses for the cute factor, but to help scientists learn more about 3D vision. A Newcastle University team discovered a novel form of 3D vision, or stereo vision, in the insects – and compared human and insect stereo vision for the very first time. Their findings could have implications for visual processing in robots.

Humans aren’t the only creatures with stereo vision, which “helps us work out the distances to the things we see,” according to the university. Cats, horses, monkeys, toads, and owls have it too – but the only insect we know about with 3D vision is the praying mantis. Six Newcastle University researchers obtained new insight into their robust stereo vision with the help of small 3D glasses temporarily attached to the insects with beeswax.

The researchers designed an insect 3D cinema, showing a praying mantis a film of prey. The insects would actually try to catch the prey because the illusion was so convincing. And the scientists were able to take their work to the next level, showing the mantises “complex dot-patterns used to investigate human 3D vision” so they could compare our 3D vision with an insect’s for the first time.

According to the university, humans see 3D in still images by matching details of the image each eye sees. “But mantises only attack moving prey so their 3D doesn’t need to work in still images. The team found mantises don’t bother about the details of the picture but just look for places where the picture is changing…Even if the scientists made the two eyes’ images completely different, mantises can still match up the places where things are changing. They did so even when humans couldn’t.”

The journal Current Biology published their work online last week. Lead author Vivek Nityananda, a behavioral ecologist, described the praying mantis’ stereo vision as “a completely new form of 3D vision.”

Future robots could benefit from these findings: instead of 3D vision based on complex human stereo vision, researchers might be able to take some tips from praying mantis stereo vision, which team member Ghaith Tarawneh said probably doesn’t require a lot of computer processing since insect brains are so small.

Praying mantises wearing tiny glasses help researchers discover new type of 3D vision

New study suggests that living in dim light can affect our brains

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By Andy Henion

Spending too much time in dimly lit rooms and offices may actually change the brain’s structure and hurt one’s ability to remember and learn, indicates groundbreaking research by Michigan State University neuroscientists.

The researchers studied the brains of Nile grass rats (which, like humans, are diurnal and sleep at night) after exposing them to dim and bright light for four weeks. The rodents exposed to dim light lost about 30 percent of capacity in the hippocampus, a critical brain region for learning and memory, and performed poorly on a spatial task they had trained on previously.

The rats exposed to bright light, on the other hand, showed significant improvement on the spatial task. Further, when the rodents that had been exposed to dim light were then exposed to bright light for four weeks (after a month-long break), their brain capacity – and performance on the task – recovered fully.

The study, funded by the National Institutes of Health, is the first to show that changes in environmental light, in a range normally experienced by humans, leads to structural changes in the brain. Americans, on average, spend about 90 percent of their time indoors, according to the Environmental Protection Agency.

“When we exposed the rats to dim light, mimicking the cloudy days of Midwestern winters or typical indoor lighting, the animals showed impairments in spatial learning,” said Antonio “Tony” Nunez, psychology professor and co-investigator on the study. “This is similar to when people can’t find their way back to their cars in a busy parking lot after spending a few hours in a shopping mall or movie theater.”

Nunez collaborated with Lily Yan, associate professor of psychology and principal investigator on the project, and Joel Soler, a doctoral graduate student in psychology. Soler is also lead author of a paper on the findings published in the journal Hippocampus.

Soler said sustained exposure to dim light led to significant reductions in a substance called brain derived neurotrophic factor – a peptide that helps maintain healthy connections and neurons in the hippocampus – and in dendritic spines, or the connections that allow neurons to “talk” to one another.

“Since there are fewer connections being made, this results in diminished learning and memory performance that is dependent upon the hippocampus,” Soler said. “In other words, dim lights are producing dimwits.”

Interestingly, light does not directly affect the hippocampus, meaning it acts first on other sites within the brain after passing through the eyes. Yan said the research team is investigating one potential site in the rodents’ brains – a group of neurons in the hypothalamus that produce a peptide called orexin that’s known to influence a variety of brain functions. One of their major research questions: If orexin is given to the rats that are exposed to dim light, will their brains recover without being re-exposed to bright light?

The project could have implications for the elderly and people with glaucoma, retinal degeneration or cognitive impairments.

“For people with eye disease who don’t receive much light, can we directly manipulate this group of neurons in the brain, bypassing the eye, and provide them with the same benefits of bright light exposure?” Yan said. “Another possibility is improving the cognitive function in the aging population and those with neurological disorders. Can we help them recover from the impairment or prevent further decline?”

http://msutoday.msu.edu/news/2018/does-dim-light-make-us-dumber/

Superdense wood is lightweight and strong as steel, and could be used to build bridges and cars

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A new wood-compacting process crushes the gaps between cell walls in natural wood (porous structure seen in the scanning electron microscopy image, left), making the densified wood (right) as strong as steel.

Newly fabricated superstrong lumber gives a whole new meaning to “hardwood.”

This ultracompact wood, described in the Feb. 8 Nature, is created by boiling a wood block in a water-based solution of sodium hydroxide and sodium sulfite. The chemicals partially strip the wood of substances called lignin and hemicellulose, which help give wood its structure and rigidity. Then the block gets squeezed between metal plates heated to 100° Celsius at a pressure of 5 megapascals — about 50 times the pressure of sea-level atmosphere. That squashes the gaps between the cell walls in the wood, shrinking the block to about 20 percent its original thickness and making it three times denser.

Researchers found that the densified wood could withstand being stretched or pulled 11.5 times harder than its natural counterpart without breaking. That makes it about as strong as steel, even though it’s more lightweight. Stainless steel pellets fired from an air gun and moving at 30 meters per second easily busted through a typical wooden plank, but got lodged in a stack of densified wood sheets with the same total thickness.

Chemicals used to process the wood work for various tree species and don’t pose any significant pollution concerns, says study coauthor Teng Li, a mechanical engineer at the University of Maryland in College Park. So this condensed wood could provide an ecofriendly alternative to steels or alloys for constructing buildings or bridges. It could also be used to manufacture more lightweight, fuel-efficient cars or trains, Li says.

J. Song et al. Processing bulk natural wood into a high-performance structural material. Nature. Vol. 554, February 8, 2018, p. 224. doi: 10.1038/nature25476.

Superdense wood is lightweight, but strong as steel