Plants can distinguish when touch starts and stops, study suggests

Even without nerves, plants can sense when something touches them and when it lets go, a Washington State University-led study has found.

In a set of experiments, individual plant cells responded to the touch of a very fine glass rod by sending slow waves of calcium signals to other plant cells, and when that pressure was released, they sent much more rapid waves. While scientists have known that plants can respond to touch, this study shows that plant cells send different signals when touch is initiated and ended.

"It is quite surprising how finely sensitive plants cells are -- that they can discriminate when something is touching them. They sense the pressure, and when it is released, they sense the drop in pressure," said Michael Knoblauch, WSU biological sciences professor and senior author of the study in the journal Nature Plants. "It's surprising that plants can do this in a very different way than animals, without nerve cells and at a really fine level."

Knoblauch and his colleagues conducted a set of 84 experiments on 12 plants using thale cress and tobacco plants that had been specially bred to include calcium sensors, a relatively new technology. After placing pieces of these plants under a microscope, they applied a slight touch to individual plant cells with a micro-cantilever, essentially a tiny glass rod about the size of a human hair. They saw many complex responses depending on the force and duration of the touch, but the difference between the touch and its removal was clear.

Within 30 seconds of the applied touch to a cell, the researchers saw slow waves of calcium ions, called cytosolic calcium, travelling from that cell through the adjacent plant cells, lasting about three to five minutes. Removal of the touch showed an almost instant set of more rapid waves that dissipated within a minute.

The authors believe these waves are likely due to the change in pressure inside the cell. Unlike animal cells with permeable membranes, plant cells also have strong cellular walls that cannot be easily breached, so just a light touch will temporarily increase pressure in a plant cell.

The researchers tested the pressure theory mechanically by inserting a tiny glass capillary pressure probe into a plant cell. Increasing and decreasing pressure inside the cell resulted in similar calcium waves elicited by the start and stop of a touch.

"Humans and animals sense touch through sensory cells. The mechanism in plants appears to be via this increase or decrease of the internal cell pressure," said Knoblauch. "And it doesn't matter which cell it is. We humans may need nerve cells, but in plants, any cell on the surface can do this."

Previous research has shown that when a pest like a caterpillar bites a plant leaf, it can initiate the plant's defensive responses such as the release of chemicals that make leaves less tasty or even toxic to the pest. An earlier study also revealed that brushing a plant triggers calcium waves that activate different genes.

The current study was able to differentiate the calcium waves between touch and letting go, but how exactly the plant's genes respond to those signals remains to be seen. With new technologies like the calcium sensors used in this study, scientists can start to untangle that mystery, Knoblauch said.

"In future studies, we have to trigger the signal in a different way than has been done before to know what signal, if touch or letting go, triggers downstream events," he said.

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A backpack full of multiple sclerosis therapy

Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients' ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.

A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the "innate" immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These "acute inflammatory lesions" then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system's second arm, known as the "adaptive immune system" and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.

Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to existing small molecule and protein therapies that leverages myeloid cells, the very type of immune cells that cause the MS-triggering nerve inflammation in patients.

To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed "backpacks," to the cells' surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells' differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions. The results are published in the Proceedings of the National Academy of Sciences (PNAS).

"Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state," said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. "In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients' peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly." Mitragotri is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS.

Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.

New spin for cellular backpacks

Mitragotri's group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells' surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells' behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.

"Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense," said first author Neha Kapate, a graduate student working with Mitragotri. "We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect."

The team fabricated their micrometer-size backpacks via a process known as serial "spin coating," in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.

Cellular backpacks get legs

To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model. "When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome," said Kapate. "The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response."

The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals' hind limbs. The treatment also extended the animals' survival -- all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent "relapsing-remitting" form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.

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Boost in nerve-growth protein helps explain why running supports brain health

Exercise increases levels of a chemical involved in brain cell growth, which bolsters the release of the "feel good" hormone dopamine, a new study shows. Dopamine is known to play a key role in movement, motivation, and learning.

Experts have long understood that regular running raises dopamine activity in the brain and may protect nerve cells from damage. In addition, past research has tied exercise-driven boosts in the dopamine-triggering chemical called brain-derived neurotrophic factor (BDNF) and in dopamine levels to improvements in learning and memory. However, the precise way these three factors interact has until now remained unclear.

Led by researchers at NYU Grossman School of Medicine, the investigation showed that mice running on a wheel for 30 days had a 40% increase in dopamine release in the dorsal stratium, the part of the brain involved in movement, compared to levels in mice that did not exercise. The runners also showed a nearly 60% increase in BDNF levels compared to their non-running counterparts. Notably, the increase in dopamine release remained elevated even after a week of rest. Additionally, when BDNF levels were artificially reduced, running did not lead to additional dopamine release.

"Our findings suggest that BDNF plays a key role in the long-lasting changes that occur in the brain as a result of running," says study lead author and neurobiologist Guendalina Bastioli, PhD. "Not only do these results help explain why exercise makes you move, think, and feel better, they also show that these benefits continue even if you do not work out every day," adds Bastioli, a postdoctoral fellow in the Department of Neuroscience at NYU Langone Health.

While researchers have previously measured dopamine activity during running, the new investigation provides insight into the longer-term behavior of the hormone and its effects on the brain well after exercise stops, according to Bastioli. The report is publishing online May 16 in the Journal of Neuroscience.

For the investigation, researchers provided dozens of male mice with unlimited access to either a freely rotating wheel or a locked wheel that could not move. After one month, the team measured dopamine release and BDNF levels in brain slices. They repeated this same process on a new group of rodents, some of which had been genetically modified to produce half as much BDNF as regular mice.

The study authors note that patients with Parkinson's disease and other movement disorders are often treated with drugs that mimic dopamine's effects on motor neurons. However, the mechanism behind dopamine's role in this protective benefit of exercise had not been thoroughly explored.

"Our results help us understand why exercise alleviates the symptoms of Parkinson's disease, as well as those of neuropsychiatric disorders such as depression," says study senior author and neuroscientist Margaret Rice, PhD. "Now that we know why physical activity helps, we can explore it as a means of augmenting or even replacing the use of dopamine-enhancing drugs in these patients."

Rice, a professor in the Departments of Neurosurgery and Neuroscience and Physiology at NYU Langone, cautions that while the preliminary findings in rodents were promising, future studies in humans will be required to fully understand the role of BDNF and dopamine in Parkinson's disease.

She adds that the study team next plans to investigate the relationship between exercise and these chemicals in female mice, which notably run more frequently than males. In addition, the researchers intend to directly examine whether active mice indeed have improved motor skills compared with those with limited physical activity.

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New UK study reveals extent of brain complications in children hospitalized with COVID-19

Although the risk of a child being admitted to hospital due to COVID-19 is small, a new UK study has found that around 1 in 20 of children hospitalised with COVID-19 develop brain or nerve complications linked to the viral infection.

The research, published in The Lancet Child and Adolescent Health and led by the University of Liverpool, identifies a wide spectrum of neurological complications in children and suggests they may be more common than in adults admitted with COVID-19.

While neurological problems have been reported in children with the newly described post-COVID condition paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), the capacity of COVID-19 to cause a broad range of nervous system complications in children has been under-recognised.

To address this, the CoroNerve Studies Group, a collaboration between the universities of Liverpool, Newcastle, Southampton and UCL, developed a real-time UK-wide notification system in partnership with the British Paediatric Neurology Association.

Between April 2020 and January 2021, they identified 52 cases of children less than 18 years old with neurological complications among 1,334 children hospitalised with COVID-19, giving an estimated prevalence of 3.8%. This compares to an estimated prevalence of 0.9% in adults admitted with COVID-19.

Eight (15%) children presenting with neurological features did not have COVID-19 symptoms although the virus was detected by PCR, underscoring the importance of screening children with acute neurological disorders for the virus.

Ethnicity was found to be a risk factor, over two thirds of children being of Black or Asian background.

For the first time, the study identified key differences between those with PIMS-TS versus those with non-PIMS-TS neurological complications. The 25 children (48%) diagnosed with PIMS-TS displayed multiple neurological features including encephalopathy, stroke, behavioural change, and hallucinations; they were more likely to require intensive care. Conversely, the non-PIMS-TS 27 (52%) children had a primary neurological disorder such as prolonged seizures, encephalitis (brain inflammation), Guillain-Barré syndrome and psychosis. In almost half of these cases, this was a recognised post-infectious neuro-immune disorder, compared to just one child in the PIMS-TS group, suggesting that different immune mechanisms are at work.

Short-term outcomes were apparently good in two thirds (65%) although a third (33%) had some degree of disability and one child died at the time of follow-up. However, the impacts on the developing brain and longer-term consequences are not yet known.

First author Dr Stephen Ray, a Wellcome Trust clinical fellow and paediatrician at the University of Liverpool said: "The risk of a child being admitted to hospital due to COVID-19 is small, but among those hospitalised, brain and nerve complications occur in almost 4%. Our nationwide study confirms that children with the novel post-infection hyper-inflammatory syndrome PIMS-TS can have brain and nerve problems; but we have also identified a wide spectrum of neurological disorders in children due to COVID-19 who didn't have PIMS-TS. These were often due to the child's immune response after COVID-19 infection."

Joint senior-author Dr Rachel Kneen, a Consultant Paediatric Neurologist at Alder Hey Children's NHS Foundation Trust and honorary clinical Senior Lecturer at the University of Liverpool said: "Many of the children identified were very unwell. Whilst they had a low risk of death, half needed intensive care support and a third had neurological disability identified. Many were given complex medication and treatments, often aimed at controlling their own immune system. We need to follow these children up to understand the impact in the long term."

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Technology that restores the sense of touch in nerves damaged as a result of injury

Tel Aviv University's new and groundbreaking technology inspires hope among people who have lost their sense of touch in the nerves of a limb following amputation or injury. The technology involves a tiny sensor that is implanted in the nerve of the injured limb, for example in the finger, and is connected directly to a healthy nerve. Each time the limb touches an object, the sensor is activated and conducts an electric current to the functioning nerve, which recreates the feeling of touch. The researchers emphasize that this is a tested and safe technology that is suited to the human body and could be implanted anywhere inside of it once clinical trials will be done.

The technology was developed under the leadership of a team of experts from Tel Aviv University: Dr. Ben M. Maoz, Iftach Shlomy, Shay Divald, and Dr. Yael Leichtmann-Bardoogo from the Department of Biomedical Engineering, Fleischman Faculty of Engineering, in collaboration with Keshet Tadmor from the Sagol School of Neuroscience and Dr. Amir Arami from the Sackler School of Medicine and the Microsurgery Unit in the Department of Hand Surgery at Sheba Medical Center. The study was published in the journal ACS Nano.

The researchers say that this unique project began with a meeting between the two Tel Aviv University colleagues -- biomedical engineer Dr. Maoz and surgeon Dr. Arami. "We were talking about the challenges we face in our work," says Dr. Maoz, "and Dr. Arami shared with me the difficulty he experiences in treating people who have lost tactile sensation in one organ or another as a result of injury. It should be understood that this loss of sensation can result from a very wide range of injuries, from minor wounds -- like someone chopping a salad and accidentally cutting himself with the knife -- to very serious injuries. Even if the wound can be healed and the injured nerve can be sutured, in many cases the sense of touch remains damaged. We decided to tackle this challenge together, and find a solution that will restore tactile sensation to those who have lost it."

In recent years, the field of neural prostheses has made promising developments to improve the lives of those who have lost sensation in their limbs by implanting sensors in place of the damaged nerves. But the existing technology has a number of significant drawbacks, such as complex manufacturing and use, as well as the need for an external power source, such as a battery. Now, the researchers at Tel Aviv University have used state-of-the-art technology called a triboelectric nanogenerator (TENG) to engineer and test on animal models a tiny sensor that restores tactile sensation via an electric current that comes directly from a healthy nerve and doesn't require a complex implantation process or charging.

The researchers developed a sensor that can be implanted on a damaged nerve under the tip of the finger; the sensor connects to another nerve that functions properly and restores some of the tactile sensation to the finger. This unique development does not require an external power source such as electricity or batteries. The researchers explain that the sensor actually works on frictional force: whenever the device senses friction, it charges itself.

The device consists of two tiny plates less than half a centimeter by half a centimeter in size. When these plates come into contact with each other, they release an electric charge that is transmitted to the undamaged nerve. When the injured finger touches something, the touch releases tension corresponding to the pressure applied to the device -- weak tension for a weak touch and strong tension for a strong touch -- just like in a normal sense of touch.

The researchers explain that the device can be implanted anywhere in the body where tactile sensation needs to be restored, and that it actually bypasses the damaged sensory organs. Moreover, the device is made from biocompatible material that is safe for use in the human body, it does not require maintenance, the implantation is simple, and the device itself is not externally visible.

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