Cell therapy is based on purifying cells from a patient, growing them up in cell culture to improve their properties, and then reinfusing them into the patient. Professor Adrian Liston, Immunology group leader at the Babraham Institute, explained their therapeutic potential: “The leading use of cell therapy is to improve T cells so that they can attack and kill a patient’s cancer, however the incredible versatility of the immune system means that, in principle, we could treat almost any immune disorder with the right cell type. Regulatory T cells are particularly promising, with their ability to shut down autoimmune disease, inflammatory disease and transplantation rejection. A key limitation in their clinical use, however, comes from the instability of regulatory T cells — we just can’t use them in cell therapy until we make ensure that they stay protective.”

T cells come in a large variety of types, each with unique functions in our immune system. “While most T cells are inflammatory, ready to attack pathogens or infected cells, regulatory T cells are potent anti-inflammatory mediators,” Professor Susan Schlenner, University of Leuven, explains. “Unfortunately this cell type is not entirely stable, and sometimes regulatory T cells convert into inflammatory cells, called effector T cells. Crucially, the converted cells inherit both inflammatory behaviour and the ability to identify our own cells, and so pose a significant risk of damage to the system they are meant to protect.”

The first key finding of this research shows that once regulatory T cells switch to becoming inflammatory, they are resistant to returning to their useful former state. Therefore, scientists need to find a way to remove the risky cells from any therapeutic cell populations, leaving behind the stable regulatory T cells.

By comparing stable and unstable cells the researchers identified molecular markers that indicate which cells are at risk of switching from regulatory to inflammatory. These markers can be used to purify cell populations before they are used as a treatment.

In addition to this method of cell purification, the researchers found that exposing regulatory T cells to a destabilising environment purges the unstable cells from the mixture. Under these conditions, the unstable cells are triggered to convert into inflammatory cells, allowing the researchers to purify the stable cells that are left. “The work needs to be translated into human cell therapies, but it suggests that we might be best off treating the cells mean,” says Professor Adrian Liston. “Currently, cell culture conditions for cell therapy aim to keep all the cells in optimal conditions, which may actually be masking the unstable cells. By treating the cultures rougher, we may be able to identify and eliminate the unstable cells and create a safer mix of cells for therapeutic transfer.”

Dr Steffie Junius, lead author on the paper who undertook the research as a PhD student at the University of Leuven, commented: “The next stage in the research is to take the lessons learned in mice and translate them into optimal protocols for patients. I hope that our research contributes to the improved design and allows the development of effective regulatory T cell therapy.”

Establishing a thorough process to improve cell population stability in mice helps to lay the groundwork for improved immune cell therapies in humans, although the methods described in this work would require validation in humans before they were used in cell therapy trials. Dr Timothy Newton, CEO of Reflection Therapeutics, a Babraham Research Campus-based company designing cell therapies against neuro-inflammation, who was not involved in this study, commented on the translational potential of the study: “This research makes a significant impact on regulatory T cell therapeutic development by characterising unstable subsets of regulatory T cells that are likely to lose their desirable therapeutic qualities and become pro-inflammatory. The successful identification of these cells is of great importance when designing manufacturing strategies required to turn potential T cell therapeutics into practical treatments for patients of a wide range of inflammatory disorders.”

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Researchers also found that people who get migraines also had more nerve cell activity in certain areas of the brain during the virtual roller coaster ride and less activity in other areas. Researchers said this abnormal processing of the visual motion stimuli in the brain was linked to migraine disability and more susceptibility to motion sickness.

“Millions of people regularly experience painful and debilitating migraine headaches that can reduce their quality of life,” said study author Arne May, MD, PhD, of the University of Hamburg in Germany. “People with migraine often complain of dizziness, balance problems and misperception of their body’s place in space during migraine. By simulating a virtual roller coaster ride, our study found that some of these problems are not only magnified in people who experience migraine, but they are also associated with changes in various areas of the brain. By identifying and pinpointing these changes, our research could lead to a better understanding of migraine which could in turn lead to the development of better treatments.”

The study involved 20 people with migraine who were compared to 20 people without migraine. Participants had an average age of 30 and more than 80% were women. People with migraine had an average of four migraines per month.

Researchers used functional magnetic resonance imaging (fMRI) to take brain scans of each participant as they watched videos to experience the virtual roller coaster rides. No participants experienced a migraine during the virtual rides. After the virtual rides, participants were surveyed about their perceived levels of dizziness, motion sickness and other symptoms.

Researchers found that 65% of people with migraine experienced dizziness compared to 30% of people without migraine. On a questionnaire about motion sickness, which scored symptom intensity on a scale of 1-180, those with migraine had an average score of 47 compared to an average score of 24 for people without migraine. People with migraine also experienced symptoms longer, an average of 1 minute and 19 seconds compared to an average of 27 seconds. Their symptoms were also more intense.

From the brain scans, researchers were able to identify changes in nerve cell activity based on blood flow to certain areas of the brain. People with migraine had increased activity in five areas of the brain, including two areas in the occipital gyrus, the visual processing area of the brain, and decreased activity in two other areas including the middle frontal gyrus. These brain changes correlated with migraine disability and motion sickness scores.

“One other area of the brain where we found pronounced nerve cell activity in people with migraine was within the pontine nuclei, which helps regulate movement and other motor activity,” said May. “This increased activity could relate to abnormal transmission of visual, auditory and sensory information within the brain. Future research should now look at larger groups of people with migraine to see if our findings can be confirmed.”

The study was supported by the German Research Foundation.

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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

That route of vaccination gives two additional layers of protection over intramuscular shots because it produces: 1) immunoglobulin A and resident memory B and T cells in the respiratory mucosa that are an effective barrier to infection at those sites, and 2) cross-reactive resident memory B and T cells that can respond earlier than other immune cells if a viral variant does start an infection.

“Given the respiratory tropism of the virus, it seems surprising that only seven of the nearly 100 SARS-CoV-2 vaccines currently in clinical trials are delivered intranasally,” Lund and Randall said. “Advantages of intranasal vaccines include needle-free administration, delivery of antigen to the site of infection, and the elicitation of mucosal immunity in the respiratory tract.”

Their viewpoint article goes on to detail the individual advantages and challenges of each of the seven intranasal vaccine candidates. Six are viral vectors, including three different adenovirus vectors, and one candidate each for live-attenuated influenza virus, live-attenuated respiratory syncytial virus and live-attenuated SARS-CoV-2. The seventh vaccine candidate is an inert protein subunit.

Among the drawbacks of using viruses that people may have encountered before is negative interference from anti-vector antibodies that impair vaccine delivery. And because of the minimal risk of reversion for the live-attenuated SARS-CoV-2 virus, it would likely be contraindicated for infants, people over 49 and immunocompromised persons.

“Notably absent from the list of intranasal vaccines are those formulated as lipid-encapsulated mRNA,” Lund and Randall said, listing some of the challenges and adverse side effects that accompany that approach.

“Ultimately, the goal of vaccination is to elicit long-lived protective immunity,” the UAB researchers concluded. Comparing the benefits and disadvantages of intranasal vaccination against intramuscular vaccinations, they suggest that perhaps effective vaccination need not be restricted to a single route.

“The ideal vaccination strategy,” the immunologists concluded, “may use an intramuscular vaccine to elicit a long-lived systemic immunoglobulin G response and a broad repertoire of central memory B and T cells, followed by an intranasal booster that recruits memory B and T cells to the nasal passages and further guides their differentiation toward mucosal protection, including immunoglobulin A secretion and tissue-resident memory cells in the respiratory tract.”

At UAB, Lund is a professor of microbiology and holds the Charles H. McCauley Chair of Microbiology. Randall is a professor of medicine in the Division of Clinical Immunology and Rheumatology, and he holds the Meyer Foundation William J. Koopman, M.D., Endowed Chair in Immunology and Rheumatology.

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Materials provided by University of Alabama at Birmingham. Original written by Jeff Hansen. Note: Content may be edited for style and length.

With inputs from more than 100 other brain regions and sophisticated control of where and when it sends out norepinephrine (NE), the LC’s tiny population of surprisingly diverse cells may represent an important regulator of learning from reward and punishment, and then applying that experience to optimize behavior, said Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT.

“What was formerly considered a homogenous nucleus exerting global, uniform influence over its many diverse target regions, is now suggested to be a heterogeneous population of NE-releasing cells, potentially exhibiting both spatial and temporal modularity that govern its functions,” wrote Sur, postdoc Vincent Breton-Provencher and graduate student Gabrielle Drummond in a review article published last month in Frontiers in Neural Circuits.

The article presents copious emerging evidence from Sur’s group and many others, suggesting that that the LC may integrate sensory inputs and internal cognitive states from across the brain to precisely exert its NE-mediated influence to affect actions — by throttling NE to the motor cortex — and the processing of resulting feedback of reward or punishment — by throttling NE to the prefrontal cortex.

To investigate that hypothesis, the team has begun working with a $2.1 million, 5-year NIH grant awarded in April. In this study they are engaging mice in learning tasks where they are cued by tones of varying pitches and volumes. Over the course of training the mice will learn that when a tone is high pitched, pressing a lever will yield a reward and when the tone is low pitched, the correct response would be to not push lest it experience an unpleasant air puff. By varying the tone volume, the experimenters will vary the certainty the mice can feel that they heard the cue correctly.

The hypothesis (borne out by preliminary data) predicts that the NE will matter in multiple crucial ways, Sur said. When the mouse hears the cue tone, if the pitch is low the LC would send less NE via a cadre of neurons to the motor cortex, reflecting the animal’s belief that the lever should not be pushed because no reward will be forthcoming. Meanwhile the lower the volume, the less certainty the animal has in its decision. Conversely, a high tone of high volume would send more NE, reflecting the animal’s certainty that pushing the lever would produce a reward.

After the mouse has acted, the more surprising the feedback, the more NE it will produce and send via a distinct group to the prefrontal cortex, stimulating greater learning. So for instance, if the mouse hears a faint, high tone and gingerly presses the lever, the surprise of a resulting reward will stimulate a strong output of NE to instruct the prefrontal cortex because its expectations weren’t very high. Whenever a mouse guesses wrong and feels an air puff, that will stimulate the strongest NE release to the prefrontal cortex. After such dynamics, Sur’s team has observed consistent performance changes on the subsequent trial.

“This is a way by which norepinephrine can be thought of as an arousal signal, but it’s also, importantly, in the context of ongoing function a learning signal,” Sur said. “It is both an execution signal and a learning signal, for both of which we can describe the actual quantitative relationships.”

Not only will the team be measuring the activity of LC-NE neurons, they’ll also take them over using optogenetics (in which neurons can be controlled with light), so that they can silence or amplify LC-NE output to show how doing each affects action and learning.

Understanding the true nature of how the LC works could be useful for improving treatments for certain disorders, Sur said. A potential treatment for PTSD, for instance, involves damping receptiveness to NE, but that also promotes drowsiness. A more principled and precise treatment could improve efficacy and reduce those side effects, he said.

“The hope is to affect the anxiety but not make you sleepy, if we understand the targets and theory behind it,” Sur said. “That is the hope of basic science for treating disorders — to make things more and more specific, to define the circuits and the specificity of functions that a system is involved in.”

Moreover the LC is an early region affected in Alzheimer’s disease, he said. Addressing that loss in the right way could help sustain forms of learning and cognition.

In the first wealth and longevity study to incorporate siblings and twin pair data, researchers from Northwestern University analyzed the midlife net worth of adults (mean age 46.7 years) and their mortality rates 24 years later. They discovered those with greater wealth at midlife tended to live longer.

The researchers used data from the Midlife in the United States (MIDUS) project, a longitudinal study on aging. Using data from the first collection wave in 1994-1996 through a censor date of 2018, the researchers used survival models to analyze the association between net worth and longevity.

To tease apart factors of genetics and wealth, the full sample was segmented into subsets of siblings and twins.

In the full sample of 5,400 adults, higher net worth was associated with lower mortality risk. Within the data set of siblings and twin pairs (n=2,490), they discovered a similar association with a tendency for the sibling or twin with more wealth to live longer than their co-sibling/twin with less. This finding suggests the wealth-longevity connection may be causal, and isn’t simply a reflection of heritable traits or early experiences that cluster in families.

“The within-family association provides strong evidence that an association between wealth accumulation and life expectancy exists, because comparing siblings within the same family to each other controls for all of the life experience and biology that they share,” said corresponding author Eric Finegood, a postdoctoral fellow in the Institute for Policy Research at Northwestern.

The researchers also considered the possibility that previous health conditions, such as heart disease or cancer, could impact an individual’s ability to accrue wealth due to activity limitations or healthcare costs — possibly confounding any association between wealth and longevity. To address this, they re-analyzed the data using only individuals without cancer or heart disease. However, even within this sub-group of healthy individuals, the within-family association between wealth and longevity remained.

The study’s senior author is Greg Miller, the Louis W. Menk Professor of Psychology and faculty fellow at the Institute for Policy Research at Northwestern. Co-authors of the study include other Northwestern faculty and trainees (Edith Chen, Daniel Mroczek, Alexa Freedman) as well as researchers from the University of Illinois, Urbana-Champaign; West Virginia University; Purdue University; and the University of Minnesota.

“Far too many American families are living paycheck to paycheck with little to no financial savings to draw on in times of need, said Miller. “At the same time, wealth inequality has skyrocketed. Our results suggest that building wealth is important for health at the individual level, even after accounting for where one starts out in life. So, from a public health perspective, policies that support and protect individuals’ ability to achieve financial security are needed.”

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Materials provided by Northwestern University. Original written by Stephanie Kulke. Note: Content may be edited for style and length.

A new study has discovered that a delayed transfer to a hospital floor is associated with greater short-term risk of delirium among patients aged 65 and over, and for those who arrive to the Emergency Department (ED) on days with higher risk of prolonged lengths of stay — found to be Sunday and Tuesday.

Delirium is an acute cognitive disorder characterised by altered awareness, attentional deficits, confusion, and disorientation. Current estimates of new-onset delirium highlight the fact that delirium overwhelmingly develops in medical settings (as high as 82 per cent in intensive care settings) compared to the community at large (between one per cent and two per cent). Research has shown that between 30 per cent and 40 per cent of all delirium cases are preventable.

Authored by Valdery Moura Junior, an Executive PhD Research student at the Business School (formerly Cass), the study explores whether a combination of the care experienced at the ED and the delayed implementation of delirium prevention measures contribute to an increased risk of the disorder. For example, it is possible that the bright lights and high ambient noise level of the ED for 24 hours a day will contribute to increased short-term risk.

The findings showed that of the 858 patients who presented to the ED with a neurological emergency, delirium was documented in 234 (30 per cent) patients within the first 72 hours from ED arrival.

This study also found that there was a connection between the onset of delirium and the day in which the patient arrived in the ED. Those arriving on Sundays and Tuesdays were more likely to demonstrate symptoms in a shorter time. Casual factors suggested include fewer hospital beds, delayed floor admission — a waiting time greater than 13 hours — and a greater proportion of elective pre-surgical admissions.

Mr. Moura has outlined several measures which can be taken to help prevent the likelihood of the onset of delirium in these settings, as well as reduce spending. These include an earlier initiation of delirium prevention measures; a quicker transfer from the ED to the hospital bed; and improving communication across healthcare managers in primary care, emergency rooms, operating rooms, and post-acute services.

Valdery Moura Junior, who is also computer scientist and technical leader at the Mass General Brigham, a Boston-based non-profit hospital and physicians network that includes Brigham and Women’s Hospital (BWH) and Massachusetts General Hospital (MGH), two of the Harvard Medical School’s most prestigious teaching hospitals, said:

“New-onset delirium in older patients alone will mean a high price for the health care system and poses a global challenge for healthcare managers, providers, and payors. Managing hospital capacity has been an enormous challenge throughout the pandemic, with many admission processes reviewed as a result with the goal of improving patient outcomes. Our study may help to identify feasible targets to improve processes between ED and the rest of the hospital.”

Professor Feng Li, Chair of Information Management at the Business School, said: “This is an excellent example where routine operational data in a hospital can be used to identify anomaly and improve patient outcomes. Valdery’s research demonstrated that more systematic use of such data can lead to significant improvement in the management of hospital capacity and operational processes, and most of all, quality of patient care.”

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Materials provided by City University London. Original written by Luke Lambert. Note: Content may be edited for style and length.

A ubiquitous neurotransmitter that carries signals between brain cells, dopamine, among its many functions, is involved in multiple aspects of cognitive processing. The chemical messenger has been extensively studied from the perspective of external cues, or “deterministic” signals. Instead, University of California San Diego researchers recently set out to investigate less understood aspects related to spontaneous impulses of dopamine. Their results, published July 23 in the journal Current Biology, have shown that mice can willfully manipulate these random dopamine pulses.

Rather than only occurring when presented with pleasurable, or reward-based expectations, UC San Diego graduate student Conrad Foo led research that found that the neocortex in mice is flooded with unpredictable impulses of dopamine that occur approximately once per minute.

Working with colleagues at UC San Diego (Department of Physics and Section of Neurobiology) and the Icahn School of Medicine at Mount Sinai in New York, Foo investigated whether mice are in fact aware that these impulses — documented in the lab through molecular and optical imaging techniques — are actually occurring. The researchers devised a feedback scheme in which mice on a treadmill received a reward if they showed they were able to control the impromptu dopamine signals. Not only were mice aware of these dopamine impulses, the data revealed, but the results confirmed that they learned to anticipate and volitionally act upon a portion of them.

“Critically, mice learned to reliably elicit (dopamine) impulses prior to receiving a reward,” the researchers note in the paper. “These effects reversed when the reward was removed. We posit that spontaneous dopamine impulses may serve as a salient cognitive event in behavioral planning.”

The researchers say the study opens a new dimension in the study of dopamine and brain dynamics. They now intend to extend this research to explore if and how unpredictable dopamine events drive foraging, which is an essential aspect of seeking sustenance, finding a mate and as a social behavior in colonizing new home bases.

“We further conjecture that an animal’s sense of spontaneous dopamine impulses may motivate it to search and forage in the absence of known reward-predictive stimuli,” the researchers noted.

In their efforts to control dopamine, the researchers clarified that dopamine appears to invigorate, rather than initiate, motor behavior.

“This started as a serendipitous finding by a talented, and curious, graduate student with intellectual support from a wonderful group of colleagues,” said study senior co-author David Kleinfeld, a professor in the Department of Physics (Division of Physical Sciences) and Section of Neurobiology (Division of Biological Sciences). “As an unanticipated result, we spent many long days expanding on the original study and of course performing control experiments to verify the claims. These led to the current conclusions.”

The full authors list of the paper includes: Conrad Foo, Adrian Lozada, Johnatan Aljadeff, Yulong Li, Jing W. Wang, Paul A. Slesinger and David Kleinfeld.

The BRAIN Initiative at the National Institutes of Health (grants DA050159, DC009597, MH111499, NS107466 and NS097265) supported the research.

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Materials provided by University of California – San Diego. Original written by Mario Aguilera. Note: Content may be edited for style and length.