Culture

Therapy using immune system cells preserves vision in mice implanted with rare eye cancer

image: Barbara Savoldo, MD, PhD, and colleagues at the University of North Carolina Lineberger Comprehensive Cancer Center report that a treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, preserved the vision of mice implanted with retinoblastoma tissue. The cancer, which is most commonly diagnosed in infants and young children, is treatable in early stages but can still lead to the loss of vision in about 5% of cases.

Image: 
UNC Lineberger

CHAPEL HILL, N.C.--A treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, was found to preserve the vision of mice implanted with tissue from a human eye cancer known as retinoblastoma. The cancer is treatable in early stages but can still lead to the loss of vision in about 5% of cases.

The research findings from scientists at the University of North Carolina Lineberger Comprehensive Cancer Center were published is Nature Cancer on Oct. 12, 2020.

Retinoblastoma is primarily diagnosed in infants and young children. It is considered rare, with approximately 200-300 children diagnosed with the cancer each year in the U.S. Current treatments for retinoblastoma use cold, heat, chemotherapy, lasers or radiation but vision loss still occurs, so the UNC researchers wanted to search for methods that could preserve vision.

"Based on our mouse study and the existence of an active cell immunotherapy program at UNC Lineberger, along with infrastructure for generation of CAR-Ts for clinical use, we feel confident that our efforts could be translated into a phase I clinical study in people," said Zongchao Han, MD, PhD, an associate professor in the UNC School of Medicine and UNC Eshelman School of Pharmacy and a UNC Lineberger member.

The researchers used an incremental process to determine the best method for treatment of retinoblastoma. First, the researchers turned to chimeric antigen receptor-T (CAR-T) cell therapy, a type of immunotherapy where T cells that comprise the immune system are modified in the laboratory to express chimeric antigen receptors, CARs, that target surface proteins on cancer cells. In a lab test, they found that a molecule, GD2, is expressed in retinoblastoma but the possibility to target this molecule to safely eliminate the tumor in the eye was unknown.

Next, to test the safety and benefit of targeting GD2, the investigators injected the CAR-T that recognizes this molecule into the retina of mice implanted with retinoblastoma cancer cells and found the therapy delayed tumor development but did not eradicate the tumor. Then they combined the CAR-Ts with interleukin (IL)-15, a protein that can boost immune response, and found that 60% of mice were tumor-free for up to 70 days.

Finally, they injected a water-based gel containing the CAR-Ts and IL-15 into the retinas of the mice. The CAR-Ts and IL-15 retained an extended ability to attack the cancer cells, control tumor growth and prevent tumor recurrence. They corroborated the lack of tumor growth with several imaging exams of the retina.

This gel-encapsulated therapy is currently being tested in clinical trials in children with neuroblastoma, an embryonal tumor that can progress rapidly and has some of the same genetic characteristics of retinoblastoma.

"We are always looking to improve the lives of children at Lineberger," said Barbara Savoldo, MD, PHD, professor of pediatric Hematology/Oncology at UNC School of Medicine and UNC Lineberger member. "Therefore, we hope to look at the safety of gel injection in a clinical trial of retinoblastoma in children, and if that proves safe, we could move on to see if our methodology can reduce or eliminate these tumors."

Credit: 
UNC Lineberger Comprehensive Cancer Center

To protect nature's benefits, focus on people

image: To calculate the true value of a forest, we need to know how people benefit from it, according to new research.

Image: 
Luis Del Rio/Pexels

To calculate the true value of a forest, we need to know how people benefit from it, according to new research published in Nature Sustainability. A healthy forest holds a treasure trove of benefits for people -- it can filter water for downstream communities, supply timber for building, and provide a place for people to connect with nature. But a forest -- or any other ecosystem -- won't necessarily provide the same things to everyone.

"Context matters," says Lisa Mandle, lead scientist at the Stanford Natural Capital Project and lead author on the paper. "If we want to protect the critical natural assets we all depend on, we need actionable policies that incorporate people's diverse needs. It shouldn't be a one-size-fits-all approach when we're talking about people and nature."

There's a growing global movement to invest in nature in order to protect vital resources and improve climate resilience. But for nature to be factored into policies, sustainable development plans, and other management decisions, the researchers say the science behind them needs to be more inclusive and people-centric.

They also say a focus on equity is crucial. People benefit from nature in different ways -- a forest might provide valuable timber for one group while providing deep cultural significance for another. When all the individuals or groups receiving those benefits aren't considered, the people who depend on nature the most can be left behind.

"If you don't know who specifically would benefit from which ecosystems, how can you prioritize where and how to conserve?" said Taylor Ricketts, director of University of Vermont's Gund Institute for Environment and co-author on the paper. "We want to make sure the benefits of ecosystems are shared equitably, so that we don't make existing racial and social inequality even worse."

Nature-based solutions can create triple-win scenarios for economies, ecosystems, and people. From securing local water supplies to informing coastal development plans, understanding the values that nature provides to people can be a powerful tool for decision-makers. But too often, the research doesn't pay enough attention to the people part.

"People need to see themselves -- their values and needs -- supported in conservation efforts. Often, research will try to assign an overall dollar value to nature without thinking about who will benefitting from it. That's like saying you have $50 of food in your pantry, but you don't know what kind of food it is or who will be eating. You can't plan your meal without knowing what you have and what your diners need," said Mandle.

The researchers recommend actions for their own scientific community that focus on building understanding around who is benefitting from nature in the communities they're hoping to serve. They emphasize direct engagement with people, so that science and policy can be better equipped to meet societal needs, increase equity, and protect vital resources.

"This is a call for us all to do a better job. We can better deliver the information needed to move towards a more sustainable and equitable future," said Mandle. "And that's what we're all working toward."

Credit: 
Stanford University - Natural Capital Project

Mental health disorders related to COVID-19-related deaths

What The Article Says: This devastating pandemic has affected nearly every aspect of daily life. While nations struggle to manage the initial waves of the death and disruption associated with the pandemic, accumulating evidence indicates another "second wave" is building: rising rates of mental health and substance use disorders.

Authors: Charles R. Marmar, M.D., of the NYU Langone Medical Center in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.19632)

Editor's Note: The article includes conflicts of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

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JAMA Network

Update on excess deaths from COVID-19, other causes

What The Study Did: This study updates a previous report of the estimated number of excess deaths in the U.S. during the COVID-19 pandemic through August 1 and describes causes of those deaths and relationships with lifting of coronavirus restrictions.

Authors: Steven H. Woolf, M.D., MP.H., of  the Virginia Commonwealth University School of Medicine in Richmond, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.19545)

Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

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Media advisory: The full study is attached to this news release.

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JAMA Network

COVID-19, excess all-cause mortality in US, 18 comparison countries

What The Study Did: COVID-19 deaths and excess all-cause mortality in the U.S. are compared with 18 countries with diverse COVID-19 responses in this study.

Authors: Ezekiel J. Emanuel, M.D., Ph.D., of the University of Pennsylvania in Philadelphia, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.20717)

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Media advisory: The full study is attached to this news release.

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JAMA Network

COVID-19 pandemic and $16 trillion virus

What The Article Says: This Viewpoint aggregates mortality, morbidity, mental health conditions, and direct economic losses to estimate the total cost of the pandemic in the U.S. on the optimistic assumption that it will be substantially contained by the fall of 2021.

Authors: David M. Cutler, Ph.D., of Harvard University in Cambridge, Massachusetts, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.19759)

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Media advisory: The full article is attached to this news release.

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JAMA Network

Excess deaths from COVID-19, community bereavement, restorative justice for communities of color

What The Article Says: Ways the COVID-19 pandemic has compounded existing health, human rights and economic disparities in communities of color are discussed in this Viewpoint, which also proposes a program of restorative justice in response, comprising investments in education and housing, reforms in lending practices and criminal justice, and more.

Authors: Lisa A. Cooper, M.D., M.P.H., the Johns Hopkins Center for Health Equity in Baltimore, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.19567)

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Media advisory: The full article is attached to this news release.

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JAMA Network

Primates aren't quite frogs

image: An experiment nearly 40 years ago in frogs showed that their leg muscles were controlled by simultaneously recruitment of two modules of neurons. It's a bit more complex in macaques.

Image: 
The National Center of Neurology and Psychiatry

Japan -- Researchers in Japan demonstrated for the first time the 'spinal motor module hypothesis' in the primate arm, opening a new pathway for recovery after disease or injury.

The human hand has 27 muscles and 18 joints, which our nervous system is able to coordinate for complex movements. However, the number of combinations -- or degrees of freedom -- is so large that attempting to artificially replicate this control and adjustment of muscle activity in real time taxes even a modern supercomputer. While the method used by the central nervous system to reduce this complexity is still being intensely studied, the "motor module" hypothesis is one possibility.

Under the motor module hypothesis, the brain recruits interneuronal modules in the spinal cord rather than individual muscles to create movement; wherein different modules can be combined to create specific movements. Nearly 40 years ago, research in frogs showed that simultaneously recruiting two modules of neurons controlling leg muscles created the same pattern of motor activity that represents a "linear summation" of the two component patterns.

An international team of researchers, led by Kazuhiko Seki at the National Center of Neurology and Psychiatry's Department of Neurophysiology, in collaboration with David Kowalski of Drexel University and Tomohiko Takei of Kyoto University's Hakubi Center for Advanced Research, attempted to determine if this motor control method is also present in the primate spinal cord. If validated, it would provide new insight into the importance of spinal interneurons in motor activity and lead to new ideas in movement disorder treatments and perhaps even a method to "reanimate" a limb post-spinal injury.

The team implanted a small array of electrodes into the cervical spinal cord in three macaques. Under anesthesia, different groups of interneurons were recruited individually using a technique called intraspinal microstimulation, or ISMS. The team found that, as in the frog leg, the force direction of the arm at the wrist during dual-site simulation was equal to the linear summation of the individually recruited outputs. However, unlike the frog leg, the force magnitude output could be many times higher than that expected from a simple linear summation of the individual outputs. When the team examined the muscle activity, they found that this supralinear summation was in a majority of the muscles, particularly in the elbow, wrist, and finger.

"This is a very interesting finding for two reasons," explains Seki. "First, it demonstrates a particular trait of the primate spinal cord related to the increased variety of finger movements. Second, we now have direct evidence primates can use motor modules in the spinal cord to control arm movement direction and force magnitude both efficiently and independently."

In effect, using paired stimulation in the primate spinal cord not only directly activate two groups of interneurons, INa and INb, which recruit their target muscle synergies, Syn-a and Syn-b, to set the arm trajectory, but can also activate a third set of interneurnons that can adapt the motor activity at the spinal level to change the force of the movement, group INc. This would let the brain plan the path the arm should take while the spinal cord adapts the muscle activity to make sure that path happens.

One example of this "plan and adapt" approach to motor control is the deceptively simple act of drinking from a can of soda. The brain can predetermine the best way to lift the can to your mouth for a sip, but the actual amount of soda in the can -- and therefore the can's weight -- is perhaps unknown. Once your brain has determined the trajectory the can should take -- in this case INa and INb -- the amount of force needed to complete that action can be modulated separately in INc, rather than redetermining which sets of muscles will be needed.

This study experimentally proves for the first time that primate arm movements may be efficiently controlled by motor modules present in the spinal cord. Based on the results of this research, it is expected that the analysis and interpretation of human limb movements based on the motor module hypothesis will further advance in the future.

In the field of robotics, this control theory may lead to more efficient methods to create complex limb movements, while in the field of clinical medicine, it is expected that new diagnostic and therapeutic methods will be created by analyzing movement disorders caused by neurodegenerative diseases and strokes.

Credit: 
Kyoto University

Tetrahedra may explain water 's uniqueness

image: Scientists at The University of Tokyo use a two-state model based on the formation of tetrahedral structures to explain water's anomalous properties and the surprising liquid-liquid transition of water

Image: 
Institute of Industrial Science, the University of Tokyo

Tokyo, Japan - Researchers at the Institute of Industrial Science at The University of Tokyo sifted through experimental data to probe the possibility that supercooled water has a liquid-to-liquid phase transition between disordered and tetrahedrally structured forms. They found evidence of a critical point based on the cooperative formation of tetrahedra, and show its minor role in water's anomalies. This work shows that water's special qualities--which are essential for life--originate predominantly from the two-state feature.

Liquid water is indispensable for life as we know it, yet many of its properties do not conform with the way other fluids behave. Some of these anomalies, such as water's maximum density at 4°C and its large heat capacity, have important implications for living organisms. The origin of these features has sparked fierce debates in the scientific community since the time of Röntgen.

Now, researchers at The University of Tokyo have utilized a two-state model that posits the dynamical coexistence of two types of molecular structures in liquid water. These are the familiar disordered normal-liquid structure and a locally favored tetrahedral structure. As with many other phase transitions, there may be a "critical point" at which the correlation between tetrahedra takes on a power-law form, which means there will no longer be any "typical" length scale.

Using computer simulations of water molecules, along with a comprehensive analysis of experimental structural, thermodynamic, and dynamic data--including X-ray scattering, density, compressibility, and viscosity measurements--the researchers were able to narrow down where a critical point should be, if it exists.

"If the formation of tetrahedral structures in liquid water is cooperative under these conditions, then a liquid-liquid phase transition with a critical point is possible," lead author Rui Shi says.

The team showed that this occurs around a temperature of ?90°C and a pressure of about 1,700 atmospheres. Experiments in this range are exceedingly difficult: because the water is so far below its normal freezing, ice crystals can quickly form. However, samples can remain liquid in a metastable "supercooled" state at these very high pressures.

"We saw evidence that the critical point is real, but its effect is almost negligible in the experimentally accessible region of liquid water because it is too far from the critical point. This means that water's anomalies come from the two-state feature and not from criticality," senior author Hajime Tanaka says. The scientists anticipate that this project will lead to the convergence of the long debate on the origin of water's anomalies and more experimental research to access the second critical point of water.

Credit: 
Institute of Industrial Science, The University of Tokyo

Professional view of vitamin D jeopardizing elderly care home residents' health

The professional perception of vitamin D as a medicine, rather than as a key nutrient, is constraining practice and jeopardising the health of elderly care home residents in England, conclude researchers in the journal BMJ Nutrition Prevention & Health.

At a time when the vulnerability of elderly care home residents is under the spotlight because of the impact of COVID-19, an urgent review is needed of the nutritional guidelines and regulations around the use of the vitamin, they argue.

The main source of vitamin D is exposure to sunlight, levels of which plummet during the winter in many countries in the northern hemisphere. With few major food sources, it's difficult to get enough vitamin D from diet alone, and vitamin D deficiency in care homes is widespread in many parts of the world, say the researchers.

Vitamin D is essential for good bone health and is thought to have a role in immunity, cardiovascular health, neurological conditions, respiratory infections, lung function and cancer. Most recently, it has been linked to susceptibility to, and severity of, COVID-19.

People who spend less time outdoors, such as the elderly in residential care, or who regularly cover up their skin, or who have darker skin tones, are all at heightened risk of vitamin D deficiency.

Vitamin D supplements have been recommended for care home residents for nearly 30 years. In 2016, recommendations for daily vitamin D supplements were extended to the entire population in the winter months, and throughout the year for those living in care homes.

National bodies from around the world have issued similar recommendations for care home residents, including Australia, Canada, France, Norway, New Zealand and the USA.

In a bid to better understand thinking and practice around the use of vitamin D, the researchers conducted semi-structured interviews with 13 people involved in elderly residential care in two different areas of South East England.

Participants included 4 family doctors (GPs), 4 care home managers, a dietician, a falls specialist, 2 public health practitioners/managers, and a senior doctor in elderly care.

None was aware of any care home routinely prescribing vitamin D supplements to its residents. And although vitamin D supplements are regulated as foods, they were nevertheless regarded as medicines.

Interviewees considered that GPs were responsible for the vitamin D status of elderly care home residents, with prescriptions only written in response to falls or a diagnosis of vitamin D deficiency or osteoporosis rather than as maintenance or preventive treatment, which reflects current NHS guidance.

Care home staff said they would feel vulnerable to malpractice allegations if they routinely provided over-the-counter vitamin D supplements to their residents: they felt this was beyond the scope of their role and expertise.

And there was considerable ambiguity about who should provide and bear the cost of these supplements, although most felt this was GPs' responsibility as prescribers, and that any change would have financial implications for care homes or the residents and their families.

What's more, NHS guidance advises against routine prescription of vitamin D because supplements can be bought easily and cheaply over the counter.

Apart from the dietitian, none of the interviewees seemed familiar with the recommendation that all elderly care home residents should receive vitamin D supplements without the need for a confirmatory blood test, which itself costs more than a year's supply of supplements.

And not everyone was aware that diet and sunlight can't provide adequate vitamin D levels even for the general population in the UK during winter months.

Current nutritional recommendations for supplementary vitamin D also heavily rely on personal responsibility, the researchers point out.

"It is questionable whether this is appropriate in populations with limited autonomy," they say, especially as it effectively creates "a two-tier system, discriminating against those with the least cognitive independence."

The researchers acknowledge the small size of their study, but the fact that participants referred to national policy drivers as key determinants of current practice suggests the finding may be generalisable more widely in England, they suggest.

"The COVID-19 pandemic has brought conditions in care homes into the public eye and on to the political agenda. While practices in care homes are in the spotlight there is an urgent need for action to ensure vitamin D recommendations can be applied in care homes," they write.

"The medical framing of vitamin D supplements in care homes is a practical barrier to implementation of longstanding nutrition guidelines. A paradigm shift is needed so that vitamin D is understood as a protective nutrient as well as a medicine, and a public health as well as a medical responsibility," they conclude.

Commenting on behalf of the NNEdPro Global Centre for Nutrition and Health, the think tank which co-founded this journal, Professor Sumantra Ray, its Executive Director, said: "This research re-emphasises the role of vitamin D in health, an issue that has become even more relevant, given the growing body of evidence, including research published in this journal suggesting that it may help lower the risk of COVID-19 infection and/or ease the severity of symptoms, particularly among those at highest risk."

Shane McAuliffe, Science Comms Lead for the NNEdPro COVID19 Taskforce, which was set up to translate nutritional evidence into best practice in the pandemic, adds: "We also know that an adequate level of vitamin D is key to the maintenance of good general health, and deficiencies can only be picked up by proactive testing, or when this isn't feasible, by adopting a preventive approach in line with Public Health England guidelines.

"This means providing those who may not be able to obtain sufficient vitamin D through sunlight alone with vitamin D supplements throughout the year. That includes care home residents and certain ethnic minority groups."

Credit: 
BMJ Group

Outcomes of babies born to mothers with SARS-CoV-2 infection

What The Study Did: The risk of mother-to-newborn transmission of SARS-CoV-2 infection was examined in this study.

Authors: Cynthia Gyamfi-Bannerman, M.D., M.Sc., and Melissa S. Stockwell, M.D., M.P.H., of the Columbia University Irving Medical Center in New York, are the corresponding authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2020.4298)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

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Media advisory: The full study and commentary are linked to this news release.

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Credit: 
JAMA Network

Scientists develop new precise therapeutic leukemia vaccine

image: High expression of Eps8 and PD-1/PD-L1 in acute leukemia and construction of microcapsule vaccine loading with new epitope Eps8 and PD-1 antibody

Image: 
WEI Wei

Exploration of new leukemia antigens and construction of appropriate delivery systems using FDA-approved material are important strategies for developing leukemia vaccines for clinic use.

Researchers from the Institute of Process Engineering (IPE) of Chinese Academy of Sciences and Zhujiang Hospital of Southern Medical University have developed a new type of precise therapeutic vaccine against leukemia. It utilizes self-healing polylactic acid microcapsules for co-encapsulating a new epitope peptide and PD-1 antibody.

The study was published in Nature Biomedical Engineering on October 12.

Although the possibility of treating leukemia through vaccination has been established, therapeutic performance still falls short of expectations in clinic.

"Our clinical findings revealed the high expression of EPS8 and PD-1/PD-L1 in leukemia patients, which could be respectively used as a new type of leukemia antigen and a checkpoint target for a leukemia vaccine," said Prof. LI Yuhua from Zhujiang Hospital.

In the novel vaccine, epitope peptides and PD-1 antibodies can be simply, mildly and efficiently loaded into polylactic acid microcapsules, facilitated by the unique self-healing feature of the microcapsule.

After a single vaccination, the deposition and degradation of microcapsules at the local injection site lead to recruitment of activated antigen-presenting cells and sustained release of both cargos.

"With the synergism of these two aspects, we observed a significant improvement in specific Cytotoxic T Lymphocyte (CTL) activation," said Prof. WEI Wei from IPE.

The researchers also verified the availability of the novel vaccine using various epitope peptides in different models, such as murine leukemia, humanized cell line-derived leukemia xenograft (CDX) and patient-derived leukemia xenograft (PDX) models.

The microcapsule-based formulation demonstrated its superior performance over that of the ISA adjuvant (commercialized adjuvant) in all leukemia therapeutic models, showing the promise of the microcapsule-based vaccine for use against various leukemia antigens in clinic.

"With the advantages of FDA-approved polylactic acid material, convenience in preparing the vaccine formulation, diversity of vaccine components, and excellent therapeutic effect, the microcapsule-based vaccine exhibits great potential for clinical translation," said Prof. MA Guanghui from IPE.

A peer reviewer from Nature Biomedical Engineering described the study as "comprehensive for a new platform". The reviewer also emphasized that the work is "exciting and convincing".

Credit: 
Chinese Academy of Sciences Headquarters

Novel map reveals how immune cells fight and remember infections

Researchers have charted the activity of tens of thousands of genes in mouse immune cells over the course of an infection. The study from the University of Melbourne, Australia, the Wellcome Sanger Institute, and their collaborators created the first full dynamic map of how cells learn to fight microbes and then preserve a memory of this for future infections.

The findings, published in the journal Nature Immunology, could help scientists develop new vaccines and therapeutics for a range of diseases by guiding their research into a particular set of immune cells, known as CD4+ T cells, that are essential for generating immunity.

The international research team studied the CD4+ T cells during an experimental infection of mice with malaria-causing parasites, which invade and multiply inside red blood cells. With the aid of machine learning techniques, the research team combined the gene activity data over four weeks of infection to generate a comprehensive map of the developmental journeys taken by CD4+ T cells.

Dr Ashraful Haque, co-lead author from the University of Melbourne's Doherty Institute, said: "We traced thousands of individual genes to generate a map from initial infection to periods when cells firstly 'decide' between various immune roles for fighting the infection, and secondly preserve memories of that encounter. Our map revealed several novel genes that were active - in particular, in a type of CD4+ T cells called T follicular helper cells. These are essential for making antibodies that protect against malaria but have not yet been well studied."

The scientists have shared their data through a freely available digital resource. This map allows immunology researchers worldwide to track the response of individual genes after infection.

Dr Sarah Teichmann, co-lead author from the Wellcome Sanger Institute, said: "Importantly, while our map was generated using an experimental model of malaria, it will be useful for studying T cell responses in almost any infectious or non-infectious disease, or treatment in which T cells are involved. Further investigations are needed to confirm that human cells have a similar map to mouse CD4+ T cells. However, we hope this discovery can point researchers in the right direction towards developing new vaccines for infectious diseases, new immune-therapies for certain cancers, and novel ways to prevent auto-immune conditions."

Credit: 
Wellcome Trust Sanger Institute

Navigating through health care data disrupted by COVID-19 pandemic

What The Study Did: The association between the COVID-19 pandemic and health care-related data collection is examined in this Viewpoint article.

Authors: Makoto Mori, M.D., of the Yale School of Medicine in New Haven, Connecticut, is the  corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.5542)

Editor's Note: The article includes conflict of interest disclosure. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Credit: 
JAMA Network

Scientists report role for dopamine and serotonin in human perception and decision-making

WINSTON-SALEM, N.C. - October 12, 2020 - Scientists at Wake Forest School of Medicine have recorded real time changes in dopamine and serotonin levels in the human brain that are involved with perception and decision-making. These same neurochemicals also are critical to movement disorders and psychiatric conditions, including substance abuse and depression.

Their findings are published in the Oct. 12 edition of the journal Neuron.

"This study provides us a unique window into the human brain that has been inaccessible until now," said principal investigator Kenneth T. Kishida, Ph.D., assistant professor of physiology and pharmacology and neurosurgery at Wake Forest School of Medicine, part of Wake Forest Baptist Health. "Almost everything we have known mechanistically about these neurochemicals was from work done in preclinical animal models, not from direct evidence from humans."

Having a clearer understanding of how these brain chemicals actually work in people may lead to improved medications or treatments for disorders like Parkinson's disease, substance use disorder or depression, Kishida said.

In this observational study, the neurotransmitters dopamine and serotonin were tracked in five patients using fast scan cyclic voltammetry, an electrochemical technique used to measure dopamine and serotonin, adapted for use in patients. Dopamine and serotonin are chemical messengers used by the nervous system to regulate countless functions and processes in the body.

Study participants - two with Parkinson's and three with essential tremor - were patients at Wake Forest Baptist who were scheduled to receive a deep brain stimulating implant to treat their condition. Working closely with neurosurgeons, Stephen B. Tatter, M.D., and Adrian W. Laxton, M.D., Kishida's team was able to piggyback on the standard surgical mapping process to insert a carbon fiber microelectrode deep into the brain to detect and record serotonin and dopamine released from neurons. The patients with essential tremor were important to the study because, unlike Parkinson's disease which is caused by loss of dopamine-producing neurons, essential tremor is not believed to be caused by changes in dopamine or serotonin function.

While the patients were awake in the operating room, they performed decision-making tasks similar to playing a simple computer game. As they performed the tasks, measurements of dopamine and serotonin were taken in the striatum, the part of the brain that controls cognition, reward and coordinated movements.

Kishida described the game as a series of dots on a computer screen that moved through a "cross-hair" reference point positioned in the center of the screen. Patients had to decide which way the dots were moving. Sometimes the dots would move in the same direction and at other times the dots would move more chaotically making the decision harder.

The dots then disappeared and the patient had to choose which way the dots had moved - clockwise or counter clockwise - relative to a fixed point. This experimental design, created by Kishida's collaborators and co-authors Dan Bang and Stephen M. Fleming, at University College London, allowed the team to tease apart different aspects of how the human brain decides what it has perceived.

This sequence was repeated 200 to 300 times per patient, varying how the dots moved and thus how difficult it was for the patient to decide what they saw. Occasionally, the patients had to indicate how confident they were in their choices.

The test was designed to track the patient's ability to perceive the dots' movement and the patient's confidence in correctly identifying the direction of that movement as a way to determine how dopamine and serotonin actually behaved. The trials were randomized so that predictability from one test trial to the next would be minimized, Kishida said.

The findings showed that the more uncertain the patient was about the direction of the dots, the higher the serotonin levels became. When their certainty increased, serotonin levels decreased.

The study also revealed that, prior to the act of choosing, dopamine rose in anticipation of the choice and serotonin levels fell, and when both reached a certain level, the person made their choice. It's as if dopamine acted like a gas pedal and serotonin acted like a brake and only when both systems were committed was the act of choice (a button press) allowed, Kishida said.

"This study sheds light on the role these neurochemicals play in learning, brain plasticity and how we perceive the environment," Kishida said. "We now have more detailed insight into how our brains build what we perceive, use those perceptions to make decisions, and interpret the consequences of the choices we make. Dopamine and serotonin appear to be critical in all of these processes.

"Importantly, studies like this will help us and other scientists develop a better understanding of how drugs or medications like serotonin reuptake inhibitors affect cognition, decision-making, and impact psychiatric conditions like depression."

Credit: 
Atrium Health Wake Forest Baptist