Human cocaine and heroin addiction is found tied to impairments in specific brain circuit initially implicated in animals

Peer-Reviewed Publication

THE MOUNT SINAI HOSPITAL / MOUNT SINAI SCHOOL OF MEDICINE

 

IMAGE: STRUCTURAL CONNECTIONS WITH THE PREFRONTAL CORTEX MODELED FROM TARGETED NUCLEI IN THE SUBCORTEX (BLUE: HABENULA, YELLOW: ANTERIOR THALAMUS, RED: VENTRAL TEGMENTAL AREA) USING DIFFUSION MRI TRACTOGRAPHY. MICROSTRUCTURAL PROPERTIES OF THE HABENULA TRACT WERE UNIQUELY REDUCED IN INDIVIDUALS WITH COCAINE OR HEROIN USE DISORDER. RESULTS HIGHLIGHT THE POTENTIAL SPECIFICITY OF DISTINCT PREFRONTAL CORTICAL CONNECTIONS TO THE NEUROPATHOLOGY OF DRUG ADDICTION view more 

CREDIT: MOUNT SINAI HEALTH SYSTEM

White matter in the brain that was previously implicated in animal studies has now been suggested to be specifically impaired in the brains of people with addiction to cocaine or heroin, according to a study conducted by researchers from the Icahn School of Medicine at Mount Sinai and Baylor College of Medicine. The study was published October 6 in Neuron.

The study looked at the connectivity of the tract between the prefrontal cortex (PFC), a brain region critical for regulating higher-order executive functions, and the habenula, a region that plays a critical role in reward and reward-associated learning. The habenula has emerged as a key driver of drug-seeking behaviors in animal models of addiction. Specifically, signaling from the PFC to the habenula is disrupted in rodent cocaine addiction models, implicating this PFC-habenula circuit in withdrawal and cue-induced relapse behaviors. However, until now, the PFC-habenula path has remained poorly understood in the human brain. Furthermore, its involvement in the neuropathological effects of drugs other than cocaine has not been previously explored.

For the first time in the human brain, a team led by Rita Z. Goldstein, PhD, and Junqian Xu, PhD, used diffusion magnetic resonance imaging (MRI) tractography to investigate the microstructural features of the PFC-habenula circuit in people with cocaine or heroin addiction compared to healthy control participants. Diffusion MRI tractography uses noninvasive brain imaging to model fiber bundles in the living human brain.

Dr. Goldstein is the Mount Sinai Professor in Neuroimaging of Addiction and Director of the Neuroimaging of Addictions and Related Conditions Research Program at Icahn Mount Sinai. Dr. Xu is Associate Professor of Radiology, and Psychiatry, at Baylor College of Medicine.

“In addition to identifying microstructural differences, specifically reduced coherence in the orientation of the white matter fibers in the cocaine-addicted group that comprised both current cocaine users and those with short-term abstinence, we extended results beyond cocaine (a stimulant) to heroin (an opioid), suggesting that abnormalities in this path may be generalized in addiction,” said Sarah King, a PhD student in Neuroscience in the Graduate School of Biomedical Sciences at Icahn Mount Sinai, who led the analyses and is first author of the paper. “Importantly, we found that across all addicted individuals, greater impairment was correlated with earlier age of first drug use, which points to a potential role for this circuit in developmental or premorbid risk factors.”

The results advance ongoing research in the field by targeting a previously unexplored circuit in the pathophysiology of addiction in humans, where deficits may predispose an individual to both the development of drug addiction and to relapse and which may be potentially amenable for individually tailored treatment or prevention efforts.

About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population. 

Ranked 14th nationwide in National Institutes of Health (NIH)  funding and among the 99th percentile in  research dollars per investigator according to the  Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.

Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System.

A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public.

Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs.

Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.

The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.
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*  Mount Sinai Health System Member Hospitals: The Mount Sinai Hospital; Mount Sinai Queens; Mount Sinai Beth Israel; Mount Sinai West (previously known as Mount Sinai Roosevelt); Mount Sinai Morningside (previously known as Mount Sinai St. Luke’s); Mount Sinai Brooklyn; New York Eye and Ear Infirmary of Mount Sinai; and Mount Sinai South Nassau (previously known as South Nassau Communities Hospital).

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JOURNAL

Neuron

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Prefrontal-habenular microstructural impairments in human cocaine and heroin addiction

On-site reactors could affordably turn CO2 into valuable chemicals

Peer-Reviewed Publication

UNIVERSITY OF WATERLOO

 

IMAGE: LEFT: A SCHEMATIC SHOWING THE KEY COMPONENTS OF THE REACTOR AND WORKING MECHANISM. RIGHT: A PICTURE OF THE CO2 STACK, WHICH IS A DEMONSTRATION OF THE COMMERCIAL REACTORS. view more 

CREDIT: DR. ZHONGWEI CHEN, A CHEMICAL ENGINEERING PROFESSOR AT THE UNIVERSITY OF WATERLOO

New technology developed at the University of Waterloo could make a significant difference in the fight against climate change by affordably converting harmful carbon dioxide (CO2) into fuels and other valuable chemicals on an industrial scale.

Outlined in a study published today in the journal Nature Energy, the system yields 10 times more carbon monoxide (CO) – which can be used to make ethanol, methane and other desirable substances – than existing, small-scale technologies now limited to testing in laboratories.

Its individual cells can also be stacked to form reactors of any size, making the technology a customizable, economically viable solution that could be installed right on site, for example, at factories with CO2 emissions.

“This is a critical bridge to connect CO2 lab technology to industrial applications,” said Dr. Zhongwei Chen, a chemical engineering professor at Waterloo. “Without it, it is very difficult for materials-based technologies to be used commercially because they are just too expensive.”

The system features devices known as electrolyzers that convert CO2, a major greenhouse gas produced by burning fossil fuels, into CO using water and electricity.

Electrolyzers developed by the researchers have new electrodes and a new kind of liquid-based electrolyte, which is saturated with CO2 and flowed through the devices for conversion into CO via an electrochemical reaction.

Their electrolyzers are essentially 10-centimetre by 10-centimetre cells, many times larger than existing devices, that can be stacked and configured in reactors of any size.

“This is a completely new model for a CO2 reactor,” said Chen, the Canada Research Chair in Advanced Materials for Clean Energy. “It makes the whole process economically viable for industrialization and can be customized to meet specific requirements.”

The researchers envision on-site reactors at coal-fired power plants and factories, perhaps the size of a house or more, that would be directly fed CO2 emissions, further reducing costs by eliminating the need to capture and collect CO2 first.

They are also developing plans to power the reactors with on-site renewable energy sources such as solar panels, contributing to the environmental benefits.

“I’m excited by the potential of this technology,” Chen said. “If we really want to make a difference by reducing emissions, we have to concentrate on reducing costs to make it affordable.”

Chen’s collaborators at Waterloo included postdoctoral fellow Dr. Guobin Wen and chemical engineering professors Dr. Aiping Yu and Dr. Jeff Gostick. Several researchers at the South China Normal University also contributed.

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JOURNAL

Nature Energy

Low-income charter school graduates had lower rates of problematic substance use as young adults, UCLA research suggests

Male graduates also reported better health, lower obesity in post graduate years – female graduates did not

Peer-Reviewed Publication

UNIVERSITY OF CALIFORNIA - LOS ANGELES HEALTH SCIENCES

An 8-year study of nearly 1300 low-income adolescents in Los Angeles found that students who attended high performing charter high schools were much less likely to engage in risky substance use by the time they reached age 21.

The study, to be published in the peer-reviewed JAMA Network Open, found males who attended the high performing schools also had better physical health and lower obesity rates as young adults while females had substantially worse outcomes in those two areas.

‘The present results suggest schools have the potential to have a substantial impact on a range of health behaviors and outcomes, including substance use and obesity--two significant and intransigent public health problems,” said lead author Dr. Mitchell Wong, professor of medicine, division of general internal medicine and health services research, at the David Geffen School of Medicine at UCLA. “The differences in health and behavior outcomes were immediate, substantial, and persistent beyond adolescence, which is a vulnerable period in students’ lives, and schools can change the trajectory of both educational and health outcomes.”

In previous research called the Reducing Inequities Through Social and Education Change (RISE) Study, Wong and his collaborators examined outcomes at grade 11. They found that low-income minority students enrolled in high-performing Los Angeles public charter schools were significantly less likely to engage in risky health behaviors such as alcohol and marijuana use than students who were on the waitlist for these schools and attended other schools in the area.

The new study, called RISE Up to reflect that it follows up on the prior research, goes beyond that by looking into post-graduate years and extending the focus to physical health and obesity. The researchers randomly selected 694 students admitted by lottery into one of five high-performing public charter high schools (the intervention group) and 576 waitlisted students (the control group) and followed them between March 2013 through June 2021. They were primarily low-income Latinos or Blacks and were monitored from grade nine through three years after high school graduation.

They found that the students in the intervention group had a 50% lower rate of alcohol use disorder compared to the controls. They also found that self-reported fair or poor health and obesity rates were 42% and 33% lower, respectively, among males.

Among women who attended high-performing schools, however, fair or poor physical health and obesity rates went in the opposite direction-- 65% and 31% higher, respectively, compared with those in the control group. While the reason for this was unclear, the researchers suggest it could be because “higher-performing schools raise expectations for success, potentially creating greater tension around decisions about education, career, and family. These expectations may differ for women and men in our study. Women and men may also cope differently with these expectations, possibly leading women to experience more stress and worse physical health.”

“Overall, these results are encouraging given that substance use and obesity are significant public health problems and risk factors for later life conditions such as cardiovascular disease, dementia, and cancer,” Wong said. “But the potential detrimental physical health and obesity outcomes among women is concerning and warrants further study.”

A strength of the study is that participants went to 147 different high schools in the area, representing a wide range of academic environments. However, the study has some limitations, including a reliance on self-reported outcomes, the authors note. The sample only included students who had applied to charter high schools in lower socioeconomic neighborhoods of Los Angeles, so the findings may not be applicable to other school models. In addition, 90% of the sample were Latino and it is unknown if the same results would be found in other student populations.

Still, the results “suggest high-performing public schools may have an impact on a range of behaviors and health outcomes with a large effect, which is particularly impressive given the marginal cost of the ‘intervention’ is zero,” the researchers write. “Finding effective, affordable, and scalable solutions to combat poverty and its negative effects on health is enormously challenging. Ultimately, improving schools has great potential as a strategy to improve health.”

STUDY/PDF

 Association of Attending a High-Performing High School With Substance Use Disorder Rate and Health Outcomes in Young Adults | Adolescent Medicine | JAMA Network Open | JAMA Network

Other study authors are Dr. Benjamin Meza, Kulwant Dosanjh, Nicholas Jackson, Teresa

Seeman, Natalia Orendain, and Dr. Rebecca Dudovitz, all of UCLA.

 

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JOURNAL

JAMA Network Open

DOI

10.1001/jamanetworkopen.2022.35083 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Association of attending a high-performing high school with substance use disorder rate and health outcomes in young adults

Good planning gets the bike rolling

Peer-Reviewed Publication

TECHNISCHE UNIVERSITÄT DRESDEN

 

IMAGE: THE ROUTE CHOICE OF CYCLISTS IS SUBJECT TO VARIOUS DECISION FACTORS. FOR EXAMPLE, MANY PREFER A SEPARATE BIKE LANE (TOP LEFT) INSTEAD OF SHARING SPACE WITH DENSE CAR TRAFFIC (TOP RIGHT). DEPENDING ON WHETHER STREETS WITH HEAVY CAR TRAFFIC (THICK EDGES) ARE EQUIPPED WITH DEDICATED BIKE PATHS (BLUE) OR NOT (GRAY), CYCLISTS TAKE THE DIRECT ROUTE (BLACK ARROW, BOTTOM LEFT), TAKE DETOURS TO STAY ON BIKE PATHS (BOTTOM CENTER) OR RIDE ON SMALL SIDE STREETS (THIN EDGES) (BOTTOM RIGHT). view more 

CREDIT: CHRISTOPH STEINACKER

In surveys, a large majority of respondents usually agree that cycling can make a significant contribution to reducing greenhouse gases and to sustainable transport, especially in densely populated areas. In contrast, for many countries in reality there is a large gap between desired and actual numbers. In Germany, for example, only 20% of the short-distance of everyday trips in residential environments are covered by bicycle.

When asked about the reasons, one point repeatedly comes up top of the list: The perceived or actual lack of safety on the bike routes used. Increasing the share of cycling trips in the modal split thus depends crucially on a well-developed bike path infrastructure. However, designing efficient bike path networks is a complex problem that involves balancing a variety of constraints while meeting overall cycling demand. In addition, many municipalities still only have small budgets available for improving bicycle infrastructure.

In their study, researchers from the Chair of Network Dynamics / Center for Advancing Electronics Dresden (cfaed) at TU Dresden propose a new approach to generate efficient bike path networks. This explicitly considers the demand distribution and route choice of cyclists based on safety preferences. Typically, minimizing the travel distance is not the only goal, but aspects such as (perceived) safety or attractiveness of a route are also taken into account.

The starting point of this approach is a reversal of the usual planning process: Under real conditions, a bike path network is created by constantly adding bike paths to more streets. The cfaed scientists, on the contrary, start with an ideal, complete network, in which all streets in a city are equipped with a bike path. In a virtual process, they gradually remove individual, less used bike path segments from this network. The route selection of the cyclists is continuously updated. Thus, a sequence of bike path networks is created that is always adapted to the current usage. Each stage of this sequence corresponds to a variant that could be implemented with less financial effort. In this way, city planners can select the version that fits their municipality's budget.

"In our study, we illustrate the applicability of this demand-driven planning scheme for dense urban areas of Dresden and Hamburg," explains Christoph Steinacker, first author of the study. "We approach a real-life issue here using the theoretic toolbox of network dynamics. Our approach allows us to compare efficient bike path networks under different conditions. For example, it allows us to measure the influence of different demand distributions on the emerging network structures." The proposed approach can thus provide a quantitative assessment of the structure of current and planned bike path networks and support demand-driven design of efficient infrastructures.

The study has been published in the journal Nature Computational Science.
Title: "Demand-driven design of bicycle infrastructure networks for improved urban bikeability".
Authors: Christoph Steinacker, David-Maximilian Storch, Marc Timme, Malte Schröder

Link to the study: https://www.nature.com/articles/s43588-022-00318-w

The study was funded by project ‘Statistische Physik von Radverkehrinfrastrukturnetzwerken’ (StaCyNet, project number 493613373) of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

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JOURNAL

Nature Computational Science

DOI

10.1038/s43588-022-00318-w 

Eye-opening discovery about adult brain’s ability to recover vision

UCI team demonstrates the adult brain has the potential to partially recover from inherited blindness

Peer-Reviewed Publication

UNIVERSITY OF CALIFORNIA - IRVINE

Irvine, Calif., Oct. 6, 2022 — A discovery about how some visually impaired adults could start to see offers a new vision of the brain’s possibilities. The finding that the adult brain has the potential to partially recover from inherited blindness comes from a collaboration between researchers in the University of California, Irvine School of Biological Sciences and the School of Medicine. Their paper appears in Current Biology.

The team was examining treatment for Leber congenital amaurosis, known as LCA. The term refers to a group of inherited retinal diseases distinguished by severe visual impairment at birth. The condition, which stems from mutations in any of over two dozen genes, causes degeneration or dysfunction in the retina’s photoreceptors.

Administering chemical compounds that target the retina, called synthetic retinoids, can restore a notable amount of vision in children with LCA. The UCI team wanted to find out if the treatment could make a difference for adults who have the condition.

“Frankly, we were blown away by how much the treatment rescued brain circuits involved in vision,” said Sunil Gandhi, professor of neurobiology and behavior and the corresponding author. Gandhi is a fellow of UCI’s Center for the Neurobiology of Learning and Memory and a member of the Center for Translational Vision Research. “Seeing involves more than intact and functioning retinae. It starts in the eye, which sends signals throughout the brain. It’s in the central circuits of the brain where visual perception actually arises.” Until now, scientists believed that the brain must receive those signals in childhood so that central circuits could wire themselves correctly.

Working with rodent models of LCA, the collaborators were surprised by what they found. “The central visual pathway signaling was significantly restored in adults, especially the circuits that deal with information coming from both eyes,” Gandhi said. “Immediately after the treatment, the signals coming from the opposite-side eye, which is the dominant pathway in the mouse, activated two times more neurons in the brain. What was even more mind-blowing was that the signals coming from the same-side eye pathway activated five-fold more neurons in the brain after the treatment and this impressive effect was long-lasting. The restoration of visual function at the level of the brain was much greater than expected from the improvements we saw at the level of the retinae. The fact that this treatment works so well in the central visual pathway in adulthood supports a new concept, which is that there is latent potential for vision that is just waiting to be triggered.”

The finding opens exciting research possibilities. “Whenever you have a discovery that breaks with your expectations about the possibility for the brain to adapt and rewire, it teaches you a broader concept,” Gandhi said. “This new paradigm could aid in the development of retinoid therapies to more completely rescue the central visual pathway of adults with this condition.”

Gandhi and first author Carey Huh, PhD, who initiated the project, teamed with Krzysztof Palczewski, Distinguished Professor of ophthalmology. Palczewski, director of the Center for Translational Vision Research, is renowned for his work on retinoids and the visual cycle. Philip Kiser, associate professor of physiology and biophysics, an expert on visual cycle biochemistry, helped lead the group. Kiser, who holds a joint appointment in ophthalmology, is a member, Center for Translational Vision Research.

The research was funded by the National Institutes of Health, the Department of Veterans Affairs and the Research to Prevent Blindness foundation.

About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

NOTE TO EDITORS: PHOTO AVAILABLE AT:
ttps://news.uci.edu/2022/10/05/eye-opening-discovery-about-adult-brains-ability-to-recover-vision/

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JOURNAL

Current Biology

ARTICLE TITLE

Retinoid therapy restores eye-specific cortical responses in adult mice with retinal degeneration

Recent advances in smart contact lenses

Peer-Reviewed Publication

AMERICAN CHEMICAL SOCIETY

Contact lenses are most often used to correct blurry vision, but sometimes, people wear differently colored ones for fun. And with Halloween just around the corner, people will soon be stocking up on red, black or cat-eye contacts to look extra spooky. Researchers are currently working hard to adapt these little hydrogels into smart devices to treat color blindness, for use in wearable virtual displays, and for drug delivery and noninvasive health monitoring. Below are some recent papers published in ACS journals that report insights into powering smart contacts, as well as new ways they can deliver drugs. Reporters can request free access to these papers by emailing newsroom@acs.org.

Powering smart lenses
“Safe, Durable, and Sustainable Self-Powered Smart Contact Lenses”
ACS Nano
Sept. 7, 2022
Here, researchers showed that the glucose in tears can power smart contact lenses. They sandwiched a microscopic glucose fuel cell between soft hydrogel layers. Combining the fuel cell with color-changing crystal arrays produced a protype sensor that visibly distinguished artificial tears simulating a diabetic condition from controls. The device still needs to be made even smaller, however, before it could be used in smart glucose-sensing contact lenses, say the researchers.

“Flexible and Semi-Transparent Silicon Solar Cells as a Power Supply to Smart Contact Lenses”
ACS Applied Electronic Materials
Aug.1, 2022
In this paper, flexible, semi-transparent solar cells were designed for running the microelectronic and optoelectronic elements in smart contact lenses. Researchers molded the 15 µm-thick silicon-based photovoltaics in arcs, embedding them into dome-shaped lenses. Based on experiments in indoor and outdoor light, the researchers estimated that their 25 and 50% transparent solar cells could generate 49.3 and 26.6 J cm-2 per day, respectively, showing their potential to deliver energy to smart contact lenses.

Delivering drugs
“Printable Metal–Polymer Conductors for Local Drug Delivery”
Nano Letters
Sept. 19, 2022
Medications, such as drops or ointments, that are administered topically can enter the body more easily with localized applications of electricity. As a step toward using this technique to treat eyes and skin, researchers printed liquid metal circuits onto stretchable and bendable pieces of polydimethylsiloxane, simulating contact lenses and skin patches. In animal model tests, electrical pulses were applied to the metal-polymer contact lens, which the researchers found improved the therapeutic effect of eye drops.

“Pressure-Triggered Microfluidic Contact Lens for Ocular Drug Delivery”
ACS Applied Polymer Materials
Sept. 7, 2022
Most eye infections are treated with drops, but blinking and tears quickly rinse them away. So, researchers have developed prototype smart contact lenses that can gradually deliver drugs directly onto the eye. The lenses have arc-shaped microfluidic channels and a micropump that’s activated by eyelid pressure. In blinking simulations, the flexible, transparent lenses released drug-like fluids in a controlled and sustained manner without the need for electronic components.

The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS’ mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.

To automatically receive news releases from the American Chemical Society, contact newsroom@acs.org.

COVID-19 vaccine developed by Brazilian scientists is ready for clinical trials

The results of animal trials were published recently in Nature Communications. The researchers have received the green light from the national health surveillance authority to proceed with testing on humans.

Peer-Reviewed Publication

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO

Testing on humans of a novel COVID-19 vaccine developed in Brazil will begin this year. It performed well in animal trials, as reported in an article published in August in Nature Communications. The scientists responsible for the vaccine have just received authorization from the National Health Surveillance Agency (ANVISA) to begin clinical trials.

“There are only some minor adjustments left to be made in the study’s protocol before we submit it once again to the approval of the National Council for Research Ethics [CONEP]. We expect to start clinical trials by late October,” Ricardo Tostes Gazzinelli, head of the Federal University of Minas Gerais’s Vaccine Technology Center (CTV-UFMG), told Agência FAPESP. Gazzinelli is also a senior researcher at Oswaldo Cruz Foundation (Fiocruz), the Ministry of Health’s research arm.

To develop the formulation for the vaccine, the group led by Gazzinelli combined two different SARS-CoV-2 proteins: N (for nucleocapsid, which contains the virus’s genetic material) and part of S (for spike, the protein used by the virus to bind to invade human cells). The resulting chimeric molecule is called SpiN. The strategy aims to trigger a cellular immune response consisting of the production of defense cells (T lymphocytes) that specialize in recognizing and killing the novel coronavirus. This type of protection should remain effective even against novel variants.

“The COVID-19 vaccines in use now are designed mainly to trigger the production of neutralizing antibodies against the S protein and prevent the virus from infecting human cells. This is what’s known as the humoral immune response. However, with the emergence of variants with many mutations in the S protein, the ability of these antibodies to recognize this antigen has weakened, whereas the N protein is better conserved in the new strains,” said PhD candidate Julia Castro, who led the preclinical trials with Gazzinelli supervising.

According to Gazzinelli, who is also a visiting professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP), the vaccine based on the chimeric protein SpiN does not itself trigger the production of neutralizing antibodies, but if given as a booster shot it can stimulate both the humoral immunity produced by prior vaccination and cellular immunity, affording double protection. 

Challenge testing

The animal trials were performed at a high-biosafety laboratory at FMRP-USP, thanks to collaboration with João Santana da Silva and Luiz Tadeu Figueiredo, both of whom are also professors there. The research was supported by FAPESP, the Ministry of Science, Technology and Innovation (MCTI) via its virus network (Rede Vírus), the Minas Gerais Research Funding Foundation (FAPEMIG), and the City of Belo Horizonte (capital of Minas Gerais).

The first step was to test the efficacy of the vaccine in mice that had been genetically modified to express ACE2, the human protein to which the virus binds via its spike (S) to infect the cells of the host. This model mimics the severe form of COVID-19.

Some of the mice were given two doses 21 days apart. The others received a placebo. A month later they were exposed intranasally to a high viral load. Different experiments were performed to test the extent to which the vaccine protected them against the wild-type strain of SARS-CoV-2 (isolated in China in 2019), the delta variant (India, 2020) and the omicron variant (South Africa, 2021).

“In the control group, which was given placebo, 100% of the animals infected with the [wild-type] Wuhan strain or delta died. The mice exposed to omicron didn’t die but developed a significant pathology in the lungs,” Castro said. “In the vaccinated group, all the animals survived infection by all three strains and lung tissue was much more preserved. In addition, viral load was between 50 and 100 times lower.”

The next step involved testing the vaccine on a moderate disease model. To do this, the scientists used hamsters, which are naturally infected by the virus but not very effectively. They were given two doses of the vaccine and after a month were exposed to the Wuhan or delta strain. Compared with the control group, the vaccinated hamsters had a viral load that was about ten times lower and fewer signs of lung damage.

Stability and safety

A platform was established at CTV-UFMG to produce the chimeric protein SpiN in genetically modified bacteria. Tests were also performed there to guarantee purity (absence of contaminants in the formulation) and stability (durability at different temperatures).

“The results showed that the vaccine remains viable for two weeks at room temperature and for at least six months when stored at 4 °C,” told Gazzinelli, according to whom safety and toxicity tests were performed on rats.

According to Gazzinelli, clinical trials are divided into Phase I and II. Phase I is expected to immunize 80 patients to make sure the vaccine is safe for humans, while Phase II will include a group of 400 volunteers for vaccine safety tests and also for evaluation of the vaccine’s immunogenicity – or, in other words, its capacity to induce an effective immune response. Trials will be conducted at UFMG’s medical school and will be led by Helton Santiago and Jorge Pinto, both of whom are professors there. They plan to vaccinate people who have already been given any of the available COVID-19 vaccines at least six months previously. 

“It will be a booster shot. Volunteers in the control group will receive the AstraZeneca vaccine. We’ll then compare levels of neutralizing antibodies to SARS-CoV-2 and T lymphocytes. We expect our formulation to trigger an even stronger cellular immune response,” Gazzinelli said.

About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe

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JOURNAL

Nature Communications

DOI

10.1038/s41467-022-32547-y 

METHOD OF RESEARCH

Randomized controlled/clinical trial

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Promotion of neutralizing antibody-independent immunity to wild-type and SARS-CoV-2 variants of concern using an RBD-Nucleocapsid fusion protein

Discovery of a new function of the cerebellum

Peer-Reviewed Publication

UNIVERSITY OF BASEL

 

IMAGE: THE CEREBELLUM (ACTIVATION IN RED) COMMUNICATES WITH VARIOUS AREAS OF THE CEREBRUM (ACTIVATIONS IN GREEN) TO ENHANCE STORAGE OF EMOTIONAL INFORMATION. view more 

CREDIT: MCN, UNIVERSITY OF BASEL

The cerebellum is known primarily for regulation of movement. Researchers at the University of Basel have now discovered that the cerebellum also plays an important role in remembering emotional experiences. The study appears in the journal PNAS.

Both positive and negative emotional experiences are stored particularly well in memory. This phenomenon is important to our survival, since we need to remember dangerous situations in order to avoid them in the future. Previous studies have shown that a brain structure called the amygdala, which is important in the processing of emotions, plays a central role in this phenomenon. Emotions activate the amygdala, which in turn facilitates the storage of information in various areas of the cerebrum.

The current research, led by Professor Dominique de Quervain and Professor Andreas Papassotiropoulos at the University of Basel, investigates the role of the cerebellum in storing emotional experiences. In a large-scale study, the researchers showed 1,418 participants emotional and neutral images and recorded the subjects’ brain activity using magnetic resonance imaging.

In a memory test conducted later, the positive and negative images were remembered by the participants much better than the neutral images. The improved storage of emotional images was linked with an increase in brain activity in the areas of the cerebrum already known to play a part. However, the team also identified increased activity in the cerebellum.

The cerebellum in communication with the cerebrum

The researchers were also able to demonstrate that the cerebellum shows stronger communication with various areas of the cerebrum during the process of enhanced storage of the emotional images. It receives information from the cingulate gyrus – a region of the brain that is important in the perception and evaluation of feelings. Furthermore, the cerebellum sends out signals to various regions of the brain, including the amygdala and hippocampus. The latter plays a central role in memory storage.

“These results indicate that the cerebellum is an integral component of a network that is responsible for the improved storage of emotional information,” says de Quervain. Although an improved memory for emotional events is a crucial mechanism for survival, it does have its downsides: in the case of very negative experiences, it can lead to recurring anxiety. This means that the findings, which have now been released, may also be relevant in understanding psychiatric conditions such as post-traumatic stress disorder.

Basel research on emotions and memory

The current study forms part of a large-scale research project conducted by the Research Platform Molecular and Cognitive Neurosciences (MCN) at the University of Basel and the University Psychiatric Clinics (UPK) Basel. The aim of this project is to gain a better understanding of emotional and cognitive processes and to transfer results from basic research to clinical projects.

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JOURNAL

Proceedings of the National Academy of Sciences

DOI

10.1073/pnas.2204900119 

ARTICLE TITLE

Human cerebellum and corticocerebellar connections involved in emotional memory enhancement

Geneticists discover new wild goat subspecies via ancient DNA

Peer-Reviewed Publication

TRINITY COLLEGE DUBLIN

Geneticists from Trinity College Dublin, together with a team of international collaborators, have discovered a previously unknown lineage of wild goats over ten millennia old. The research was subject to open peer review and recommendation at PCI Genomics and has just been published in the journal eLife. 

The new goat type, discovered from genetic screening of bone remains and referred to as “the Taurasian tur”, likely survived the Last Glacial Maximum (the ice age), which stranded their ancestors in the high peaks of the Taurus Mountains in Turkey where their remains were found.

A chance discovery at Direkli Cave

Over 12,000 years ago, hunter-gatherers in the Taurus Mountains of southern Turkey relied heavily on local game for food and subsistence. Located near the present-day village of Döngel and at an elevation of ~1,100 m above sea level, Direkli Cave was used for roughly three millennia (~14,000-11,000 years ago) as a seasonal camp for these hunters and may have been inhabited year-round. 

“Among the artefacts found at Direkli Cave were large amounts of bone remains with distinct processing marks, indicating that wild goats were butchered there for consumption,” says Dr Kevin Daly, from Trinity’s School of Genetics and Microbiology, who is first author of the research article. 

“With the cave surrounded by high peaks, reaching ~2,200 m, the wild goat or bezoar ibex (Capra aegagrus) that inhabit the region today were likely the target of these Late Pleistocene hunters.” 

During genetic screening of goat bone remains from Direkli, the geneticists noticed something unusual: many of the goats carried mitochondrial genomes similar to a different species of wild goat. 

Whereas the domestic goat is derived from the bezoar ibex, other species of wild goat are still alive today and are found in relatively restricted regions. These include the East and West Caucasus tur, two sister species (or subspecies) of wild goat now found only in the Caucasus Mountains in Georgia. Many of the Direkli Cave samples carried mitochondria related to these Caucasus tur, despite Direkli Cave being around 800 km from their current habitat.

Dr Daly added: “An even greater surprise came when we examined the Direkli Cave goats’ nuclear genomes: while most looked like the bezoar ibex, as expected, one sample appeared different from the rest. This sample, Direkli4, showed more ancestral genetic variants than other Direkli goats, indicating it might have been a different species than the others.” 

To better understand this, the Trinity team collaborated with researchers from Muséum national d'Histoire naturelle of Paris to generate genetic data from other species in the Capra group. 

A new lineage of Tur

The team was surprised to see that the Direkli4 sample in fact grouped with the Caucasian tur – appearing to be a sister group to both East and West types. Intrigued, the team screened more material from Direkli Cave and found an additional two samples with a “tur-like” genome, suggesting that a population of these tur relatives lived in the Taurus Mountains close to local bezoar ibex, with both hunted by humans in pre-historic times. 

The team suggest a name for the discovered Taurasian tur: Capra taurensis or Capra caucasica taurensis; researchers still classify living tur as either subspecies or two distinct species.

As tur are larger and heavier than other wild goats, with a distinctive horn shape, it should be possible to identify a group of tur relatives in animal remains. Horn remains are absent at Direkli Cave, despite the large numbers of remains – possibly pointing to these being a valuable prize among hunters. But archaeozoologists in the team showed there were a lot of large-bodied goats at Direkli Cave – and possibly at other mountainous locations in southwest Asia. 

“We hope that this will encourage re-evaluation and analysis of faunal remains in the region as there could be some exciting discoveries still to be found,” added Dr Daly.

A victim of climatic change and human activity?

The team suggest that the ancestors of tur lived across a broader geographical area over the past 100,000 years, from the Caucasus Mountains to the Taurus Mountains by the Mediterranean - and that climate change may have caused habitat fragmentation. 

Dr Daly said: “The Last Glacial Maximum, or ice age, may have made many areas inhospitable, forcing these goats to compete with other species. The Taurasian tur may have been a leftover group, restricted to the peaks in the Taurus Mountains. Increasing human activity would have placed additional pressure on the Taurasian tur, with hunting evidenced at Direkli Cave. 

“While we don’t know exactly when or how this goat lineage became extinct, additional genomic surveys in the region might show that their genomes live on in present day wild goats.” 

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JOURNAL

eLife

DOI

10.7554/eLife.82984