A new method developed by Institute for Systems Biology (ISB) and University of California, Riverside provides new insights into cancer biology by allowing researchers to show how fatty acids are absorbed by single cells.
Fatty acids, along with glucose and amino acids, are a major energy source for cellular growth and proliferation, and abnormal fatty acid metabolism is often seen in cancer. Dr. Wei Wei’s lab at ISB and Dr. Min Xue’s lab at UC Riverside have been collaborating for years to develop a series of chemical probes and analytical approaches for quantifying cellular glucose uptake, lactate production, amino acid uptake, and other cancer-related metabolites.
Unlike glucose and amino acids, however, the mechanisms underlying the uptake of fatty acids into cells have been lesser known and difficult to discern. The technical tools for measuring fatty acid uptake at the single-cell level are extremely limited.
“This work is the first example of profiling fatty acid uptake in conjunction with aberrant protein signaling in cancer cells at single-cell resolution and represents an important advance in the single-cell metabolic assay,” said ISB Assistant Professor Dr. Wei Wei, co-corresponding author of a just-published paper in the Journal of the American Chemical Society.
To profile the fatty acid uptake, the researchers chose a surrogate molecule that was structurally similar to natural fatty acids. This similarity tricked the cells into taking up these surrogates like the native ones. Then, using a unique dendrimer molecule — a tree-like polymer — the researchers achieved precise quantitation of those surrogates from single cells.
Applying this new single-cell tool to a brain cancer model, the researchers identified that fatty acid uptake was differentially regulated by two downstream effectors of the Mammalian Target of Rapamycin (mTOR) — a critical regulator of cell proliferation and protein synthesis. The results revealed a compensatory activation of fatty acid metabolism upon oncogene inhibition or attenuation of glucose metabolism in these brain cancer cells and uncovered a novel combination therapy that targets this bioenergetic flexibility to synergistically block the tumor growth.
“This novel tool opens new avenues for studying how fatty acid metabolism affects biological systems. It has also inspired us to develop more metabolic probes for single-cell analysis,” said UC Riverside Assistant Professor Dr. Min Xue, co-corresponding author on the paper.
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A UC San Francisco study has found that the antibiotic azithromycin was no more effective than a placebo in preventing symptoms of COVID-19 among non-hospitalized patients, and may increase their chance of hospitalization, despite widespread prescription of the antibiotic for the disease.
“These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection,” said lead author Catherine E. Oldenburg, ScD, MPH, an assistant professor with the UCSF Proctor Foundation. SARS-CoV-2 is the virus that causes COVID-19.
Azithromycin, a broad-spectrum antibiotic, is widely prescribed as a treatment for COVID-19 in the United States and the rest of the world. “The hypothesis is that it has anti-inflammatory properties that may help prevent progression if treated early in the disease,” said Oldenburg. “We did not find this to be the case.”
The study, which was conducted in collaboration with Stanford University, appears July 16, 2021, in the Journal of the American Medical Association.
The study included 263 participants who all tested positive for SARS-CoV-2 within seven days before entering the study. None were hospitalized at the time of enrollment. In a random selection process, 171 participants received a single, 1.2 gram oral dose of azithromycin and 92 received an identical placebo.
At day 14 of the study, 50 percent of the participants remained symptom free in both groups. By day 21, five of the participants who received azithromycin had been hospitalized with severe symptoms of COVID-19 and none of the placebo group had been hospitalized.
The researchers concluded that treatment with a single dose of azithromycin compared to placebo did not result in greater likelihood of being symptom-free.
“Most of the trials done so far with azithromycin have focused on hospitalized patients with pretty severe disease,” said Oldenburg. “Our paper is one of the first placebo-controlled studies showing no role for azithromycin in outpatients.”
Co-authors included Jessica Brogdon, MPH&TM; Cindi Chen, MS; Kevin Ruder; Lina Zhong; Fanice Nyatigo; Catherine A. Cook, MPH; Armin Hinterwirth, PhD; Elodie Lebas, RN; Travis Redd, MD, MPH; Travis C. Porco, PhD, MPH; Thomas M. Lietman, MD; and Benjamin F. Arnold, PhD, MPH, all of UCSF; senior investigator Thuy Doan, MD, PhD, with the UCSF Proctor Foundation, and Benjamin A. Pinsky, MD, PhD, of Stanford University.
The trial was supported by the Bill and Melinda Gates Foundation (INV-017026). Azithromycin and matching placebo were donated by Pfizer, Inc. (New York, NY). Thuy Doan was supported in part by a Research to Prevent Blindness Career Development Award. The authors had no conflicts of interest.
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As the first Black woman to earn a medical degree in the United States, she persevered to make care accessible to women and Black communities, regardless of their ability to pay.This article is part of Overlooked, a series of obituaries about remarkable people whose deaths, beginning in 1851, went unreported in The Times.For more than 125 years, people trampled — unknowingly — across the grass where Rebecca Lee Crumpler rests in peace alongside her husband, Arthur, at Fairview Cemetery in Boston.Her burial plot was devoid of a gravestone even though she held a unique distinction: She was the first Black woman to receive a medical degree in the United States.It would take more than a century, from her death in 1895 until last year, for Crumpler to be given proper recognition by a group of Black historians and physicians. Were it not for them, she might still be languishing in anonymity.They had learned of Crumpler through the Rebecca Lee Society, a support group for Black women physicians in the 1980s, now believed to be defunct, that would occasionally roam the tree-lined grounds of the cemetery, near the edge of Mill Pond, in the Hyde Park neighborhood, looking for any evidence of her plot. People knew she had died in that neighborhood, and had consulted city records, but all they found was a brown patch of dirt where a gravestone should have been placed after interment.Since her death, Crumpler’s legacy has been muddled by incorrect information. Some mistakenly thought that she was the second Black woman to be awarded a medical school degree, after Rebecca Cole, but Cole graduated from the Woman’s Medical College of Pennsylvania three years after Crumpler earned her degree from the New England Female Medical College (now part of the Boston University School of Medicine) in 1864.Several books and articles have featured photographs of a woman purported to be Crumpler, even though no pictures of her are known to exist. In “Gutsy Women,” a 2019 book by Hillary and Chelsea Clinton that celebrates historically significant women, there is a photo alongside an entry on Crumpler — but it is actually a photo of Mary Eliza Mahoney, the country’s first Black licensed nurse.After the Civil War, Crumpler worked for the medical division of the United States Bureau of Refugees, also known as the Freedmen’s Bureau, an agency created by Congress during Reconstruction to provide services for emancipated slaves whom white physicians refused to see. But throughout her life, she was ignored, slighted or rendered insignificant, even invisible.Because of her race and gender, Crumpler was denied admitting privileges to local hospitals, had trouble getting prescriptions filled by pharmacists and was often ridiculed by administrators and fellow doctors. Still she persevered, with the knowledge that Black communities had an increased risk of illness because they were subjected to difficult living conditions and a lack of access to preventive care.“She focused on prevention, nutrition and attaining financial stability for one’s family, all relevant factors today,” Melody McCloud, an obstetrician-gynecologist in Atlanta, said by phone. “Dr. Crumpler was a pioneer who blazed a trail upon which many other Black female physicians have trod, and now tread.”McCloud, who urged Gov. Ralph Northam of Virginia to declare March 30, 2019, Dr. Rebecca Lee Crumpler Day — and who is trying to get a monument for Crumpler erected in Richmond, where she practiced medicine from 1865 to 1869 — was also a curator of an exhibition about Crumpler’s career at the Boston University School of Medicine.Rebecca Crumpler was born Rebecca Davis on Feb. 8, 1831, in Christiana, Del., to Matilda Weber and Absolum Davis. She explained her initial interest in healing in “A Book of Medical Discourses” (1883):“Having been reared by a kind aunt in Pennsylvania, whose usefulness with the sick was continually sought, I early conceived a liking for, and sought every opportunity to be in a position to relieve the sufferings of others.”After marrying Wyatt Lee, a Virginia laborer, in 1852, she relocated to Charlestown, Mass. She worked as a nurse there, assisting several doctors in the Boston area. They in turn supported her application to the New England Female Medical College, where she was awarded a state-funded scholarship.After two years, however, she took a leave of absence to care for her ailing husband, who died of tuberculosis in 1863. She returned seven months later to complete her final term but was nearly stymied after some faculty members expressed reservations regarding the amount of time it had taken her to complete her coursework.Several of the school’s patrons who were involved in the abolitionist movement offered their support. On March 1, 1864, the trustees voted to confer on her a “Doctress of Medicine” degree. She was 33.At the time, said Vanessa Northington Gamble, a physician, historian and professor at George Washington University, there were 54,543 physicians in the country; 270 of them were women — all white — and 180 were Black men.The New England Female Medical College would close in 1873 without ever conferring another medical degree on a Black woman.In 1865, Rebecca Lee married Arthur Crumpler, who had arrived in Boston three years earlier as a fugitive slave and later worked as a porter. The couple had one daughter, Lizzie Sinclair Crumpler, in 1870, but she is believed to have died young.The burial plot for Crumpler and her husband, Arthur, at Fairview Cemetery in Boston. Their graves were unmarked until a group of physicians and historians raised the money for their gravestones.Friends of the Hyde Park LibraryBy 1869, the Crumplers had moved back to Boston. They lived in the North Slope of Beacon Hill, then a predominantly Black community.“A cheerful home,” Crumpler wrote, “with a small tract of land in the country with wholesome food and water is worth more to preserve health and life than a house in a crowded city with luxuries and 20 rooms.”Her house, at 67 Joy Street, now has a plaque honoring her and is a stop on the Boston Women’s Heritage Trail.From that house, Crumpler treated mostly women and children, regardless of their ability to pay. Her book, dedicated to nurses and mothers, is seen as a precursor to “What to Expect When You’re Expecting” (1984), considered the prenatal bible for countless pregnant women. It is full of admonishments.“Children should not be asked if they like such and such things to eat, with the privilege of choosing that which will give them no nourishment to the blood,” Crumpler wrote. She also said, “Parents should hold onto their children, and children should stand by their parents, until the last strand of the silken cord is broken.”An article in 1894 in The Boston Globe described her book as “valuable” and Crumpler as “a very pleasant and intellectual woman” and “an indefatigable church worker.”Crumpler died of fibroid tumors on March 9, 1895. She was 64. Her husband died in 1910.In 2019 Vicki Gall, a history buff and president of the Friends of the Hyde Park Library, began a fund-raising campaign to have gravestones installed for them both. They were added at a ceremony on July 16, 2020, which Gall led.“I didn’t do this as a feel-good moment,” Gall said by phone. “It was a historical moment. She didn’t know the importance of what she was doing at the time, but we recognize it now.”There is no more trampled grass near the resting site of Rebecca Lee Crumpler. Instead, there is an awakening of her contributions to the medical community. As she wrote in “A Book of Medical Discourses”: “What we need today in every community is not a shrinking or flagging of womanly usefulness in this field of labor, but renewed and courageous readiness to do when and wherever duty calls.”

A number of new organizations aim to digitally connect patients with mental health providers who value and understand different cultures.Several years ago, while Charmain Jackman was going through a rough patch in her marriage, she started looking for a Black, female therapist. At the time, she said, she was desperate to find someone who would understand who she was, as a Black woman.“I wanted to come in fully as myself and not worry, ‘Is this person going to get it? Am I going to have to explain everything?’” she said.But even Dr. Jackman, a psychologist from Massachusetts with decades of experience, kept running into roadblocks. Her insurance carrier did not offer demographic data on any of her in-network providers. A search on Psychology Today, one of the most commonly used internet directories of mental health professionals, was returning results that did not include women of color. And, at the time, the website Therapy for Black Girls only had a couple of therapists in her state who took her insurance.“So,” she said, “I decided I would create the site that I would want to use.”In recent years there has been an expanding number of digital companies and nonprofits created to help people of color find a therapist they can trust — someone who is not only skilled in the best evidence-based treatments, but also culturally competent. In other words, a provider who is aware of their own world views, knowledgeable about diversity and trained to connect with different types of clients.The founders of these organizations say there has always been a need for such services, and even more so now that people are coping with the stressors of the pandemic and the racial reckoning that followed the killing of George Floyd by the Minneapolis police.Studies have shown that mental health treatments can be more effective when a client feels that their therapist values culture.“What we’re speaking to with cultural competence is not how much do you know about individual cultures, it is more how do you show up in any space in a way that allows other people to feel welcome, to feel heard and to feel understood,” said Alfiee M. Breland-Noble, a psychologist in Arlington, Va., who has taught cultural competence and multicultural counseling skills to mental health professionals for more than two decades.Dr. Jackman’s website, InnoPsych, which officially went live in January of last year, has a free, searchable directory of potential therapists. Users can filter providers by several categories, including their state; the type of insurance accepted; and the therapist’s availability, ethnicity and specialty.The list of therapists — all of whom are people of color — nearly numbers 450, and keeps growing.“Our goal is to feature 2,021 therapists of color in 2021,” she said.Other organizations go a step further and help patients set up therapy appointments. The nonprofit Black Men Heal, for example, offers up to eight free online counseling sessions. About 70 percent of clients choose to pay for additional sessions, said the executive director, Tasnim Sulaiman, a psychotherapist in private practice in the Philadelphia area who founded the organization in 2018.It can be difficult for people of color to locate a therapist with a shared cultural background. According to the Census Bureau, about 18 percent of people in the United States identify as Hispanic and 13 percent as Black, but an American Psychological Association report found that only 5 percent of psychologists are Hispanic and 4 percent are Black — 86 percent are white. A similar disparity exists among the country’s social workers and psychiatrists.Eric Coly, who formerly worked in finance, founded Ayana Therapy in 2020, about eight years after hitting “rock bottom” while facing anxiety and depression.Back then, he struggled to find a therapist who could understand the intersection of his different identities as a Black man and an immigrant from Senegal who has lived in different parts of the world.“This product was almost meant to heal my former self,” he said.Ayana, which means “mirror” in Bengali, asks users to fill out a questionnaire that is meant to capture “your many nuances,” Mr. Coly said, and then matches you with a culturally competent therapist. The cost of each online session is currently $60.Providers are vetted through a process that includes two interviews and reference checks.While Ayana was created for a multitude of races and cultures, as well as those who identify as L.G.B.T.Q., some websites cater to a more niche set of users like LatinxTherapy, Therapy for Black Girls, Therapy for Black Men, the Asian Mental Health Collective and the National Queer and Trans Therapists of Color Network. Melanin and Mental Health features a directory of therapists of color, many of whom are in Houston. The Black Emotional and Mental Health Collective, a wellness nonprofit that trains people to respond to mental health crises, has an online directory with a variety of Black practitioners including therapists, yoga instructors, doulas and mediators.Employers are also starting to recognize the need for culturally competent providers. The companies Indeed, Thumbtack and Critical Mass, which is part of Omnicom Group, have recently partnered with Therify, which uses artificial intelligence technology to match employees with providers in their state. Half of Therify’s nearly 300 online therapists are people of color and 20 percent specialize in serving clients who identify as L.G.B.T.Q., said the company’s chief executive, James Edward Murray, who interviews each provider.About four years ago, when Mr. Murray was searching for a therapist to process the trauma of having lost his father at a young age, he had seven consultations with different providers before finally landing on a therapist he felt comfortable with.“I had countless friends who just gave up, who needed care but didn’t get it because it was so hard to find a good fit,” said Mr. Murray, who founded Therify in November 2020.While racial matching can be helpful, he added, “the most important thing is someone who leads with empathy and understanding.”Hurdle, previously known as Henry Health, likewise does not select providers based on the color of their skin. The company is unique in that it not only vets its therapists, it also trains them using a cultural competence curriculum developed by Norma L. Day-Vines, an associate dean in the School of Education at Johns Hopkins University.“We look for therapists with a foundation in cognitive behavior therapy and trauma-informed care, and layer our technique over those techniques,” said Kevin Dedner, the chief executive of Hurdle. He founded the company in 2018 after struggling with depression for years.After a client registers for therapy, Hurdle sends them a link to an app, and the company’s customer service team assigns a therapist from a group of providers located in Washington, D.C., Maryland or Virginia. (Hurdle plans to expand into four more states this year.) Many types of commercial insurance are accepted, but if a patient is paying out of pocket, each session costs $99.Tips on finding a culturally competent therapistKeep in mind that online therapist directories do not always have the resources to verify licensing or vet the quality of the therapist, so it’s important to do your own due diligence. First, make sure that your therapist is licensed and in good standing with their licensing board. If you were researching a psychologist, for example, you would start by looking them up on the Association of State and Provincial Psychology Boards.After you’ve located someone promising, ask for a free “get to know you” session where you can interview the therapist about treatments and cultural competence, said Melanie M. Domenech Rodríguez, a professor at Utah State University and an expert in multicultural psychology.Dr. Rodríguez suggested asking the following questions:What is your approach to treating my issue?Do you use an evidence-based treatment? If so, what it is called?How often do you work with Black, Indigenous and other people of color?What challenges have you faced in providing services to people of color and how have you addressed them?When you eventually start seeing someone, the National Alliance on Mental Illness recommends asking yourself the following questions:Did my provider communicate effectively with me?Is my provider willing to integrate my beliefs, practices, identity and cultural background into my treatment plan?Was I treated with respect and dignity?Do I feel like my provider understands and relates well with me?If you can answer yes to each of these questions, you’re off to a great start.“Cultural competence matters,” Dr. Domenech Rodríguez said. “But it is defined by the clients, not the therapists.”

The foundations are adding $5 million to the Disability Futures program, which will continue through 2025 with two more classes of 20 fellows each.The Disability Futures initiative, a fellowship established by the Ford and Andrew W. Mellon Foundations last fall to support disabled artists, is expanding. The foundations announced on Friday that they will commit an additional $5 million to support the initiative through 2025, which will include support for two more cohorts of 20 fellows.The fellowship, which was created by and for disabled individuals, was conceived as an 18-month initiative. It provided 20 disabled artists, filmmakers and journalists, selected from across the United States, with unrestricted $50,000 grants administered by the arts funding group United States Artists.But Margaret Morton, the director of creativity and free expression at the Ford Foundation, said it was clear from the beginning that it couldn’t just be a one-off venture.Projects undertaken by members of the first cohort will be showcased at the first Disability Futures virtual festival, on Monday and Tuesday, with programming from some of the country’s leading disabled artists, writers, thinkers and designers. It is free and open to the public.Among the highlights: A session on disability portraiture with the filmmakers Jim LeBrecht and Rodney Evans, the painter Riva Lehrer and the journalist Alice Wong; a conversation exploring the connections between climate justice and disability justice led by Patty Berne; and a virtual dance party hosted by the garment maker Sky Cubacub, with music by DJ Who Girl (Kevin Gotkin). Evening runway performances from models wearing items from Cubacub’s Rebirth Garments and a meditation experience with the initiative Black Power Naps, featuring Navild Acosta and Fannie Sosa, are also on tap.“It’s been really profound for me to see how much the fellows chosen in the first cohort were interested in elevating others in the community,” Emil J. Kang, the program director for arts and culture at the Mellon Foundation, said in an interview on Thursday.The next class of fellows will be announced in 2022. They are chosen by peer advisers who are themselves disabled artists.But the feedback from the first class, Morton said, was frank: Do even better in the selection process.“One of the fellows challenged us,” she said, about there being only one Native American fellow. “And we appreciated that and were challenged to get it right and make sure we have a deeper pool.”The grants offer flexible compensation options. The money can be distributed in a lump sum, in payments or even be deferred, depending on what works best for the artist.The fellowship “has made an incredible difference in my life and career,” the writer and photographer Jen Deerinwater said in an email. “It’s allowed me more financial freedom, without the risk of losing my disability and health care services, to pursue more artistic pursuits such as music.”The pandemic has made foundation leaders “deeply aware” of the challenges disabled professionals face, Morton said. About one in four adults in the United States has a disability, according to the Centers for Disease Control and Prevention.“We gained a deeper impression and perspective about what it’s like to navigate through the world,” she said.The program’s overarching goal is to help the artists make connections, Morton said.“Our biggest dream is visibility,” she said. For audiences to see the artists and for funders to see that “they should start investing in disabled practitioners.”

Messenger RNA vaccines against COVID-19 were not detected in human milk, according to a small study by UC San Francisco, providing early evidence that the vaccine mRNA is not transferred to the infant.
The study, which analyzed the breast milk of seven women after they received the mRNA vaccines and found no trace of the vaccine, offers the first direct data of vaccine safety during breastfeeding and could allay concerns among those who have declined vaccination or discontinued breastfeeding due to concern that vaccination might alter human milk. The paper appears in JAMA Pediatrics.
Research has demonstrated that vaccines with mRNA inhibit transmission of the virus that causes COVID-19. The study analyzed the Pfizer and Moderna vaccines, both of which contain mRNA.
The World Health Organization recommends that breastfeeding people be vaccinated, and the Academy of Breastfeeding Medicine has said there is little risk of vaccine nanoparticles or mRNA entering breast tissue or being transferred to milk, which theoretically could affect infant immunity.
“The results strengthen current recommendations that the mRNA vaccines are safe in lactation, and that lactating individuals who receive the COVID vaccine should not stop breastfeeding,” said corresponding author Stephanie L. Gaw, MD, PhD, assistant professor of Maternal-Fetal Medicine at UCSF.
“We didn’t detect the vaccine associated mRNA in any of the milk samples tested,” said lead author Yarden Golan, PhD, a postdoctoral fellow at UCSF. “These findings provide an experimental evidence regarding the safety of the use of mRNA-based vaccines during lactation.”
The study was conducted from December 2020 to February 2021. The mothers’ mean age was 37.8 years and their children ranged in age from one month to three years. Milk samples were collected prior to vaccination and at various times up to 48 hours after vaccination.
Researchers found that none of the samples showed detectable levels of vaccine mRNA in any component of the milk.
The authors noted that the study was limited by the small sample size and said that further clinical data from larger populations were needed to better estimate the effect of the vaccines on lactation outcomes.
Co-authors are Mary Prahl, MD; Arianna Cassidy, MD; Christine Y. Lin, BA; Nadav Ahituv, PhD; and Valerie J. Flaherman, MD, MPH, all of UCSF.
The study was supported by the Marino Family Foundation; the National Institutes of Health (grant numbers K23AI127886 and K08AI141728); the Weizmann Institute of Science-National Postdoctoral Award Program for Advancing Women in Science; the International Society for Research in Human Milk and Lactation Trainee Bridge Fund; and the Human Frontier Science Program. Disclosures can be found in the paper.
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Primary immunodeficiencies, such as severe combined immunodeficiency disease (SCID), occur when the immune system does not work properly, leading to increased susceptibility to various infections, autoimmunity, and cancers. Most of these are inherited and have an underlying genetic causes. A team at TMDU has identified a novel disorder resulting from a mutation in a protein called AIOLOS, which functions through a previously unknown pathogenic mechanism called heterodimeric interference.
The gene family known as IKAROS zinc finger proteins (IKZFs) is associated with the development of lymphocyte, a type of white blood cell involved in the immune response — meaning that mutations in this family can be involved in immune system deficiencies. Most research so far has focused on IKAROS protein, encoded by the gene IKZF1, although the underlying mechanism by which IKAROS mutations cause the deficiencies is not yet fully understood. A mutation in AIOLOS — another member of the IKZF family that is encoded by the gene IKZF3 — has now also been revealed to cause a hereditary immune deficiency. In addition to not functioning properly itself, the resultant mutant protein interferes with the functioning of IKAROS protein.
TMDU researchers uncovered this new mechanism while investigating the cause of a previously undescribed inherited B cell deficiency observed in a family of patients. After sequencing all of the protein-coding genes, the team focused their research on AIOLOS as IKAROS is known to be the cause of B cell deficiency. They showed that the mutant form of AIOLOS that was present in this family did not just fail to function, but actively bound to a different DNA sequence than the normal version of the protein.
They went on to use a mouse model that harbors equivalent AIOLOS mutation identified in the patients to outline the underlying pathogenic mechanism. AIOLOS and IKAROS bind together to form a “heterodimer.” The mutant form of AIOLOS retained the ability to bind IKAROS but then interfered with the normal function of IKAROS, and led to the heterodimer being recruited to the incorrect regions of the genome.
“This is a novel pathogenic mechanism that we termed heterodimeric interference,” says lead author Motoi Yamashita, “where a mutant protein in a heterodimer hijacks the function of the normal partner protein.”
The team were then able to rescue some of the immune function in the mouse model by deleting the dimerization domain of the mutant AIOLOS.
“The fact we could rescue the phenotype in our mouse model indicates a potential therapeutic approach,” says Tomohiro Morio, senior author. “The deletion of the domain responsible for binding IKAROS in the mutant AIOLOS protein could ameliorate the immunodeficiency observed in the patients.”
The discovery of this new pathogenic mechanism, heterodimeric interference, may well help to shed light on many other disease processes such as autoimmunity and cancer development where mutant proteins act in the same way.
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Fear is an important reaction that warns and protects us from danger. But when fear responses are out of control, this can lead to persistent fears and anxiety disorders. In Europe, about 15 percent of the population is affected by anxiety disorders. Existing therapies remain largely unspecific or are not generally effective, because the detailed neurobiological understanding of these disorders is lacking.
What was known so far is that distinct nerve cells interact together to regulate fear responses by promoting or suppressing them. Different circuits of nerve cells are involved in this process. A kind of “tug-of-war” takes place, with one brain circuit “winning” and overriding the other, depending on the context. If this system is disturbed, for example if fear reactions are no longer suppressed, this can lead to anxiety disorders.
Recent studies have shown that certain groups of neurons in the amygdala are crucial for the regulation of fear responses. The amygdala is a small almond-shaped brain structure in the center of the brain that receives information about fearful stimuli and transmits it to other brain regions to generate fear responses. This causes the body to release stress hormones, change heart rate or trigger fight, flight or freezing responses.
Now, a group led by Professors Stephane Ciocchi of the University of Bern and Andreas Luthi of the Friedrich Miescher Institute in Basel has discovered that the amygdala plays a much more active role in these processes than previously thought: Not only is the central amygdala a “hub” to generate fear responses, but it contains neuronal microcircuits that regulate the suppression of fear responses. In animal models, it has been shown that inhibition of these microcircuits leads to long-lasting fear behaviour. However, when they are activated, behaviour returns to normal despite previous fear responses. This shows that neurons in the central amygdala are highly adaptive and essential for suppressing fear. These results were published in the journal Nature Communications.
“Disturbed” suppression leads to long-lasting fear
The researchers led by Stephane Ciocchi and Andreas Luthi studied the activity of neurons of the central amygdala in mice during the suppression of fear responses. They were able to identify different cell types that influence the animals’ behaviour. For their study, the researchers used several methods, including a technique called optogenetics with which they could precisely shut down — with pulses of light — the activity of an identified neuronal population within the central amygdala that produces a specific enzyme. This impaired the suppression of fear responses, whereupon animals became excessively fearful. “We were surprised how strongly our targeted intervention in specific cell types of the central amygdala affected fear responses,” says Ciocchi, Assistant Professor at the Institute of Physiology, University of Bern. “The optogenetic silencing of these specific neurons completely abolished the suppression of fear and provoked a state of pathological fear.”
Important for developing more effective therapies
In humans, dysfunction of this system, including deficient plasticity in the nerve cells of the central amygdala described here, could contribute to the impaired suppression of fear memories reported in patients with anxiety and trauma-related disorders. A better understanding of these processes will help develop more specific therapies for these disorders. “However, further studies are necessary to investigate whether discoveries obtained in simple animal models can be extrapolated to human anxiety disorders,” Ciocchi adds.
This study was carried out in partnership with the University of Bern, the Friedrich Miescher Institute and international collaborators. It was funded by the University of Bern, the Swiss National Science Foundation and the European Research Council (ERC).
Systems Neuroscience Group, Institute of Physiology, University of Bern
Neuronal diversity is a hallmark of cortical networks. In the hippocampus, distinct neuronal cell-types interact together by selective synaptic contacts and neural activity patterns. We investigate how different forms of emotional and cognitive behaviours emerge within intricate neuronal circuits of the ventral CA1 hippocampus, a brain region instrumental for context-specific emotional memories, anxiety and goal-directed actions. We hypothesize that distinct behavioural programs are implemented by the selective recruitment of micro- and large-scale neural circuits of the ventral CA1 hippocampus. To identify these circuit motifs, we are combining single-unit recordings of ventral CA1 GABAergic interneurons and projection neurons, selective optogenetic strategies, cell-type specific viral tracing and behavioural paradigms in rodents. The results of our experimental approaches will determine fundamental neural computations underlying learning and memory within higher cortical brain regions.
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A scientific review has found evidence that a disruption in blood clotting and the first line immune system could be contributing factors in the development of psychosis.
The article, a joint collaborative effort by researchers at RCSI University of Medicine and Health Sciences, Cardiff University and the UCD Conway Institute, is published in Molecular Psychiatry.
Recent studies have identified blood proteins involved in the innate immune system and blood clotting networks as key players implicated in psychosis.
The researchers analysed these studies and developed a new theory that proposes the imbalance of both of these systems leads to inflammation, which in turn contributes to the development of psychosis.
The work proposes that alterations in immune defense mechanisms — including blood clotting — lead to an increased risk of inflammation, which is thought to contribute to the development of psychosis.
The new theory further refines the prevailing ‘two-hit’ hypothesis, where early genetic and/or environmental factors disrupt the developing central nervous system (the “first-hit”) and increases the vulnerability of the individual to subsequent, late environmental disruptions (the “second-hit”).
“Early identification and treatment significantly improves clinical outcomes of psychotic disorders. Our theory may provide a further step to biomarkers of psychosis and allow the identification of therapeutic targets for early and more effective treatment,” said Dr Melanie Föcking, joint first author on the paper and Lecturer in Psychiatric Neuroscience at RCSI Department of Psychiatry.
“While the idea of psychosis resulting from some form of inflammation and immune activation is not new, our data suggest a new understanding and change of focus towards a combined function of the innate immune complement system and coagulation pathways to the progression to psychotic disorder,” said Dr Meike Heurich, joint first author on the paper and lecturer at School of Pharmacy and Pharmaceutical Sciences, Cardiff University.
“The works builds on our recent studies which increasingly implicate dysregulation of the complement and coagulation pathways both in and preceding psychotic disorder,” said Professor David Cotter, senior author of the paper and Professor of Molecular Psychiatry at RCSI Department of Psychiatry.
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Although the risk of a child being admitted to hospital due to COVID-19 is small, a new UK study has found that around 1 in 20 of children hospitalised with COVID-19 develop brain or nerve complications linked to the viral infection.
The research, published in The Lancet Child and Adolescent Health and led by the University of Liverpool, identifies a wide spectrum of neurological complications in children and suggests they may be more common than in adults admitted with COVID-19.
While neurological problems have been reported in children with the newly described post-COVID condition paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), the capacity of COVID-19 to cause a broad range of nervous system complications in children has been under-recognised.
To address this, the CoroNerve Studies Group, a collaboration between the universities of Liverpool, Newcastle, Southampton and UCL, developed a real-time UK-wide notification system in partnership with the British Paediatric Neurology Association.
Between April 2020 and January 2021, they identified 52 cases of children less than 18 years old with neurological complications among 1,334 children hospitalised with COVID-19, giving an estimated prevalence of 3.8%. This compares to an estimated prevalence of 0.9% in adults admitted with COVID-19.
Eight (15%) children presenting with neurological features did not have COVID-19 symptoms although the virus was detected by PCR, underscoring the importance of screening children with acute neurological disorders for the virus.
Ethnicity was found to be a risk factor, over two thirds of children being of Black or Asian background.
For the first time, the study identified key differences between those with PIMS-TS versus those with non-PIMS-TS neurological complications. The 25 children (48%) diagnosed with PIMS-TS displayed multiple neurological features including encephalopathy, stroke, behavioural change, and hallucinations; they were more likely to require intensive care. Conversely, the non-PIMS-TS 27 (52%) children had a primary neurological disorder such as prolonged seizures, encephalitis (brain inflammation), Guillain-Barré syndrome and psychosis. In almost half of these cases, this was a recognised post-infectious neuro-immune disorder, compared to just one child in the PIMS-TS group, suggesting that different immune mechanisms are at work.
Short-term outcomes were apparently good in two thirds (65%) although a third (33%) had some degree of disability and one child died at the time of follow-up. However, the impacts on the developing brain and longer-term consequences are not yet known.
First author Dr Stephen Ray, a Wellcome Trust clinical fellow and paediatrician at the University of Liverpool said: “The risk of a child being admitted to hospital due to COVID-19 is small, but among those hospitalised, brain and nerve complications occur in almost 4%. Our nationwide study confirms that children with the novel post-infection hyper-inflammatory syndrome PIMS-TS can have brain and nerve problems; but we have also identified a wide spectrum of neurological disorders in children due to COVID-19 who didn’t have PIMS-TS. These were often due to the child’s immune response after COVID-19 infection.”
Joint senior-author Dr Rachel Kneen, a Consultant Paediatric Neurologist at Alder Hey Children’s NHS Foundation Trust and honorary clinical Senior Lecturer at the University of Liverpool said: “Many of the children identified were very unwell. Whilst they had a low risk of death, half needed intensive care support and a third had neurological disability identified. Many were given complex medication and treatments, often aimed at controlling their own immune system. We need to follow these children up to understand the impact in the long term.”
Joint senior-author Dr Benedict Michael, a senior clinician scientist and MRC Fellow at the University of Liverpool said: “Now we appreciate the capacity for COVID-19 to cause a wide range of brain complications in those children who are hospitalised with this disease, with the potential to cause life-long disability, we desperately need research to understand the immune mechanisms which drive this. Most importantly- How do we identify those children at risk and how should we treat them to prevent lasting brain injury? We are so pleased that the UK government has funded our COVID-CNS study to understand exactly these questions so that we can help inform doctors to better recognise and treat these children.”