How a single gene alteration may have separated modern humans from predecessors

Summary: Researchers discovered a single gene alteration that may help explain cognitive differences between modern humans and our predecessor, and used that information to develop Neanderthal-like brain organoids in the lab.

As a professor of pediatrics and cellular and molecular medicine at University of California San Diego School of Medicine, Alysson R. Muotri, PhD, has long studied how the brain develops and what goes wrong in neurological disorders. For almost as long, he has also been curious about the evolution of the human brain — what changed that makes us so different from preceding Neanderthals and Denisovans, our closest evolutionary relatives, now extinct?

Evolutionary studies rely heavily on two tools — genetics and fossil analysis — to explore how a species changes over time. But neither approach can reveal much about brain development and function because brains do not fossilize, Muotri said. There is no physical record to study.

So Muotri decided to try stem cells, a tool not often applied in evolutionary reconstructions. Stem cells, the self-renewing precursors of other cell types, can be used to build brain organoids — “mini brains” in a laboratory dish. Muotri and colleagues have pioneered the use of stem cells to compare humans to other primates, such as chimpanzees and bonobos, but until now a comparison with extinct species was not thought possible.

In a study published February 11, 2021 in Science, Muotri’s team catalogued the differences between the genomes of diverse modern human populations and the Neanderthals and Denisovans, who lived during the Pleistocene Epoch, approximately 2.6 million to 11,700 years ago. Mimicking an alteration they found in one gene, the researchers used stem cells to engineer “Neanderthal-ized” brain organoids.

“It’s fascinating to see that a single base-pair alteration in human DNA can change how the brain is wired,” said Muotri, senior author of the study and director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. “We don’t know exactly how and when in our evolutionary history that change occurred. But it seems to be significant, and could help explain some of our modern capabilities in social behavior, language, adaptation, creativity and use of technology.”

The team initially found 61 genes that differed between modern humans and our extinct relatives. One of these altered genes — NOVA1 — caught Muotri’s attention because it’s a master gene regulator, influencing many other genes during early brain development. The researchers used CRISPR gene editing to engineer modern human stem cells with the Neanderthal-like mutation in NOVA1. Then they coaxed the stem cells into forming brain cells and ultimately Neanderthal-ized brain organoids.

Brain organoids are little clusters of brain cells formed by stem cells, but they aren’t exactly brains (for one, they lack connections to other organ systems, such as blood vessels). Yet organoids are useful models for studying genetics, disease development and responses to infections and therapeutic drugs. Muotri’s team has even optimized the brain organoid-building process to achieve organized electrical oscillatory waves similar to those produced by the human brain.

The Neanderthal-ized brain organoids looked very different than modern human brain organoids, even to the naked eye. They had a distinctly different shape. Peering deeper, the team found that modern and Neanderthal-ized brain organoids also differ in the way their cells proliferate and how their synapses — the connections between neurons — form. Even the proteins involved in synapses differed. And electrical impulses displayed higher activity at earlier stages, but didn’t synchronize in networks in Neanderthal-ized brain organoids.

According to Muotri, the neural network changes in Neanderthal-ized brain organoids parallel the way newborn non-human primates acquire new abilities more rapidly than human newborns.

“This study focused on only one gene that differed between modern humans and our extinct relatives. Next we want to take a look at the other 60 genes, and what happens when each, or a combination of two or more, are altered,” Muotri said.

“We’re looking forward to this new combination of stem cell biology, neuroscience and paleogenomics. The ability to apply the comparative approach of modern humans to other extinct hominins, such as Neanderthals and Denisovans, using brain organoids carrying ancestral genetic variants is an entirely new field of study.”

To continue this work, Muotri has teamed up with Katerina Semendeferi, professor of anthropology at UC San Diego and study co-author, to co-direct the new UC San Diego Archealization Center, or ArchC.

“We will merge and integrate this amazing stem cell work with anatomic comparisons from several species and neurological conditions to create downstream hypotheses about brain function of our extinct relatives,” Semendeferi said. “This neuro-archealization approach will complement efforts to understand the mind of our ancestors and close relatives, like the Neanderthals.”

Co-authors of the study include: Cleber A. Trujillo, Isaac A. Chaim, Emily C. Wheeler, Assael A. Madrigal, Justin Buchanan, Sebastian Preissl, Allen Wang, Priscilla D. Negraes, and Ryan Szeto, UC San Diego; Edward S. Rice, Nathan K. Schaefer, Ashley Byrne, Maximillian Marin, Christopher Vollmers, Angela N. Brooks, Richard E. Green, UC Santa Cruz; Roberto H. Herai, Pontifícia Universidade Católica do Paraná; Alik Huseynov, Imperial College London; Mariana S.A. Ferraz, Fernando da S. Borges, Alexandre H. Kihara, Universidade Federal do ABC; Jonathan D. Lautz, Stephen E.P. Smith, Seattle Children’s Research Institute and University of Washington; Beth Shapiro, UC Santa Cruz and Howard Hughes Medical Institute; and Gene W. Yeo, UC San Diego, Agency for Science, Technology and Research (Singapore) and National University of Singapore.

Funding for this research came, in part, from the Neanderthal Brain Foundation, National Institutes of Health (grants U19MH1073671, K12GM068524, K01AA026911), Brain and Behavior Research Foundation (NARSAD Independent Investigator Grant), National Science foundation (grant 1754451), Gordon and Betty Moore Foundation (grant GBMF3804), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes, Brazil), FAPESP (São Paulo Research Foundation, grant 2017/26439-0), CNPq (Brazil’s National Council for Scientific and Technological Development, grants 431000/2016-6, 312047/2017-7) and Loulou Foundation.

Disclosure: Alysson R. Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and brain organoid modeling focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders with genetic origins. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

https://www.sciencedaily.com/releases/2021/02/210211144418.htm

Thanks to Kebmodee for bringing this to the It’s Interesting community.

Common anti-depressant (Paxil) may be the first-ever treatment for osteoarthritis

Researchers found that Paroxetine not only slows down cartilage degeneration, but also promotes cartilage health in both mice and human cartilage in vitro. Credit: Fadia Kamal, Penn State

A disease of the joints, osteoarthritis affects more than 30 million adults and is the fifth-leading cause of disability in the United States. In a new study, scientists have discovered the cellular pathway that leads to osteoarthritis and have identified a commonly used anti-depressant—paroxetine—that inhibits this pathway. The team found that Paroxetine not only slows down cartilage degeneration, but also promotes cartilage health in both mice and human cartilage in vitro. The drug may be the first-ever treatment for this debilitating, degenerative disease.

“Osteoarthritis destroys joint cartilage and results in pain and disability,” said Fadia Kamal, assistant professor of orthopedics and rehabilitation at Penn State College of Medicine. “Patients live with this pain until their cartilage is extremely degenerated. Unfortunately, an invasive artificial joint replacement surgery is the only treatment orthopedists are currently able to offer. There has been a dire need to identify novel therapeutic targets, approaches or agents that can actively halt or reverse the osteoarthritis disease process.”

In previous research, Kamal and her colleagues found that elevated expression and activity of the enzyme G protein-coupled receptor kinase 2 (GRK2) leads to pathologic cell growth in heart and kidney disease.

Kamal explained that osteoarthritis is similarly driven by pathological growth of cartilage cells, a process called chondrocyte hypertrophy, but how this proliferation occurs had been a mystery. Given their knowledge of the role of GRK2 in heart and kidney disease, Kamal and her team decided to investigate the enzyme in osteoarthritis patients. They found that patients with osteoarthritis or acute injury to the joint had high levels of GRK2 in their cartilage cells, or chondrocytes.

“We discovered a central role for GRK2 in cartilage degeneration, where GRK2 pushes chondrocytes to destroy the cartilage matrix surrounding them instead of replenishing and maintaining it.” said Kamal. “In other words, the cells receive a bad signal to destroy cartilage.”

The researchers confirmed the role of GRK2 in cartilage degeneration in two experiments: in one, they performed a genetic deletion of GRK2 from cartilage cells in mice, and in the other, they administered paroxetine—an FDA-approved selective serotonin reuptake inhibitor (SSRI) that is a potent GRK2 inhibitor—to the mice. In both cases, they found that not only did GRK2 deletion prevent chondrocyte hypertrophy and halt osteoarthritis progression, but it also promoted cartilage regeneration.

“We found that paroxetine could return cartilage cells back to a normal state and preserve the cartilage surface,” said Kamal.

In other experiments with cultured human osteoarthritic cartilage, obtained from patients undergoing knee replacement surgery, the team also confirmed the ability of paroxetine to mitigate chondrocyte hypertrophy and cartilage degradation.

The results will appear on Feb. 10 in the journal Science Translational Medicine.

“Our findings present elevated GRK2 signaling in chondrocytes as a driver of chondrocyte hypertrophy and cartilage degradation and identify paroxetine as a disease-modifying drug for OA treatment,” said Kamal. “This is important given that around 80% of the U.S. population will develop radiographic evidence of osteoarthritis by age 65 and with the growing prevalence of osteoarthritis risk factors, such as obesity and diabetes, osteoarthritis will likely carry an even greater burden in the future.”

The team is currently seeking approval from the FDA for a new trial of this drug to treat osteoarthritis.

“If this trial works, we will have found a new solution to an age-old problem of joints in the body wearing out because of cartilage destruction and loss,” said Kamal. “We hope to intervene with this disease-modifying treatment for the benefit of our patients.”

https://medicalxpress.com/news/2021-02-common-anti-depressant-first-ever-treatment-osteoarthritis.html

Bimagrumab, a monoclonal antibody to activin type II receptors, reduces body fat and increases muscle in obesity and diabetes in phase II clinical study.

Adults with type 2 diabetes and overweight or obesity assigned a once-monthly monoclonal antibody infusion experienced a marked decrease in fat mass and gains in muscle vs. those assigned placebo, according to findings from a phase 2 study.

Bimagrumab, a human monoclonal antibody that blocks activin type II receptors and stimulates muscle growth, was not initially investigated as an obesity treatment, Steven B. Heymsfield, MD, FTOS, professor in the department of metabolism and body composition at Pennington Biomedical Research Center, Louisiana State University, told Healio. The drug was initially heralded as a potential breakthrough therapy for people with sporadic inclusion body myositis, a rare muscle-wasting disease. However, the drug did not meet its primary endpoint in a phase 2b/3 trial, Novartis announced in a press release in 2016.

“When researchers did the preclinical work, there was absolutely no signal on adipose tissue; it was all muscle growth,” Heymsfield said in an interview. “They had no reason to suspect it, because [activin type II receptors] are mainly muscle. When they did first-in-man studies, they did see some adipose tissue signal and conducted a proof-of-concept study to see if adipose tissue effects were significant. That is what prompted the current investigation — a phase 2 trial with body fat as the primary endpoint. As of today, there is not a clear mechanism.”

Study design

Heymsfield and colleagues analyzed data from 75 adults with type 2 diabetes with overweight or obesity, defined as a BMI between 28 kg/m² and 40 kg/m² (mean age, 60 years; mean BMI 32.9 kg/m²; mean body weight, 93.6 kg; mean fat mass, 35.4 kg; mean HbA1c, 7.8%). The trial was conducted from February 2017 to May 2019. Researchers randomly assigned participants an IV infusion of bimagrumab (10 mg/kg up to 1,200 mg in 5% dextrose solution; n = 37; 62.2% women) or placebo (5% dextrose solution; n = 38; 77.3% women) every 4 weeks for 48 weeks. Both groups received diet and exercise counseling. The primary endpoint was least square mean change from baseline to week 48 in total body fat mass as measured by DXA; secondary and exploratory endpoints were lean mass, waist circumference, HbA1c and body weight changes from baseline to week 48.

Fat mass vs. body weight

At week 48, participants in the bimagrumab groups experienced a mean –20.5% loss in fat mass (mean, –7.5 kg; 80% CI, –8.3 to –6.6) vs. a mean –0.5% reduction for those in the placebo group (–0.18 kg; 80% CI, –0.99 to –0.63).

Participants assigned bimagrumab also experienced a mean gain of 3.6% in lean mass (mean, 1.7 kg; 80% CI, 1.1-2.3) compared with a mean –0.8% reduction in lean mass for the placebo group (mean, –0.4 kg; 80% CI, –1 to 0.1).

Waist circumference decreased by a mean of 9 cm in the bimagrumab group vs. a 0.5 cm gain in the placebo group (P < .001), and HbA1c fell by 0.76 percentage points in the bimagrumab group vs. 0.04 percentage points in the placebo group (P = .005).

Weight loss was also greater in the bimagrumab group vs. placebo (mean, –5.9 kg vs. –0.8 kg; P < .001).

Bimagrumab’s safety and tolerability profile was consistent with prior studies. Mild diarrhea and muscle spasms were the most commonly reported adverse events in the bimagrumab group; one patient in the bimagrumab group developed pancreatitis.

“What surprised me the most was the magnitude of the effects on body fat,” Heymsfield said. “The effect is real; this is not a one-off. People lost 7.5 kg of fat, or almost 16 to 20 pounds of fat. That is significant fat loss, particularly for people with diabetes, who tend not to respond very well to anti-obesity treatment.”

There is excitement about bimagrumab and the possible mechanism behind the new findings; however, next steps in the drug’s pipeline are unclear, Heymsfield said. Novartis opted to license the drug and has not disclosed who the licensee is, he added.

“It’s not dead,” Heymsfield said of the therapy. “To be candid, the diabetes space is pretty crowded. You can take metformin for a penny a day. Monoclonal antibodies are also expensive.”

Researchers also noted a signal for elevated pancreatic enzymes, the origin or significance of which is unclear, he said.

“The real future of this drug involves figuring out the mechanism, working through that and finding targets that are druggable,” Heymsfield said. “This study demonstrates the beguiling nature of weight changes. These people lost more fat than body weight. You cannot always rely on weight as an index of efficacy.”

For more information:

Steven B. Heymsfield, MD, FTOS, can be reached at steven.heymsfield@pbrc.edu.

The full moon may influence sleep and menstrual cycles, scientists say

People go to bed later and sleep fewer hours the night before a full moon, and menstrual cycles seem to temporarily synchronize with moon cycles, scientists have found in two new studies. 

By Chelsea Gohd 

Does the full moon change how we sleep? Does it synchronize with menstrual cycles? 

What might sound like old-school myths might actually hold some truth. People go to bed later and sleep fewer hours before a full moon and menstrual cycles seem to temporarily synchronize with moon cycles, scientists have found in two new studies. 

Throughout history, humans have connected our daily lives to the changing skies, specifically the changing faces of the moon. Lore surrounding the moon’s phases has ranged from full moons inciting werewolves to the moon’s cycle affecting how we feel and our day-to-day moods. 

But, strangely, a couple of these tall tales seem to have roots in real science. 

In a study published January 27 in the journal Science Advances, a team of scientists from the University of Washington, the National University of Quilmes in Argentina and Yale University show how sleep cycles seem to change with the lunar cycle. 

They found that, in the days leading up to a full moon, people tend to go to sleep later and sleep for fewer hours. For this work, the team studied college students in the city of Seattle, Washington, and also with those living in indigenous communities in northern Argentina, two different environments where there is a variety in individual access to electricity because of how artificial light might affect the participants. 

Using sleep-monitoring wrist devices, they studied 98 individuals living in three Toba-Qom indigenous communities in Formosa, Argentina and additionally used sleep data from 464 college students in the Seattle area (the data from the college students was originally collected for a separate study). 

The team found that, while the connection between sleep cycles and lunar cycles is a bit more obvious in communities without electricity access, the connection still seems to be present in areas with electricity as well. 

“We see a clear lunar modulation of sleep, with sleep decreasing and a later onset of sleep in the days preceding a full moon,” lead author Horacio de la Iglesia, a professor of biology at the University of Washington, said in a statement. “And although the effect is more robust in communities without access to electricity, the effect is present in communities with electricity, including undergraduates at the University of Washington.”

In these groups, they showed that the nights leading up to a full moon was when people slept the least and went to bed the latest. These nights also had more light in the night sky after dusk as the waxing moon got brighter. 

“We hypothesize that the patterns we observed are an innate adaptation that allowed our ancestors to take advantage of this natural source of evening light that occurred at a specific time during the lunar cycle,” study author Leandro Casiraghi, a University of Washington postdoctoral researcher in the biology department.

Menstrual and lunar cycles

Sleep cycles aren’t the only human function that seems to be affected by the moon, scientists are finding. This is not a new notion. In fact, for a long time, people have suggested that there is a connection between lunar and menstrual cycles, some myths even suggesting that fertility and lunar cycles have some sort of connection, a controversial tale.

In a separate study, also published today in  Science Advances, researchers showed that, while all of the myths surrounding this connection might not hold up, there could be some link between menstrual cycles and moon cycles. 

By analyzing menstrual cycle records that 22 women kept for up to 32 years. They examined long-term data on menstrual cycle onset with data averaging a length of 15 years and including information from women both under and over age 35. They compared this data with fluctuations in the lunar cycles to see how the two lined up. 

They found that, of the women who participated, those whose menstrual cycles last longer than 27 days showed “intermittently synchronized with cycles that affect the intensity of moonlight,” according to a statement. The team determined that this synchronization was slowly lost over time as the participants grew older, and found that the link was lessened with increased exposure to artificial light. 

More specifically, they concluded that “menstrual cycles also aligned with the tropical month (the 27.32 days it takes the moon to pass twice through the same equinox point) 13.1% of the time in women 35 years and younger and 17.7% of the time in women over 35, suggesting that menstruation is also affected by shifts in the moon’s gravimetric forces,” according to the statement.

https://www.space.com/full–moon-affects-human-sleep-menstrual-cycle

Schizophrenia second only to age as greatest risk factor for COVID-19 death

Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

People with schizophrenia, a mental disorder that affects mood and perception of reality, are almost three times more likely to die from the coronavirus than those without the psychiatric illness, a new study shows. Their higher risk, the investigators say, cannot be explained by other factors that often accompany serious mental health disorders, such as higher rates of heart disease, diabetes, and smoking.

Led by researchers at NYU Grossman School of Medicine, the investigation showed that schizophrenia is by far the biggest risk factor (2.7 times increased odds of dying) after age (being 75 or older increased the odds of dying 35.7 times). Male sex, heart disease, and race ranked next after schizophrenia in order.

“Our findings illustrate that people with schizophrenia are extremely vulnerable to the effects of COVID-19,” says study lead author Katlyn Nemani, MD. “With this newfound understanding, health care providers can better prioritize vaccine distribution, testing, and medical care for this group,” adds Nemani, a research assistant professor in the Department of Psychiatry at NYU Langone Health.

The study also showed that people with other mental health problems such as mood or anxiety disorders were not at increased risk of death from coronavirus infection.

Since the beginning of the pandemic, experts have searched for risk factors that make people more likely to succumb to the disease to bolster protective measures and allocate limited resources to people with the greatest need. Although previous studies have linked psychiatric disorders in general to an increased risk of dying from the virus, the relationship between the coronavirus and schizophrenia specifically has remained unclear. A higher risk of mortality was expected among those with schizophrenia, but not at the magnitude the study found, the researchers say.

The new investigation is publishing Jan. 27 in the journal JAMA Psychiatry. Researchers believed that other issues such as heart disease, depression, and barriers in getting care were behind the low life expectancy seen in schizophrenia patients, who on average die 15 years earlier than those without the disorder. The results of the new study, however, suggest that there may be something about the biology of schizophrenia itself that is making those who have it more vulnerable to COVID-19 and other viral infections. One likely explanation is an immune system disturbance, possibly tied to the genetics of the disorder, says Nemani.

For the investigation, the research team analyzed 7,348 patient records of men and women treated for COVID-19 at the height of the pandemic in NYU Langone hospitals in New York City and Long Island between March 3 and May 31, 2020. Of these cases, they identified 14 percent who were diagnosed with schizophrenia, mood disorders, or anxiety. Then, the researchers calculated patient death rates within 45 days of testing positive for the virus.

They note that this large sample of patients who all were infected with the same virus provided a unique opportunity to study the underlying effects of schizophrenia on the body.

“Now that we have a better understanding of the disease, we can more deeply examine what, if any, immune system problems might contribute to the high death rates seen in these patients with schizophrenia,” says study senior author Donald Goff, MD. Goff is the Marvin Stern Professor of Psychiatry at NYU Langone.

Goff, also the director of the Nathan S. Kline Institute for Psychiatric Research at NYU Langone, says the study investigators plan to explore whether medications used to treat schizophrenia, such as antipsychotic drugs, may play a role as well.

He cautions that the study authors could only determine the risk for patients with schizophrenia who had access to testing and medical care. Further research is needed, he says, to clarify how dangerous the virus may be for those who lack these resources. Goff is also the vice chair for research in the Department of Psychiatry at NYU Langone.

https://medicalxpress.com/news/2021-01-schizophrenia-age-greatest-factor-covid-.html

Iowa and Ohio Researchers Discover New, Protective Strategy for Embryonic Development during Prenatal Stress in Animal Model

Hormones during pregnancy. Depressed expectant lady closing her face and crying, grey studio background

New research from the University of Iowa and University Hospitals Cleveland Medical Center demonstrates that offspring can be protected from the effects of prenatal stress by administering a neuroprotective compound during pregnancy.

Working in a mouse model, Rachel Schroeder, a student in the UI Interdisciplinary Graduate Program in Neuroscience, drew a connection between the work of her two mentors, Hanna Stevens, MD, PhD, UI associate professor of psychiatry and Ida P. Haller Chair of Child and Adolescent Psychiatry, and Andrew A. Pieper, MD, PhD, a former UI faculty member, now Morley-Mather Chair of Neuropsychiatry at Case Western Reserve University and Investigator and Director of the Neurotherapeutics Center at The Harrington Discovery Institute at University Hospitals.

Stevens’s lab studies the long-lasting impact of stress during pregnancy, which can lead to neuropsychiatric impairment in offspring during early life and in adulthood. Pieper’s lab focuses on discovery of neuroprotective treatments, exemplified by the pharmacologic agent used here, known as P7C3-A20, which has previously been shown to protect the adult brain from injury.

Schroeder spent time in both labs early in her graduate school career and was inspired to bring the two lines of research together in her own work, investigating the potential impact that P7C3-A20 might have in protecting the embryonic brain during adverse events in pregnancy.  Her work is the first to explore the therapeutic potential of prenatal exposure to P7C3 compounds. 

“Prenatal stress increases the risk for offspring to have neurodevelopmental problems,” Schroeder said. “We wanted to know whether the P7C3-A20 compound protected the embryonic brain from damage. Our results show that offspring are protected from the negative effects of stress when the mothers are treated with P7C3-A20 during the same time.”

The research was published online today in the journal Antioxidants & Redox Signaling.

Previous work by Pieper’s lab has shown that P7C3-A20 enables nerve cells to maintain normal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD+), under toxic or injury conditions that are otherwise overwhelming and energy-depleting for the cell.

Schroeder’s research showed that chronic prenatal stress in mice disrupted the embryonic brain’s NAD+-synthesis machinery, which led to degeneration of nerve cell axons, learning deficits, and depression-like behavior when the offspring reached adulthood. Schroeder demonstrated that when prenatally-stressed pregnant mice were simultaneously treated with P7C3-A20, their offspring were protected from these negative effects.

“By stabilizing critical NAD+-producing mechanisms, we enabled the developing embryonic brain to continue developing normally despite the stress,” Schroeder said.

“Though there are many challenges associated with administering medicines during pregnancy, Rachel Schroeder’s discovery represents an exciting move forward in understanding how prenatal stress harms the brain, and strategies for protecting the developing embryo.” said Pieper, who is also Psychiatrist at the Louis Stokes VA Medical Center in Cleveland.

This study represents an important proof of concept for a new approach to early prevention of neuropsychiatric problems, Stevens said. “Neuropsychiatric problems are the most common chronic illnesses of young people, which means we need many more ways to protect the brain as it develops. Our lab is focused on mechanisms of brain development prenatally, a critical time when we could make a difference.”

In addition to Schroeder, Pieper and Stevens, the research team included Lynn Nguyen and Alexandra Loren in the Stevens Lab at UI; Preethy Sridharan, Coral J. Cintrón-Pérez, and Edwin Vázquez-Rosa in the Pieper Lab at the Harrington Discovery Institute; and Noelle S. Williams and Kavitha P. Kettimuthu at the University of Texas Southwestern Medical Center.

###

Funding was provided by the Brockman Foundation, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, G.R. Lincoln Family Foundation, Wick Foundation, Gordon & Evie Safran, the Leonard Krieger Fund of the Cleveland Foundation, the Maxine and Lester Stoller Parkinson’s Research Fund, the Louis Stokes VA Medical Center resources and facilities, Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment, a Junior Research Program of Excellence from the Roy J. Carver Charitable Trust, Nellie Ball Trust, NIH grant R01 MH122485-01, UI Environmental Health Science Research Center and the UI Graduate College.

About University of Iowa Health Care
University of Iowa Health Care is the state’s only comprehensive academic medical center, dedicated to providing world-class health care and health-related outreach services to all Iowans. Based in Iowa City, UI Health Care includes University of Iowa Hospitals & ClinicsUniversity of Iowa Roy J. and Lucille A. Carver College of Medicine, and University of Iowa Physicians, the state’s most comprehensive multi-specialty physician group practice.

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 19 hospitals, more than 50 health centers and outpatient facilities, and 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship academic medical center, University Hospitals Cleveland Medical Center, located in Cleveland’s University Circle, is affiliated with Case Western Reserve University School of Medicine. The main campus also includes University Hospitals Rainbow Babies & Children’s Hospital, ranked among the top children’s hospitals in the nation; University Hospitals MacDonald Women’s Hospital, Ohio’s only hospital for women; University Hospitals Harrington Heart & Vascular Institute, a high-volume national referral center for complex cardiovascular procedures; and University Hospitals Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, including cancer, pediatrics, women’s health, orthopedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and urology. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to Harrington Discovery Institute at University Hospitals – part of The Harrington Project for Discovery & Development. UH is one of the largest employers in Northeast Ohio with 28,000 physicians and employees. Advancing the Science of Health and the Art of Compassion is UH’s vision for benefitting its patients into the future, and the organization’s unwavering mission is To Heal. To Teach. To Discover. Follow UH on LinkedInFacebook @UniversityHospitals and Twitter @UHhospitals. For more information, visit UHhospitals.org.

About Harrington Discovery Institute
The Harrington Discovery Institute at University Hospitals in Cleveland, OH—part of The Harrington Project for Discovery & Development—aims to advance medicine and society by enabling our nation’s most inventive scientists to turn their discoveries into medicines that improve human health. The institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a ‘Better World’. For more information, visit: HarringtonDiscovery.org.

Case Western Reserve University is one of the country’s leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 5,100 undergraduate and 6,700 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible.

Louis Stokes Cleveland VA Medical Center is the hub of VA Northeast Ohio Healthcare System, providing and coordinating primary, acute and specialty care. Focusing on treating the whole Veteran through health promotion and disease prevention, VA Northeast Ohio Healthcare System delivers comprehensive, seamless health care and social services for more than 112,000 Veterans at 18 locations across Northeast Ohio. VA Northeast Ohio Healthcare System contributes to the future of medicine through education, training and research programs. For more information visit www.cleveland.va.gov

https://www.newswise.com/articles/iowa-and-ohio-researchers-discover-new-protective-strategy-for-embryonic-development-during-prenatal-stress-in-animal-model?ta=home

Why cats are crazy for catnip

By Sofia Moutinho

Cat owners flood the internet with videos of their kitties euphorically rolling and flipping out over catnip-filled bags and toys. But exactly how catnip—and a substitute, known as silver vine—produces this feline high has long been a mystery. Now, a study suggests the key intoxicating chemicals in the plants activate cats’ opioid systems much like heroin and morphine do in people. Moreover, the study concludes that rubbing the plants protects the felines against mosquito bites.

“This study essentially has revealed a new potential mosquito repellent” by examining the “pharmaceutical knowledge” of cats, says Emory University biologist Jacobus de Roode, who did not participate in the study.

Catnip (Nepeta cataria) and silver vine (Actinidia polygama) both contain chemical compounds called iridoids that protect the plants against aphids and are known to be the key to the euphoria produced in cats. To determine the physiological effect of these compounds, Iwate University biologist Masao Miyazaki spent 5 years running different experiments using the plants and their chemicals.

First, his team extracted chemicals present in both catnip and silver vine leaves and identified the most potent component that produces the feline high: a minty silver vine chemical called nepetalactol that had not been shown to affect cats until this study. (The substance is similar to nepetalactone, the key iridoid in catnip.) Then, they put 10 leaves’ worth of nepetalactol into paper pouches and presented them, together with pouches containing only a saline substance, to 25 domestic cats to gauge their response. Most of the animals only showed interest in the pouches with nepetalactol.

To make sure this was the object of the felines’ attraction, they repeated the experiment with 30 feral cats—and one leopard, two lynxes, and two jaguars living in Japan’s Tennoji and Oji zoos. Big or small, the felines surrendered to the substance, rubbing their heads and bodies in the patches for an average of 10 minutes (see video, above). In contrast, dogs and mice that were tested showed no interest in the compound.

Next, the researchers measured beta-endorphins—one of the hormones that naturally relieves pain and induces pleasure by activating the body’s opioid system—in the bloodstreams of five cats 5 minutes before and after exposure. The researchers found that levels of this “happiness hormone” became significantly elevated after exposure to nepetalactol compared with controls. Five cats that had their opioid systems blocked did not rub on the nepetalactol-infused pouches.

But the researchers wanted to know whether there was a reason for the cats to go wild, beyond pure pleasure. That is when one of the scientists heard about the insect-repelling properties of nepetalactone, which about 2 decades ago was shown to be as good as the famed mosquito-stopper DEET. The researchers hypothesized that when felines in the wild rub on catnip or silver vine, they’re essentially applying an insect repellant.

They first showed cats can transfer the chemical to their skin, and then conducted a live mosquito challenge—similar to when people’s arms are used to evaluate insect repellants. They put the nepetalactol-treated heads of sedated cats into chambers full of mosquitoes and counted how many landed on them—it was about half the number that landed on feline heads treated with a neutral substance, they report today in Science Advances.

Most scientists and pet owners assumed the only reason that cats roll around in catnip was for the euphoric experience, Miyazaki says“Our findings suggest instead that rolling is rather a functional behavior.”

The researchers speculate that cat ancestors might have rubbed their bodies against the plants by chance, enjoyed the feeling, and kept doing it. It is not clear, though, whether it was the euphoric response—or the insect-repelling properties of the plant—that kept them rolling. “Anyone who has ever sat in the field to observe animals ambushing prey knows just how difficult it is for them to keep still when there are many biting mosquitoes around,” Miyazaki says. “It does not seem unreasonable, therefore, to argue that there is a strong selection pressure” to keep away annoying bugs.

The team, which has already patented an insect repellent based on nepetalactol, plans next to identify the cat genes involved in the catnip response and examine the substance’s action against other insect pests. De Roode, who is impressed by how thorough the experiments were, says the work provides a “really interesting” example of how insects can shape animal behavior. “It is amazing how much we can learn from animals.

https://www.sciencemag.org/news/2021/01/why-cats-are-crazy-catnip

A Tweak to Immune Cells Reverses Aging in Mice

by Abby Olena

Excess inflammation is a problem in aging, contributing to issues such as atherosclerosis, cancer, and cognitive decline. But the mechanisms behind age-related inflammation are not well understood. In a study published today (January 20) in Natureresearchers show that older immune cells have a defect in metabolism that when corrected in a mouse model of Alzheimer’s disease can decrease inflammation and restore cognitive function.

After a decade of progress in understanding metabolism and nutrient usage in immune cells and how that affects their function, this study is a “beautiful example” of now knowing enough to intervene, push buttons, and influence outcomes, says Eyal Amiel, who studies immune cell metabolism at the University of Vermont and was not involved in the new work. “To have a specific metabolic signature associated with a pathology is one thing. To be able to manipulate it is another thing. To be able to manipulate it and reverse the pathology is an incredible sequence of events.”

As a postdoc in the late 1990s, Katrin Andreasson, now a neurologist and researcher at Stanford University School of Medicine, was intrigued by epidemiological studies showing that people who took nonsteroidal anti-inflammatory drugs—such as ibuprofen and naproxen—occasionally for aches and pains had a decreased risk of Alzheimer’s disease. During her postdoc in Paul Worley’s lab at Johns Hopkins School of Medicine, she and her colleagues showed that overexpression of cyclooxygenase-2 (COX-2)—a major mediator of inflammation—in the brain led to Alzheimer’s disease-like symptoms in mice: age-dependent inflammation and cognitive loss.

COX-2 activation is the first step in the production of a lipid called prostaglandin E2 (PGE2), which can bind to one of its receptors, EP2, on immune cells and promote inflammation. To plug up the pathway, Andreasson’s group has shown that deleting the EP2 receptor in mouse macrophages and brain-specific microglia—the cells normally responsible for detecting and destroying immune invaders and cellular debris—reduces inflammation and increases neuronal survival in response to both a bacterial toxin and a neurotoxin. 

In the current study, the researchers wanted to understand how eliminating PGE2 signaling in macrophages could have these effects. They started by comparing macrophages from human blood donors either younger than 35 or older than 65. The cells from older donors made much more PGE2 and had higher abundance of the EP2 receptor than did macrophages from younger donors. When the researchers exposed human macrophages to PGE2, the cells altered their metabolism. Rather than using glucose to make energy, the cells converted it to glycogen and stored it, locking it up where the mitochondria couldn’t access it for ATP production.

“The result of that is that the cells are basically energy-depleted. They’re just fatigued, and they don’t work well,” explains Andreasson. “They don’t phagocytose. They don’t clear debris.” This debris includes misfolded proteins associated with neurodegeneration, the authors write in the paper.

When the scientists treated human macrophages from donors with an average age of about 48 with one of two EP2 receptor inhibitors, glycogen storage decreased, energy production increased, and cells shifted to express anti-inflammatory markers. As in human cells, aged mice also have higher levels of PGE2 in the blood and brain and EP2 receptor levels in macrophages, compared to younger mice. When the researchers knocked down the receptor in macrophages throughout the body in a mouse model of Alzheimer’s disease or treated animals with either of two drugs to suppress EP2 function, cells had improved metabolism. The mice’s age-associated inflammation also reversed and, with it, age-associated cognitive decline. Treating animals with an EP2 antagonist that couldn’t get in the brain and thus only targeted the receptor in peripheral macrophages also led to cognitive improvement in older mice.

“The most interesting thing that they were able to show is that the macrophages are causal in driving age-associated cognitive decline, and, in particular, that it’s sufficient to reprogram the macrophages outside of the brain,” says Jonas Neher, a neuroimmunologist at the German Center for Neurodegenerative Diseases and the University of Tübingen in Germany who authored an accompanying commentary. The next steps are “to figure out what the signal is that comes from the periphery and changes the microglia in the brain. If you can identify this particular signal, then you have another handle on how to reprogram microglia.”

“The hypothetical clinical promise of these findings is obviously outstanding because as you can imagine, it wouldn’t require brain surgery or any kind of gross-level, high-risk intervention,” says Amiel. “Rather, you can manipulate cells systemically and see these outcomes.”

Investigating how those systemic effects work is just one of the questions that Andreasson’s group is currently pursuing. They’re also interested in how and why metabolism declines during aging, as well as other mechanisms that might prevent it. In terms of translating the work to the clinic, one of the only ways to target the EP2 receptor is to go far upstream with COX-2 inhibitors, such as Vioxx, a drug that was withdrawn from the market after some people who took it experienced strokes or heart attacks. There aren’t any drugs that specifically block the EP2 receptor yet, Andreasson tells The Scientist. “There have been attempts made by pharmaceutical companies, but my understanding is it’s been very, very difficult to do.”

P.S. Minhas et al., “Restoring metabolism of myeloid cells reverses cognitive decline in ageing,” Naturedoi:10.1038/s41586-020-03160-0, 2021.

Gut bacteria help digest dietary fiber, release important antioxidant

Dietary fiber found in grains is a large component of many diets, but little is understood about how we digest the fiber, as humans lack enzymes to break down the complex molecules. Some species of gut bacteria break down the fiber in such a way that it not only becomes digestible, but releases ferulic acid, an important antioxidant with multiple health benefits, according to a new study led by researchers at the University of Illinois Urbana-Champaign.

Grains such as rice, oats, rye and wheat are rich in a class of dietary fiber called arabinoxylans, which humans cannot digest on their own. Many gut bacteria have enzymes to break down simple components of arabinoxylans; however, they lack the ability to break down complex ones—including those containing ferulic acid.

“Ferulic acid has been shown to have antioxidant, immunomodulatory and anti-inflammatory activities, and many reports have documented its protective activities in different disease conditions including diabetes, allergic inflammation, Alzheimer’s disease, cardiovascular disorders, microbial infections and cancer,” said study leader Isaac Cann, a professor of animal sciences and microbiology and a member of the Carl R. Woese Institute for Genomic Biology at Illinois.

“The question, then, is what is the benefit of arabinoxylans to us, since our human genomes do not encode the enzymes that can degrade them or access the ferulic acid they contain?” Cann said.

To answer that question, Cann’s group and collaborators at the University of Michigan and Mie University in Japan studied the genomes and digestive activity of bacteria in the intestine. They found that a group of Bacteroides bacteria have several enzymes that break down arabinoxylans, some of which had not been seen or catalogued before. One enzyme the group discovered is so active that it cuts off any ferulic acid it comes across, releasing large amounts of the antioxidant, Cann said. The group published its findings in the journal Nature Communications.

“These bacteria can sense the difference between simple and complex arabinoxylans to deploy a large set of enzymes that function like scissors to cut the linkages in complex arabinoxylans into their unit sugars, and at the same time release the ferulic acid,” Cann said.

Importantly, none of the bacteria the group studied used the ferulic acid after releasing it—thus making it available for absorption in the human gut.

Understanding this mechanism of how bacteria in the colon help the body break down dietary fiber and access ferulic acid has applications for personalized nutrition. With the compound’s protective activity against certain diseases and its role in modulating inflammation and immune response, patients may benefit from probiotic ingestion of the ferulic acid-releasing bacteria or from consuming a diet rich in arabinoxylan fiber, Cann said.

“This is one example of how the microbiome impacts human health and nutrition,” Cann said.

https://medicalxpress.com/news/2021-01-gut-bacteria-digest-dietary-fiber.html

A blood test could diagnose depression and bipolar disorder

Researchers found that levels of a nerve growth factor were lower in people with depression or bipolar disorder than in healthy controls. Doctors could potentially use levels of the growth factor to monitor the effects of antidepressant treatment.

In adults, a protein called brain-derived neurotrophic factor (BDNF) promotes the growth and survival of nerve cells and is known to play a vital role in learning, memory, and maintaining brain flexibility, or “plasticity.”

Psychological stress reduces blood levels of one form of the protein, called mature BDNF (mBDNF), and low levels are associated with depression.

However, commercially available blood tests are unable to differentiate accurately between mBDNF and its precursor, known as proBDNF.

This matters because proBDNF binds to a different receptor and causes inflammation and nerve degeneration.

“Growing evidence indicates that inflammation in brain cells is linked with depressive behaviors, and proBDNF seems to activate the immune system,” says Prof. Xin-Fu Zhou of the University of South Australia in Adelaide. “Therefore, we must separate it from mature BDNF to get an accurate reading.”

Recent studies in animals by Prof. Zhou and his colleagues found that injecting proBDNF into the brain or muscle triggers depressive behaviors.

Prof. Zhou and his team have now developed a test that can measure mBDNF much more accurately.

In collaboration with the University of Adelaide and Kunming Medical University in Yunnan, China, they used the new test to show that people with depression or bipolar disorder have significantly lower levels of mBDNF in their blood than healthy controls.

In a paper that appears in the Journal of Psychiatric Research, the study authors say that doctors could use the test to diagnose these conditions and monitor the success of treatment.

“This could be an objective biomarker, in addition to a clinical assessment by a doctor,” says Prof. Zhou.

Antibody-based test

This type of test, known as an “enzyme-linked immunosorbent assay,” or ELISA, uses antibodies to detect the presence of specific proteins.

The researchers applied their new test to blood samples from 90 inpatients with major depressive disorder, 15 inpatients with bipolar disorder, and 96 healthy controls. The healthy controls were people who had attended the medical center at the psychiatric hospital for a general medical examination and did not have a severe mental illness.

They also tested samples from 14 other people with a history of suicide attempts in the past 10 years. All of these individuals were living in the community and should, therefore, have had better mental health than the current inpatients.

The test revealed that the participants with major depression or bipolar disorder had significantly lower levels of mBDNF in their blood compared with the controls.

Those with severe symptoms of depression had significantly lower levels than those with moderate symptoms.

In addition, people who were taking antidepressants had higher levels than those who were not.

Interestingly, there was no significant difference in mBDNF levels between the individuals who had attempted suicide in the past and the healthy controls. However, the former group was living in the community at the time of the study and may or may not have had symptoms of depression.

The authors estimate that a diagnostic test based on their assay, with a cutoff point of 12.4 nanograms per milliliter of serum, would have a sensitivity of 82.2% and a specificity of 83.3%. This means that the test will miss approximately 1 in 5 people who have depression and deem 1 in 5 people without depression to be depressed.

There were similar findings in the small subgroup with bipolar disorder.

Electroconvulsive therapy

In the future, the team plans to investigate whether electroconvulsive therapy (ECT) can restore imbalances between proBDNF and mBDNF.

ECT is often effective in patients who do not respond to antidepressants or psychotherapy.

Prof. Zhou explains:

“Mood disorders affect millions of people worldwide. However, about one-third of people with depression and bipolar disorder are resistant to antidepressants or alternative therapies. The reasons are not understood, but it could have something to do with the imbalances between the different forms of BDNF, which we hope to investigate next.”

The authors acknowledge that their study had some limitations.

For example, they originally wanted to measure serum levels of proBDNF, in addition to mBDNF. However, for technical reasons, this was not possible. As a result, the researchers were unable to determine whether the balance between these two forms of BDNF or their absolute values had the most significant effect.

They also note that confounding variables, such as whether participants smoked and their body mass index (BMI), may have affected the levels of mBDNF in their blood.

It is important to note that the study participants with MDD were inpatients and, therefore, represent a very small proportion of all people with MDD. As the control group was attending a mental health hospital for a general medical examination, they do not represent the general population.

Further studies are necessary to see how the levels of mBDNF in people living in the community with MDD compare with those in the general population. By doing this, researchers could determine the relevance of these findings to psychiatric care for people with depression.

https://www.medicalnewstoday.com/articles/a-blood-test-could-diagnose-depression-and-bipolar-disorder#Electroconvulsive-therapy