Drugs that selectively kill senescent cells may benefit otherwise healthy older women but are not a “one-size-fits-all” remedy, Mayo Clinic researchers have found. Specifically, these drugs may only benefit people with a high number of senescent cells, according to findings publishing July 2 in Nature Medicine.
Senescent cells are malfunctioning cells in the body that lapse into a state of dormancy. These cells, also known as “zombie cells,” can’t divide but can drive chronic inflammation and tissue dysfunction linked to aging and chronic diseases. Senolytic drugs clear tissues of senescent cells.
In the 20-week, phase 2 randomized controlled trial, 60 healthy women past menopause intermittently received a senolytic combination composed of FDA-approved dasatinib and quercetin, a natural product found in some foods. It is the first randomized controlled trial of intermittent senolytic treatment in healthy aging women, and the investigators used bone metabolism as a marker for efficacy.
Researchers found that this combination, known as D+Q, had beneficial effects on bone formation but did not reduce bone resorption or the breakdown and removal of bone tissue. Furthermore, D+Q mainly benefited people with evidence of a high number of senescent cells. This group had more robust increases in bone formation, decreases in bone resorption, and an increase in bone mineral density at the wrist.
“Our findings argue against what many people are already doing — using commercial products like quercetin or related compounds like fisetin that may show some senolytic properties,” says senior author Sundeep Khosla, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota. “They’re using them as anti-aging agents without knowing if they have high enough senescent cell numbers to benefit, or what dose or dosing regimen is needed to be effective yet safe.”
Dr. Khosla says more research is needed to better identify people who may benefit from senolytic treatments and to develop more specific and potent senolytic drugs that may show efficacy in more people. People who have experienced “accelerated aging” — such as cancer survivors after chemotherapy, or those with progeroid syndromes — may have increased numbers of senescent cells.
Besides their application to aging, senolytic drugs may be useful against certain diseases, such as idiopathic pulmonary fibrosis, dementia, diabetes, heart disease and others, Dr. Khosla says. However, these drugs will likely need to be customized according to their potency and the amounts of senescent cells in the diseased tissues.
The study was supported by National Institutes of Health grant nos. R21 AG065868, P01 AG062413, R01 AG 076515, R01 DK128552, R01 AG055529, R37 AG13925 and R33 AG61456.
Co-authors are Joshua Farr, Ph.D., Elizabeth Atkinson, Sara Achenbach, Tammie Volkman, Amanda Tweed, Stephanie Vos, Ming Ruan, Jad Sfeir, M.D., Matthew Drake, M.D., Ph.D., Dominik Saul, M.D., Madison Doolittle, Ph.D., Irina Bancos, M.D., Kai Yu, M.D., Tamara Tchkonia, Ph.D., Nathan LeBrasseur, Ph.D., James Kirkland, M.D., Ph.D., and David Monroe, Ph.D.
Drs. LeBrasseur, Tchkonia and Kirkland have financial interests related to this research, including Mayo Clinic patents and pending patents covering senolytic drugs and their uses. The remaining authors declare no competing interests.

Two new species of psychoactive mushrooms in the genus Psilocybe have been described from southern Africa, bringing the list to six known species indigenous to Africa.
This is even though Psilocybe species are amongst the most well-known and well-studied species of psychoactive mushrooms in the world, with around 140 described species.
In a paper published in the journal Mycologia this week, researchers from Stellenbosch University (SU) and citizen mycologists describe the two new species as Psilocybe ingeli and Psilocybe maluti.
Psilocybe ingeli was first found in 2023 growing in pastureland in KwaZulu-Natal by Talan Moult, a self-taught citizen mycologist. Psilocybe maluti was first found on a Free State small holding in 2021 by Daniella Mulder, who sent photos of the mushrooms for identification to Andrew Killian, one of South Africa’s leading citizen mycologists based in Somerset West.
In both instances, the unusual looking specimens were sent to Breyten van der Merwe for DNA sequencing and analysis in the lab of Prof. Karin Jacobs in SU’s Department of Microbiology. Van der Merwe, now a postgraduate student in chemical engineering at SU, is a trained mycologist and first author of the paper.
The paper also contains information on the traditional use of P. maluti by Basotho traditional healers from the mountain kingdom of Lesotho. According to the researchers, this appears to be the only recorded first-hand report of hallucinogenic mushrooms being used traditionally in Africa.
Cullen Taylor Clark, a citizen mycologist and co-author, worked with Mamosebetsi Sethathi, a Mosotho traditional healer, to document the use of P. maluti (locally known as koae-ea-lekhoaba) in traditional healing practices. This forms part of a larger effort, led by Clark, to document the use of mushrooms by indigenous groups in southern Africa.
Van der Merwe says there are very likely more southern African species in this genus, and that more citizen scientists need to become involved: “These two species were sent to me by citizen scientists. It would be impossible for a single researcher to cover a fraction of an area these mushroom enthusiasts have access to. This is the only way we will be able to further studies in African mycology.”
Prof. Jacobs echoes this sentiment: “There are only a handful of mycologists in Africa documenting local biodiversity. Considering the vast mycological diversity on the continent, it is a daunting task. Collaborating with citizen mycologists is therefore hugely beneficial. In addition to more material, collaboration also opens avenues for conversation and exploration, which can lead to documenting mycophilia (the love of mushrooms) on the African continent.”

University of Michigan chemists have discovered a way to use visible light to synthesize a class of compounds particularly well suited for use in pharmaceuticals.
The class of compounds, called azetidines, had been previously identified as a good candidate to build therapeutic drugs, but the compounds are difficult to produce in chemical reactions. Now, a team led by University of Michigan chemist Corinna Schindler has developed a method to produce a specific class of azetidines called monocyclic azetidines using visible light and a photocatalyst. Their results are published in the journal Science.
Approximately 60% of pharmaceutical drugs contain building blocks in the form of compounds called nitrogen heterocycles. Nitrogen heterocycles are structures of atoms organized in a ring that contain at least one nitrogen atom, the most common of which have five- and six-membered ring systems. These systems are often used as building blocks in pharmaceuticals.
“These building blocks are very accessible and you can put them together like Legos to build compounds that we can then use for chemical or medicinal testing. But the problem is that a lot of these five or six membered ring systems are not as stable as you’d want them to be,” Schindler said.
“The ring systems can break down in the body after a patient has ingested a therapeutic drug. Because the compound can be metabolized by the human body, what you give initially to a patient may not necessarily be what you would find in the body after the patient has taken it, and that is a problem.”
Instead, researchers suggest using monocyclic azetidines, a more stable four-membered ring system. But, says Emily Wearing, lead author of the study who recently earned her doctorate from Schindler’s lab, the key reactions chemists use to produce azetidines have specific challenges.
The reactions either can’t be widely applied or they only produce azetidines with specific substitution patterns. Researchers want to produce azetidines with different substitution patterns because this allows researchers to try a variety of the molecule as building blocks in drug synthesis and drug screening.

Further, the U-M researchers used a method called a [2+2]-cycloaddition to create monocyclic azetidines. This method usually requires photoexcitation, or the excitation of atoms or molecules in a compound through the absorption of energy, according to Schindler. In other words, the reaction needs light.
In the reaction, the researchers used two classes of compounds called acyclic imines and alkenes, which are highly desirable as starting materials because they can be easily varied to produce different products, Wearing says. However, when you use light to excite the imine, the acyclic imine decays from the excited state before it can undergo the cycloaddition, Schindler says.
Previously, there has been a successful example of this reaction, Wearing says, but it used ultraviolet light, which presents safety challenges, and it used different imines and alkenes.
“This also means access to these highly desirable monocyclic azetidine building blocks is much more limited using this approach,” Wearing said. “The use of visible light versus UV light is an important benefit, but our key discovery was being able to use a visible light approach to produce monocyclic azetidines.”
Their method uses visible light and a photocatalyst to allow access to the required excited state intermediates in what’s called an aza Paternò-Büchi reaction. To determine exactly why the reaction worked, Schindler’s lab teamed up with the lab of Heather Kulik, associate professor of chemical engineering at the Massachusetts Institute of Technology.
Her lab ran a computational analysis that found using specific classes of the imines and alkenes starting materials would facilitate a better match in energy between those starting materials, which lowered the barrier for reaction. They also analyzed what factors led to high yields of azetidines.

When researchers develop a new reaction like this, they also need to show that it can work for many combinations of substrates, according to Seren Parikh, a graduate student in Schindler’s lab. He and postdoctoral research fellow Yu-Cheng Yeh showed that the team’s reaction could work on multiple versions of imine and alkene compounds.
“Someone might show that a new reaction works, but if it only works on a single compound, it is not useful to anyone because pharmaceutical companies are likely wanting to use the reaction on their unique compound,” Parikh said. “What we can do is show that the reaction works on a diverse range of substrates to essentially prove that the reaction is worth the pharmaceutical company’s time to try.”
Parikh and Yeh were able to show that they could produce six biologically relevant azetidine compounds, including using the reaction to attach an azetidine to an estrogen derivative, a natural steroid in the human body. Yeh also used this method to synthesize analogues of penaresidin B, which has been shown to be toxic to tumor cells. This is the first total synthesis of this natural product using the [2+2]-cycloaddition
“The synthesis of these azetidine compounds are examples to demonstrate that this synthetic methodology can be applied to make complicated molecules and medicine-like molecules,” Yeh said.
Understanding what makes this chemical reaction work will allow the group and the field of medicinal chemistry to design related reactions in the future. New work can build upon this design principle to access other azetidines to be incorporated into new pharmaceuticals, Schindler says.
“Now we can access these types of building blocks that people have wanted for a long time, but couldn’t directly access,” she said. “The process we have developed can now be used in the future as basically a blueprint for future reaction development.”

The incidence of low birth weight rose sharply in India amid the COVID-19 pandemic, according to new research from the University of Notre Dame.
Globally, 1 in 4 newborns has a low birth weight (less than 5.5 pounds), and the problem disproportionately affects low- and middle-income countries — particularly in South Asia, home to approximately one-fourth of the world’s population.
Santosh Kumar, associate professor of development and global health economics at Notre Dame’s Keough School of Global Affairs, co-authored the study published in Communications Medicine, a Nature series journal.
“This research shows that low birth weight became more common in India during the pandemic,” Kumar said. “We saw the exacerbation of a global health problem that affects educational outcomes and poverty rates.
“Children who have lower birth weight as infants often go on to struggle with school, and this limits their capacity to develop what economists often call ‘human capital’ — the key knowledge and skills that will affect their ability to earn a good living and support themselves and their families.”
The study found that babies born between April 2020 and April 2021 had lower birth weights than previous birth cohorts (those born before the pandemic), Kumar said. Researchers analyzed data from more than 200,000 infants, Kumar said, including a pandemic cohort that included almost 12,000 infants and a pre-pandemic cohort of approximately 192,000.
The prevalence of low birth weight was 20 percent in the pandemic group, up from 17 percent in the pre-pandemic group, Kumar said, and infants in the pandemic group weighed about four-tenths of an ounce less than those in the pre-pandemic group.

Multiple factors related to the pandemic may have affected the health behaviors of pregnant women and contributed to lower birth weights, Kumar said, including the SARS-CoV-2 virus, stress related to social distancing, economic upheaval and the disruption of maternal and neonatal care.
The study’s co-authors were Clare Hill, a Notre Dame undergraduate student majoring in political science and global affairs with a minor in data science, and Timothy J. Halliday, an economist at the University of Hawaii. The study received funding from the Keough School’s Kellogg Institute for International Studies.
Kumar said this latest research, which expands on his work at the intersection of poverty and global health, highlights the need for targeted policies that reduce the incidence of low birth weights — for instance, ensuring that women from low-income populations have adequate nutrients and caloric intake during pregnancy and also have access to quality prenatal care.
“Our research underscores the need for targeted policies to reduce the risk of low birth weight,” Kumar said. “This will help create greater educational and economic opportunity and, ultimately, reduce poverty.”

In a recent study, researchers at Johns Hopkins Medicine suggest the cell’s messenger RNA (mRNA) — the major translator and regulator of genetic material — along with a critical protein called ZAK, spur the cell’s initial response to UV radiation damage and play a critical role in whether the cell lives or dies.
While UV radiation has long been known to damage DNA, it also damages mRNA, and the latest findings, published June 5 in Cell, indicate that mRNAs act as first responders in telling the cells how to manage the stress.
“RNA is a canary in the coal mine. It’s telling the cell, ‘We’ve got major damage here and we need to do something,'” says Rachel Green, Ph.D., a Bloomberg Distinguished Professor of Molecular Biology and Genetics and Daniel Nathans Director of the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. Green, also an investigator at Howard Hughes Medical Institute, is the corresponding author of the new study.
ZAK is a key player in a process that identifies cellular damage by sensing the collisions of ribosomes, tiny macromolecular machines that help RNA translate the language of genes into the language of proteins. Collisions occur when ribosomes move along UV-damaged mRNAs and, unable to decode the damaged message, cause stalled ribosomes to get “rear-ended” by upstream ribosomes. Ribosome collisions activate ZAK, which triggers a cellular signaling program known as the ribotoxic stress response. ZAK then instigates a cascade of downstream events that decide the cell’s fate.
A more comprehensive understanding of how cellular life-and-death decisions are made upon encountering UV radiation could help investigators understand underlying causes of skin and other cancers, says Niladri Sinha, Ph.D., Jane Coffin Childs Memorial Fund Postdoctoral Fellow at Johns Hopkins School of Medicine. Companies developing drugs that target ribosomes may also find that ZAK could be a driver of cell death across cancer types, he says.
The findings indicate that ZAK senses the extent of cellular damage and responds depending on how much UV radiation the cell receives, offering a more nuanced understanding of UV-caused cell death and identifying new ways to keep ZAK’s activity under control, Green says.
“There are graded ways that ZAK responds, it’s not all or nothing,” she says.

The research also “very clearly shows” that, for example, a skin cell’s fate in the immediate aftermath of UV radiation is “driven primarily by the extent of colliding ribosomes and ZAK signaling,” Green says.
“In this regime, DNA damage and the well-characterized DNA damage response pathway, including the key protein p53, do not significantly determine cell fate decisions,” she says.
DNA damage repair is critical and occurs in a subset of cells that are copying their genetic material, but these pathways are not the major “deciders” of cell fate, she says.
Green co-led the research with Sergi Regot, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, and Alban Ordureau, Ph.D., assistant member of the Cell Biology Program at Memorial Sloan Kettering Cancer Center’s Sloan Kettering Institute and an assistant professor at Weill Cornell.
To conduct their research, the scientists exposed human cellular models to a UV lamp mimicking the sun’s radiation. Using proteomics to understand cell signaling in an approach led by Ordureau, they evaluated ZAK’s role and made predictions about how cells would respond to different levels of stress. From there, live cell imaging experiments led by Regot, in addition to in-house ribosome biochemistry — the workhorse of Green’s laboratory — helped characterize how cellular death is regulated as a consequence of ZAK-mediated UV radiation.
In the future, the researchers plan to investigate cell types with different protein synthesis regimes, including those in melanoma and other cancers. The researchers suspect that fast-growing cells will rely on ZAK-mediated regulation more than others, Green says.
Funding for this research was provided by the Howard Hughes Medical Institute, the National Institutes of Health (NIH 1R35GM133499), a National Science Foundation Career grant, the Jane Coffin Childs Memorial Fund for Medical Research Fellowship, and the National Institute of General Medical Sciences, Sloan Kettering Institute startup funds, Pew Charitable Trusts, a Memorial Sloan Kettering Cancer Center support grant, and the Basic Science Research Program from the National Research Foundation of Korea; Ministry of Education.
Other scientists who contributed to this study are Connor McKenney, Zhong Y. Yeow, and Jeffrey J. Li of Johns Hopkins; Ki Hong Nam of Memorial Sloan Kettering Cancer Center’s Sloan Kettering Institute; and Tomer M. Yaron-Barir, Jared L. Johnson, Emily M. Huntsman and Lewis C. Cantley of Weill Cornell Medicine.
Green is a member of the scientific advisory board of Alltrna, Initial Therapeutics and Arrakis Pharmaceuticals, consults for Vertex Pharmaceuticals, Bristol-Myers Squibb (Celgene), Monta Rosa Therapeutics and Flagship Pioneering, and served on the scientific advisory board at Moderna.

A common infection-causing bacteria was much less likely to evolve antibiotic resistance when treated with a mixture of antimicrobial peptides rather than a single peptide, making these mixtures a viable strategy for developing new antibiotic treatments. Jens Rolff of the Freie Universitat Berlin, Germany, and colleagues report these findings in a new study publishing July 2 in the open-access journal PLOS Biology.
Antibiotic-resistant bacteria have become a major threat to public health. The World Health Organization estimates that 1.27 million people died directly from drug-resistant strains in 2019 and these strains contributed to 4.95 million deaths. While bacteria naturally evolve resistance to antibiotics, misuse and overuse of these drugs has accelerated the problem, rendering many antibiotics ineffective. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides, which are chains of amino acids that function as broad-spectrum antimicrobial compounds and are key components of the innate immune system in animals, fungi and plants.
In the new study, researchers investigated whether antimicrobial peptide mixtures synthesized in the lab could reduce the risk of the pathogen Pseudomonas aeruginosa from evolving antimicrobial resistance, compared to exposure to a single antimicrobial peptide. They found that using antimicrobial peptide mixtures carried a much lower risk of the bacteria developing resistance. The mixtures also helped prevent the bacteria from developing cross-resistance to other antimicrobial drugs, while maintaining — or even improving — drug sensitivity.
Overall, the findings suggest that the use of antimicrobial peptide mixtures is a strategy worth pursuing in the search for new, longer-lasting treatments for bacteria. The researchers suspect that using a cocktail of multiple antimicrobial peptides creates a larger set of challenges for bacteria to overcome, which can potentially delay the evolution of resistance, compared to traditional antibiotics. Furthermore, these cocktails can be synthesized affordably, and previous studies have shown them to be non-toxic in mice.
Lead author Bernardo Antunes adds, “Even after four weeks of exposure, a usual treatment duration for Pseudomonas infections, we could not find resistance against our new random peptide, but against other antimicrobials.”

A major challenge in developing a vaccine for HIV is that the virus mutates fast — very fast. Although a person initially becomes infected with one or a few HIV strains, the virus replicates and mutates quickly, resulting in a “swarm” of viral strains existing in a single body. But scientists at Scripps Research; IAVI; the Ragon Institute of Mass General, MIT, and Harvard; La Jolla Institute for Immunology; and additional institutions have conducted a series of preclinical trials indicating that they’re potentially closer to an immunization regimen than ever before — one that could produce rare antibodies that would be effective against a wide range of HIV strains.
Published in Science, Science Immunology, and Science Translation Medicine on May 16, 2024, the findings are outlined in four individual papers and build on a 2022 phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key step forward in an immunization strategy that could protect against the virus.
“All in all, these studies show that we have a good chance at creating an effective HIV vaccine — we just need to keep iterating and build on these findings in future clinical trials,” says co-senior author of all four studies, William Schief, PhD, who is also a Scripps Research professor; vice president for antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at IAVI’s Neutralizing Antibody Center.
The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are among the immune system’s key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, spearheaded in part by Schief, focused on inducing the immune cells that could eventually evolve into the right bnAbs — ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen — a customized molecule to “prime” the immune system and elicit responses from the correct precursor cells.
But the primer also requires additional “booster” immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs — a rare and specific class of antibodies known to neutralize more than 90 percent of diverse HIV strains. Boosters are also needed for the production of BG18 — another important bnAb class that binds to sugars on the HIV spike protein. That’s where the new studies come in: Researchers developed immunization regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path toward becoming bnAbs.
“The results contained in these papers are deeply exciting and further support the germline-targeting strategy to HIV vaccine development that IAVI and our partners are pursuing,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “We look forward to continuing our collaboration with Scripps Research and partners to advance further research building on these promising findings.”
This groundbreaking science is enabled by collaboration between scientific institutions and funding partners. Without the ongoing, critical support of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna (the manufacturer of the mRNA used in these studies), this research would not have been possible.

Priming rare antibodies
In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president, discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.
To confirm they were able to prime the correct precursors, the researchers then teamed up with Andrew Ward, PhD, Scripps Research integrative structural and computational biology professor and co-senior author of the study. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.
“The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans,” says co-first author, Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.
Steichen was also co-first author on a second study, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that this time, they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognize more native-like versions of HIV.
“This study showed that we can start to walk the B cells along toward bnAb development,” Steichen explains.

Supercharging the immune system into action
For the third study, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response toward becoming matured bnAbs — the next vital step in a sequential immunization series that could effectively fight HIV. The results: a “prime-boost” regimen that can drive VRC01-class B cells toward bnAb development.
“The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster, which administers a different version of the vaccine than was given previously,” says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author on this study.
Understanding the immunology
In the fourth and final study, on which Cottrell was also a co-first author, the team worked again with Batista’s team at the Ragon Institute and used the same immunogens — but in a different mouse model where his team could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to take a deeper dive into the immunology associated with HIV vaccination by examining the germinal centers — specialized microstructures in the body that protect against viral reinfection. Germinal centers provide B cells with a space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight off viral strains.
In addition, the researchers examined how germinal centers accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B-cell activity in germinal centers across different lineages, which could eventually lead to an increase in matured VRC01-class bnAbs.
What’s next
Overall, all four papers confirm that the priming step to turn on the right bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it’s also possible to guide antibody precursors toward becoming bnAbs that can fight HIV.
“Taken together, the findings give us more confidence that we’re able to prime precursors from multiple bnAb targets, and they also show that we’re starting to learn the rules for how to advance precursor maturation through heterologous boosting,” Schief added.
Following these results, the researchers are advancing phase 1, experimental medicine trials for both the VRC01 and BG18 projects. Vaccines aiming to prime and boost VRC01-class antibodies are being further evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies use both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).
The results of these studies will guide the critical next steps on the discovery path to an HIV vaccine.

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. The discovery, reported today in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.
Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.
While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.
Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. The mothers also had obesity, but in addition had experienced postnatal depression.
To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).
Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.
Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”
TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons — nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.
Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.
In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.
Professor Sadaf Farooqi from the Institute of Metabolic Science at the University of Cambridge said: “There’s a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ — which enable humans and animals to survive — such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”
While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people — around three-quarters of whom were women — that carried variants of the gene and had a higher-than-average body mass index.
The researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”
There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. The team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.
Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”
This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Randomized controlled trials, or RCTs, are believed to be the best way to study the safety and efficacy of new treatments in clinical research. However, a recent study from Michigan State University found that people of color and white women are significantly underrepresented in RCTs due to systematic biases.
The study, published in the Journal of Ethnicity in Substance Abuse, reviewed 18 RCTs conducted over the last 15 years that tested treatments for post-traumatic stress and alcohol use disorder. The researchers found that despite women having double the rates of post-traumatic stress and alcohol use disorder than men, and people of color having worse chronicity than white people, most participants were white (59.5%) and male (about 78%).
“Because RCTs are the gold standard for treatment studies and drug trials, we rarely ask the important questions about their limitations and failings,” said Nicole Buchanan, co-author of the study and professor in MSU’s Department of Psychology. “For RCTs to meet their full potential, investigators need to fix barriers to inclusion. Increasing representation in RCTs is not simply an issue for equity, but it is also essential to enhancing the quality of our science and meeting the needs of the public that funds these studies through their hard-earned tax dollars.”
The researchers found that the design and implementation of the randomized controlled trials contributed to the lack of representation of people of color and women. This happened because trials were conducted in areas where white men were the majority demographic group and study samples almost always reflected the demographic makeup where studies occurred. Additionally, those designing the studies seldom acknowledged race or gender differences, meaning they did not intentionally recruit diverse samples.
Furthermore, the journals publishing these studies did not have regulations requiring sample diversity, equity or inclusion as appropriate to the conditions under investigation.
“Marginalized groups have unique experiences from privileged groups, and when marginalized groups are poorly included in research, we remain in the dark about their experiences, insights, needs and strengths,” said Mallet Reid, co-author of the study and doctoral candidate in MSU’s Department of Psychology. “This means that clinicians and researchers may unknowinglyremain ignorant to how to attend to the trauma and addiction challenges facing marginalized groups and may unwittingly perpetuate microaggressions against marginalized groups in clinical settings or fail to meet their needs.”

A class of proteins that regulates cell repair and enhances cell growth-signaling systems could be a promising new target for the treatment of Alzheimer’s and other neurodegenerative diseases, according to a new study led by researchers at Penn State. They found that disrupting necessary sugar modifications of these proteins promotes cell repair and reverses cellular abnormalities that occur in neurodegenerative diseases.
The study appeared today (July 2) in the journal iScience, and the researchers have a patent related to this work.
“Strategies to treat Alzheimer’s disease to date have largely focused on pathological changes prominent in the late stages of the disease,” said Scott Selleck, professor of biochemistry and molecular biology in the Penn State Eberly College of Science and leader of the research team. “Although recently [U.S. Food and Drug Administration]-approved drugs have shown the ability to modestly slow the disease by targeting one of these changes, amyloid accumulation, drugs that affect the earliest cellular deficits might provide important tools to stop or reverse the disease process. We are interested in understanding the earliest cellular changes that are found not only in Alzheimer’s, but shared across other neurodegenerative diseases, including Parkinson’s and amyotrophic lateral sclerosis (ALS).”
Roughly 6.9 million Americans over the age of 65 are estimated to be living with Alzheimer’s disease, according to the Alzheimer’s Association. Despite its widespread impact, there is no agreed upon biological cause or mechanism for the disease. Cell-signaling molecules called heparan sulfate-modified proteins have been implicated in the development of Alzheimer’s, but their specific role has remained unclear, Selleck said. In this study, the research team first performed a series of analyses in human cell lines and mouse brain cells that express aspects of Alzheimer’s, showing that these proteins regulate cellular processes known to be affected in several neurodegenerative diseases.
Heparan sulfate-modified proteins are found both on the surface of animal cells and in the matrix between cells. This class of proteins are named for a sugar polymer that bears many sulfate groups, called heparan sulfate. Heparan sulfate chains are attached to specific proteins, and this modification allows these proteins to assemble signaling complexes that affect cell growth and influence how the cell interacts with its environment. These signaling pathways also regulate autophagy, a process of cell repair that clears out damaged or dysfunctional components in the cell.
“In the early stages of several neurodegenerative diseases, autophagy is compromised, which means cells have a reduced repair capacity,” Selleck said. “In this study, we determined that heparan sulfate-modified proteins suppress autophagy-dependent cell repair. What’s more, we show that by compromising the structure and function of the sugar modifications of these proteins, the levels of autophagy increase so cells can take care of damage.”
The researchers found that, in human and mouse cells, reducing the function of heparan sulfate-modified proteins also rescued other pathologies that arise early in neurodegenerative diseases, improving the function of mitochondria — which are responsible for energy production in the cell — and reducing build-up of lipids, or fatty compounds, inside cells.

The researchers then evaluated the role of heparan sulfate-modified proteins in an animal model of Alzheimer’s, a fruit fly with deficits in a presenilin protein. Presenilin mutations cause early onset disease in humans and likewise in fruit flies; defective presenilin causes cell death and brain degeneration. In flies with deficits in presenilin, reducing the function of heparan sulfate chains suppressed the death of neurons and corrected other cell defects as well. These results are directly relevant to recent human genetics research, the researchers said.
“Individuals with mutations in a presenilin gene, PSEN1, develop Alzheimer’s in their mid-40s. But if they also inherit a rare genetic change in a specific protein called APOE, the disease is delayed, sometimes by decades,” Selleck said, explaining that APOE plays an important role in lipid transport and binds to heparan sulfate. “This change in APOE — which has been in the news lately — greatly reduces APOE binding to heparan sulfate. Our work builds on and extends these findings, directly implicating heparan sulfate in Alzheimer’s pathology involving both PSEN1 and APOE. Targeting the enzymes that make heparan sulfate could provide a means of blocking neurodegeneration in humans.”
Collectively, these results show that disrupting the structure of heparan sulfate modifications, blocks or reverses early cellular problems in these models of Alzheimer’s.
“We save the animal from neuron cell loss, mitochondrial defects and rescue behavior deficits that serve as a measure of nervous system function,” Selleck said. “These findings suggest a promising target for future treatments that could rescue the earliest abnormalities that occur in many neurodegenerative diseases.”
The researchers also explored how gene expression changed when they eliminated the capacity of human cells to make heparan sulfate chains. They found that expression levels of more than 50% of approximately 70 genes known to be associated with late-onset Alzheimer’s disease were modulated, including APOE, suggesting a link between heparan sulfate-modified proteins and the more common and late onset forms of Alzheimer’s disease.
“There is a critical need to focus on cellular changes that occur at the earliest times in disease progression and develop treatments that block or reverse them,” Selleck said. “We demonstrate that reduced autophagy, mitochondrial defects and lipid build-up — all common changes in neurodegenerative disease — can be blocked by altering one class of proteins, those with heparan sulfate modifications. We think these molecules are promising targets for drug development.”
The researchers suspect that disrupting this pathway to promote cell repair systems could be important for a wide variety of other diseases where autophagy defects occur.

“The applications of manipulating this pathway may be broadly useful across a number of human medical conditions,” Selleck said.
The research team at Penn State also includes co-authors Nicholas Schultheis, doctoral student in the Biochemistry, Microbiology and Molecular Biology program; Alyssa Connell, research assistant; and Richard Mueller, Alexander Kapral, Robert Becker, Shalini Shah, Mackenzie O’Donnell, Matthew Roseman, Lindsey Swanson and Sophia DeGuara, all undergraduate students. Contributions were also made by researcher Weihua Wang and Associate Professor of Pharmacology Fei Yin at the University of Arizona and graduate student Tripti Saini and Assistant Professor of Biochemistry and Molecular Biology Ryan Weiss at the University of Georgia.
Funding from the National Institutes of Health and the Penn State Eberly College of Science supported this research.