Treatments that may protect eggs against ageing

 

The spindle is responsible for separating the chromosomes equally when the oocyte goes through specialist meiotic cell divisions. The spindle is made of fibers called microtubules (green) to which the chromosomes (red) are attached. The use of MitoQ or BGP-15 improves the organization of the microtubules and alignment of the chromosomes to the center of the spindle. The oocyte has an improved chance of properly separating chromosomes and thereby avoiding aneuploidy when the egg is activated by the fertilizing sperm.

A woman’s fertility decreases as she ages – largely because of fewer healthy oocytes or eggs, and those that are available for fertilization often have chromosomal abnormalities which result in a higher incidence of miscarriage and genetic disorders such as Down’s syndrome.

Now a team at the Monash Biomedicine Discovery Institute (BDI) and Robinson Research Institute, collaborating with Monash IVF, has found a potential treatment that targets mitochondria to help prevent these chromosomal errors in mouse and human eggs.

In a paper published in the journal Human Reproduction, researchers led by Professors John Carroll and Rebecca Robker used two mitochondria-targeted therapeutics – called MitoQ and BGP-15 – which appeared to protect eggs from the chromosomal disturbances seen in older or abnormal eggs.

In particular, the addition of these agents improved how immature human eggs organize their chromosomes when matured in laboratory conditions. If this effect holds true for eggs maturing in the body it may also prevent chromosomal abnormalities in human eggs, effectively protecting them against miscarriage or genetic consequences such as Down’s syndrome.

The first author, Dr Usama Al-Zubaidi from the Monash BDI says: “Given that increasing numbers of women delay childbearing there is an imperative to improve fertility and reduce miscarriage and chromosomal anomalies associated with maternal ageing.”

The study identified “two excellent candidates that may one day help to improve fertility in older women.”

The age-related decline in fertility is strongly attributed to ovarian ageing, diminished ovarian reserves, and a decline in oocyte quality. One cause of this is due to increased oxidative stress within the oocytes.

Mitochondria – whether in an oocyte or any other cell in the body - use oxygen to create energy and one of the by-products is the production of free radicals. Oocytes are made during fetal life so have a lot of time to accumulate oxidative damage. Also, as eggs age, their defenses against oxidative damage become compromised. MitoQ and BGP-15 appear to be protecting eggs at least in part by improving mitochondrial function and minimizing oxidative stress during critical periods when the eggs are dividing their chromosomes.

Next steps involve finding the best conditions for these therapies to work when eggs are maturing inside the ovary and if the effects seen on chromosome organization translate into healthier eggs that have a better chance to develop into healthy pregnancies.

“Increasingly, fertility science is turning to therapies that specifically target these mitochondria with a view to preventing the chromosomal abnormalities that occur due to ageing and oxidative stress,” Professor Carroll said.

“Our study looked at two of these candidates to see whether they in fact made a difference to older eggs from humans and mice and found they can make the older eggs ‘younger’ again.” They were very effective at one level, but we are now working on seeing if this approach can work in patients.”

Both MitoQ and BGP-15 are used in humans already, – with MitoQ used to treat age associated hypertension while BGP-15 has been used in clinical trials for diabetes where it was given orally.

Medical Director Monash IVF, Professor Luk Rombauts said that improving function of the mitochondria, which he calls “the little energy factories within the eggs”, is one of the potential strategies to enhance egg quality and reproductive success, even more so in older women. “Monash IVF is keen to continue its collaboration with Professor John Carroll’s lab to find meaningful ways to turn this research into new treatment strategies.”

Source/Credit: Monash University

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Plasma doesn’t help severely ill COVID-19 patients

 

Giving severely ill COVID-19 patients a transfusion of blood from donors who have already recovered from the virus did not help them improve — and in some cases made them sicker, according to a major Canadian-led clinical trial reporting results in Nature Medicine.

“Convalescent plasma had been found to boost immunity in patients infected with some other viral entities, including SARS, in the past,” said local principal investigator Susan Nahirniak, professor of laboratory medicine and pathology in the University of Alberta’s Faculty of Medicine & Dentistry and medical/scientific lead for the Alberta Precision Laboratories transfusion and transplantation medicine program.

“But this trial did not demonstrate any benefit in terms of changing the course for patients who were admitted to hospital needing oxygen for SARS-CoV-2,” Nahirniak said. “It did not prevent intubation or death.”

The randomized controlled study followed 921 COVID-19 patients in Canada, the United States and Brazil who were admitted to hospital within 12 days of the onset of their respiratory symptoms. Two-thirds (614 patients) received convalescent plasma transfusions and one-third (307 patients) did not.

Of the convalescent plasma group, 199 of the patients required intubation or died, while 86 patients in the control group had these outcomes. Patients in the convalescent arm also experienced more serious adverse events such as needing more oxygen or worsening respiratory failure. The trial was terminated early when researchers realized the outcomes were not positive.

Varying immune responses

Another finding of the trial was that the level of neutralizing antibodies, or titres, in the blood of recovered COVID-19 patients was highly variable, which may have implications for how the population responds to vaccination.

“We were finding that several of the people who had signed up as donors were dropping their titres fairly quickly, so maintaining that donor pool was a challenge,” said Nahirniak. 

“It is proof that just because you’ve had COVID once doesn’t mean you can’t have it again,” she said. “It reinforces the need to be vigilant and possibly give boosters, similar to what we do with influenza.”

At the same time, the research team found that some donors had higher levels of non-functional antibodies against the virus’s spike protein. They reported that recipients of this plasma seemed to have poorer outcomes and recommended continued research on the prevalence and impact of these antibodies.

“If COVID is part of our lives going forward and there are certain antibodies that could be potentially harmful, is that something we need to be testing for and screening out for plasma donors?” Nahirniak posited.

Nahirniak noted that participating in the trial during the early days of the COVID-19 pandemic, when few treatments had been identified, helped to boost morale for both patients and clinical staff.

“We felt like we could do nothing, so at least this was an option, identifying the patients early on and getting them monitored.”

Nahirniak noted she was surprised by the disappointing results, but “that’s why we do a trial — we anticipated better success against the virus.”

The study was funded by the Canadian Institutes of Health Research and numerous local health agencies, including the University of Alberta Hospital Foundation and Alberta Health Services.

Source/Credit: University of Alberta

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Targeting tickborne diseases

"Benedict Khoo" Source: University of Minnesota

For Benedict Khoo, making a breakthrough discovery in health-related research doesn’t mean much if it can’t be put to use bettering people’s lives.

For Benedict Khoo, making a breakthrough discovery in health-related research doesn’t mean much if it can’t be put to use bettering people’s lives.

He knows from experience. When he worked in a research lab in Ohio, he felt “divorced from having a tangible impact,” due largely to regulatory hurdles in the field.

But that all changed when he turned to public health. There, he says, however his work turns out, he learns something that could help people make their own health decisions or influence policies. 

“That’s what drove me—to have that impact on the world and feel like I’m doing something,” says Khoo, a doctoral student in the School of Public Health (SPH). 

He found his niche with Jonathan Oliver, an assistant professor of environmental health sciences in SPH, who is now his adviser. Together they study the prevalence of Lyme disease and other tickborne diseases of humans, in a study area comprising Minnesota and adjacent northern Iowa and western Wisconsin. 

How a plant virus could protect and save your lungs from metastatic cancer

 

Nanoparticles engineered from the cowpea mosaic virus have shown efficacy
in treating and greatly reducing the spread of metastatic cancers in the lungs of mice.

Using a virus that grows in black-eyed pea plants, nanoengineers at the University of California San Diego developed a new treatment that could keep metastatic cancers at bay from the lungs. The treatment not only slowed tumor growth in the lungs of mice with either metastatic breast cancer or melanoma, it also prevented or drastically minimized the spread of these cancers to the lungs of healthy mice that were challenged with the disease.

The research was published in the journal Advanced Science.

Cancer spread to the lungs is one of the most common forms of metastasis in various cancers. Once there, it is extremely deadly and difficult to treat.

Researchers at the UC San Diego Jacobs School of Engineering developed an experimental treatment that combats this spread. It involves a bodily injection of a plant virus called the cowpea mosaic virus. The virus is harmless to animals and humans, but it still registers as a foreign invader, thus triggering an immune response that could make the body more effective at fighting cancer.

The idea is to use the plant virus to help the body’s immune system recognize and destroy cancer cells in the lungs. The virus itself is not infectious in our bodies, but it has all these danger signals that alarm immune cells to go into attack mode and search for a pathogen, said Nicole Steinmetz, professor of nanoengineering at UC San Diego and director of the university’s Center for Nano-ImmunoEngineering.

To draw this immune response to lung tumors, Steinmetz’s lab engineered nanoparticles made from the cowpea mosaic virus to target a protein in the lungs. The protein, called S100A9, is expressed and secreted by immune cells that help fight infection in the lungs. And there is another reason that motivated Steinmetz’s team to target this protein: overexpression of S100A9 has been observed to play a role in tumor growth and spread.

“For our immunotherapy to work in the setting of lung metastasis, we need to target our nanoparticles to the lung,” said Steinmetz. “Therefore, we created these plant virus nanoparticles to home in on the lungs by making use of S100A9 as the target protein. Within the lung, the nanoparticles recruit immune cells so that the tumors don’t take.”

“Because these nanoparticles tend to localize in the lungs, they can change the tumor microenvironment there to become more adept at fighting off cancer—not just established tumors, but future tumors as well,” said Eric Chung, a bioengineering Ph.D. student in Steinmetz’s lab who is one of the co-first authors on the paper.

To make the nanoparticles, the researchers grew black-eyed pea plants in the lab, infected them with cowpea mosaic virus, and harvested the virus in the form of ball-shaped nanoparticles. They then attached S100A9-targeting molecules to the surfaces of the particles.

The researchers performed both prevention and treatment studies. In the prevention studies, they first injected the plant virus nanoparticles into the bloodstreams of healthy mice, and then later injected either triple negative breast cancer or melanoma cells in these mice. Treated mice showed a dramatic reduction in the cancers spreading to their lungs compared to untreated mice.

In the treatment studies, the researchers administered the nanoparticles to mice with metastatic tumor in their lungs. These mice exhibited smaller lung tumors and survived longer than untreated mice.

What’s remarkable about these results, the researchers point out, is that they show efficacy against extremely aggressive cancer cell lines. “So, any change in survival or lung metastasis is pretty striking,” said Chung. “And the fact that we get the level of prevention that we do is really, really amazing.”

Steinmetz envisions that such a treatment could be especially helpful to patients after they have had a cancerous tumor removed. “It wouldn’t be meant as an injection that’s given to everyone to prevent lung tumors. Rather, it would be given to patients who are at high risk of their tumors growing back as a metastatic disease, which often manifests in the lung. This would offer their lungs protection against cancer metastasis,” she said.

Before the new treatment can reach that stage, the researchers need to do more detailed immunotoxicity and pharmacology studies. Future studies will also explore combining this with other treatments such as chemotherapy, checkpoint drugs or radiation.

Source/Credit: UC San Diego Jacobs School of Engineering

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Black Hole Snacks on a Star

 

This illustration shows a glowing stream of material from a star, torn to shreds as it was being devoured by a supermassive black hole. The feeding black hole is surrounded by a ring of dust, not unlike the plate of a toddler is surrounded by crumbs after a meal. NASA/JPL-Caltech

While black holes and toddlers don't seem to have much in common, they are remarkably similar in one aspect: Both are messy eaters, generating ample evidence that a meal has taken place.

But whereas one might leave behind droppings of pasta or splatters of yogurt, the other creates an aftermath of mind-boggling proportions. When a black hole gobbles up a star, it produces what astronomers call a "tidal disruption event." The shredding of the hapless star is accompanied by an outburst of radiation that can outshine the combined light of every star in the black hole's host galaxy for months, even years. 

In a paper published in The Astrophysical Journal, a team of astronomers led by Sixiang Wen, a postdoctoral research associate at the University of Arizona Steward Observatory, use the X-rays emitted by a tidal disruption event known as J2150 to make the first measurements of both the black hole's mass and spin. This black hole is of a particular type – an intermediate-mass black hole – which has long eluded observation.

"The fact that we were able to catch this black hole while it was devouring a star offers a remarkable opportunity to observe what otherwise would be invisible," said Ann Zabludoff, UArizona professor of astronomy and co-author on the paper. "Not only that, by analyzing the flare we were able to better understand this elusive category of black holes, which may well account for the majority of black holes in the centers of galaxies."

Study links severe COVID-19 to increase in self-attacking antibodies

 

Hospitalized COVID-19 patients are substantially more likely to harbor autoantibodies — antibodies directed at their own tissues or at substances their immune cells secrete into the blood — than people without COVID-19, according to a new study.

Autoantibodies can be early harbingers of full-blown autoimmune disease.

“If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover,” said PJ Utz, MD, professor of immunology and rheumatology at Stanford Medicine.

Utz shares senior authorship of the study, which was published Sept. 14 in Nature Communications, with Chrysanthi Skevaki, MD, PhD, instructor of virology and laboratory medicine at Philipps University Marburg in Germany, and Eline Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania. The study’s lead authors are Sarah Chang, a former technician in Utz’s lab; recent Stanford undergraduate Allen Feng, now a technician in the Utz lab; and senior research investigator Wenshao Meng, PhD, and postdoctoral scholar Sokratis Apostolidis, MD, both at the University of Pennsylvania.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found. This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them, Utz said.

If any of these antibodies block a cytokine’s ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.

Cartilage Resurfacing Implant Reduces Pain, Restores Hip Joint Function in Dogs

 

Chinni Credit: Heidi-Ann Fourkiller

A textile-based implant containing cartilage derived from stem cells reduced pain and restored hip joint function to baseline levels in a study of dogs with symptoms of moderate osteoarthritis. The study, led by researchers at North Carolina State University, Washington University in St. Louis and Cytex Therapeutics Inc., could be a significant first step toward preventative, less invasive joint resurfacing in dogs and humans.

In humans – and in dogs – a single, millimeter-thick layer of cartilage can mean the difference between an active lifestyle or painful osteoarthritis. That tiny cap of cartilage is what protects joint surfaces and allows the bones to glide over one another smoothly. Age or joint injury can cause the cartilage to degrade, leading to osteoarthritis and progressive joint pain.

“One of the holy grails of orthopedics is to replace cartilage, but there hasn’t been an effective way to do it,” says Duncan Lascelles, professor of surgery and translational pain research and management at NC State and co-corresponding author of the research. “Most of the focus is on replacing or restoring the cartilage surface with artificial materials, but regenerating cartilage isn’t possible right now. And many of the artificial products in use don’t integrate with the body.”

Farshid Guilak, the Mildred B. Simon Professor of Orthopedic Surgery at Washington University and Shriners Hospitals for Children, along with Bradley Estes and Frank Moutos, founded Cytex Therapeutics to develop an implant that could replace damaged or missing cartilage. The implant is made using a unique combination of manufacturing techniques that result in a part textile, part 3D-printed structure, which can be seeded with the patient’s own stem cells.

Cancer Cells’ Unexpected Genetic Tricks for Evading the Immune System

 

Defective versions of genes known as tumor suppressors can help cancer cells (melanoma shown) evade the immune system. Until now, scientists believed these genes’ main role was encouraging tumor growth. Credit: Julio C. Valencia, NCI Center for Cancer Research/CC BY-NC 2.0

In a surprising new finding in mice, researchers have discovered that many genes linked to human cancer block the body’s natural defense against malignancies.

Hundreds of cancer-linked genes play a different role in causing disease than scientists had expected.

So-called tumor suppressor genes have long been known to block cell growth, preventing cancerous cells from spreading. Mutations in these genes, scientists believed, thus allow tumors to flourish unchecked.

Now, Howard Hughes Medical Institute Investigator Stephen Elledge’s team has uncovered a surprising new action for many of these defective genes. More than 100 mutated tumor suppressor genes can prevent the immune system from spotting and destroying malignant cells in mice, Elledge, a geneticist at Brigham and Women’s Hospital, reports September 16, 2021, in the journal Science. “The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’” he says.

Conventional wisdom had suggested that, for the vast major of tumor suppressor genes, mutations allow cells to run amok, growing and dividing uncontrollably. But that explanation had some gaps. For example, mutated versions of many of these genes don’t actually cause rampant growth when put into cells in a petri dish. And scientists couldn’t explain why the immune system, which is normally highly proficient at attacking abnormal cells, doesn’t do more to nip new tumors in the bud.

“The shock was that these genes are all about getting around the immune system, as opposed to simply saying ‘grow, grow, grow!’”
Steve Elledge, HHMI Investigator at Brigham and Women’s Hospital

Elledge’s new paper offers some answers. His team probed the effects of 7,500 genes, including genes known to be involved in human cancer. A third or more of those cancer-linked genes, when mutated, trigger mechanisms that prevent the immune system from rooting out tumors, often in a tissue-specific manner.

“These results reveal a fascinating and unexpected relationship between tumor suppressor genes and the immune system,” says HHMI Investigator Bert Vogelstein, a cancer geneticist at the Johns Hopkins University who was not involved in the research.

Reforestation could help save coral reefs from catastrophe

Increasing reforestation efforts in coastal regions could substantially reduce the amount of sediment run-off reaching coral reefs and improve their resilience, a University of Queensland-led study has found.

The study analyzed more than 5,500 coastal areas from around the world and found that nearly 85 per cent of them leached sediment to coral reefs, the second most serious threat facing the world’s reefs behind climate change.

Dr Andrés Suárez-Castro from UQ’s Centre for Biodiversity and Conservation Science said it was important to address the issue of sediment runoff if efforts to reduce the human impact on reefs were to be successful.

“Increased sedimentation can cause aquatic ecosystems to be more sensitive to heat stress, which decreases the resilience of corals to pressures caused by climate change,” Dr Suárez-Castro said.

“If the link between the land and sea is not recognized and managed separately, any future efforts to conserve marine habitats and species are likely to be ineffective.”

Excess sediment runoff from land clearing and agrichemical pollution along coastlines can increase sediment transport to coastal waters.

Dr Suárez-Castro said one of the impacts of sediment runoff on coral reefs is a massive reduction in light levels that were key for coral and sea grass growth and reproduction.

Image credit: Diego Correa Gomez

One solution proposed by Dr Suárez-Castro and his team is for countries to commit to land and forest restoration in coastal regions, which will help reduce the amount of sediment runoff.

“Reforestation is hugely important as it maintains the stability of soils that are vital in limiting erosion risk – it also helps to trap more sediments and prevent them from reaching aquatic systems,” he said.

“Building coral resilience through reducing sediment and pollution is also key to improving a coral reef’s potential for recovery.

“If land management to reduce sediment runoff does not become a global priority, it will become increasingly challenging, if not impossible, to protect marine ecosystems in the face of climate change.”

The researchers said that while the benefits of land restoration activities were clear, it would be a challenge to get countries and governments to commit to restoration activities.

“It’s encouraging to see many countries with high coral diversity committing large areas to land restoration, however the cost of reforestation, as well as political and social barriers may make it difficult to achieve these ambitious goals,” Dr Suárez-Castro said.

“If an average of 1000 hectares of forest was restored per coastal basin, land-based sediments reaching coral reefs could be cut by an average of 8.5 per cent among 63,000 square kilometers of reefs.”

Dr Suárez-Castro and his team hope that local authorities can use their results to identify areas where reforestation can have the highest benefit on coral reefs.

“Our approach can be adapted with local data to identify optimal actions for preserving ‘win-wins’ for multiple ecosystems spanning the land and sea,” Dr Suárez-Castro said.

“Several global initiatives such as the Paris Climate Agreement are bringing forest restoration to the forefront of global conservation discussions and our hope is that our study can facilitate more informed and educated conversations around the importance of a more integrated land-sea approach.”

The research has been published in Global Change Biology

Source/Credit: University of Queensland

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Have we detected dark energy?

 

A new study, led by researchers at the University of Cambridge and reported in the journal Physical Review D, suggests that some unexplained results from the XENON1T experiment in Italy may have been caused by dark energy, and not the dark matter the experiment was designed to detect.

They constructed a physical model to help explain the results, which may have originated from dark energy particles produced in a region of the Sun with strong magnetic fields, although future experiments will be required to confirm this explanation. The researchers say their study could be an important step toward the direct detection of dark energy.

Everything our eyes can see in the skies and in our everyday world – from tiny moons to massive galaxies, from ants to blue whales – makes up less than five percent of the universe. The rest is dark. About 27% is dark matter – the invisible force holding galaxies and the cosmic web together – while 68% is dark energy, which causes the universe to expand at an accelerated rate.

“Despite both components being invisible, we know a lot more about dark matter, since its existence was suggested as early as the 1920s, while dark energy wasn’t discovered until 1998,” said Dr Sunny Vagnozzi from Cambridge’s Kavli Institute for Cosmology, the paper’s first author. “Large-scale experiments like XENON1T have been designed to directly detect dark matter, by searching for signs of dark matter ‘hitting’ ordinary matter, but dark energy is even more elusive.”

To detect dark energy, scientists generally look for gravitational interactions: the way gravity pulls objects around. And on the largest scales, the gravitational effect of dark energy is repulsive, pulling things away from each other and making the Universe’s expansion accelerate.

About a year ago, the XENON1T experiment reported an unexpected signal, or excess, over the expected background. “These sorts of excesses are often flukes, but once in a while they can also lead to fundamental discoveries,” said Dr Luca Visinelli, a researcher at Frascati National Laboratories in Italy, a co-author of the study. “We explored a model in which this signal could be attributable to dark energy, rather than the dark matter the experiment was originally devised to detect.”

At the time, the most popular explanation for the excess were axions – hypothetical, extremely light particles – produced in the Sun. However, this explanation does not stand up to observations, since the amount of axions that would be required to explain the XENON1T signal would drastically alter the evolution of stars much heavier than the Sun, in conflict with what we observe.

We are far from fully understanding what dark energy is, but most physical models for dark energy would lead to the existence of a so-called fifth force. There are four fundamental forces in the universe, and anything that can’t be explained by one of these forces is sometimes referred to as the result of an unknown fifth force.

However, we know that Einstein’s theory of gravity works extremely well in the local universe. Therefore, any fifth force associated to dark energy is unwanted and must be ‘hidden’ or ‘screened’ when it comes to small scales, and can only operate on the largest scales where Einstein's theory of gravity fails to explain the acceleration of the Universe. To hide the fifth force, many models for dark energy are equipped with so-called screening mechanisms, which dynamically hide the fifth force.

Vagnozzi and his co-authors constructed a physical model, which used a type of screening mechanism known as chameleon screening, to show that dark energy particles produced in the Sun’s strong magnetic fields could explain the XENON1T excess.

“Our chameleon screening shuts down the production of dark energy particles in very dense objects, avoiding the problems faced by solar axions,” said Vagnozzi. “It also allows us to decouple what happens in the local very dense Universe from what happens on the largest scales, where the density is extremely low.”

The researchers used their model to show what would happen in the detector if the dark energy was produced in a particular region of the Sun, called the tachocline, where the magnetic fields are particularly strong.

“It was really surprising that this excess could in principle have been caused by dark energy rather than dark matter,” said Vagnozzi. “When things click together like that, it’s really special.”

Their calculations suggest that experiments like XENON1T, which are designed to detect dark matter, could also be used to detect dark energy. However, the original excess still needs to be convincingly confirmed. “We first need to know that this wasn’t simply a fluke,” said Visinelli. “If XENON1T actually saw something, you’d expect to see a similar excess again in future experiments, but this time with a much stronger signal.”

If the excess was the result of dark energy, upcoming upgrades to the XENON1T experiment, as well as experiments pursuing similar goals such as LUX-Zeplin and PandaX-xT, mean that it could be possible to directly detect dark energy within the next decade.

Source/Credit: University of Cambridge / Sarah Collins

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