Das and colleagues studied the effect of mass loss driven by stellar winds on the formation and evolution of Supermassive Stars (SMSs) in dense Nuclear Star Clusters (NSCs) using idealised N-body simulations. They found that the interaction of stellar wind and the gas inside the cluster play an important role in the evolution of SMS. Their study recently appeared in Arxiv.
So far, we have discovered more than two hundred supermassive black holes (SMBHs) with masses ≳ 109 M within the first ∼ Gyr after the Big Bang, which have challenged our general understanding of black hole growth and formation. How these massive objects actually formed and grew over cosmic time is one of the biggest puzzles to solve in astrophysics. These SMBHs are created from ‘seed’ black holes that grow via gas accretion and mergers. The ‘seed’ black holes are categorized into two categories: (i) low mass seeds (≲ 10² M) and (ii) high mass seeds (∼ 104¯6 M). These seeds were formed at redshift, 𝑧 ∼ 20 − 30, and then they rapidly grew to their final masses by gas accretion and mergers.
Low mass seeds are believed to be formed from Pop III stellar remnants. While, high mass seeds are believed to be formed from massive black holes via direct collapse. A key requirement for this scenario is large inflow rate of ∼ 0.1 Myr¯1 which can be obtained easily in metal free halos. In this scenario supermassive stars (SMSs) of masses ∼ 104¯5 M are formed, which are massive enough to grow to 109 M by 𝑧 ∼ 7. These SMSs collapse into seed BHs with minimal mass loss at the end of their lifetime. A possible formation channel of these SMSs is the interplay of gas accretion and runaway stellar collisions inside dense nuclear star clusters (NSCs). However, mass loss due to stellar winds could be an important limitation for the formation of the SMSs and affect the final mass. So, Das and colleagues now explored the effect of mass loss due to stellar winds on the final mass of SMSs produced in Nuclear Star Clusters (NSCs) via gas accretion and runaway collisions, using idealised N-body simulations.
Considering different accretion scenarios, they have studied the effect of the mass loss rates over a wide range of metallicities 𝑍∗ = [.001 − 1]Z and Eddington factors 𝑓Edd = 𝐿∗/𝐿Edd = 0.5, 0.7, & 0.9.
They found that,
For a high accretion rate of 10¯4 Myr¯1, SMSs with masses ≳ 10³ M could be formed even in a high metallicity environment.
For a lower accretion rate of 10¯5 Myr¯1, SMSs of masses ∼ 104 M can be formed for all adopted values of 𝑍∗ and 𝑓Edd, except for 𝑍∗ = Z and 𝑓Edd = 0.7 or 0.9.
For Eddington accretion, SMSs of masses ∼ 103 M can be formed in low metallicity environments with 𝑍∗ ≲ 0.01Z. While, it will not be formed in regime 𝑍∗ ≳ 0.01Z
The most massive SMSs of masses ∼ 105 M can be formed for Bondi-Hoyle accretion in environments with 𝑍∗ ≲ 0.5Z. While, the formation of SMS will not be possible in the high metallicity regime of 𝑍∗ ≳ 0.5Z.
Finally, authors mentioned that the interaction of the stellar wind and the gas inside the cluster play an important role in the evolution of the SMSs.
Interestingly, previous study have found that for a Salpeter type mass function stellar wind cannot remove the gas inside the cluster. Hence, we do not expect the stellar wind to remove gas from the cluster.
— wrote authors of the study
They suggested, an intermediate regime is likely to exist where the mass loss from the winds might no longer be relevant, while the kinetic energy deposition from the wind could still inhibit the formation of a very massive object.
“In future work, it will be important to study detailed gas dynamics where the kinetic energy deposition of winds as well as the supernova feedback is taken into account.“
— concluded authors of the study
Reference: Arpan Das, Dominik R. G. Schleicher, Shantanu Basu, Tjarda C. N. Boekholt, “Effect of mass loss due to stellar winds on the formation of supermassive black hole seeds in dense nuclear star clusters”, pp. 1-9, 2021. https://arxiv.org/abs/2105.03450
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This image, the last one taken by the spacecraft, shows crescent Bennu with its night side merging with the complete black of space as the spacecraft pushed away from Bennu.
For two years, OSIRIS-REx studied the asteroid, revealing the many secrets of this ancient body and delivering clues about its rubble-pile-like consistency and surface terrain, which turned out to be much rockier and more rugged than initially expected from the observations of ground-based telescope.
On May 10, 2021, the spacecraft embarked on its return voyage to Earth. On Sept. 24, 2023, the spacecraft will jettison the sealed capsule containing the sample and send it onto a trajectory to touch down in the Utah desert.
Image Credits: NASA/Goddard/University of Arizona; Writer Daniel Stolte, University of Arizona
Spacewalking is a major highlight of any astronaut’s career. But there is a downside: putting on your spacesuit means sharing some previously-worn underlayers. A new ESA study is looking into how best to keep these items clean and hygienic as humans venture on to the Moon and beyond.
During the Space Shuttle era, each astronaut was issued with their own ‘External Mobility Unit’, the official term for a spacesuit. But crews aboard the International Space Station have shifted to sharing suits, with differently sized segments put together to fit a given spacewalker.
The first item spacewalkers put on is a (disposable) ‘Maximum Absorbency Garment’ diaper, then their own ‘Thermal Comfort Undergarment’, followed by the long-underwear-like Liquid Cooling and Ventilation Garment (LCVG). Worn next to the skin, the LCVG incorporates liquid cooling tubes and gas ventilation to keep its wearer cool and comfortable during the sustained physical exertion of work in hard vacuum.
But the LCVG is reused by different spacewalkers along with the spacesuits themselves. Such reuse is expected to grow once crews are established aboard the Gateway later this decade, a new international space station in lunar orbit.
With such long-term sharing in mind, ESA has commenced a new project called ‘Biocidal Advanced Coating Technology for Reducing Microbial Activity’, or BACTeRMA for short.
“Spaceflight textiles, especially when subject to biological contamination – for example, spacesuit underwear – may pose both engineering and medical risks during long duration flights,” explains ESA material engineer Malgorzata Holynska.
ESA life support specialist Christophe Lasseur adds: “Hygiene is always a concern aboard the International Space Station. Astronauts wear their clothes on alternating days then eventually they are disposed of – burnt up inside reentering spacecraft. But there are some items and surfaces which have to be shared.”
The standard method of preventing biological contamination is the use of antimicrobial materials such as silver or copper, whose ions in the presence of oxygen or water disrupt the normal working of microbial physiology.
“The problem is that their long-term use can provoke skin irritation, while the metals themselves may tarnish over time,” explains Seda Özdemir-Fritz Bacterma project scientistof the Austrian Space Forum (Österreichisches Weltraum Forum /OeWF), the project’s prime contractor.
“To provide an alternative, we are collaborating with the Vienna Textile Lab. They have exclusive access to a unique bacteriographic collection. Those microorganisms produce so-called secondary metabolites. These compounds are typically colourful, and some exhibit versatile properties: antimicrobial, antiviral and antifungal.
“It might sound counterintuitive to get rid of microbes using the products of microbes, but all kinds of organisms use secondary metabolites to protect themselves from an extreme environmental conditions . The project will examine them as an innovative antimicrobial textile finish.”
The project will develop, and test further innovative textile finishes with antimicrobial properties. The Austrian Space Forum together with Vienna Textile Lab will test processed textiles for their antimicrobial properties and will expose them to perspiration and radiation. Simulated lunar dust will also be added to the mix, because the expectation is that the astronauts’ working environment may become dusty after repeated trips to the surface of the Moon or Mars.
“Radiation testing will simulate prolonged storage in the deep space environment,” adds Malgorzata. “Radiation is known to age and degrade textiles in complex ways.”
The idea for the two-year BACTeRMA project was proposed by OeWF in cooperation with the Vienna Textile Lab as subcontractor, through ESA’s Open Space Innovation Platform, seeking out promising ideas for space research from any source.
OeWF is a space research organisation: different experts across various science domains come together in the OeWF to work on space topics, with a special focus on spacesuit technology.
“Christopher Columbus needed ship builders to make his journey happen, and that’s the kind of contribution we in the OeWF hope to make,” says Seda Özdemir-Fritz. “We’re interested in the human factors involved in future Moon Mars missions, so we perform ‘analogue astronaut’ simulations and analysis.”
Scientists at the Skolkovo Institute of Science and Technology (Skoltech) and their colleagues from the University of Graz & the Kanzelhöhe Observatory (Austria) and the ESA European Space Operations Centre developed a method and software called RESONANCE to predict the solar radio flux activity for 1-24 months ahead. RESONANCE will serve to improve the specification of satellite orbits, re-entry services, modeling of space debris evolution, and collision avoidance maneuvers. The research results werepublished in the high-profile Astrophysical Journal Supplement Series.
Since the launch of Sputnik, the Earth’s first artificial satellite, in 1957, more than 41,500 tons of manmade objects have been placed in orbit around the Sun, the Earth, and other planetary bodies. Since that time, the majority of objects, such as rocket bodies and large pieces of space debris, re-entered the Earth’s atmosphere in an uncontrolled way, posing a potential hazard to people and infrastructure. Predicting the re-entry date and time is a challenging task, as one needs to specify the density of the upper Earth atmosphere that strongly depends on solar activity which, in turn, is hard to predict. Earth atmosphere can become very heated due to solar activity which causes it to expand, and a satellite can decay in its orbit and fall back to the Earth due to the effect known as atmospheric drag. In addition, there is a lot of space debris, much of it very small; if a spacecraft unexpectedly changes its orbit and encounters even a small piece of debris, this would be equivalent to hitting a bomb because of the high speed.
Video: Europe’s space freighter Automated Transfer Vehicle Jules Verne burning up over an uninhabited area of the Pacific Ocean at the end of its mission. Credit: ESA.
An international group of scientists led by Skoltech professor Tatiana Podladchikova developed a new method and software called RESONANCE (“Radio Emissions from the Sun: ONline ANalytical Computer-aided Estimator”) which provides predictions of the solar radio flux at F10.7 and F30 cm with a lead time of 1 to 24 months. The F10.7 and F30 indices represent the flux density of solar radio emissions at a wavelength of 10.7 and 30 cm averaged over an hour and serve as a solar proxy of the ultraviolet solar emission which heats the Earth’s upper atmosphere. The method combines state-of-art physics-based models and advanced data assimilation methods, where the resulting F10.7 and F30 forecasts are used as solar input in the re-entry prediction tool for further estimation of an object re-entry time.
“We systematically evaluated the performance of RESONANCE in providing re-entry predictions on past ESA re-entry campaigns for 602 payloads and rocket bodies as well as 2,344 objects of space debris that re-entered from 2006 to 2019 over the full 11-year solar cycle. The test results demonstrated that the predictions obtained by RESONANCE in general also lead to improvements in the forecasts of re-entry epochs and can thus be recommended as a new operational service for re-entry predictions and other space weather applications,” says lead author and Skoltech’s MSc graduate Elena Petrova who is currently pursuing her Ph.D. studies at the Centre for Mathematical Plasma Astrophysics, Catholic University of Leuven (KU Leuven).
“The number of re-entered objects is closely related to the solar activity level: the majority of objects return during the maximum solar activity phase within the 11-year cycle. Interestingly, the space debris re-entry time closely follows the evolution of the cycle, reacting immediately to changes in solar activity. At the same time, payloads and rocket bodies also show a large number of re-entries during the declining phase of the cycle, which may be related to the time delay between solar activity and re-entry for large objects”, says professor Astrid Veronig, a co-author of the study and director of Kanzelhöhe Observatory at the University of Graz.
“It is very important to monitor and predict solar activity for orbit prediction needs. For example, Skylab which was intended to perform a controlled re-entry in the 1970s dropped on Earth in an uncontrolled way due to inaccurate calculations of the atmospheric drag due to solar activity. Another example is the most recent launch of the Chinese Long March 5B rocket on May 9, 2021: the remnants from its second stage that carried China’s first space station module made an uncontrolled re-entry and landed in the Indian Ocean. Thus the development of robust and reliable space weather operational services bringing together the forefront of research with engineering applications is of prime importance for the protection of space and ground-based infrastructures and advancement of space exploration. And whatever storms may rage, we wish everyone a good weather in space,” says Tatiana Podladchikova, assistant professor at the Skoltech Space Center (SSC) and a research co-author.
Currently, the team is preparing RESONANCE for operational use as part of a new space weather service for continuous prediction of solar radio flux activity.
Featured image: A piece of a re-entering space object found in Indonesia. The sphere measures about 50 cm in diameter and weighs 7.4 kg. Credit: ESA
Reference: Elena Petrova et al. Medium-term Predictions of F10.7 and F30 cm Solar Radio Flux with the Adaptive Kalman Filter, The Astrophysical Journal Supplement Series (2021). DOI: 10.3847/1538-4365/abef6d
Since the discovery of Alzheimer’s disease over a century ago, two hallmarks of the devastating illness have taken center stage.
The first, known as amyloid plaques, are dense accumulations of misfolded amyloid protein, occurring in the spaces between nerve cells. Most efforts to halt the advance of Alzheimer’s disease have targeted amyloid protein plaques. To date, all have met dispiriting failure.
The second classic trait has, until recently, received less scrutiny. It consists of string-like formations within the bodies of neurons, produced by another crucial protein— tau. These are known as neurofibrillary tangles.
In a new study, researchers with the ASU-Banner Neurodegenerative Disease Center at the Biodesign Institute and their colleagues investigate these tangles in the brain — pathologies not only characteristic of Alzheimer’s but other neurodegenerative conditions as well.
The research homes in on a particular protein known as Rbbp7, whose dysregulation appears linked to the eventual formation of tau protein tangles and the rampant cell death associated with Alzheimer’s and other neurodegenerative diseases.
“We had a hunch that this protein was involved in Alzheimer’s disease, particularly because we know that the protein was decreased in Alzheimer’s disease post-mortem brain tissue when compared with normal brains,” says Nikhil Dave, lead author of the new study.
The research shows a correlation between decreased Rbbp7 levels and increased tangle formation and associated neuronal loss and brain weight reduction in Alzheimer’s diseased brains. Intriguingly, cell loss and tangle formation were reversed in transgenic mice whose levels of Rbbp7 were restored to baseline levels.
The findings open a new avenue of research that could aid in the development of effective treatments for Alzheimer’s disease along with a broad range of tau-related afflictions, collectively known as tauopathies, including Pick’s disease, frontotemporal dementia and traumatic brain injury.
Alzheimer’s disease remains one of the most enigmatic illnesses known to medical science. Its clinical symptoms stealthily appear over a period of years and can be masked by the normal processes of aging. Once it has taken command of the brain however, the advance of the disease is often swift and merciless.
Patients may experience a bewildering range of symptoms including confusion, physical disorientation, delusions, forgetfulness, aggression, agitation, and progressive loss of motor control.
Researchers now know that by the time the first outward appearances of the disease become apparent, Alzheimer’s disease has been silently ravaging the brain for decades, typically leaving its calling card in the form of plaques and tangles.
Alzheimer’s disease remains the leading cause of dementia, with advancing age being the primary risk factor. The disease has been on a frightening upward trajectory, as life expectancy increases and other once-deadly illnesses have become treatable, if not curable. Currently, 5.8 million people in the United States alone suffer from Alzheimer’s disease, with the number expected to swell to 14 million by 2060, according to the Centers for Disease Research.
Many other factors apart from advancing age play a role in this complex disorder, from hereditary predisposition to vascular afflictions such as diabetes and obesity. Lifestyle choices, including diet and exercise, can also affect vulnerability. The disease typically afflicts those over 65, though early onset versions of the disorder can strike much sooner.
The new study examines another area of risk for neurodegenerative illness, one bearing on an individual’s genes and how they are expressed. Although the three billion letter DNA code making up an individual’s genome remains fixed throughout life, researchers now know that chemical messengers of great variety and complexity can act on the genome, delivering instructions to the DNA and guiding its behavior.
These epigenetic changes as they are known can turn genes on and off or regulate the amount of protein these genes produce. Earlier notions in biology emphasizing a static view of genomic destinies have given way to a new picture of life in which environmental changes can profoundly affect the way our genes behave. Scientists are just beginning to learn the far-reaching influence of the epigenome on human health and disease.
The current research describes epigenetic changes that take place in the brain when the level of the protein Rbbp7 is reduced, something the researchers detected in post-mortem brain tissue from Alzheimer’s patients.
One function of Rbbp7 is to regulate gene expression. It does this by altering the interaction of DNA with proteins known as histones, which DNA wraps around like sewing thread around a spool. When the DNA thread is loosely wrapped around the histone spool, the cell machinery can read the exposed DNA message and transcribe it into mRNA, which is then translated into protein. If the DNA thread is tightly wrapped around the histone however, the DNA genes are hidden from view and transcription maybe partially or entirely blocked, thereby reducing or disabling protein expression.
The researchers observed that when Rbbp7 levels are reduced, the level of another protein known as p300 increases, causing a post-translational modification of tau protein, known as acetylation. The effect of this is to cause tau protein to detach from cell structures known as microtubules, which tau typically binds with. The detached tau is then free to accumulate within neurons, eventually forming the telltale tangles associated with Alzheimer’s disease. (See accompanying graphic.)
The acetylation of tau caused by low Rbbp7 results in increased phosphorylation of tau, further promoting tangle formation and subsequent neuronal loss in the brain.
In the new study, transgenic mice displaying tau pathology showed decreased levels of Rbbp7 and increased neuronal loss. Restoring Rbbp7 to normal levels in the mice reversed these pathologies, though the cognitive deficits remained.
Ramon Velazquez, corresponding senior author of the new study, speculates that the reason for this is that the study targeted only a small subregion of the hippocampus, while other brain areas associated with cognition were still rampant with tangle formation. “We plan to look at the global effect of overexpressing Rbbp7 in our future research to see if we can rescue learning, memory and other facets of cognition.”
Light at the end of the tunnel?
The associations outlined in the study between Rbbp7 levels and the formation of tau tangles, cell death and loss of cognitive function in the brain are compelling. The results suggest that Rbbp7 may be an attractive target for drug discovery and the development of effective therapies for Alzheimer’s disease and other tau-associated afflictions. Treatments based on studies of this kind could be ready for clinical trials within the next five years.
Nevertheless, the authors stress that other molecular players are likely involved in these complex processes. In future studies, the researchers plan to perform extensive, unbiased probing of protein interactions, transcription pathways from DNA to mRNA and the epigenetic modifications that can lead to neurodegenerative disease.
Reference: Dave, N., Vural, A.S., Piras, I.S. et al. Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer’s disease and related tauopathies. Acta Neuropathol (2021). https://doi.org/10.1007/s00401-021-02323-1
Low-cost biosensor test developed by Penn Medicine could extend reliable COVID-19 testing to remote and disadvantaged areas
A low-cost, rapid diagnostic test for COVID-19 developed by Penn Medicine provides COVID-19 results within four minutes with 90 percent accuracy. A paper published this week in Matterdetails the fast and inexpensive diagnostic test, called RAPID 1.0 (Real-time Accurate Portable Impedimetric Detection prototype 1.0). Compared to existing methods for COVID-19 detection, RAPID is inexpensive and highly scalable, allowing the production of millions of units per week.
Despite the urgency of the pandemic, most available methods for COVID-19 testing use RT-PCR—reverse transcription polymerase chain reaction—to detect SARS-CoV-2. Though effective, the technique requires large laboratory space and trained workers to employ. These tests are also costly, they run a risk of cross-contamination, and can take hours or days to provide results.
RAPID was developed by a team led by César de la Fuente, PhD, a Presidential Assistant Professor in Psychiatry, Microbiology, Chemical and Biomolecular Engineering, and Bioengineering, to quickly and accurately detect the virus while remaining cheap enough to be widely accessible. An electrode printed using a screen printer—thousands of which can be printed in a day at very low cost—can detect the virus in nasal swab or saliva samples. The results can be read on a benchtop instrument or on a smartphone.
“Prior to the pandemic, our lab was working on diagnostics for bacterial infections. But then, COVID-19 hit. We felt a responsibility to use our expertise to help—and the diagnostic space was ripe for improvements,” de la Fuente said. “We feel strongly about the health inequities witnessed during the pandemic, with testing access and the vaccine rollout, for example. We believe inexpensive diagnostic tests like RAPID could help bridge some of those gaps.”
The RAPID technology uses electrochemical impedance spectroscopy (EIS), which transforms the binding event between the SARS-CoV-2 viral spike protein and its receptor in the human body, the protein ACE2 (which provides the entry point for the coronavirus to hook into and infect human cells), into an electrical signal that clinicians and technicians can detect. That signal allows the test to discriminate between infected and healthy human samples. The signal can be read through a desktop instrument or a smartphone.
The team assessed the performance of RAPID using both COVID-19 positive and negative clinical samples from the Hospital of the University of Pennsylvania, including samples of the highly contagious UK B117 variant. In blinded tests, they analyzed 139 nasal swab samples—109 of which were COVID-19 positive and 30 COVID-19 negative, as determined by standard RT-PCR clinical assessments. The team also analyzed 50 saliva samples from patients. For the nasal swab samples, RAPID was 87.1 percent accurate. For saliva samples, RAPID was 90 percent accurate.
RAPID provides results in four minutes, which is faster than most methods currently available for diagnosing COVID-19. For example, serological tests can take around 15 to 20 minutes, and they are about 60 to 70 percent accurate. In addition, RAPID is able to detect COVID-19 at extremely low concentrations (1.16 PFU mL), which corresponds to a viral load that correlates with the initial stages of COVID-19 (about two to three days after onset of symptoms). This is beneficial for detecting individuals at the earliest stages of infection, allowing for rapid care and the potential decrease of further viral spread.
“Quick and reliable tests like RAPID allow for high-frequency testing, which can help identify asymptomatic individuals who, once they learn they are infected, will stay home and decrease spread. We envision this type of test being able to be used at high-populated locations such as schools, airports, stadiums, companies—or even in one’s own home,” said first author Marcelo Der Torossian Torres, PhD, a postdoctoral researcher at Penn.
Importantly, the technology is affordable and scalable. Each test, which can be performed at room temperature, costs $4.67 to produce. Additionally, the electrodes used in the test can be quickly mass-produced using commercially available screen-printers to print the circuit board (named eChip). One laboratory-sized unit is able to produce 35,000 electrodes daily (about 1.05 million per month).
The team also constructed an electrode for RAPID composed of filter paper, which is a more accessible and inexpensive material. Named ePAD, the researchers demonstrated the applicability of ePAD for RAPID in a portable method, connected to a smart device, which may enable further scale and on-demand testing capabilities at the point-of-care.
“Having low-cost tests which are quick and easy to read extends testing to not only people who can afford it, but to remote or disadvantaged areas,” de la Fuente said.
De la Fuente lab’s research focuses primarily on developing technologies that help understand, prevent, and treat infectious diseases. Though RAPID was developed as a COVID-19 test, the technology can be used to detect other viruses and diagnose a variety of diseases such as the flu or sexually transmitted diseases.
The research was supported by the Nemirovsky Prize, the Dean’s Innovation Fund from the Perelman School of Medicine at the University of Pennsylvania, Brazil’s Coordination for the Improvement of Higher Education Personnel (88887.479793/2020-00), São Paulo Research Foundation (2018/08782-1), FAEPEX/PRP/UNICAMP (3374/19), and Brazil’s National Council for Scientific and Technological Development (438828/2018-6, 401256/2020-0). A provisional patent application has been filed on the technology described in this manuscript (Invention Disclosure 21-9515).
Study further supports targeting lipid kinases as potential therapy for cancer
Scientists at Sanford Burnham Prebys Medical Discovery Institute have taken a deep dive into a previously overlooked family of proteins and discovered that they are essential to maintaining the energy that cells need to grow and survive. The proteins, known as lipid kinases, produce messengers that help balance cellular metabolism and promote overall health. The findings, published in Developmental Cell, provide further support to pursue lipid kinases as promising therapeutic targets for diseases that demand excess energy, such as cancer.
“Cancer cells are hungry—they grow faster than most cell types and need energy to support their aggressive attempts to metastasize,” says Brooke Emerling, Ph.D., assistant professor in the Cell and Molecular Biology of Cancer Program at Sanford Burnham Prebys and corresponding author of the study. “Our study is one of the first to look at how PI5P4Ks—lipid kinases with known links to sarcomas and certain types of breast cancer—facilitate communications within the cell and maintain an energy balance to support cell growth.”
For years scientists have tried to halt cancer by blocking nutrients from reaching tumor cells. But these attempts have been disappointing because cancer cells are tricky and create back up routes to source food to sustain their growth. Emerling’s approach is to find and attack metabolic vulnerabilities within cells, which would deprive them of energy even in an abundance of nutrients and special tactics.
Using a combination of cell lines, imaging technology and mouse tumor models, Emerling’s team revealed that PI5P4Ks produce an active messenger that coordinates communications between peroxisomes and mitochondria—two organelles intimately involved in making and using fuel to support cellular growth. In the absence of the messenger, the interplay between the organelles breaks down, mitochondria become overworked, and cells starve and die.
“Mitochondria are the powerhouses of the cell, says Archna Ravi, Ph.D., a postdoctoral researcher in Emerling’s lab and first author of the paper. “They play an essential role in generatin energy to drive cellular function and basically all biological processes. This research supports targeting PI5P4Ks as a cancer treatment strategy because it would deprive tumors of the one thing they can’t live without: energy.”
Emerling’s team previously discovered the essential role of PI5P4K in tumor formation. The new study indicates a role for PI5P4Ks not only in tumor establishment, but for the first time in tumor maintenance.
“We use sarcomas as a tumor model because PI5P4Ks are highly expressed in high grade sarcomas, and their expression correlates with patient survival,” says Emerling. “Sarcomas are a rare group of cancers that affect the body’s connective tissues, and about half of all cases can be cured, but for the other half, better therapies are desperately needed.”
Targeting PI5P4K may also be valuable for other tumor types that have developed profound metabolic alterations to source nutrients, such as triple negative breast cancer. Like sarcomas, triple negative breast cancer therapies remain woefully inadequate.
“Our goal is to develop drugs in the near future that inhibit PI5P4K and test the drugs in mice. If successful, we hope to advance to human clinical trials. I think the future for our research is very bright now,” concludes Emerling.
Additional study authors include Lavinia Palamiuc, Ryan M. Loughran, Gurpreet K. Arora and Vivian Tieu at Sanford Burnham Prebys; Joanna Triscott, Matthias Reist and Mark A. Rubin at the University of Bern, Switzerland; Avi Kumar and Christian Metallo at UCSD, La Jolla, CA; Chantal Pauli at University Hospital Zürich and the University of Zurich; Rachel J. Lew at the Gladstone Institutes, San Francisco; Shauna L. Houlihan at Memorial Sloan Kettering Cancer Center, New York; and Christof Fellmann at UCSF, San Francisco.
Research reported in this press release was supported by grants from DOD (W81XWH-14-10440), NCI (R01 CA237536), and ACS (RSG-20-064-01-TBE) to Brooke Emerling, MSCA (797949) to Joanna Triscott, NIGMS (R00GM118909) to Christof Fellmann, SNSF (31003A_175609) to Mark A. Rubin, and Weill Cornell Medicine Englander Institute for Precision Medicine.
Chantal Pauli is a scientific adviser for SEngine Precision Medicine and is currently a study pathologist for the CUPISCO trial, which is sponsored by Roche. Pauli receives reimbursement for study-related travels and remuneration for her work as a study pathologist for the benefit of her employer. Christof Fellmann is a co-founder of Mirimus.
The acidity of the atmosphere is increasingly determined by carbon dioxide and organic acids such as formic acid. The second of these contribute to the formation of aerosol particles as a precursor of raindrops and therefore impact the growth of clouds and pH of rainwater. In previous atmospheric chemistry models of acid formation, formic acid tended to play a small role. The chemical processes behind its formation were not well understood. An international team of researchers under the aegis of Forschungszentrum Jülich has now succeeded in filling this gap and deciphering the dominant mechanism in the formation of formic acid. This makes it possible to further refine atmosphere and climate models. The results of the study have now been published in the peer-reviewed journal Nature.
In Germany, we are familiar with acid rain, particularly from our experience in the 1980s. The cause of it was that nitrogen oxides and sulfur oxides released into the atmosphere by human beings reacted with the water droplets in the clouds to form sulfuric acid and nitric acid. Acid rain has a pH of about 4.2-4.8, lower than that of pure rainwater (5.5-5.7), which results from the natural carbon dioxide content of the atmosphere.
However, the chemical process that forms the bulk of the formic acid present in the atmosphere was unknown up to now. Dr. Bruno Franco and Dr. Domenico Taraborrelli from Jülich’s Institute of Energy and Climate Research – Troposphere have now deciphered it: Formaldehyde is formed naturally by photo-oxidation of volatile organic compounds. Formaldehyde reacts in cloud droplets with water molecules to form methanediol. The majority of this is outgassed and reacts with OH radicals, sometimes called the “detergent of the atmosphere”, in a photochemical process to form formic acid. A smaller portion reacts with the liquid phase of the water droplets to also form formic acid that is spread by rain.
“According to our calculations, the oxidation of methanediol in the gas phase produces up to four times as much formic acid as what is produced in other known chemical processes in the atmosphere,” says Domenico Taraborrelli. This amount reduces the pH of clouds and rainwater by up to 0.3, which highlights the contribution of organic carbon to the natural acidity in the atmosphere.
As a first step, the two scientists tested their theory using MESSy, a global atmospheric chemistry model, and compared the results with remote sensing data. To carry out the modelling, they used the Jülich supercomputer JURECA. Subsequent experiments in Jülich’s SAPHIR atmosphere simulation chamber confirmed the results. “We assume that the mechanism demonstrated is also active in aqueous aerosols and applies to other organic acids such as oxalic acid, which are not adequately accounted for in atmospheric chemistry models to date,” says Taraborrelli. One of the effects of this could be an improved understanding of the growth of aerosol particles and the development of clouds.
Melanocytic nevi, or moles, are nonmalignant growths that arise from pigment producing cells of the skin. They are mostly found in sun-exposed areas; however, they also can be found in sun-protected areas, such as the palms, soles of feet and nail beds, where they are known as acral nevi. While the mutation profile of nevi in sun-exposed areas is well understood, less is known about the genes that are commonly mutated in acral nevi. And while a subset of melanoma of sun-exposed skin arises in nevi, the link between nevi and melanoma in acral skin is poorly understood. In a new study published in JAMA Dermatology, Moffitt Cancer Center researchers report on the mutation profile of acral nevi and describe differences between acral nevi and acral melanoma.
Melanoma is one of the most common types of cancer, with an estimated 100,000 new cases diagnosed in 2020 in the United States. Acral melanoma is a subtype on nonsun-exposed areas of the skin and is not linked to ultraviolet radiation exposure. Despite both conditions being derived from pigment-producing melanocytes, melanoma and acral melanoma differ in several ways. Patients with acral melanoma tend to have a poorer response to treatment and a higher mortality rate than patients with typical melanoma. Additionally, the two types of melanoma differ in their mutation profile.
Approximately 30% of malignant melanoma are derived from nonmalignant melanocytic nevi. One of the most common genetic alterations in melanocytic nevi, as well as melanoma, are mutations in the BRAF gene.
To determine if there is a genetic link between acral nevi and acral melanoma, Moffitt researchers performed a genetic analysis on 50 acral nevi from 49 patients – 19 males and 30 females. They discovered that unlike acral melanoma, activating mutations in the BRAF gene were very common in the nevi, with 86% of patients having a mutation in the BRAF gene. Additionally, 10% of the patients had activating mutations in the NRAS gene, which were mutually exclusive from BRAF mutations.
These observations demonstrate that acral nevi and acral melanoma have different mutation patterns. “Acral nevi demonstrated a mutational spectrum very similar to that of nevi on sun-exposed skin, suggesting that acral nevi are unlikely to be the precursor lesion for the majority of acral melanomas,” said Keiran Smalley, Ph.D., study author and director of Moffitt’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence. “We hope our findings will lead to a better understanding of how acral melanoma develops.”
“This is the largest series of acral nevi that have been sequenced to date, and the results were surprising to me,” said Jane Messina, M.D., senior study author and senior member in the Department of Cutaneous Oncology. “Additionally, most of our patients were white/European in origin, while previous studies were mostly performed in Asian populations where there is a much higher frequency of acral nevi. The frequent presence of a mutation with a strong link to sun exposure suggests that even acral skin may be subject to the ravages of the sun.”
This study was supported by the Melanoma Research Alliance and National Cancer Institute (P30-CA076292).
Reference: Keiran S. M. Smalley, Jamie K. Teer, Y. Ann Chen, Jheng-Yu Wu, Jiqiang Yao, John M. Koomen, Wei-Shen Chen, Paul Rodriguez-Waitkus, Florian A. Karreth, Jane L. Messina, “A Mutational Survey of Acral Nevi”, JAMA Dermatol. Published online May 12, 2021. doi:10.1001/jamadermatol.2021.0793