It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Monday, September 09, 2024
Study reveals new female-determining pathway in turtles
The signaling pathways leading to female development are not well known in many animal species, probably because development of embryos into females was traditionally considered the default developmental pathway.
Recently, in a study published in Proceedings of the National Academy of Sciences (PNAS), a research group led by Prof. DU Weiguo from the Institute of Zoology of the Chinese Academy of Sciences revealed that the transcription factor pSTAT3 initiates the female pathway in temperature-dependent sex determination.
The research group studied the molecular mechanisms of sex determination in the red-eared slider turtle, a species with temperature-dependent sex determination (TSD). In this species, embryos develop into males if incubated at 26 °C or into females if incubated at 31 °C.
Researchers found that the expression level of the transcription factor pSTAT3 and the sex-determining gene FoxI2 were temperature-dependent and differed between the sexes.
Their study revealed that inhibition and activation of pSTAT3 led to female-to-male or male-to-female sex reversal in embryos at the female-producing temperature of 31 °C or male-producing temperature of 26 °C, respectively.
Nonetheless, the sex reversal of these embryos could be rescued by knocking down or overexpressing FoxI2, respectively.
Researchers discovered that pSTAT3 directly binds to the promoter locus of FoxI2 and thereby initiates the female pathway.
“This is the first time that we have established a direct genetic link between warm-temperature-induced STAT3 phosphorylation and female pathway initiation in a TSD system,” said first author Dr. WU Pengfei.
More importantly, these findings provide a mechanistic explanation of sex determination in fluctuating temperatures, revealing that it results from antagonism between male and female signals, with the female outcome not being the default.
pSTAT3 activation of Foxl2 initiates the female pathway underlying temperature-dependent sex determination
Article Publication Date
3-Sep-2024
One antibody to neutralize them all?
Antibody developed in part by Associate Professor Greg Ippolito, Ph.D., works against a wide range of COVID-19 variants and related coronaviruses, including past, present and potentially future strains
Like two hands working together to form a tight grip, monoclonal antibody SC27 attaches to the SARS-CoV-2 spike protein (purple) using both of its binding domains (orange and yellow). This may explain, in part, the exquisite potency of SC27 and its ability to protect against all tested COVID-19 variants.
SAN ANTONIO -- A monoclonal antibody appears effective at neutralizing the numerous variants of SARS-CoV-2, as well as related viruses in animals that could pose a threat if they were to begin spreading in people. The antibody, called SC27, was recently described in Cell Reports Medicine.
The finding opens the possibility of broader, more effective treatments to work against current and future COVID variants.
Monoclonal antibody SC27 was identified, developed and provisionally patented by a team of researchers led by Greg Ippolito, Ph.D., who recently joined Texas Biomedical Research Institute (Texas Biomed) from University of Texas at Austin. Other team leaders included Jason Lavinder, Ph.D., at UT and Ralph Baric, Ph.D., at University of North Carolina at Chapel Hill.
“Other COVID-19 antibodies have been rendered ineffective as SARS-CoV-2 has evolved over the past several years,” says Dr. Ippolito, an Associate Professor. “Our new study suggests the virus is less likely to escape this treatment because SC27 targets and attaches to multiple parts of the virus’s spike protein, including sections that are not mutating as frequently.”
SC27 appears to work in two ways: it blocks the ACE2 binding site, which the virus uses to bind to, enter and infect cells. It also binds to a hidden or “cryptic” site on the underside of the spike protein that is largely unchanged or “conserved” between variants, which means SC27 can broadly recognize variants and related viruses. This is critical because if an antibody’s shape does not match enough with a virus – like two puzzle pieces that don’t quite fit – the antibody can’t effectively neutralize the virus and the virus sneaks by the body’s immune defense system.
The researchers tested SC27 against 12 viruses, from the original SARS-CoV-2 to currently circulating variants, as well as related SARS-1 and several other coronaviruses found in bats and pangolins. The antibody was effective against all of them in a petri dish and protected mice against both variants tested.
“This makes it broader and more effective than any other monoclonal antibody reported in scientific literature to date and the former FDA-approved cocktails,” says Dr. Ippolito, adding the caveat that SC27 still needs to be tested in human clinical trials.
The team is looking to collaborate with industry to further develop the SC27 monoclonal antibody treatment, which could potentially benefit immunocompromised patients who are unable to get vaccines. It also could serve as an emergency treatment during future outbreaks of new variants or coronaviruses. Next steps would include preclinical studies in larger animal models, including nonhuman primates, which are the gold standard to evaluate how complete immune systems respond to a treatment before safely moving to human clinical trials.
Notably, SC27 was found in individuals following vaccination with mRNA COVID-19 vaccines. Previously, this type of “class 1/4” antibody – which attaches to two distinct areas or “epitopes” of the spike protein – was only detected following natural infection from SARS-1.
“This is fantastic news that vaccines can prompt the generation of these more robust and effective antibodies,” explains Dr. Ippolito. “It means that future vaccine development can be tailored to generate these antibodies and have a clear metric for measuring which vaccines will be most effective.”
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About Texas Biomed
Texas Biomed is a nonprofit research institute dedicated to protecting the global community from infectious diseases. Through basic research, preclinical testing and applied innovation, we accelerate diagnostics, therapies and vaccines for the world’s deadliest pathogens. Our San Antonio campus hosts high containment laboratories and the Southwest National Primate Research Center. Our scientists collaborate with industry and researchers globally, and have helped deliver the first COVID-19 vaccine, the first Ebola treatment and first Hepatitis C therapy. For more information, visit txbiomed.org.
Deep-sea Bathymodiolus mussels are found worldwide at hydrothermal vents and cold seeps. The mussels live in symbiosis with beneficial bacteria that provide them with nutrition. The mussels also have a pathogenic bacterium that infects their nuclei. Intriguingly, the only cells not infected by the pathogen are those with symbiotic bacteria.
Most animals live in intimate relationships with bacteria. Some of these bacteria live inside the cells of their hosts, but only very few are able to live inside cell organelles (structures inside the cell, like organs in the body). One group of bacteria have figured out how to colonize the nuclei of their hosts, a remarkable feat given that the nucleus is the control center of the cell.
To date, nothing is known about the molecular and cellular processes that these intranuclear bacteria use to infect and reproduce in animal hosts. A group of scientists from the Max Planck Institute for Marine Microbiology in Bremen, Germany, now presents the first in-depth analysis of an intranuclear parasite of animals in a study published in Nature Microbiology.
How to massively reproduce within a cell without killing it
This intranuclear parasite, Candidatus Endonucleobacter, infects the nuclei of deep-sea mussels from hydrothermal vents and cold seeps around the world. A single bacterial cell penetrates into the mussels' nucleus and then reproduces to over 80,000 cells, causing the nucleus to swell to 50 times its original size. “We wanted to understand how the bacterium infects and reproduces inside nuclei, and in particular how these bacteria acquire the nutrients they need for their massive replication, yet keep their host cells from dying,“ says Niko Leisch, co-senior author together with Nicole Dubilier from the Symbiosis Department at the Max Planck Institute for Marine Microbiology.
Using a suite of molecular and imaging methods, the scientists revealed that Ca. Endonucleobacter lives on sugars, lipids and other cell components from its host. It does not digest its host nucleic acids, like many other intranuclear bacteria. This feeding strategy ensures that the host cell functions long enough to provide Ca. Endonucleobacter with the nutrients it needs to reproduce to such massive numbers.
Arms race for the control of the cell
A common response of animal cells to infection is apoptosis – a suicide program that cells initiate when they are damaged or infected by bacteria or viruses. “Interestingly, these bacteria have come up with a sophisticated strategy to keep their host cells from killing themselves,” says first author Miguel Ángel González Porras. “They produce proteins that suppress apoptosis called inhibitors of apoptosis (IAPs).” An arms race for the control of cell death then ensues: As the bacteria produce more and more IAPs, the host cell ramps up its production of proteins that induce apoptosis. Eventually, after the parasite has had enough time to multiply in masses, the host cell ruptures, releasing the bacteria and allowing them to infect new host cells.
Nicole Dubilier adds: “The discovery of IAPs in Ca. Endonucleobacter was one of the most surprising results of our study, because these proteins are only known from animals and a few viruses, but have never been found in bacteria.” The authors' analyses of the evolutionary relationships of the IAPs revealed that the parasite likely acquired these genes from its host through horizontal gene transfer (HGT). While HGT from bacteria to eukaryotes is well known, only very few examples of HGT in the opposite direction – as the authors now found – are known.
Implications from evolution to medicine
“Our discovery expands our understanding of host-microbe interactions and highlights the complex strategies parasites have evolved to thrive in their hosts”, explains Nicole Dubilier. These findings could have broader implications for studying parasitic infections and immune evasion strategies in other organisms. “Our research sheds light on an overlooked mechanism of genetic exchange — HGT from eukaryotes to bacteria — potentially influencing how we understand microbial evolution and pathogenesis. Moreover, our study offers insights into apoptosis regulation, which is relevant to cancer research and cell biology,” Niko Leisch concludes.
The bacteria under the microscope
Microscopy image (fluorescence in situ hybridization (FISH) confocal microscopy) of tissues from a deep-sea mussel showing the intranuclear parasite Ca. Endonucleobacter in yellow, and the beneficial symbiotic bacteria in green and red. Cell nuclei are stained blue. The right panel is a zoom-in of the white square in the left panel.
Credit
Miguel Angel Gonzalez-Porras/Max Planck Institute for Marine Microbiology
An intranuclear bacterial parasite of deep-sea mussels expresses apoptosis inhibitors acquired from its host
Article Publication Date
6-Sep-2024
The heat generated by the tissues of some plants has played a crucial role in the evolutionary history of insect pollination
A new study suggests that the ability of some plants to generate heat, known as thermogenesis, has played a key role in attracting pollinating insects for at least 200 million years
Spanish National Research Council (CSIC)
image:
Thermogenesis is present in plants such as 'Macrozamia communis', which raise the temperature of their reproductive organs when in bloom to attract pollinating insects.
Thermogenesis is a process by which organisms generate internal heat. Although it is usually associated with animals, some plants have also developed this ability. This metabolic process allows certain parts of the plant, such as flowers and inflorescences, to raise their temperature above that of the surrounding environment. Today, these plants, which include cycads and some angiosperms (flowering plants), rely on insects for pollination. The heat they generate helps volatilize and disperse floral fragrances and other chemical compounds that attract insects such as beetles, flies, and trips to the plants. Additionally, thermogenesis stabilizes the development of reproductive organs in cold climates and facilitates the growth of pollen tubes.
Evidence in the Fossil Record
Although thermogenesis cannot be directly preserved in the fossil record, scientists can infer its presence in ancient plants by studying anatomical structures similar to those of current thermogenic plants. A new study led by the Botanical Institute of Barcelona (IBB), a joint center of the Spanish National Research Council (CSIC) and the Consorci Museu Ciències Naturals de Barcelona, in collaboration with the Complutense University of Madrid and other institutions such as the Geological and Mining Institute of Spain (IGME–CSIC), the Smithsonian Institution, the University of Barcelona, and the Royal Botanic Gardens of Sydney, has examined the characteristics of present-day thermogenic plants and compared them with fossil plant lineages.
"Our findings suggest that thermogenesis in plants is an older phenomenon than previously thought," explains David Peris, a researcher at the IBB and the lead author of the study. "200 million years ago, the diversification of flowering plants had not yet occurred. Therefore, thermogenesis could have been a crucial factor in the evolutionary success of seed plants in general, and flowering plants in particular, as well as their pollinators."
A Discovery with Evolutionary Implications In thermogenic plants, female structures mature before male structures to avoid self-fertilization. This relates to the early divergence lines of angiosperms, which had floral chambers where the stamens and carpels closed independently. The presence of reproductive chambers in fossil plants that could have trapped pollinating insects also suggests that this feature existed in the past.
Large reproductive structures, such as perianths or cones, could also indicate thermogenesis, as they retain heat more effectively. This study has allowed scientists to identify which fossil plant lineages might have exhibited thermogenic activity, suggesting that thermogenesis has been present in seed plants for longer than previously thought.
The ability to generate heat may have given certain Mesozoic plants, more than 200 million years ago, a competitive advantage over non-thermogenic plants by attracting pollinating insects more efficiently, thus contributing to their reproductive success. This strategy for attracting pollinators could have preceded others, such as bright flower colours, and may have been influenced by past climatic changes. Moreover, thermogenesis is closely linked to the emission of fragrances, another crucial factor in attracting insects.
This study opens new lines for exploring how these interactions influenced the diversification of plants and their pollinators throughout evolutionary history. "Thermogenesis in plants is not just a botanical curiosity," notes Iván Pérez-Lorenzo, a researcher at the IBB and a participant in the study, "it is an important factor that has contributed to the success of the two most diverse groups of organisms today: insects and angiosperms, and it has key implications for understanding the evolution of pollination strategies."
A study led by the UAB Institut de Neurociències and published in the journal Nature Communications demonstrates in animal models how daily administration of cannabidiol (CBD), a substance obtained from the cannabis plant, extends lifespan and improves symptoms associated with Leigh syndrome. This severe mitochondrial disease affecting children is characterised by a progressive decline in cognitive and motor functions and premature death. The research group also demonstrated in both mice and fibroblasts from children with the disease that CBD improves cellular function.
Leigh syndrome is a rare mitochondrial disease particularly affecting the organs and tissues that require most energy: the muscles and nervous system. It is characterized by progressive neuromuscular decline and premature death, and there are currently no approved treatments. That is why it is urgent to find a solution for patients suffering from this disease.
Drs. Emma Puighermanal and Albert Quintana, researchers from the Laboratory of Mitochondrial Neuropathology of the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB), have spent years studying the disease. They seek to understand the processes causing dysfunction of mitochondria, organelles in charge of providing energy to cells, and to find therapies capable of reverting this.
In a study published in Nature Communications, researchers have now demonstrated that daily administration of CBD is a promising treatment option. Through its multiple action it provides antioxidant, anti-inflammatory and anticonvulsant effects, which improve the symptomatology and help recover cell functions in patients. The study was conducted with two different Leigh syndrome mouse models, as well as with fibroblast cells from patients.
The results revealed that CBD acts at many levels within the cell, including activating a protein inside the cell nucleus known as PPARγ. This protein regulates the expression of many genes involved in the immune response, oxidation and mitochondrial function, and has been seen to be altered by the disease. Moreover, CBD increases the expression of the metallothionein protein, which enhances its antioxidant response.
In the animal models, cannabidiol administration improved neuropathology in the affected brain regions, breathing abnormalities and social deficits, and also delayed motor decline and neurodegenerative signs. In addition, mice receiving treatment lived significantly longer than those with no treatment. In the fibroblast cells from patients, CBD improved their antioxidant processes.
"The benefits we observed, together with CBD’s safe and well-tolerated profile, show it to be a truly promising treatment for patients with Leigh syndrome", explains Dr. Albert Quintana, researcher at the INc-UAB and lecturer in the Department of Cellular Biology, Physiology and Immunology at the UAB.
One year ago, the researchers obtained an orphan drug designation for CBD by the European Medicines Agency, which entails many benefits such as a reduction in the costs of developing the drug. “CBD has already been approved by the US regulatory agency FDA for the treatment of other rare paediatric diseases. We hope all of this will help in the translation of our results to clinical practices”, concludes Dr. Emma Puighermanal, researcher at the INc-UAB and lead author of the article.
The research, conceived and coordinated by the INc-UAB, also included the collaboration of the Institute for Neuroscience of Alicante (UMH-CSIC), the Institute of Neurosciences of the University of Barcelona (UBneuro), the Neurocentre Magendie of France, and the company Minoryx Therapeutics.
Cannabidiol demonstrated to alleviate symptoms of Leigh syndrome
Cannabidiol ameliorates mitochondrial disease via PPARγ activation in preclinical models
Article Publication Date
5-Sep-2024
Cannabis laws and utilization of medications for the treatment of mental health disorders
JAMA Network
About The Study: This cross-sectional study of commercially insured patients suggests that there may have been meaningful heterogeneous associations between cannabis policy and state and between cannabis policy and drug class (e.g., decreases in dispensing of benzodiazepines but increases in dispensing of antidepressants and antipsychotics). This finding suggests additional clinical research is needed to understand the association between cannabis use and mental health. The results have implications for patient substance use and mental health–related outcomes.
Corresponding Author: To contact the corresponding author, Ashley C. Bradford, PhD, email bradford@gatech.edu.
Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.
About JAMA Network Open: JAMA Network Open is an online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.
Journal
JAMA Network Open
Being able to see inside a flow battery
Using neutrons, TU/e scientists visualize the internal processes of a redox flow battery
An international collaboration - between TU/e, the Massachusetts Institute of Technology (MIT), and the Paul Scherrer Institute in Switzerland (PSI) - led by TU/e researcher Antoni Forner-Cuenca, developed this new method using neutron imaging. The breakthrough provides extraordinary moving images (see video further down) that help understand redox flow batteries' inner workings.
Curiosity-driven research across disciplines
More importantly, the images provide inspiration and guidelines for new ideas and solutions. More directly, the method can aid the development of redox flow batteries, although the new imaging technique devised by Forner Cuenca's team may also help other scientific disciplines move forward. “Our method is the result of experimenting on and borrowing from different fields. It is an exciting example of the importance of curiosity-driven research across disciplines.”
Neutron radiography plays a crucial role in the research entitled 'Quantifying concentration distributions in redox flow batteries with neutron radiography'. Forner Cuenca learned a lot about this imaging technique during his PhD training, which started in 2013 at the PSI. Then, in 2017, he performed postdoctoral research at MIT, where he learned about redox flow batteries. That's when the light bulb went on in his head.
System remained a black box
“Inside the flow battery, there are moving fluids – the so-called electrolytes. An electrical current flows through the cell when the battery runs in charge or discharge. Consequently, ions and redox molecules in the electrolyte start to move in different directions, resulting in changes in the concentration of molecules. That movement determines the battery's performance and durability, but to date, the system has remained as a black box. The ability to look inside a working battery and visualize concentration distributions would enormously improve our understanding of the system.”
So, a key factor in how that battery works remained uncharted territory, which got Forner Cuenca thinking. “Our bodies are also mostly composed of fluids, namely water. X-rays pass through that and interact with heavier elements in your bones, allowing you to see them without cutting open a body. Neutrons work the opposite way: they pass through the battery casing materials easily but interact strongly with the molecules in the liquid electrolytes.”
A new application of existing science
“Using this fundamental property of neutrons interacting with certain molecules, we are using neutron radiography for the first time to look at concentrations of molecules in flow batteries.” A new application of existing science, in other words. “That technique itself is not new; it is already used by museums, for example, to see what historical objects are made of without damaging them. But now we can also use it to visualize moving fluids, as in redox flow batteries.”
The method used by Forner-Cuenca and his team is still much more laborious than X-ray photography, though, and similar to stop-motion animation. “To track in real time how the concentration of liquids changes in the battery, we continuously take pictures every 30 seconds of the collection of neutrons that travels through the battery. We piece those pictures together, so to speak, providing us with a video that shows how the concentration changes during battery operation.”
Measuring for 24 hours in 10 day shifts
These experiments were conducted at the neutron source of the PSI. A collaborative team of three PhD students was in charge of the experiments with Forner-Cuenca - Remy Jacquemond, Maxime van der Heijden, and Emre Boz, who are now successfully graduated doctors. Since the experiments were intense, the team measured for 24 hours in various shifts for around 10 days to maximize productivity.
“Having the opportunity to use neutrons is an extraordinary experience; we only get to use equipment like that once every two years, on average. The PSI (the Paul Scherrer Institute in Switzerland, where the experiments took place, ed.) has an annual international experiment competition ranked by importance. We have been privileged to perform four successful experiments.”
“In terms of effort and expertise, this project was challenging, and having three PhD students collaborating was essential for its success. I am very proud of these three colleagues, who worked hard and collaborated as a true team. It shows the strong value of working in teams, both in our research team and with international collaborators at PSI and MIT.”
Plenty of areas for improvement
According to Forner Cuenca, visualizing fluid action in Redox flow batteries is important for several reasons. “Of course, understanding processes occurring inside the battery means that we can develop better-performing systems that work more efficiently and have longer lifetimes. Therefore, since they are mainly used to store renewable energy from solar and wind, we hope to contribute to the energy transition.” There are still plenty of areas for improvement, as Forner Cuenca explained in this earlier article on our website.
However, as with any new technology, it also offers other possibilities in the future. “For example, chemical reactors are used to make all kinds of products such as plastics, cosmetics, and medicines. Since our method enables visualization of organic molecules in a solution, we anticipate that other industrial applications can benefit from our imaging technique.”
These new insights may, in turn, lead to completely different methods or ideas. “That's what excites me the most: fueling curiosity. After all, this is how we developed this new methodology. Collaborative research and curiosity-driven ideas are two critical elements of scientific discoveries. Supported by an ERC grant that embraces blue-sky projects, we were able to develop this method and we have many new ideas to pursue in the future.”
The TU/e team that was in charge of the experiments, with from left to right Emre Boz, Maxime van der Heijden, Remy Jacquemond and Antoni Forner Cuenca.
of the experiments that allowed Forner Cuenca's team to literally look inside the flow battery.
