Japanese, Italian, US Physicists Reveal New Measurements of High-energy Cosmic Rays (Planetary Science)

LSU researchers contribute to a discovery that adds a new wrinkle to our understanding of the origins of matter accelerated to high energies in the galaxy

New findings published this week in Physical Review Letters, Measurement of the Iron Spectrum in Cosmic Rays from 10 GeV/n to 2.0 TeV/n with the Calorimetric Electron Telescope on the International Space Station, suggest that cosmic ray nuclei of hydrogen, carbon and oxygen travel through the galaxy toward Earth in a similar way, but, surprisingly, that iron arrives at Earth differently.

A series of recent publications based on results from the CALorimetric Electron Telescope, or CALET, instrument on the International Space Station, or ISS, have cast new light on the abundance of high-energy cosmic ray nuclei — atoms stripped of their electrons moving through space at nearly the speed of light – that arrive at Earth from outside the Solar System.

“For many years, the standard model to explain the origin of high-energy cosmic rays, or HECR, has been based on the assumption that these particles are produced by nuclear reactions inside stars, accelerated to high energies by the turbulent shock waves in sources like supernovae, and then ejected into the interstellar medium and scattered by the magnetic fields they encounter as they propagate through the Galaxy to Earth,” said Michael Cherry, LSU Department of Physics & Astronomy professor emeritus and co-author on the new publication.

“The study of cosmic rays is the study of how the universe generates and distributes matter, and how that affects the evolution of the galaxy,” said John Krizmanic, senior scientist at the University of Maryland’s Center for Space Science and Technology, or CSST, and co-author.

Measurements of the HECR nuclear composition and precise energy spectra – the intensity of particles at each energy – provide a means to understand the sources of high-energy matter and how those cosmic ray nuclei propagate from their distant sources through the galaxy to Earth.

The new CALET results in the December 18, 2020 and June 18, 2021 issues of the journal Physical Review Letters confirm the previously observed flattening of the carbon and oxygen spectra in detail at energies around 200 billion electron volts or giga-electron volts, or GeV, per nucleon, but not for iron, and extend the earlier results to higher energies with improved statistics.

CALET has been collecting data about cosmic rays since 2015. The data include details such as how many and what kinds of particles are arriving, and how much energy they’re arriving with. The Japanese, Italian and American teams that manage CALET collaborated on the new research.

The current HECR measurements suggest that the particles travel well outside the disk of the Milky Way Galaxy and are confined in a diffuse halo extending well beyond the disk. Independent evidence of the halo can be obtained from observations of radio synchrotron emission of cosmic ray electrons and gamma rays produced by HECR interactions in the halo material. As a result, the diffusion of the HECR through the galaxy provides a measurement of the structure of the galaxy and how the particles propagate through the galaxy, in particular through observations of the abundances of individual HECR elements and their intensity vs. the particle energy, i.e. their energy spectra.

Iron on the move

CALET detects cosmic ray nuclei at energies from a few billion electron volts per nucleon to over 2 trillion electron volts per nucleon. The CALET instrument is one of extremely few in space that is able to deliver fine detail about the cosmic rays it detects. Graphs of the spectra for hydrogen, carbon and oxygen cosmic rays are very similar, showing a characteristic change in slope near 200 billion electron volts per nucleon. The key finding from the new paper is that the spectrum for iron is different, with no change in slope at that energy. Iron behaves differently from the lighter elements.

Interestingly, the CALET results agree well with the results from the earlier PAMELA and CREAM experiments as well as agree with the flattening of the curves reported by the AMS experiment and also on the space station — but differ from AMS in the absolute magnitudes of the fluxes measured. These results are also consistent with the results CALET published previously in Physical Review Letters in May 2019 on the measurement of the cosmic ray proton spectrum from 50 GeV to 10 trillion electron volts, or TeV. The similarity of the nature of the spectral breaks in the proton, carbon and oxygen spectra indicate a potential common source, but the cause of these changes in the nature of the spectra is not understood.

“There are several possibilities to explain the differences between iron and the three lighter elements. The cosmic rays could accelerate and travel through the Galaxy differently, although scientists generally believe they understand how cosmic rays propagate,” explains Krizmanic.

Scientists generally believe that exploding stars, or supernovae, are a primary source of high-energy cosmic rays, but neutron stars or very massive stars could be other potential sources.

“The new measurements may indicate that the sources of the hydrogen, carbon and oxygen may be different from the sources of the iron,” Cherry said.

Next-level precision

The largest cosmic ray detectors have been located on the ground or flown on balloons high in the atmosphere. But by the time cosmic rays reach those instruments, they have already interacted with Earth’s atmosphere and broken down into secondary particles. Identifying precisely how many primary cosmic rays are arriving, which elements and their energies requires observations from space. CALET, being on the ISS above the atmosphere, can measure the particles directly and distinguish individual elements precisely.

Iron is a particularly useful element to analyze, explains Nick Cannady, a postdoctoral researcher with CSST and NASA Goddard Space Flight Center and former PhD student at LSU. On their way to Earth, cosmic rays can break down into secondary particles, and it can be hard to distinguish between original particles ejected from a source, like a supernova, and secondary particles. That complicates deductions about where the particles originally came from.

“As things interact on their way to us, then you’ll get essentially conversions from one element to another,” Cannady said. “Iron is unique, in that being one of the heaviest things that can be synthesized in regular stellar evolution, we’re pretty certain that it is pretty much all primary cosmic rays. It’s the only pure primary cosmic ray, where with others you’ll have some secondary components feeding into that as well.”

CALET was optimized to detect cosmic ray electrons and positrons, but also detects the atomic nuclei of cosmic rays very precisely. The electrons and positrons are important because their spectrum potentially contains information about their specific sources. Now the cosmic ray nuclei are providing additional information about the sources and/or propagation through the galaxy.

“We didn’t expect that the nuclei – the carbon, oxygen, protons, iron – would really start showing some of these detailed differences that are clearly pointing at things we don’t know,” Cherry said.

A global effort

The Japanese space agency launched CALET and today leads the mission in collaboration with the U.S. and Italian teams. In the U.S., the CALET team consists of researchers from LSU, NASA Goddard, University of Maryland – Baltimore County, University of Maryland – College Park, University of Denver and Washington University. The LSU scientists include Professor T. Gregory Guzik, Professor Emeritus John Wefel, PhD student Anthony Ficklin, Research Associates Doug Granger and Aaron Ryan and Cherry. The new paper is the fifth from this highly successful international collaboration published in Physical Review Letters.

The current data set based on five years of exposure has allowed CALET to directly measure the rare flux of cosmic rays up to energies of 2 trillion electron volts per nucleon. CALET has been approved to continue operating at least through 2024.

The latest finding creates more questions than it answers, emphasizing that there is still more to learn about how matter is generated and moves around the galaxy.

“The study of cosmic rays is the study of how the universe generates and distributes matter, and how that affects the evolution of the galaxy,” Krizmanic adds. “So really it’s studying the astrophysics of this engine we call the Milky Way that’s throwing all these elements around.”

Featured image: Iron spectrum (multiplied by E2.6) measured by CALET and other experiments. © CALET


Reference: O. Adriani et al. (CALET Collaboration), “Measurement of the Iron Spectrum in Cosmic Rays from 10  GeV/n to 2.0  TeV/n with the Calorimetric Electron Telescope on the International Space Station”, Phys. Rev. Lett. 126, 241101 – Published 14 June 2021. DOI: https://doi.org/10.1103/PhysRevLett.126.241101


Provided by LSU

Researchers Discover How the Intestinal Epithelium Folds and Moves by Measuring its Forces (Biology)

An international team led by Xavier Trepat at IBEC, with support from “La Caixa Foundation, measures the cellular forces in mini-intestines grown in the laboratory, deciphering how the inner wall of this vital organ folds and moves.

The study, published in Nature Cell Biology, opens the doors to a better understanding of the bases of diseases such as celiac disease or cancer, and to the ability to find solutions for gut diseases through the development of new therapies.

The human intestine is made up of more than 40 square meters of tissue, with a multitude of folds on its internal surface that resemble valleys and mountain peaks in order to increase the absorption of nutrients. The intestine also has the unique characteristic of being in a continuous state of self-renewal. This means that approximately every 5 days all the cells of its inner walls are renewed to guarantee correct intestinal function. Until now, scientists knew that this renewal could take place thanks to stem cells, which are protected in the so-called intestinal crypts, and which give rise to new differentiated cells. However, the process that leads to the concave shape of the crypts and the migration of new cells towards the intestinal peaks was unknown.  

Now, an international team led by Xavier Trepat, ICREA Research Professor and Group Leader at IBEC, in collaboration with the IRB, researchers from the UB and UPC universities in Barcelona, and the Curie Institute of Paris, has deciphered the mechanisms leading the crypts to adopt and maintain their concave shape, and how the migration movement of the cells towards the peaks occurs, without the intestine losing its characteristic folded shape. The study, published in the prestigious journal Nature Cell Biology, has combined computer modelling, led by Marino Arroyo, professor at the UPC, researcher associated with IBEC and member of CIMNE, with experiments with intestinal organoids from mouse cells, and shows that this process is possible thanks to the mechanical forces exerted by the cells. An important part of this study has been supported by the “la Caixa” Foundation within the framework of the CaixaResearch programme. The entity has also awarded a scholarship to the first co-author, Gerardo Ceada, to carry out his PhD at IBEC.

The forces determine and control the shape of the intestine and the movement of the cells

Using mouse stem cells and bioengineering and mechanobiology techniques, researchers have developed mini-intestines, organoids that resemble the three-dimensional structure of peaks and valleys, recapitulating tissue functions in vivo. Using microscopy technologies developed by the same group, researchers carried out high-resolution experiments for the first time that have allowed them to obtain 3D maps showing the forces exerted by each cell. 

In addition, with this in vitro model, scientists have shown that the movement of new cells to the peak is also controlled by mechanical forces exerted by the cells themselves, specifically by the cytoskeleton, a network of filaments that determines and maintains cell shape. 

Contrary to what was believed up until now, we have been able to determine that it is not the cells of the intestinal crypt that push the new ones up, but that it is the cells at the peak pulling the new ones up, akin to a mountaineer who helps another climber by pulling them up.

Gerardo Ceada (IBEC) 

With this system, we have discovered that the crypt is concave because the cells have more tension on their upper surface than on the bottom, which causes them to adopt a conical shape. When this occurs in several cells next to each other, the result is that the tissue folds, giving rise to a pattern of peaks and valleys.

Carlos Pérez-González, (IBEC and Curie Institute)

The new mini-intestine model will allow further studies of diseases such as cancer, celiac disease or colitis to be conducted in reproducible and real conditions, in which there is an uncontrolled proliferation of stem cells or a destructuring of the folds. In addition, intestinal organoids can be manufactured with human cells and used for the development of new drugs or for the study of the intestinal microbiota.  

X. Trepat is a member of the Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN). E. Batlle is a member of the Center for Biomedical Research in Cancer Network (CIBERONC). Both are research professors at the Catalan Institution for Research and Advanced Studies (ICREA).

Featured image: Intestine cross section showing its characteristic folded structure. Credit: Amy Engevik


Reference article:  C. Pérez-González, G. Ceada, F. Greco, M. Matejčić, M. Gómez-González, N. Castro, A. Menendez, S. Kale, D. Krndija, A. G. Clark, V. Ram Gannavarapu, A. Álvarez-Varela, P. Roca-Cusachs, E. Batlle, D. Matic Vignjevic, M. Arroyo and X. Trepat. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration. Nature Cell Biology, 2021.


Provided by IBEC

Running in the Blood: Blood Lipids Are Linked To Cancer, But Depending On Family History (Biology)

Medical researchers identify the role of family history in the link between blood lipids and esophageal cancer

Fat biomolecules in the blood, called “serum lipids,” are necessary evils. They play important roles in the lipid metabolism and are integral for the normal functioning of the body. However, they have a darker side; according to several studies, they are associated with various cancers. The medical community has fathoms to go before truly understanding the implications of different serum lipid levels in cancer.

As a major step in this direction, a group of scientists from the Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University Cancer Hospital and Institute; Hua County People’s Hospital; and Anyang Cancer Hospital, have successfully determined that a family history of esophageal cancer modifies the association between serum lipids and risk of developing cancerous esophageal lesions, according to a pioneering study published in Chinese Medical Journal.

Many individuals undergo routine lipid profile checkups, but most people and doctors only focus on the risk of cardiovascular diseases, and unwittingly fail to look deeper into the results. What if the change in serum lipid levels is an sign of the risk of having malignant esophageal lesions?

To answer this question, Chinese medical researchers analyzed data from the “Endoscopic Screening for Esophageal Cancer in China” trial. The trial included analysis of serum lipids like total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol from 211 individuals with malignant esophageal lesions, and 2101 “control” individuals who didn’t have the lesion.

Although the team’s initial analysis of data showed that there is no consistent association between serum lipid levels and risk of developing malignant esophageal lesions, a simple family history check–and deeper analysis–told a different story. Particularly for cases with a family history of esophageal cancer, high levels of TC and LDL-C were linked to a significantly higher risk of developing malignant esophageal lesions. Also, when such family history was not identified, there was a notable negative association between the same parameters. Better to know late, than never, right?

Professor Yang Ke from Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Genetics, Peking University Cancer Hospital and Institute, Beijing, who is also one of the lead scientists of the study, thinks so. In this regard, Professor Ke jubilantly says, “We found that the association of serum lipids and malignant esophageal lesions might be modified by esophageal cancer family history. This finding provides population-level evidence in research at the interface of serum lipid biology and esophageal carcinogenesis.”

Further, the findings of this study shed light on the importance of considering a ‘stratified’ analysis on such population-based studies. A relevant example is a stratification this study proposes, in terms of those with and without esophageal cancer family history. This stratification helped the researchers have a better understanding of the data from the trial considered. Moreover, Dr. Meng-Fei Liu, from Laboratory of Carcinogenesis and Translational Research, and the other corresponding author of this study, thinks that this research is far from its endpoint. He says, “The stratified analysis would be crucial for population-based studies investigating the association of serum lipids and cancer. However, the mechanism by which a family history of esophageal cancer modifies this association warrants further investigation.”

Overall, this study has paved the way for a better understanding of the role of serum lipids in esophageal carcinogenesis in cases involving esophageal cancer family history. While the medical community continues to look for further advances, which could be translated into future clinical applications in such population-based cancer research, this study has definitely given us much to think about; the signs of cancer may be in our blood, in more ways than one!

Featured image: The association between serum lipids and risk of developing malignant esophageal lesions might be influenced by the status of esophageal cancer family history, scientists say. © Chinese Medical Journal


Reference

  • Title of original paper: Family history of esophageal cancer modifies the association of serum lipids and malignant esophageal lesions: a nested case-control study from the “Endoscopic Screening for Esophageal Cancer in China” trial
  • Journal: Chinese Medical Journal
  • DOI: https://doi.org/10.1097/CM9.0000000000001432

Provided by Cactus Communications

There’s More To Genes Than DNA: How Mum and Dad Add Something Extra, Just For You (Biology)

Biologists at the University of Bath and the University of Vienna in Austria have discovered 71 new imprinted genes in the mouse genome.

Biologists at the Universities of Bath and Vienna have discovered 71 new ‘imprinted’ genes in the mouse genome, a finding that takes them a step closer to unravelling some of the mysteries of epigenetics – an area of science that describes how genes are switched on (and off) in different cells at different stages in development and adulthood.

To understand the importance of imprinted genes to inheritance, we need to step back and ask how inheritance works in general. Most of the thirty trillion cells in a person’s body contain genes that come from both their mother and father, with each parent contributing one version of each gene. The unique combination of genes goes part of the way to making an individual unique. Usually, each gene in a pair is equally active or inactive in a given cell. This is not the case for imprinted genes. These genes – which make up less than one percent of the total of 20,000+ genes – tend to be more active (sometimes much more active) in one parental version than the other.

Until now, researchers were aware of around 130 well-documented imprinted genes in the mouse genome – the new additions take this number to over 200. Professor Tony Perry, who led the research from the Department of Biology & Biochemistry at Bath, said: “Imprinting affects an important family of genes, with different implications for health and disease, so the seventy-plus new ones add an important piece of the jigsaw.”

The importance of histones

Close examination of the newly identified genes has allowed Professor Perry and his colleagues to make a second important discovery: the switching on and off of imprinted genes is not always related to DNA methylation, where methyl groups are added to genomic DNA (a process that is known to repress gene activity, switching them off). DNA methylation was the first known type of imprint, and was discovered around thirty years ago. From the results of the new work, it seems that a greater contribution to imprinting is made by histones – structures that are wrapped up with genomic DNA in chromosomes.

Although scientists have known for some time that histones act as ‘dimmer’ switches for genes, fading them off (or back on), until now it was thought that DNA methylation provided the major switch for imprinted gene activity. The findings from the new study cast doubt on this assumption: many of the newly identified genes were found to be associated with changes to the histone 3 lysine 27 (H3K27me3), and only a minority with DNA methylation.

Why imprinting matters

Scientists have yet to work out how one parental version of a given gene can be switched (or faded) on or off and maintained that way while the other is in the opposite state. It is known that much of the on/off switching occurs during the formation of gametes (sperm and egg), but the precise mechanisms remain unclear. This new study points to the intriguing possibility that some imprinted genes may not be marked in gametes, but become active later in development, or even in adulthood.

Embryos
A normal 4-day-old mouse embryo (L) and an embryo of the same age that has been manipulated to contain maternal chromosomes only (parthenogenote). At this stage, the embryos (blastocysts) appear similar, but the parthenogenote will soon die, underscoring the importance of inheriting imprinted genes from both parents. Different cell types are stained green or red. Credit: Dr Maki Asami.

Although it only involves a small proportion of genes, imprinting is important in later life. If it goes wrong, and the imprinted gene copy from one parent is switched on when it should be off (or vice versa), disease or death occur. Faulty imprinted genes are associated with many diseases, including neurological and metabolic disorders, and cancer.

“We may underestimate how important the relationship between imprinting and disease is, as well as the relationship of imprinting to the inheritance of parentally-acquired disease, such as obesity,” said Professor Perry. “Hopefully, this improved picture of imprinting will increase our understanding of disease.”

The paper ‘Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3’ is published today in Nature Communications.

Featured image: Genetic imprinting – genes that are more active when they come from one parent than the other – impacts health at all stages of life © University of Bath


Provided by University of Bath

New High-speed Method For Spectroscopic Measurements (Physics)

Researchers at Tampere University and their collaborators have shown how spectroscopic measurements can be made much faster. By correlating polarization to the colour of a pulsed laser, the team can track changes in the spectrum of the light by simple and extremely fast polarization measurements. The method opens new possibilities to measure spectral changes on a nanosecond time scale over the entire colour spectrum of light.

In spectroscopy, often the changes of the wavelength, i.e. colour, of a probe light are measured after interaction with a sample. Studying these changes is one of the key methods to gain a deeper understanding of the properties of materials down to the atomic level. Its applications range from astronomical observations and material studies, to fundamental investigations of atoms and molecules.

The research team has demonstrated a novel spectroscopic method which has the potential to speed up measurements to read-out rates that are impossible with conventional schemes. The results have now been published in the prestigious journal Optica.

Spectroscopic measurements usually rely on separating the different colour components to different positions, where the spectrum can then be read-out by a detector array similar to a camera chip. While this approach enables a direct inspection of the spectrum, it is rather slow due to the limited speed of the large read-out array. The new method that the researchers implemented circumvents this restriction by generating a more complex state of laser light and thereby allowing a faster measurements scheme.

Our work shows a simple way to have different polarizations for all colour components of the laser. By using this light as a probe, we can simply measure the polarization to gain information about changes in the colour spectrum,” explains Doctoral Researcher Lea Kopf, lead author of the study.

The trick the researchers use is to perform a modulation in the temporal domain by coherently splitting a femto-second pulse of a laser into two parts – each having a different polarization slightly delayed in time with respect to each other.

“Such a modulation can easily be done using a birefringence crystal, where differently polarized light travels at different speeds. This leads to the spectrally-changing polarization required for our method,” describes Associate Professor Robert Fickler, who leads the Experimental Quantum Optics group in which the experiment was performed.

High-speed spectroscopic measurements open new possibilities

The researchers have not only demonstrated how such complex states of light can be generated in the lab; they also tested their application in reconstructing spectral changes using only polarization analysis. As the latter only requires up to four simultaneous intensity measurements, a few very fast photodiodes can be used.

Using this approach, the researchers can determine the effect of narrowband modulations of the spectrum at a precision that is comparable to standard spectrometers but at high speed.

“However, we couldn’t push our measurement scheme to its limits in terms of possible read-out rates, as we are limited by the speed of our modulation scheme to a few million samples per second,” continues Lea Kopf.

Building on these promising initial results, future tasks will include to apply the idea to more broadband light, such as super continuum light sources, and to apply the scheme in spectroscopic measurements of naturally fast varying samples to use its full potential.

“We are happy that our fundamental interest in structuring light in different ways has now found a new direction, which seems to be helpful for spectroscopy tasks which are usually not our focus. As a quantum optics group, we have already started discussing how to apply and benefit from these ideas in our quantum photonics experiments,” adds Robert Fickler.

Read more on Spectral vector beams for high-speed spectroscopic measurements in Optica.

Featured image: Conceptual image of the method of using spectrally varying polarization states for high-speed spectroscopic measurements. Image: Frédéric Bouchard / National Research Council of Canada.


Provided by Tampere University

This Molecule is Made From Sugar, Shaped Like A Doughnut, and Formed Using Light (Chemistry)

New research makes popular compound cheaper and better for the environment

A process using a light-sensitive chemical can drastically reduce cost and energy consumption to produce gamma-cyclodextrin, a compound that is widely used in manufacturing, according to a Dartmouth study.

The research, published in Chem, demonstrates how a hydrazone template can replace energy-intensive distillation to produce and isolate gamma-cyclodextrin–a water-soluble chemical that attracts other molecules and is used to enhance food, pharmaceuticals, and a wide range of consumer products.

“These compounds are biodegradable, biocompatible, benign and commonly used,” said Ivan Aprahamian, a professor of chemistry at Dartmouth. “We are making production much more efficient so that they can be even more available to industry.”

Cyclodextrins are naturally occurring compounds that encapsulate and preserve active ingredients in a product until it is used. The water-soluble compounds are made of glucose and are produced when enzymes are added to starch. Their doughnut-like shape allows them to act as molecular containers that surround other compounds until they are released by heat or other physical processes.

Compared to other common cyclodextrins–such as alpha-cyclodextrin and beta-cyclodextrin–gamma-cyclodextrin is the largest and most water soluble.

“The unique structure of this molecule helps it hold bulky molecules like vitamins and sensitive dyes,” said Sirun Yang, first author of the paper and a graduate student in the Aprahamian Research Group at Dartmouth. “Gamma-cyclodextrin was already useful to industry, now we’re making it more accessible for producers of pharmaceuticals, food and household products.”

In pharmaceuticals, the compound gives medications longer shelf lives and allows them to be formed into easily eaten and digestible forms. Air fresheners use the compound to capture smelly molecules, lowering their concentration in the air. Fragrances use it to slowly release pleasant-smelling compounds.

According to Aprahamian, the challenge for industry is that gamma-cyclodextrin is also energy-intensive and expensive to prepare and isolate. Until now, a costly steam distillation process was required to remove the molecular template that is used to form the compound.

Through the use of a template made from light-sensitive hydrazone, the new process guides gamma-cyclodextrin into its distinctive container-like doughnut shape during its enzymatic production, but can then be removed using a cost-effective and environmentally friendly photoirradiation process.

“Our method relies on using hydrazone, which is a photoswitch that can be easily added into the gamma-cyclodextrin cavity,” said Aprahamian. “Once you introduce light, it changes shape and leaves the cavity, facilitating the isolation of the compound. There is no more need for steam distillation.”

The new process makes the highly functional compound more resource and price competitive when compared to the more readily available cyclodextrins.

With cheaper production costs, gamma-cyclodextrin could become more available for use in a wide range of consumer products. For pharmaceuticals, increased use of the compound would allow manufacturers to formulate lower dosages of active ingredients, making medication less expensive and reducing side effects.

Maria Pellegrini and Dale Mierke from Dartmouth, and Sophie Beeren, Dennis Larsen and Sebastian Meier from the Technical University of Denmark also contributed to this study.

The study, “Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template”, published in Chem on June 21, 2021. DOI: https://doi.org/10.1016/j.chempr.2021.05.013

Featured image: Gamma-cyclodextrin’s water-soluble, doughnut shaped structure allows it to trap other molecules and makes it useful in the production of pharmaceuticals, food, and household products. Figure by Sirun Yang from Harata, Bull. Chem. Soc. Of Japan, 60, 2763 (1987). © Figure by Sirun Yang from Harata, Bull. Chem. Soc. Of Japan, 60, 2763 (1987).


Provided by Dartmouth College

Cel­lu­lar Mech­an­isms of Early Mam­mary Gland De­vel­op­ment Un­raveled (Biology)

Helsinki University research group used live tissue imaging for the first time to visualise the emergence of the mammary gland.

Despite long-standing interest, the cellular mechanisms driving the initiation of mammary gland development have remained elusive for decades, mostly due to technical limitations in studying dynamic cell behaviors in live tissues. Recent advances in microscopic methods and availability of various mouse models allowed the research group of Marja Mikkola from HiLIFE Institute of Biotechnology, University of Helsinki to address this question. This is the first time when live tissue imaging has been used to visualise the emergence of the mammary gland.

Mammary gland is the class-defining organ of mammals, yet we know surprisingly little how its development commences. In their recent study published in Journal of Cell Biology, the research group of Marja Mikkola used time-lapse imaging to show that the growth of the mammary bud is primarily fueled by migration of cells to the bud. In contrast, although increase in cellular size and cell proliferation contribute to this process, the role of these mechanisms remains minor.

“Interestingly, mammary bud cells, unlike most of other skin derivatives such as hair follicle and tooth bud, do not divide for several days, indicating that this might be a unique feature of early mammary gland development” says graduate student Ewelina Trela, the lead author of the study. “However, we do not yet know why this happens”, she continues.

Mam­mary buds use a pre­vi­ously un­des­cribed mech­an­ism for in­va­gin­a­tion

Tissue invagination, or tissue folding inwards into the underlying stroma, is a fundamental mechanism that occurs to generate the architecture of many organs.  In the same piece of work, the authors describe a novel mechanism for tissue invagination.
 
“Using confocal fluorescence microscopy, we found thin and elongated epidermal keratinocytes surrounding mammary bud in a rim like fashion: their appearance and disappearance coincided with the invagination process suggesting that these cells, named ring cells, could be functionally important” details principal investigator Marja Mikkola.

Next, the Mikkola group teamed up with the group of Sara Wickström at HiLIFE and Faculty of Medicine, University of Helsinki to establish live imaging of the forming mammary bud, which confirmed that ring cells move circumferentially around the mammary bud.  

The study also revealed that the ring cells exert contractile force through the actomyosin network, via non-muscle myosin IIA (NMIIA). The functionality of ring cells was impaired in NMIIA deficient mice leading to compromised mammary bud shape. Whether other developing organs utilize a similar cellular mechanism for invagination remains an open question.

Featured image: Optical section of a confocal microscopy image of the mammary bud (marked with dashed line) stained with an epithelial marker in green at the time when ring cells form (left) and analysis of cell roundness of segmented cells with ring cells in dark blue (right). © EWELINA TRELA


Ori­ginal art­icle

Trela E, Lan Q, Myllymäki SM, Villeneuve C, Lindström R, Kumar V, Wickström SA, Mikkola ML. Cell influx and contractile actomyosin force drive mammary bud growth and invagination. J Cell Biol 220(8):e202008062, 2021. doi: 10.1083/jcb.202008062.


Provided by University of Helsinki

A Tapeworm Drug Against SARS-CoV-2? (Medicine)

Charité conducts clinical trial to test potential new treatment

A joint press release by Charité, the University of Bonn and the DZIF

Researchers from the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin and the University of Bonn have examined the way in which SARS-CoV-2 reprograms the metabolism of the host cell in order to gain an overall advantage. According to their report in Nature Communications*, the researchers were able to identify four substances which inhibit SARS-CoV-2 replication in the host cell: spermine and spermidine, substances naturally found in the body; MK-2206, an experimental cancer drug; and niclosamide, a tapeworm drug. Charité is currently conducting a trial to determine whether niclosamide is also effective against COVID-19 in humans.

Viral replication depends on host cell machinery and the use of the host’s molecular building blocks. In order to avoid detection by the immune system, viruses also have to ensure that they can evade cellular surveillance systems. To do this, they manipulate various processes in the infected host cell – and every virus pursues a different strategy. This is why a team of researchers led by PD Dr. Marcel Müller of Charité’s Institute of Virology and Dr. Nils Gassen of the Psychiatry and Psychotherapy Clinic and Outpatient Clinic at the University Hospital Bonn (UKB) have investigated the way in which SARS-CoV-2 reprograms host cells for its own benefit. Their key finding was as follows: The new coronavirus slows down the cell’s own recycling mechanism, a process known as autophagy. The purpose of this ‘auto-digestion’ mechanism is to enable the cell to dispose of damaged cell materials and waste products while recycling usable molecular building blocks for incorporation into new cellular structures.

“In our study, we were able to show that at the same time as using the cell’s building blocks for its own benefit, SARS-CoV-2 deceives the cell by simulating a nutrient-rich status, thereby slowing cellular recycling,” explains first author Dr. Gassen. As part of this work, the researchers undertook a detailed analysis of SARS-CoV-2 infected cells and the lung tissue of COVID-19 patients, studying cellular metabolism and the processing of molecular signals. “It is likely that SARS-CoV-2 uses this to avoid dismantling by the cell. After all, viruses are also subject to autophagic disposal,” adds the study’s last author, DZIF researcher PD Dr. Müller. He adds: “The same reprogramming strategy is also used by the MERS coronavirus, whose autophagy-inhibiting action we were able to demonstrate more than a year ago. However, there are other coronaviruses which, quite in contrast to this, induce autophagy. These mainly infect animals.”

When results from the study suggested that the recycling mechanism might be a potential target for COVID-19 therapy, the researchers tested whether substances which induce cellular recycling also reduce the replication of SARS-CoV-2 inside infected cells. Interestingly, the researchers found four substances which proved effective – all of them already in use in humans. These included the polyamine spermidine, an autophagy-enhancing metabolite which is produced in all human cells and by bacteria in the human gut. It occurs naturally in foods such as wheat germ, soya, mushrooms, and mature cheese and is freely available as a food supplement. When the researchers added spermidine to cells infected with SARS-CoV-2, this resulted in an 85 percent reduction in the numbers of virus particles produced. Similar results were produced by spermine, another polyamine which occurs naturally in the body. This derivative of spermidine was found to reduce viral replication by more than 90 percent in human lung cells and in a human gut model comprising clusters of cells known as ‘organoids’.

“The obvious effects produced by spermidine and, in particular, spermine are certainly encouraging. For one thing, substances which occur naturally in the body are less likely to induce side effects,” says PD Dr. Müller. “Having said that, we worked with pure forms of these substances which are not suitable for medical use. Spermidine, in particular, has to be used at relatively high concentrations to achieve an appreciable effect in cell culture. Many questions therefore remain to be answered before we can consider polyamines as a potential treatment against COVID-19: When used in the body, will it be possible to achieve blood levels high enough to inhibit viral replication in the respiratory tract? And, if yes: would administration before or during the infection be advisable? Are there any side effects? Even so, our findings from cell culture are a good starting point for research involving animal models. Self-medication is not advisable, one of the reasons being that viruses also use polyamines to help boost replication; the correct dosage is therefore crucial. The same applies to fasting, which can stimulate the body’s autophagy process. Given that the body needs energy to mount an immune response, it remains unclear whether fasting is advisable in SARS-CoV-2 infected patients.”

The third substance to prove effective against SARS-CoV-2 was the ‘AKT inhibitor’ MK-2206. The substance is currently at the clinical trial stage and undergoing testing for its tolerability and efficacy against a range of different cancers. In the current study, MK-2206 reduced the production of infectious SARS-CoV-2 virus by approximately 90%. It did so at plasma concentrations which had already been achieved during a previous study. “Based on our data, I would consider MK-2206 as an interesting treatment candidate against COVID-19 which, after a careful analysis of risks and benefits, would justify further study in clinical trials,” explains PD Dr. Müller.

The most pronounced antiviral effect was associated with niclosamide, which the researchers had shown to be effective against the MERS coronavirus during an earlier study. The tapeworm drug was found to reduce the production of infectious SARS-CoV-2 particles by more than 99 percent. “Niclosamide showed the strongest effect in our cell culture-based experiments. What is more, it has been licensed for use against tapeworm infections in humans for a very long time and is well tolerated at potentially relevant doses,” says PD Dr. Müller. He adds: “Out of the four new candidate substances, we consider it to be the most promising one. This is why we are now conducting a clinical trial at Charité to test whether niclosamide might also have a positive effect on people with COVID-19. I am delighted at this development. It shows how quickly findings from basic research can reach patients if research and clinical practice are closely interlinked and work together in an efficient manner.”

The Phase II clinical trial – entitled ‘NICCAM’ – is being led by Prof. Dr. Martin Witzenrath, Deputy Head of Charité’s Department of Infectious Diseases and Respiratory Medicine. The study will test the safety, tolerability, and efficacy of niclosamide combined with camostat (another licenced drug) in patients recently (within the last few days) diagnosed with COVID-19. The study is currently recruiting and looking for participants. Potential participants wishing to find out more information on the study should contact the team at ‘Charité Research Organisation’ on +49 30 450 539 210 or by emailing patienten(at)charite-research.org.

About the NICCAM trial
The ‘NICCAM’ Phase II trial is being conducted by ‘Charité Research Organisation’ in cooperation with the German pharmaceutical company Bayer and funded by the Berlin Institute of Health (BIH). In addition to investigating the safety and tolerability of the treatment combination niclosamide and camostat, the study also collects preliminary data on treatment efficacy. Approved in Japan for the treatment of pancreatitis and esophagitis, camostat has also been shown to reduce viral replication of SARS-CoV-2 in preclincal studies.  Recruitment to the study is open to men and women who have recently tested positive for SARS-CoV-2 (either via rapid antigen testing or PCR).

Featured image: When SARS-CoV-2 (yellow) infects monkey kidney cells, it reduces the cellular recycling mechanism, meaning there are fewer autophagy signals (green) than in non-infected cells. Blue staining depicts nuclei. © University Hospital Bonn | Daniel Heinz


Reference: Gassen NC et al. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat Commun (2021), doi: 10.1038/s41467-021-24007-w


Provided by Charite

‘Suffocating’ Cancer: A New Headway in Melanoma Immunotherapy (Medicine)

Disrupting cancer cell ability to adapt to low oxygen conditions shows promise in melanoma 

Hypoxia, or the inadequate oxygenation of a tissue, is a condition occurring frequently in all solid tumours such as melanoma skin cancer. Melanoma cells are not only able to survive oxygen deprivation, but also to use it to their own advantage by hijacking the anti-tumour immune response and developing resistance mechanisms to conventional anti-cancer therapies. A key gene responsible for cancer cell adaptation to hypoxia is HIF-1α (Hypoxia Inducible Factor-1 alpha). Led by Dr Bassam Janji, head of the Tumor Immunotherapy and Microenvironment (TIME) research group at the Luxembourg Institute of Health (LIH) and in collaboration with Gustave Roussy Cancer Center in France and the Thumbay Research Institute of Precision Medicine at Gulf Medical University in the United Arab Emirates, the team used gene editing technologies to show how targeting HIF-1α could not only inhibit tumour growth, but also drive cytotoxic (toxic to cells) immune cells to the cancer tissue. This discovery provided a valuable new target to make resistant melanomas more vulnerable to available anti-cancer treatments. Their findings were recently published in the reputable ‘Oncogene Journal’.

Melanoma is a type of skin cancer that develops from melanocytes, cells that are responsible for the production of pigments. Melanomas become harder to treat if not detected early, with emerging treatment resistance being an important barrier to their effective management. Due to their rapid growth rate and low blood supply, solid tumours including melanoma often exhibit areas of hypoxia. Hypoxia, or the decrease of oxygen in the tumour microenvironment, would normally cause tumour cell death. “However, certain solid tumours have evolved to survive this hostile microenvironment by activating HIF-1α, a gene reported to be a major factor mediating the adaptive response to changes in tissue oxygen level,” explains Dr Janji. William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019 for their discovery of HIF-1 and how cells use it to sense hypoxia. Hypoxia has also been reported to be responsible for the failure of tumour response to conventional anti-cancer therapies and can prevent the infiltration of immune cells into the tumour. It is therefore crucial to understand the mechanisms by which cancer cells overcome this hypoxic environment to improve the effectiveness of available anti-cancer therapies.

In this context, the team led by Dr Janji sought to inactivate the functionality of the HIF-1α gene using CRISPR gene editing technology and investigate the impact of such inactivation on tumour growth, immune cell infiltration and response to immunotherapy in a preclinical melanoma mouse model.

Our study revealed that blocking the activity of HIF-1α significantly inhibited melanoma growth and amplified the infiltration of immune cells into the tumour microenvironment by increasing the release of CCL5, a well-defined mediator involved in driving cytotoxic immune cells to the tumour battlefield”, summarises Dr Audrey Lequeux, first author of the publication. Importantly, the study also showed that combining a drug devised to stop hypoxia significantly improves melanoma immunotherapy. When the results were validated retrospectively in a cohort of 473 melanoma patients, the hypoxic signature of tumours was correlated to worsened outcomes and the lack of immune cell infiltration into tumours, which is considered as a major characteristic of tumour resistance to immunotherapies.
Together, our data strongly argue that therapeutic strategies disrupting HIF-1α would be able to modulate the tumour microenvironment to permit the infiltration of immune cells. Such strategies could be used to improve vaccine-based and immune checkpoint blockade-based cancer immunotherapies in non-responder melanoma patients,” conclude Dr Chouaib and Dr Janji from Gulf Medical University and Luxembourg Institute of Health, respectively.

The study was published in June in the Oncogene journal, part of the prestigious Nature publishing group, with the full title “Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy”. The article was listed under the category of ‘brief communication’, a category reserved for articles of exceptional interest due to their significance and timely contribution to cancer biology.


FUNDING AND RESEARCH TEAMS

This study was supported by grants from FNRS Televie (grants 7.4535.16, 7.6505.18 and n°7.4606.18), the Luxembourg National Research Fund (C18/BM/12670304/COMBATIC and PRIDE15/10675146/CANBIO), the Fondation Cancer, Luxembourg (FC/2018/06), the Kriibskrank Kanner Foundation, Luxembourg, Janssen Cilag Pharma, Roche Pharma, Action LIONS Vaincre le Cancer Luxembourg and Sheik Hamdan Bin Rashid Al Maktoum Foundation (United Arab Emirates). It was performed in close collaboration with national and international partners including the Department of Hemato-oncology at the Centre Hospitalier du Luxembourg, the French National Institute of Health and Medical Research (INSERM), Gustave Roussy Cancer Center, France and the Thumbay Research Institute of Precision Medicine of the Gulf Medical University (UAE).


Reference: Lequeux, A., Noman, M.Z., Xiao, M. et al. Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy. Oncogene (2021). https://doi.org/10.1038/s41388-021-01846-x


Provided by Luxembourg Institute of Health