Mayo Clinic Researchers Develop Test to Measure Effect of Breast Cancer Gene Variants (Medicine)

Researchers at Mayo Clinic have combined results from a functional test measuring the effect of inherited variants in the BRCA2 breast and ovarian cancer gene with clinical information from women who received genetic testing to determine the clinical importance of many BRCA2 variants of uncertain significance (VUS). The findings were published today in a study in the American Journal of Human Genetics.

“There are 4,565 different VUS in the BRCA2 gene listed in the National Institutes for Health (NIH) Clinical Variant Database,” says Fergus Couch, Ph.D., a breast cancer researcher at Mayo Clinic. The database lists variants submitted by genetic testing laboratories and research groups.

Dr. Couch says the 4,565 variants represent about 50% of all reported BRCA2 variants in the NIH database. He says many thousands of individuals tested around the world have these variants, but they have no way to know the clinical significance of their particular variants. And their doctors have no way to use this information to select methods for preventing breast or ovarian cancer, or to select targeted treatment approaches for tumors with BRCA2 alterations.

“The current method for attempting to determine the clinical relevance of BRCA2 variants of uncertain significance relies on a series of rules from the American College of Medical Genetics and Genomics ACMG/AMP that use genetic information about the variants and information from patients and patients’ families,” says Dr. Couch.

Dr. Couch and his team used a functional test to determine the influence of many VUS on BRCA2 DNA damage repair activity. They first showed that the functional test was able to clearly discriminate between known pathogenic cancer-causing variants and known benign BRCA2 variants that do not increase risk of cancer. Next, they applied the test to the VUS and combined the results with other ACMG/AMP rules-based information.

“We found that 86% of the VUS we studied were reclassified as benign or pathogenic, which is a major step forward from the 10% or so missense variants in the DNA binding domain that have previously been classified,” says Dr. Couch. “This is the first time that a functional test has been combined with ACMG/AMP information in this way, and the results show that it is highly effective.”

Dr. Couch says the results will have a positive effect on patient care because patients will know whether breast cancer VUS are benign or pathogenic.

“Patients whose VUS are benign will now be evaluated based on their personal and family history of breast and ovarian cancer, and not on the basis of the genetic testing result,” says Dr. Couch. “And patients who are classified as having pathogenic variants will be able to benefit from more frequent cancer screening or prophylactic mastectomy to reduce risk of developing breast cancer.”

The findings also mean that women with ovarian cancer now may know if they would qualify for targeted therapy with PARP inhibitors.

Dr. Couch’s research was funded by the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer to the Mayo Clinic (P50 CA116201).

Reference: Marcy E. Richardson, Chunling Hu, Kun Y. Lee, Holly LaDuca, Kelly Fulk, Kate M. Durda, Ashley M. Deckman, David E. Goldgar, Alvaro N.A. Monteiro, Rohan Gnanaolivu, Steven N. Hart, Eric C. Polley, Elizabeth Chao, Tina Pesaran, Fergus J. Couch, Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance, The American Journal of Human Genetics, 2021, , ISSN 0002-9297, (

Provided by Mayo Clinic

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Targeting MAPK4 Emerges as a Promising Therapy for Prostate Cancer (Medicine)

The battle against late-stage prostate cancer might have found a potential new strategy to combat this deadly disease. Research led by Baylor College of Medicine reveals in the Journal of Clinical Investigation that the enzyme MAPK4 concertedly activates androgen receptor (AR) and AKT, molecules at the core of two cellular signaling pathways known to promote prostate cancer growth and resistance to standard therapy. Importantly, inhibiting MAPK4 simultaneously inactivated both AR and AKT and stopped cancer growth in animal models. The findings open the possibility that targeting MAPK4 in human prostate cancer might provide a novel therapeutic strategy for this disease that is the second leading cause of cancer death in American men.

“Scientists already knew that both the AR and the AKT pathways can drive prostate cancer,” said corresponding author Dr. Feng Yang, assistant professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “One complication with targeting AR (for instance, with medical castration therapy, including the most advanced agents such as enzalutamide, apalutamide and abiraterone) or AKT is that there is a reciprocal crosstalk between these pathways. When AR is inhibited, AKT gets activated, and vice-versa, therefore tackling these pathways to control cancer growth is complex.”

In previous work, the Yang lab studied the little-known enzyme MAPK4.

“One interesting aspect of MAPK4 is that it is rather unique because it does not work as conventional MAPK enzymes do,” Yang said. “To our knowledge, we are one of the few groups studying MAPK4 and the first to uncover its critical roles in human cancers.”

In their previous study, Yang and his colleagues discovered that MAPK4 can trigger the AKT pathway, not only in prostate cancer but in other cancers as well, such as lung and colon cancers.

In the current study, the researchers found that MAPK4 also activates the AR signaling pathway by enhancing the production and stabilization of GATA2, a factor that is crucial for the synthesis and activation of AR.

Further experiments showed that MAPK4 triggered the concerted activation of both AR and AKT pathways by independent mechanisms, and this promoted prostate cancer growth and resistance to castration therapy, a standard medical treatment for advanced/metastatic prostate cancer. Importantly, genetically knocking down MAPK4 reduced the activation of both AR and AKT pathways and inhibited the growth, including castration-resistant growth, of prostate cancer in animal models. The researchers anticipate that knocking down MAPK4 also could reduce the growth of other cancer types in which MAPK4 is involved.

“Our findings suggest the possibility that regulating MAPK4 activity could result in a novel therapeutic approach for prostate cancer,” Yang said. “We are interested in finding an inhibitor of MAPK4 activity that could help better treat prostate cancer and other cancer types in the future.”

Other contributors to this work include Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M. Ittmann, Chad J. Creighton, Yingnan Bian, Yanling Meng, David R. Rowley, Peter S. Nelson and David D. Moore. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; Fred Hutchinson Cancer Research Center, Seattle; Adrienne Helis Malvin Medical Research Foundation, New Orleans and University of Washington, Seattle.

This research was supported by grants from the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-13-1-0162, W81XWH-13-1-0163, W81XWH-17-1-0043) and the Cancer Prevention Research Institute of Texas (RP130651).

Reference: Tao Shen, … , David D. Moore, Feng Yang, “MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT”, J Clin Invest. 2021;131(4):e135465.

Provided by Baylor College of Medicine

Study Reveals How a Longevity Gene Protects Brain Stem Cells From Stress (Neuroscience)

A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.

“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she said.

The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.

“This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons,” Dr. Paik explained. “If new cells were made in such stressful conditions they would be killed. It’s better for stem cells to remain dormant and wait until the stress is gone to produce neurons.”

The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives—they may help people keep a good reserve of brain stem cells. It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness. But Dr. Paik cautioned it is too early to know whether this new information could be used to create new therapies for brain diseases.

“It could be a double-edged sword,” Dr. Paik explained. “Over activating FOXO3 could be very harmful. We don’t want to keep this on all the time.”

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.

Featured image: Antioxidant treatment boosts the birth of new neurons from stem cells by suppressing stress signaling. Image courtesy of the Paik lab.

Reference: Hwang, I., Uchida, H., Dai, Z. et al. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nat Commun 12, 640 (2021).

Provided by Weill Cornell Medicine

A Speed Limit Also Applies in the Quantum World (Quantum)

Study by the University of Bonn determines minimum time for complex quantum operations

Even in the world of the smallest particles with their own special rules, things cannot proceed infinitely fast. Physicists at the University of Bonn have now shown what the speed limit is for complex quantum operations. The study also involved scientists from MIT, the universities of Hamburg, Cologne and Padua, and the Jülich Research Center. The results are important for the realization of quantum computers, among other things. They are published in the prestigious journal Physical Review X, and covered by the Physics Magazine of the American Physical Society.

Suppose you observe a waiter (the lockdown is already history) who on New Year’s Eve has to serve an entire tray of champagne glasses just a few minutes before midnight. He rushes from guest to guest at top speed. Thanks to his technique, perfected over many years of work, he nevertheless manages not to spill even a single drop of the precious liquid.

A little trick helps him to do this: While the waiter accelerates his steps, he tilts the tray a bit so that the champagne does not spill out of the glasses. Halfway to the table, he tilts it in the opposite direction and slows down. Only when he has come to a complete stop does he hold it upright again.

Atoms are in some ways similar to champagne. They can be described as waves of matter, which behave not like a billiard ball but more like a liquid. Anyone who wants to transport atoms from one place to another as quickly as possible must therefore be as skillful as the waiter on New Year’s Eve. “And even then, there is a speed limit that this transport cannot exceed,” explains Dr. Andrea Alberti, who led this study at the Institute of Applied Physics of the University of Bonn.

Cesium atom as a champagne substitute

In their study, the researchers experimentally investigated exactly where this limit lies. They used a cesium atom as a champagne substitute and two laser beams perfectly superimposed but directed against each other as a tray. This superposition, called interference by physicists, creates a standing wave of light: a sequence of mountains and valleys that initially do not move. “We loaded the atom into one of these valleys, and then set the standing wave in motion – this displaced the position of the valley itself,” says Alberti. “Our goal was to get the atom to the target location in the shortest possible time without it spilling out of the valley, so to speak.”

in the foyer of the Institute of Applied Physics at the University of Bonn (from left): Thorsten Groh, Manolo Rivera Lam, Prof. Dr. Dieter Meschede and Dr. Andrea Alberti (all at a distance for corona safety reasons). © Volker Lannert/Uni Bonn

The fact that there is a speed limit in the microcosm was already theoretically demonstrated by two Soviet physicists, Leonid Mandelstam and Igor Tamm more than 60 years ago. They showed that the maximum speed of a quantum process depends on the energy uncertainty, i.e., how “free” the manipulated particle is with respect to its possible energy states: the more energetic freedom it has, the faster it is. In the case of the transport of an atom, for example, the deeper the valley into which the cesium atom is trapped, the more spread the energies of the quantum states in the valley are, and ultimately the faster the atom can be transported. Something similar can be seen in the example of the waiter: If he only fills the glasses half full (to the chagrin of the guests), he runs less risk that the champagne spills over as he accelerates and decelerates. However, the energetic freedom of a particle cannot be increased arbitrarily. “We can’t make our valley infinitely deep – it would cost us too much energy,” stresses Alberti.

Beam me up, Scotty!

The speed limit of Mandelstam and Tamm is a fundamental limit. However, one can only reach it under certain circumstances, namely in systems with only two quantum states. “In our case, for example, this happens when the point of origin and destination are very close to each other,” the physicist explains. “Then the matter waves of the atom at both locations overlap, and the atom could be transported directly to its destination in one go, that is, without any stops in between – almost like the teleportation in the Starship Enterprise of Star Trek.”

However, the situation is different when the distance grows to several dozens of matter wave widths as in the Bonn experiment. For these distances, direct teleportation is impossible. Instead, the particle must go through several intermediate states to reach its final destination: The two-level system becomes a multi-level system. The study shows that a lower speed limit applies to such processes than that predicted by the two Soviet physicists: It is determined not only by the energy uncertainty, but also by the number of intermediate states. In this way, the work improves the theoretical understanding of complex quantum processes and their constraints.

The physicists’ findings are important not least for quantum computing. The computations that are possible with quantum computers are mostly based on the manipulation of multi-level systems. Quantum states are very fragile, though. They last only a short lapse of time, which physicists call coherence time. It is therefore important to pack as many computational operations as possible into this time. “Our study reveals the maximum number of operations we can perform in the coherence time,” Alberti explains. “This makes it possible to make optimal use of it.”


The study was funded by the German Research Foundation (DFG) as part of the Collaborative Research Center SFB/TR 185 OSCAR. Funding was also provided by the Reinhard Frank Foundation in collaboration with the German Technion Society, and by the German Academic Exchange Service.

Featured image: First author Manolo Rivera Lam (left) and principal investigator Dr. Andrea Alberti (right) at the Institute of Applied Physics at the University of Bonn. © Volker Lannert/Uni Bonn

Publication: Manolo R. Lam, Natalie Peter, Thorsten Groh, Wolfgang Alt, Carsten Robens, Dieter Meschede, Antonio Negretti, Simone Montangero, Tommaso Calarco und Andrea Alberti: Demonstration of Quantum Brachistochrones between Distant States of an Atom; Physical Review X;

Provided by University of Bonn

Language is More Than Speaking: How the Brain Processes Sign Language (Neuroscience)

Over 70 million deaf people around the world use one of more than 200 different sign languages as their preferred form of communication. Although they access similar structures in the brain as spoken languages, it has been difficult to identify the brain regions that process both forms of language equally. Scientists at the Max Planck Institute for Human Cognitive and Brain Sciences (MPI CBS) have now discovered in a meta-analysis that Broca’s area in the left hemisphere of the brain, which has already been shown to be the central hub for spoken languages, is also the crucial brain region for sign languages. This is where the grammar and meaning of language are processed, regardless of whether it is spoken or signed language. This shows that our brain is generally specialized in processing linguistic information. Whether this information is spoken or signed seems to be of secondary importance.

The ability to speak is one of the essential characteristics that distinguishes humans from other animals. Many people would probably intuitively equate speech and language. However, cognitive science research on sign languages since the 1960s paints a different picture: Today it is clear, sign languages are fully autonomous languages and have a complex organization on several linguistic levels such as grammar and meaning. Previous studies on the processing of sign language in the human brain had already found some similarities and also differences between sign languages and spoken languages. Until now, however, it has been difficult to derive a consistent picture of how both forms of language are processed in the brain.

Researchers at the MPI CBS now wanted to know which brain regions are actually involved in the processing of sign language across different studies – and how large the overlap is with brain regions that hearing people use for spoken language processing. In a meta-study recently published in the journal Human Brain Mapping, they pooled data from sign language processing experiments conducted around the world. “A meta-study gives us the opportunity to get an overall picture of the neural basis of sign language. So, for the first time, we were able to statistically and robustly identify the brain regions that were involved in sign language processing across all studies,” explains Emiliano Zaccarella, last author of the paper and group leader in the Department of Neuropsychology at the MPI CBS.

The researchers found that especially the so-called Broca’s area in the frontal brain of the left hemisphere is one of the regions that was involved in the processing of sign language in almost every study evaluated. This brain region has long been known to play a central role in spoken language, where it is used for grammar and meaning. In order to better classify their results from the current meta-study, the scientists compared their findings with a database containing several thousand studies with brain scans.

The Leipzig-based researchers were indeed able to confirm that there is an overlap between spoken and signed language in Broca’s area. They also succeeded in showing the role played by the right frontal brain – the counterpart to Broca’s area on the left side of the brain. This also appeared repeatedly in many of the sign language studies evaluated, because it processes non-linguistic aspects such as spatial or social information of its counterpart. This means that movements of the hands, face and body – of which signs consist – are in principle perceived similarly by deaf and hearing people. Only in the case of deaf people, however, do they additionally activate the language network in the left hemisphere of the brain, including Broca’s area. They therefore perceive the gestures as gestures with linguistic content – instead of as pure movement sequences, as would be the case with hearing people.

The results demonstrate that Broca’s area in the left hemisphere is a central node in the language network of the human brain. Depending on whether people use language in the form of signs, sounds or writing, it works together with other networks. Broca’s area thus processes not only spoken and written language, as has been known up to now, but also abstract linguistic information in any form of language in general. “The brain is therefore specialized in language per se, not in speaking,” explains Patrick C. Trettenbrein, first author of the publication and doctoral student at the MPI CBS. In a follow-up study, the research team now aims to find out whether the different parts of Broca’s area are also specialized in either the meaning or the grammar of sign language in deaf people, similar to hearing people.

Featured image: Our brain is generally specialized in processing linguistic information. Whether this information is spoken or signed seems to be of secondary importance. © shutterstock

Reference: Trettenbrein, P. C., Papitto, G., Friederici, A. D., & Zaccarella, E. (2020), “The functional neuroanatomy of language without speech: An ALE meta-analysis of sign language”, Human Brain Mapping, 42(3), 699–712.

Provided by Max Planck Institute for Human Cognitive and Brain Sciences

Insight-HXMT Gives Insight into Origin of Fast Radio Bursts (Astronomy)

The latest observations from Insight-HXMT were published online in Nature Astronomy on Feb. 18. Insight-HXMT has discovered the very first X-ray burst associated with a fast radio burst (FRB) and has identified that it originated from soft-gamma repeater (SGR) J1935+2154, which is a magnetar in our Milky Way.

Insight-HXMT is the first to identify the double-spike structure of this X-ray burst as the high energy counterpart of FRB 200428. This discovery, together with results from other telescopes, proves that FRBs can come from magnetar bursts, thus resolving the longstanding puzzle concerning the origin of FRBs.

These results from Insight-HXMT also help explain the emission mechanism of FRBs, as well as the trigger mechanism of magnetar bursts.

This work was conducted by scientists from the Institute of High Energy Physics (IHEP) of the Chinese Academy of Sciences, Beijing Normal University, University of Nevada Las Vegas, Tsinghua University and other institutions.

FRBs, first discovered in 2007, are a great mystery in astronomy. They release a huge amount of energy in only several milliseconds. About a hundred such events have been detected in different regions of our universe. Moreover, repeated FRBs have been found from the same direction.

Considering the narrow field of view of radio telescopes, the event rate of FRBs is very high: Every day thousands of such bursts reach Earth. However, before this discovery by Insight-HXMT and several other space X-ray instruments, no FRB radiation at any other wavelength had ever been detected, and all FRBs with fairly good localization were from distant extragalactic sources, whose identity and nature are yet unknown. The origin and mechanisms of such mysterious phenomena constitute one of the biggest questions in astronomy today.

Scientists have proposed many models to explain the physical origin of FRBs, such as the merger of two compact objects, the collapse of a compact star, magnetar bursts, the collision of a neutron star and an asteroid, or even signals from aliens. In recent years, more observations have revealed more properties of FRBs, intensifying the debate on their origin.

In order to understand the nature of FRBs, we need to answer two questions: What is the source of FRBs, and what do FRBs look like in other wavebands?

On April 28, 2020 at 14:34 GMT, the Canadian CHIME experiment and the STARE2 experiment in the U.S. independently detected a very bright FRB, which was named FRB 200428. It came from roughly the same direction as the Galactic magnetar SGR J1935+2154. Based on the FRB’s dispersion measurement, the source of this FRB was located about 30,000 light-years away, which approximately agrees with the distance to SGR J1935+2154.

Magnetars are a group of neutron stars with extreme surface magnetic fields that are around 100 trillions of times stronger than the Earth’s magnetic field. When it’s active, a magnetar can emit bright short X-ray bursts. Therefore, theorists speculate that magnetars can also emit FRBs. In mid-April 2020, SGR J1935+2154 entered a new active period and hundreds of X-ray bursts were released.

In response to this opportunity, Insight-HXMT changed its observation plan and began a very long-duration pointing observation of SGR J1935+2154. About 8.6 second before FRB 200428, Insight-HXMT detected a very bright X-ray burst from SGR J1935+2154. This X-ray burst was also detected by the European satellite INTEGRAL, the Russian detector Konus-Wind and the Italian satellite AGILE.

The time difference is consistent with the time delay of the radio signal due to the interstellar medium. This indicates that the X-ray and radio emissions are from the same explosion.

Furthermore, Insight-HXMT was well able to localize this bright X-ray burst based on the unique design of its collimators, thus proving that both the X-ray burst and FRB 200428 originated from magnetar SGR J1935+2154. This represents not only the first confirmed source of an FRB, but also the first FRB originating in our Galaxy. It is a milestone in understanding the nature of FRBs and magnetars. The discovery of FRB 200428 and related research were recognized as one of the top 10 discoveries of 2020 by Nature and Science magazines.

In comparison with observational data from other high energy satellites, the observational data on FRB 200428 from Insight-HXMT are the most statistically rich and cover the broadest energy band, thus providing the most detailed temporal and spectral information on the X-ray burst.

Insight-HXMT is one of two satellites that independently localized this X-ray burst, showing much greater accuracy than two radio telescopes that detected FRB 200428. Insight-HXMT also detected, in the light curve of this X-ray burst, two X-ray spikes very closely aligned temporally with the FRB, a result later confirmed by other satellite data.

Finally, Insight-HXMT is the only instrument providing data for detailed analysis of the spectral evolution of this X-ray burst. Specifically, the X-ray spectrum of these two spikes is significantly different from spectra from other parts of the burst as well as from the majority of X-ray bursts from magnetars. These results are critical to understanding the physical mechanism of FRBs.

In summary, Insight-HXMT has discovered that this X-ray burst is from magnetar SGR J1935+2154, the two spikes of this X-ray burst are the high energy counterpart of FRB 200428, and the spectrum of this X-ray burst is special. These observations also show that Insight-HXMT is very powerful as a space observatory.

Insight-HXMT is China’s first X-ray observatory in space. It was first proposed by LI Tipei and WU Mei of IHEP in 1993. Insight-HXMT is funded by the China National Space Administration and CAS. IHEP is responsible for satellite payloads, the science data center and scientific research. The China Academy of Space Technology is the builder of the Insight-HXMT satellite platform. Tsinghua University, the National Space Science Center, Beijing Normal University and other institutes have also contributed to the Insight-HXMT mission. The calibration of the detectors on board Insight-HXMT was supported by the National Institute of Metrology, Ferrara University in Italy and the Max Planck Institute for Extraterrestrial Physics.

Since its launch on June 15, 2017, Insight-HXMT has successfully operated in orbit for more than 3.5 years. It has achieved a series of important scientific results on black holes, neutron stars and other phenomena.

As Insight-HXMT smoothly operates in orbit, the enhanced X-ray Timing and Polarimetry (eXTP) space mission, developed by IHEP and many other domestic and international partner institutions, has entered phase-B (design phase), after more than 10 years of preliminary study and key technology development. It will increase the capacity for studying neutron stars and black holes by an order of magnitude or more, compared with other similar satellites.

eXTP will bring China and the eXTP international consortium to the frontier of high energy space astronomy. The high energy counterparts of extragalactic FRBs are very weak due to their great distance. eXTP will be an ideal instrument for detecting them.

Reference: Li, C.K., Lin, L., Xiong, S.L. et al. HXMT identification of a non-thermal X-ray burst from SGR J1935+2154 and with FRB 200428. Nat Astron (2021).

Provided by Chinese Academy of Sciences

Life of a Pure Martian Design (Planetary Science)

Experimental microbially assisted chemolithotrophy provides an opportunity to trace the putative bioalteration processes of the Martian crust. A study on the Noachian Martian breccia Northwest Africa (NWA) 7034 composed of ancient (ca. 4.5 Gyr old) crustal materials from Mars, led by ERC grantee Tetyana Milojevic from the Faculty of Chemistry of the University of Vienna, now delivered a unique prototype of microbial life experimentally designed on a real Martian material. As the researchers show in the current issue of “Nature Communications Earth and Environment”, this life of a pure Martian design is a rich source of Martian-relevant biosignatures.

Early Mars is considered as an environment where life could possibly have existed. There was a time in the geological history of Mars when it could have been very similar to Earth and harbored life as we know it. In opposite to the current Mars conditions, bodies of liquid water, warmer temperature, and higher atmospheric pressure could have existed in Mars’ early history. Potential early forms of life on Mars should have been able to use accessible inventories of the red planet: derive energy from inorganic mineral sources and transform CO2 into biomass. Such living entities are rock-eating microorganisms, called “chemolithotrophs”, which are capable of transforming energy of stones to energy of life.

Martian rocks as energy source for ancient life forms

“We can assume that life forms similar to chemolithotrophs existed there in the early years of the red planet,” says astrobiologist Tetyana Milojevic, the head of Space Biochemistry group at the University of Vienna.  The traces of this ancient life (biosignatures) could have been preserved within the Noachian terrains with moisture-rich ancient geological history and mineral springs that could have been colonized by chemolithotrophs. In order to properly assess Martian relevant biosignatures, it is crucially important to consider chemolithotrophs in Martian relevant mineralogical settings.

A unique prototype of microbial life designed on a real Martian material: elemental ultrastructural analysis of an M. sedula cell grown on the genuine Noachian Martian breccia Black Beauty. (© Tetyana Milojevic)

One of rare pieces of Mars’ rocks was recently crushed to envisage how life based on Martian materials may look like. The researches used the genuine Noachian Martian breccia Northwest Africa (NWA) 7034 (nicknamed “Black Beauty”) to grow the extreme thermoacidophile Metallosphaera sedula, an ancient inhabitant of terrestrial thermal springs. This brecciated regolith sample represents the oldest known Martian crust of the ancient crystallization ages (ca. 4.5 Ga).

A specimen of “Black Beauty”

“Black Beauty is among the rarest substances on Earth, it is a unique Martian breccia formed by various pieces of Martian crust (some of them are dated at 4.42 ± 0.07 billion years) and ejected millions years ago from the Martian surface. We had to choose a pretty bold approach of crushing few grams of precious Martian rock to recreate the possible look of Mars’ earliest and simplest life form,” says Tetyana Milojevic, corresponding author of the study, about the probe that was provided by colleagues from Colorado, USA.

As a result, the researchers observed how a dark fine-grained groundmass of Black Beauty was biotransformed and used in order to build up constitutive parts of microbial cells in form of biomineral deposits. Utilizing a comprehensive toolbox of cutting edge techniques in fruitful cooperation with the Austrian Center for Electron Microscopy and Nanoanalysis in Graz, the researchers explored unique microbial interactions with the genuine Noachian Martian breccia down to nanoscale and atomic resolution. M. sedula living on Martian crustal material produced distinct mineralogical and metabolic fingerprints, which can provide an opportunity to trace the putative bioalteration processes of the Martian crust.

Analysing metabolic and mineralogical fingerprints

“Grown on Martian crustal material, the microbe formed a robust mineral capsule comprised of complexed iron, manganese and aluminum phosphates. Apart from the massive encrustation of the cell surface, we have observed intracellular formation of crystalline deposits of a very complex nature (Fe, Mn oxides, mixed Mn silicates). These are distinguishable unique features of growth on the Noachian Martian breccia, which we did not observe previously when cultivating this microbe on terrestrial mineral sources and a stony chondritic meteorite”, says Milojevic, who recently received an ERC Consolidator Grant for her research further investigating biogenicity of Martian materials.

4.42 billion years old Black Beauty specimen arrived at the Space Biochemistry Group, Vienna University (Milojevic Tetyana (left), Kölbl Denise) from Colorado, USA. A fragment of the genuine Noachian Martian breccia NWA 7034 (Black Beauty) used in the study. (© Oleksandra Kirpenko)

The observed multifaceted and complex biomineralization patterns of M. sedula grown on Black Beauty can be well stated by rich, diverse mineralogy and multimetallic nature of this ancient Martian meteorite. The unique biomineralization patterns of Black Beauty-grown cells of M. sedula emphasize the importance of experiments on genuine Martian materials for Mars-relevant astrobiological investigations. “Astrobiology research on Black Beauty and other similar ‘Flowers of the Universe’ can deliver priceless knowledge for the analysis of returned Mars samples in order to assess their potential biogenicity”, concludes Milojevic.

Featured image: A unique prototype of microbial life designed on a real Martian material: the scanning transmission electron microscopy image of M. sedula cell grown on Black Beauty. Image reveals nonhomogeneous, rugged and coarse cellular interior of M. sedula filled with crystalline deposits. (© Tetyana Milojevic)

Publication in Communications Earth & Environment:
T. Milojevic, M. Albu, D. Kölbl, G. Kothleitner, R. Bruner, M. Morgan “Chemolithotrophy on the Noachian Martian breccia NWA 7034 via experimental microbial biotransformation. Nature Communications Earth & Environment (2021), DOI: 10.1038/s43247-021-00105-x

Provided by University of Wein

Tuberculosis: New Biomarker Indicates Individual Treatment Duration (Medicine)

The treatment of tuberculosis (TB) is long, demanding, and expensive. In particular, the ever increasing emergence of resistant tuberculosis bacteria requires a lot of patience: In these cases, the WHO generally recommends a standard treatment duration of at least 18 months, as there are no reliable biomarkers for an early termination. Under the leadership of the DZIF scientists at the Research Center Borstel, six years of research have now succeeded in identifying a biomarker that points to an individual end of therapy based on the activity of 22 genes. In many cases, this probably allows the treatment to be shortened safely.

When can tuberculosis therapy be stopped without risk of relapse? Doctors are faced with this question time and again, because the lack of detection of the tuberculosis pathogen Mycobacterium tuberculosis is no guarantee for a permanent cure of the lung infection. Patients who respond to the standard therapy may be out of treatment after six months. But for resistant cases, more than 18 months of treatment duration is currently advised. “This is a very long time for those affected, who often have to take more than four antibiotics every day and suffer from side effects”, explains Prof. Dr Christoph Lange, Clinical Director at the Research Center Borstel and director of the study, conducted at the German Center for Infection Research (DZIF) in cooperation with the German Center for Lung Research (DZL). “We urgently need a biomarker that enables the implementation of an individualised treatment duration,” he emphasises. After all, not every patient needs so long to recover. 

Since the absence of bacteria in the sputum does not justify a safe stop in therapy, the team around Christoph Lange set out to find alternative biomarkers in the patient. In collaboration with international tuberculosis centres, on the basis of patient cohorts a model for the end of therapy could be developed that is based on an RNA determination in the blood. From many thousands of genes, 22 have been identified whose activity correlates with the course of the disease. “The production of RNA of these 22 genes in human blood can tell us whether the patient is cured,“ PD Dr Jan Heyckendorf from the FZ Borstel sums it up. Together with Maja Reimann and Dr Sebastian Marwitz, he is the lead author of the study. “It is an RNA signature from 22 genes identified on two cohorts and validated on another three cohorts,” adds the scientist. “No other published transcriptom marker shows comparable properties so far.”

To identify this individual biomarker, the scientists within the DZIF have established five different patient cohorts. In all cases, these were adults who had contracted pulmonary TB, partly from non-resistant, partly from resistant forms. In addition to cohorts in Germany, patients in Bucharest (Romania) were also included, where the DZIF supports a study centre.

”The individualisation of the treatment duration is an important milestone on the road to precision medicine for tuberculosis,” affirms Christoph Lange. Even without progression values, one could risk to end a patient’s treatment on the basis of this RNA determination. As a next step, the researchers are planning a prospective study at the DZIF. The aim is for patients in one study arm to receive treatment for as long as the biomarker suggests, while patients in the other arm receive treatment for as long as the national tuberculosis programme recommends. The scientists then want to see whether the biomarker makes a shorter treatment duration possible. The team around Christoph Lange is confident.

“Hopefully, it will then be possible for patients with multidrug-resistant tuberculosis to save about one-third of treatment on average,” says Lange.

Featured image: The treatment of tuberculosis (TB) is long, demanding, and expensive.© DZIF/scienceRELATIONS

Reference: Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew DiNardo, Gunar Günther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H.E. Kaufmann, Irina Kontsevaya, Frank van Leth, Anna Maria Mandalakas, Florian P. Maurer, Marius Müller, Dörte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J.F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner 3rd, Torsten Goldmann, Christoph Lange, “Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model”, European Respiratory Journal 2021; DOI: 10.1183/13993003.03492-2020

Provided by DZIF

Atomic Nuclei In The Quantum Swing (Quantum)

The extremely precise control of nuclear excitations opens up possibilities of ultra-precise atomic clocks and powerful nuclear batteries

From atomic clocks to secure communication to quantum computers: these developments are based on the increasingly better control of the quantum behaviour of electrons in atomic shells with the help of laser light. Now, for the first time, physicists at the Max Planck Institute for Nuclear Physics in Heidelberg have succeeded in precisely controlling quantum jumps in atomic nuclei using X-ray light. Compared with electron systems, nuclear quantum jumps are extreme – with energies up to millions of times higher and incredibly short zeptosecond processes. A zeptosecond is one trillionth of a billionth of a second. The rewards include profound insight into the quantum world, ultra-precise nuclear clocks, and nuclear batteries with enormous storage capacity. The experiment required a sophisticated X-ray flash facility developed by a Heidelberg group led by Jörg Evers as part of an international collaboration.

One of the great successes of modern physics is the increasingly precise control of dynamic quantum processes. It enables a deeper understanding of the quantum world with all its oddities and is also a driving force of new quantum technologies. But from the perspective of the atoms, “coherent control” has so far remained superficial: it is the quantum jump of the electrons in the outer shell of the atoms that has become increasingly controllable by lasers. But as Christoph Keitel explains, the atomic nuclei themselves are also quantum systems in which the nuclear building blocks can make quantum jumps between different quantum states.

Energy-rich quantum jumps for nuclear batteries

“In addition to this analogy to electron shells, there are huge differences”, explains the Director at the Max Planck Institute for Nuclear Physics in Heidelberg: “They’ve got us so excited!” Quantum jumps between different quantum states are actually jumps on a kind of energy ladder. “And the energies of these quantum jumps are often six orders of magnitude greater than in the electron shell”, says Keitel. A single quantum jump made by a nuclear component can thus pump up to a million times more energy into it – or get it out again. This has given rise to the idea of nuclear batteries with an unprecedented storage capacity.

Such technical applications are still visions of the future. At the moment, research entails addressing and controlling these quantum jumps in a targeted manner. This requires precisely controlled, high-energy X-ray light. The Heidelberg team has been working on such an experimental technique for over 10 years. It has now been used for the first time.

Accurate frequencies enable ultra-precise atomic clocks

The quantum states of atomic nuclei offer another important advantage over electron states. Compared with the electronic quantum jumps, they are much more sharply defined. Because this translates directly into more accurate frequencies according to the laws of physics, they can, in principle, be used for extremely precise measurements. For example, this could enable the development of ultra-precise nuclear clocks that would make today’s atomic clocks look like antiquated pendulum clocks. In addition to technical applications of such clocks (e.g. in navigation), they could be used to examine the fundamentals of today’s physics much more precisely. This includes the fundamental question of whether the constants of nature really are constant. However, such precision techniques require the control of quantum transitions in the nuclei.

Scheme of the experiment. The first sample generates a double pulse from the synchrotron pulse. By moving the sample, the second pulse is delayed with respect to the first. The first pulse then excites atomic nuclei of the second sample. The strength of the excitation can be controlled by delaying the second pulse. © MPI for Nuclear Physics

Coordinated light flashes enhance or reduce the excitation

The principle of the Heidelberg experimental technique sounds quite simple at first. It uses pulses (i.e. flashes) of high-energy X-ray light, which are currently provided by the European Synchrotron Radiation Source ESRF in Grenoble. The experiment splits these X-ray pulses in a first sample in such a way that a second  pulse follows behind the rest of the first pulse with a time delay. One after the other, both encounter a second sample, the actual object of investigation.

The first pulse is very brief and contains a broad mix of frequencies. Like a shotgun blast, it stimulates a quantum jump in the nuclei; in the first experiment, this was a special quantum state in  nuclei of  iron atoms. The second pulse is much longer and has an energy that is precisely tuned to the quantum jump. In this way, it can specifically manipulate the quantum dynamics triggered by Pulse 1. The time span between the two pulses can be adjusted. This allows the team to adjust whether the second pulse is more constructive or destructive for the quantum state.

The Heidelberg physicists compare this control mechanism to a swing. With the first pulse, you push it. Depending on the phase of its oscillation in which you give it a second push, it oscillates even stronger or is slowed down.

Pulse control accurate to a few zeptoseconds

But what sounds simple is a technical challenge that required years of research. A controlled change in the quantum dynamics of an atomic nucleus requires that the delay of the second pulse is stable on the unimaginably short time scale of a few zeptoseconds. Because only then do the two pulses work together in a controlling way.

A zeptosecond is one trillionth of a billionth of a second – or a decimal point followed by 20 zeroes and a 1. In one zeptosecond, light does not even manage to pass through one per cent of a medium-sized atom. How can you imagine this in relation to our world? “If you imagine that an atom were as big as the Earth, that would be about 50 km, says Jörg Evers, who initiated the project.

The sample is shifted by 45 trillionths of a metre

Principle of coherent control using the example of tuning forks representing the two samples in the experiment. A bang (left, blue) excites both tuning forks to oscillate – analogous to the synchrotron pulse. After the bang, the sound of the first fork additionally hits the second fork as the second part of the double pulse. Depending on the delay with which the sound from the first fork hits the second, the vibration of the second fork is either dampened (a) or amplified (b). The control of quantum dynamics in atomic nuclei works in an analogous way. © MPI for Nuclear Physics

The second X-ray pulse is delayed by a tiny displacement of the first sample, also containing iron nuclei with the appropriate quantum transition. “The nuclei selectively store energy from the first X-ray pulse for a short period of time during which the sample is rapidly shifted by about half a wavelength of X-ray light”, explains Thomas Pfeifer, Director at the Max Planck Institute for Nuclear Physics in Heidelberg. This corresponds to about 45 trillionths of a metre. After this tiny movement, the sample emits the second pulse.

The physicists compare their experiment to two tuning forks that are at different distances from a firecracker (Figure 2). The bang first strikes the closer tuning fork, making it vibrate, and then moves on to the second tuning fork. In the meantime, the first tuning fork, now excited, emits sound waves itself, which arrive with a delay at the second fork. Depending on the delay time, this sound either amplifies or dampens the vibrations of the second fork – just like the second push on the oscillating swing, as well as for the case of the excited nuclei.

With this experiment, Jörg Evers, Christoph Keitel, and Thomas Pfeifer and their team from the Max Planck Institute for Nuclear Physics in cooperation with researchers from DESY in Hamburg and the Helmholtz Institute/Friedrich Schiller University in Jena succeeded for the first time in demonstrating coherent control of nuclear excitations. In addition to synchrotron facilities such as those at the ESRF, free-electron lasers (FELs) such as the European XFEL at DESY have recently provided powerful sources of X-ray radiation – even in laser-like quality. This opens up a dynamic future for the emerging field of nuclear quantum optics.

Featured image: Max Planck Institute in Heidelberg excites nuclei of iron atoms with a flash of X-ray light and then sends a second such flash onto the sample with different delays and detuning. Then, over a period of about 200 nanoseconds, the researchers measure the intensity of the light with which the nuclei release the absorbed energy (light yellow: high intensity; violet: low intensity). They can choose the delay so that the second flash reduces the excitation and the nuclei release their energy quickly and with high intensity (a). After only 50 nanoseconds, the emission has decreased significantly. In contrast, they still emit a relatively large amount of light after more than 100 nanoseconds if the second pulse amplifies the excitation from the first (b). © MPI for Nuclear Physics

Reference: Heeg, K.P., Kaldun, A., Strohm, C. et al. Coherent X-ray−optical control of nuclear excitons. Nature 590, 401–404 (2021).

Provided by Max Planck Gesellschaft