Appearance Of Cystic Fibrosis At the Molecular Scale (Biology)

Despite remarkable medical advances over the last years, cystic fibrosis remains the most prevalent lethal genetic disease. It is due to mutations in the CFTR protein which is normally required to maintain proper fluid balances in key organs such as lungs, pancreas or the digestive system.

In most cases, the causative mutation, called F508del, involves only one of the 1.480 amino acids that make up the CFTR protein. This apparently minor change leads to strong deleterious effects in the protein, which becomes unable to perform its normal biological function, leading to the emergence of the disease. For years, researchers have attempted to understand how and why a simple mutation triggers such large effects on the protein structure and function, with dramatic consequences for the patients.

Using a combination of cutting-edge methods such as single-molecule fluorescence, X-ray crystallography, hydrogen-deuterium exchange and single molecule electrophysiology, researchers led by Cédric Govaerts—Laboratoire Structure & Fonction des membranes biologiques, Faculté des Sciences, Université libre de Bruxelles—have uncovered a completely new phenomenon in CFTR: while proteins are expected to adopt a single conformation that enables a single biological function, they have observed a new conformation of CFTR.

This structure had not been observed before and demonstrates that CFTR is not a fixed molecule but can alternate between (at least) two different conformations with potentially different functions.

Astonishingly, researchers have also observed that the most prevalent mutation, F508del, does not affect the structures themselves, but rather the transitions between them. In other words, they propose that disease-causing mutations such as F508del may not, like previously believed, perturb the final conformation of the protein but, rather the dynamics, specifically the ability of the protein to exchange between different states within the cell.

This observation changes our understanding of CFTR biology and of cystic fibrosis. In addition, his phenomenon could apply to other proteins and thus allow to understand other genetic diseases.

Featured image: Graphical abstract. Credit: DOI: 10.1038/s41589-021-00844-0


Reference: Daniel Scholl et al, A topological switch in CFTR modulates channel activity and sensitivity to unfolding, Nature Chemical Biology (2021). DOI: 10.1038/s41589-021-00844-0


Provided by Université libre de Bruxelles

Researchers Developed Photoirradiation-based Super-resolution Gene Analysis Technology (Biology)

High potentiality for applications in various fields including pathological diagnosis of cancer cells hiding out in a biological tissue

A Japanese research group developed a technology termed Photo-Isolation Chemistry (PIC) and successfully detected genes acting in very small cell populations and in intracellular microstructures by photoirradiation.

Humans and other multicellular organisms are known to be composed of at least 100 different types of cells, which are subdivided into smaller groups of cells with unique functions and characteristics depending on their spatial localizations. As these cells lose their intrinsic characters once they are isolated from an organ or tissue, analysis focusing exclusively on a specific type of cells has to be done without tissue destruction; however, conventional techniques did not have the capacity of meeting such a requirement.

Figure 2. PIC for the hippocampus of mouse brains(a) Sections of the brain were prepared and PIC was performed by photo-irradiation to CA1, CA3, or dentate gyrus (DG) regions of the mouse hippocampus. (b) As a result, the expression levels of Ociad2 and Wfs1 in CA1, Dkk3 in CA3, and Prox1 and Pdzd2 in the DG were determined to be high, which is consistent with the results of a previous paper analyzing their gene expression patterns. © Shinya Oki and Yasuyuki Ohkawa

A research group led by Professor Yasuyuki Ohkawa at the Medical Institute of Bioregulation, Kyushu University and Program-specific Associate Professor Shinya Oki at Graduate School of Medicine, Kyoto University developed a technology to isolate information on gene expression only from a photo-irradiated area, inspired by an ultrafine technology with photo-etching in a semiconductor manufacturing process. With this technology termed PIC, they photo-irradiated various areas in the brain and successfully detected the genes expressed in a specific domain of hippocampus. They also applied PIC to comprehensively detect the genes in very small cell populations of a mouse fetus, as well as those in intracellular microstructures smaller than one micron (1/1000 mm), which cannot be detected with conventional methods.

PIC is characterized as one of the technologies called “spatial transcriptomics”, where many researchers are competitively developing new technologies worldwide to link the gene expression with spatial information. Many of the spatial transcriptomics technologies require a large cost to use. In contrast, PIC requires only several dollars in addition to the cost for existing gene analysis techniques. In the future, PIC is expected to be used in pathological diagnosis involving clinical tissue specimens containing mixed normal and abnormal cells, such as diagnosis of cancer and inflammatory responses associated with COVID-19.

Figure 3. PIC for the nuclear speckles
(a) PIC was performed by photo-irradiating to the nuclear speckles in the nucleus of the cell or to other nuclear regions. (b) As a result, AKR1C2 and MALAT1 genes were identified as abundant.
© Shinya Oki and Yasuyuki Ohkawa

This research is conducted under the JST’s Strategic Basic Research Programs CREST (Team type) “Innovative Technology Platforms for Integrated Single Cell Analysis” and PRESTO (Individual researcher type) “Dynamics of Cellular Interactions in Multicellular System.”

Featured image: A principle of PIC technology to detect gene expression from photo-irradiated areas.1) A primer with a photocleavable blocker is dropped onto the section. The RNA of the gene is then converted to DNA by the reverse transcription reaction. 2) The blocker is then removed from the primer when the target cells are photo-irradiated. 3) Only the gene from the photo-irradiated areas are amplified and detected. © Shinya Oki and Yasuyuki Ohkawa


Journal Information

Mizuki Honda, Shinya Oki, Ryuichi Kimura, Akihito Harada, Kazumitsu Maehara, Kaori Tanaka, Chikara Meno and Yasuyuki Ohkawa, “High-depth spatial transcriptome analysis by photo-isolation chemistry” Nature Communications. Published online July 20, 2021,doi: 10.1038/s41467-021-24691-8


Provided by JSTA

Giraffes Are As Socially Complex As Elephants, Study Finds (Biology)

Scientists at the University of Bristol have discovered evidence that giraffes are a highly socially complex species.

Traditionally, giraffes were thought to have little or no social structure, and only fleeting, weak relationships. However in the last ten years, research has shown that giraffe social organisation is much more advanced than once thought.

In a paper published in today in the journal Mammal ReviewZoe Muller, of Bristol’s School of Biological Sciences, has demonstrated that giraffes spend up to 30% of their lives in a post-reproductive state.  This is comparable to other species with highly complex social structures and cooperative care, such as elephants and killer-whales which spend 23% and 35% of their lives in a post-reproductive state respectively. In these species, it has been demonstrated that the presence of post-menopausal females offers survival benefits for related offspring. In mammals – and –ncluding humans – this is known as the ‘Grandmother hypothesis’ which suggests that females live long past menopause so that they can help raise successive generations of offspring, thereby ensuring the preservation of their genes. Researchers propose that the presence of post-reproductive adult female giraffes could also function in the same way, and supports the author’s assertion that  giraffes are likely to engage in cooperative parenting, along matrilines, and contribute to the shared parental care of related kin.

Zoe said: “It is baffling to me that such a large, iconic and charismatic African species has been understudied for so long. This paper collates all the evidence to suggest that giraffes are actually a highly complex social species, with intricate and high-functioning social systems, potentially comparable to elephants, cetaceans and chimpanzees.

“I hope that this study draws a line in the sand, from which point forwards, giraffes will be regarded as intelligent, group-living mammals which have evolved highly successful and complex societies, which have facilitated their survival in tough, predator-filled ecosystems.” 

For scientists to recognise giraffes as a socially complex species, Zoe has suggested eight key areas for future research, including the need to understand the role that older, post-reproductive adults play in society and what fitness benefits they bring for group survival.

Zoe added: “Recognising that giraffes have a complex cooperative social system and live in matrilineal societies will further our understanding of their behavioural ecology and conservation needs.

“Conservation measures will be more successful if we have an accurate understanding of the species’ behavioural ecology. If we view giraffes as a highly socially complex species, this also raises their ‘status’ towards being a more complex and intelligent mammal that is increasingly worthy of protection.”

Paper:

‘A review of the social behaviour of the giraffe Giraffa camelopardalis: a misunderstood but socially complex species’ in Mammal Review by Zoe Muller and Professor Stephen Harris.


Provided by University of Bristol

Skull of 340 Million Year Old Animal Digitally Recreated Revealing Secrets of Ancient Amphibian (Paleontology)

Researchers from the University of Bristol and University College London have used cutting-edge techniques to digitally reconstruct the skull of one of the earliest limbed animals.

Tetrapods include mammals, reptiles and amphibians – everything from salamanders to humans. Their origin represents a crucial time in animal evolution, from the development of limbs with digits and the shift from water on to land. The study, which was recently published in the Journal of Vertebrate Paleontology, depicts the reconstructed skull of a prehistoric amphibian, the 340-million year old Whatcheeria deltae, to reveal what this animal looked like and how it may have fed.

First discovered in Iowa in 1995, the fossils of Whatcheeria were originally squashed flat after being buried by mud at the bottom of an ancient swamp, but palaeontologists were able to use computational methods to restore the bones to their original arrangement. The fossils were put through a CT scanner to create exact digital copies, and software was used to separate each bone from the surrounding rock. These digital bones were then repaired and reassembled to produce a 3D model of the skull as it would have appeared while the animal was alive.

The authors found that Whatcheeria possessed a tall and narrow skull quite unlike many other early tetrapods that were alive at the time. Lead author James Rawson, who worked on this project alongside his undergraduate degree in palaeontology and evolution, said: “Most early tetrapods had very flat heads which might hint that Whatcheeria was feeding in a slightly different way to its relatives, so we decided to look at the way the skull bones were connected to investigate further.”

By tracing the connecting edges of the skull bones, known as sutures, the authors were able to figure out how this animal tackled its prey. Professor Emily Rayfield, of the University of Bristol’s School of Earth Sciences, who also worked on the study, said: “We found that the skull of Whatcheeria would have made it well-adapted to delivering powerful bites using its large fangs.”

Co-author Dr Laura Porro said: “There are a few types of sutures that connect skull bones together and they all respond differently to various types of force. Some are better at dealing with compression, some can handle more tension, twisting and so on. By mapping these suture types across the skull, we can predict what forces were acting on it and what type of feeding may have caused those forces.”

The authors found that the snout had lots of overlapping sutures to resist twisting forces from struggling prey, while the back of the skull was more solidly connected to resist compression during biting.

Mr Rawson added: “Although this animal was still probably doing most of its hunting in the water, a bit like a modern crocodilian, we’re starting to see the sorts of adaptations that enabled later tetrapods to feed more efficiently on land.”

Paper:

‘Osteology and digital reconstruction of the skull of the early tetrapod Whatcheeria deltae’ in Journal of Vertebrate Paleontology by James Rawson, Dr Laura Porro, Dr Elizabeth Martin-Silverstone and Professor Emily Rayfield.

Featured image: Skull fossils of amphibian. Credit: Field Museum of Natural History, Chicago


Provided by University of Bristol

New Viable Ways Of Storing Information For Quantum Technologies? (Quantum)

Quantum information could be the source of the next technological revolution. By analogy with the bit in classical computing, the qubit is the basic element of quantum computing. But demonstrating the existence of this information storage unit and using it is still complex and therefore limited. In a study published on August 3, 2021 in Physical Review X , an international research team, composed by Fabio Pistolesi, CNRS researcher and two foreign researchers, succeeded by theoretical calculations to show that it is possible to realize a new type of qubit where information is stored in the oscillation amplitude of a carbon nanotube. 

Indeed, these nanotubes are able to perform a large number of oscillations without fading, which shows their weak interaction with the environment and makes them excellent potential qubits. This property would allow greater reliability in quantum computation. However, a problem persisted in reading and writing the information stored in the first two energy levels of these oscillators. 

Scientists have succeeded in proving that it is possible to read this information by exploiting the coupling between electrons, a negatively charged particle, and the bending mode of these nanotubes. This makes it possible to sufficiently change the spacing between the first energy levels and thus make them accessible independently of the other levels to read the information they contain. It now remains to experimentally verify these promising theoretical predictions.

To find out more: A computer to be reinvented for quantum computing

Featured image: Representation of the bending mode of a nanotube shown here in turquoise blue, and the locations of electrons in red and brown in the tube. © Fabio Pistolesi


Bibliography

Proposal for a Nanomechanical Qubit . F. Pistolesi, AN Cleland and A. Bachtold. Physical Review X , August 3, 2021. https://doi.org/10.1103/PhysRevX.11.031027


Provided by CNRS

Researchers Discovered Molecular Dance That Could Eliminate Soot Pollution (Chemistry)

A hidden molecular dance has been revealed that could hold the answer to the problem of soot pollution.

Soot pollution invades our bodies, causing cancer and blood clots as well as weakening us to respiratory viruses. Our atmosphere and glaciers are also blanketed by soot, leading to global heating and increased ice loss. Surprisingly, the way that soot particles form is still unknown but is of pressing concern to solve these global problems.

The reason for this long-running mystery is due to the extreme environment in which soot forms, the rapid speed of the reactions and the complex collection of molecules present in the flame. All of these obscure the pathway to soot formation.

An international team from the UK, Singapore, Switzerland and Italy has used two different microscopes to reveal the molecules and reactions taking place in a flame.

The first microscope operates by touch, feeling for the arrangement of atoms in the molecules of soot. These tactile maps provide the first picture of soot’s molecular chicken wire shape. Quantum chemistry was then used to show that one of the molecules was a reactive diradical. A diradical is a type of molecule with two reactive sites, allowing it to undergo a succession of chain reactions.

The second microscope is entirely virtual and shows the reaction between the diradicals. Quantum mechanics guided a supercomputer to virtually and realistically collide the molecules together and reveal the molecular dance in slow motion.

This simulation showed that the individual molecules are held together by intermolecular forces after they collide. This gives the reactive sites time to find each other and create a permanent chemical bond. Even after they have bonded they remain reactive, allowing more molecules to “stick” to what is now a rapidly growing soot particle.

This discovery could resolve the problems with previous attempts to explain soot formation via either a physical condensation or chemical reaction. In fact, both are required to adequately explain the rapid and high-temperature reactions.

One of the paper’s lead authors, Jacob Martin, commented, “If the concentration of these species is high enough in flames, this pathway could provide an explanation for the rapid formation of soot.”

Co-author Markus Kraft, from the University of Cambridge’s Department of Chemical Engineering and Biotechnology, said, “The project brought together cutting-edge computational modelling and experiments to reveal a completely new reaction pathway which potentially explains how soot is formed. Scientists and engineers have been working on solving this important problem for decades.”

The researchers hope to target these reactive sites to see whether the soot formation process can be halted in its tracks. One promising option is the injection of ozone into a flame, which has already been found to effectively eliminate soot in some preliminary results in other work.

“Diradical aromatic soot precursors in flames” (DOI: 10.1021/jacs.1c05030) is published in Journal of the American Chemical Society by researchers from Cambridge Centre for Advanced Research and Education in Singapore Ltd, University of Cambridge, IBM Research Zurich, Consiglio Nazionale delle Ricerche and Università degli Studi di Napoli Federico II. 

This research is supported by the National Research Foundation, Prime Minister’s Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme.


Provided by Cambridge Cares

Researchers Observed an Unexpected Response To Electron Injection In The Mott Insulator (Physics)

Unexpected peaks in a spectrum upset conventional models of an exotic quantum material

In a finding that will give theorists plenty to ponder, an all-RIKEN team has observed an unexpected response in an exotic material known as a Mott insulator when they injected electrons into it1. This observation promises to give physicists new insights into such materials, which are closely related to high-temperature superconductors.

Neither a chunk of silicon nor a Mott insulator conduct electricity—but for very different reasons. In silicon, electrons are tightly bound to atoms and require a lot of energy to become mobile conduction electrons. In contrast, in a Mott insulator, electrons may not be strongly bound to the atoms, but their movement is instead curbed by their mutual repulsion.

The Mott state’s emergence from interactions between electrons leads to unusual properties. “A small excess or deficit of electrons in a Mott insulator can lead to high-temperature superconductivity, which could be of enormous practical value in the future,” says Christopher Butler of the RIKEN Center for Emergent Matter Science (CEMS). “In Mott-insulating tantalum disulphide, electrons are localized not at each atom, but instead on the crests of a pre-existing ‘charge density wave’. Because the charge density wave is rather delicate, the Mott state can easily be tweaked.”

But to harness the potential of this Mott-insulating state and the charge density wave that hosts it, scientists need to better understand the physics connecting them.

Now, Butler and three colleagues, all at CEMS, have added excess electrons to a Mott insulator using the tip of a scanning tunneling microscope (Fig. 1) and observed a surprising response—tunneling spectra showed a sharp feature, a distinct state that set off vibrations in the ionic lattice.

The conventional theoretical model for Mott insulators predicts that the spectrum should be smooth and non-descript. “It was most surprising that we saw such sharp features in our tunneling spectroscopy measurements,” says Butler. “They may indicate that something is going on that is outside the bounds of the usual theory.”

Butler notes that some theoretical calculations do predict sharp features similar to those his team saw, but they involve particle-like entities known as quasiparticles, which are controversial since they are not thought to exist in true Mott insulators. “There are competing explanations for the observation that are less controversial,” says Butler. “But if it eventually turns out that the calculation results indicating the existence of quasiparticles are right, it might shake up the theoretical understanding of Mott insulators.”

Figure 1: RIKEN physicists used the tip of a scanning tunneling microscope (gray inverted pyramid) to inject single electrons (gold sphere) into the surface of a Mott insulator). © RIKEN Center for Emergent Matter Science


Reference

  • 1.Butler, C.  J., Yoshida, M., Hanaguri, T. & Iwasa, Y. Doublonlike excitations and their phononic coupling in a Mott charge-density-wave system. Physical Review X 11 011059 (2021). doi: 10.1103/PhysRevX.11.011059

Provided by RIKEN

Does Visual Feedback of Our Tongues Help in Speech Motor Learning? (Biology)

When we speak, although we may not be aware of it, we use our auditory and somatosensory systems to monitor the results of the movements of our tongue or lips.

This sensory information plays a critical role in how we learn to speak and maintain accuracy in these behaviors throughout our lives. Since we cannot typically see our own faces and tongues while we speak, however, the potential role of visual feedback has remained less clear.

In the Journal of the Acoustical Society of America, University of Montreal and McGill University researchers present a study exploring how readily speakers will integrate visual information about their tongue movements — captured in real time via ultrasound — during a speech motor learning task.

“Participants in our study, all typical speakers of Quebec French, wore a custom-molded prosthesis in their mouths to change the shape of their hard palate, just behind their upper teeth, to disrupt their ability to pronounce the sound ‘s’ — in effect causing a temporary speech disorder related to this sound,” said Douglas Shiller, an associate professor at the University of Montreal.

One group received visual feedback of their tongue with a sensor under their chin oriented to provide an ultrasound image within the sagittal plane (a slice down the midline, front to back).

A second group also received visual feedback of their tongue. In this case, the sensor was oriented at 90 degrees to the previous condition with an image of the tongue within the coronal plane (across the tongue from left to right).

A third group, the control group, received no visual feedback of their tongue.

All participants were given the opportunity to practice the “s” sound with the prosthesis in place for 20 minutes.

“We compared the acoustic properties of the ‘s’ across the three groups to determine to what degree visual feedback enhanced the ability to adapt tongue movements to the perturbing effects of the prosthesis,” said Shiller.

As expected, participants in the coronal visual feedback group improved their “s” production to a greater degree than those receiving no visual feedback.

“We were surprised, however, to find participants in the sagittal visual feedback group performed even worse than the control group that received no visual feedback,” said Shiller. “In other words, visual feedback of the tongue was found to either enhance motor learning or interfere with it, depending on the nature of the images being presented.”

The group’s findings broadly support the idea that ultrasound tools can improve speech learning outcomes when used, for example, in the treatment of speech disorders or learning new sounds in a second language.

“But care must be taken in precisely how visual information is selected and presented to a patient,” said Shiller. “Visual feedback that isn’t compatible with the demands of the speaking task may interfere with the person’s natural mechanisms of speech learning — potentially leading to worse outcomes than no visual feedback at all.”

Featured image: These images show the real-time visual feedback of the tongue in sagittal (A) and coronal (B) planes, and for each condition the orientation of the ultrasound transducer is shown below. CREDIT: Guillaume Barbier, Ryme Merzouki, Mathilde Bal, Shari R. Baum, and Douglas M. Shiller

Reference

ARTICLE TITLE

Visual feedback of the tongue influences speech adaptation to a physical modification of the oral cavity

AUTHORS

Guillaume Barbier, Ryme Merzouki, Mathilde Bal, Shari R. Baum, and Douglas M. Shiller

AUTHOR AFFILIATIONS

University of Montreal and McGill University


Link to article: Visual feedback of the tongue influences speech adaptation to a physical modification of the oral cavity
DOI: 10.1121/10.0005520


Provided by AIP Publishing

How Physical Forces Influence Food Digestion Based on Fluid Dynamics? (Biology)

In efforts to fight obesity and enhance drug absorption, scientists have extensively studied how gastric juices in the stomach break down ingested food and other substances. However, less is known about how the complex flow patterns and mechanical stresses produced in the stomach contribute to digestion.

Researchers from France, Michigan, and Switzerland built a prototype of an artificial antrum, or lower stomach, to present a deeper understanding of how physical forces influence food digestion based on fluid dynamics. In Physics of Fluids, by AIP Publishing, they reveal a classifying effect based on the breakup of liquid drops combined with transport phenomena derived from complementary computer simulations.

The relevant parts of the stomach are the corpus, where food is stored; the antrum, where food is ground; and the pylorus, or pyloric sphincter, the tissue valve that connects to the small intestine. Slow-wave muscle contractions begin in the corpus, with wave speed and amplitude increasing to form the antral contraction waves (ACWs) as they propagate toward the pylorus.

The researchers’ antrum device consists of a cylinder, capped at one end to imitate a closed pylorus, and a hollow piston that moves inside the cylinder to replicate ACWs. As verified through computer simulations and experimental measurements, the protype produces the characteristics of retropulsive jet flow that exist in the antrum.

Food disintegration is quantified by determining the breakup of liquid drops in flow fields produced by ACWs. The researchers studied different model fluid systems with various viscosity to account for the broad physical properties of digested food. The drop size and other parameters resemble conditions in a real stomach.

Drop breakup occurred near the surface of the hollow piston, where the flow field exhibited slower velocities but higher strain rates, thus exposing the drop to higher shear stresses during a longer period of time. No breakup occurred for drops near the center of the piston, because the stresses and residence times are smaller and shorter.

“The results extracted from this simple prototype have deepened insights into the disintegration process that takes place in the stomach,” co-author Damien Dufour said. “Drops near the wall will break up as they are transported toward the pylorus. The drops in the center return toward the corpus, without major size reduction, to disintegrate later. One may perceive this combined action of the ACWs as a classifying effect.”

Reference

ARTICLE TITLE

Investigation of the dispersing characteristics of antral contraction wave flow in a simplified model of the distal stomach

AUTHORS

Damien Dufour, Franz X. Tanner, Kathleen Feigl, and Erich J. Windhab

AUTHOR AFFILIATIONS

Technology and Strategy Group, France; Michigan Technological University, and the Swiss Federal Institute of Technology

Featured image: Illustration depicts the flow field and the drop breakup around antral contraction waves. CREDIT: Damien Dufour


Link to article: Investigation of the dispersing characteristics of antral contraction wave flow in a simplified model of the distal stomach
DOI: 10.1063/5.0053996


Provided by AIP Publishing