Category Archives: Biology

How Molecular Clusters in the Nucleus Interact With Chromosomes? (Biology)

A new study finds the clusters form small, stable droplets and may give the genome a gel-like structure.

A cell stores all of its genetic material in its nucleus, in the form of chromosomes, but that’s not all that’s tucked away in there. The nucleus is also home to small bodies called nucleoli — clusters of proteins and RNA that help build ribosomes.

Using computer simulations, MIT chemists have now discovered how these bodies interact with chromosomes in the nucleus, and how those interactions help the nucleoli exist as stable droplets within the nucleus.

Their findings also suggest that chromatin-nuclear body interactions lead the genome to take on a gel-like structure, which helps to promote stable interactions between the genome and transcription machineries. These interactions help control gene expression.

“This model has inspired us to think that the genome may have gel-like features that could help the system encode important contacts and help further translate those contacts into functional outputs,” says Bin Zhang, the Pfizer-Laubach Career Development Associate Professor of Chemistry at MIT, an associate member of the Broad Institute of Harvard and MIT, and the senior author of the study.

MIT graduate student Yifeng Qi is the lead author of the paper, which appears today in Nature Communications.

Modeling droplets

Much of Zhang’s research focuses on modeling the three-dimensional structure of the genome and analyzing how that structure influences gene regulation.

In the new study, he wanted to extend his modeling to include the nucleoli. These small bodies, which break down at the beginning of cell division and then re-form later in the process, consist of more than a thousand different molecules of RNA and proteins. One of the key functions of the nucleoli is to produce ribosomal RNA, a component of ribosomes.

Recent studies have suggested that nucleoli exist as multiple liquid droplets. This was puzzling because under normal conditions, multiple droplets should eventually fuse together into one large droplet, to minimize the surface tension of the system, Zhang says.

“That’s where the problem gets interesting, because in the nucleus, somehow those multiple droplets can remain stable across an entire cell cycle, over about 24 hours,” he says.

To explore this phenomenon, Zhang and Qi used a technique called molecular dynamics simulation, which can model how a molecular system changes over time. At the beginning of the simulation, the proteins and RNA that make up the nucleoli are randomly distributed throughout the nucleus, and the simulation tracks how they gradually form small droplets.

In their simulation, the researchers also included chromatin, the substance that makes up chromosomes and incudes proteins as well as DNA. Using data from previous experiments that analyzed the structure of chromosomes, the MIT team calculated the interaction energy of individual chromosomes, which allowed them to provide realistic representations of 3D genome structures.

Using this model, the researchers were able to observe how nucleoli droplets form. They found that if they modeled the nucleolar components on their own, with no chromatin, they would eventually fuse into one large droplet, as expected. However, once chromatin was introduced into the model, the researchers found that the nucleoli formed multiple droplets, just as they do in living cells.

The researchers also discovered why that happens: The nucleoli droplets become tethered to certain regions of the chromatin, and once that happens, the chromatin acts as a drag that prevents the nucleoli from fusing to each other.

“Those forces essentially arrest the system into those small droplets and hinder them from fusing together,” Zhang says. “Our study is the first to highlight the importance of this chromatin network that could significantly slow down the fusion and arrest the system in its droplet state.”

Gene control
 

The nucleoli are not the only small structures found in the nucleus — others include nuclear speckles and the nuclear lamina, an envelope that surrounds the genome and can bind to chromatin. Zhang’s group is now working on modeling the contributions of these nuclear structures, and their initial findings suggest that they help to give the genome more gel-like properties, Zhang says.

“This coupling that we have observed between chromatin and nuclear bodies is not specific to the nucleoli. It’s general to other nuclear bodies as well,” he says. “This nuclear body concentration will fundamentally change the dynamics of the genome organization and will very likely turn the genome from a liquid to a gel.”

This gel-like state would make it easier for different regions of the chromatin to interact with each other than if the structure existed in a liquid state, he says. Maintaining stable interactions between distant regions of the genome is important because genes are often controlled by stretches of chromatin that are physically distant from them.

The research was funded by the National Institutes of Health and the Gordon and Betty Moore Foundation.

Featured image: Using computer simulations, MIT chemists have discovered how nuclear bodies called nucleoli, depicted in orange, interact with chromosomes in the nucleus, and how those interactions help the nucleoli exist as stable droplets within the nucleus.Credits:Image: Courtesy of the researchers. Edited by MIT News


Reference: Qi, Y., Zhang, B. Chromatin network retards nucleoli coalescence. Nat Commun 12, 6824 (2021). https://doi.org/10.1038/s41467-021-27123-9


Provided by MIT

What Makes Us Human? The Answer May be Found in Overlooked DNA (Biology)

Our DNA is very similar to that of the chimpanzee, which in evolutionary terms is our closest living relative. Stem cell researchers at Lund University in Sweden have now found a previously overlooked part of our DNA, so-called non-coded DNA, that appears to contribute to a difference which, despite all our similarities, may explain why our brains work differently. The study is published in the journal Cell Stem Cell.

The chimpanzee is our closest living relative in evolutionary terms and research suggests our kinship derives from a common ancestor. About five to six million years ago, our evolutionary paths separated, leading to the chimpanzee of today, and Homo Sapiens, humankind in the 21st century.

In a new study, stem cell researchers at Lund examined what it is in our DNA that makes human and chimpanzee brains different – and they have found answers.

“Instead of studying living humans and chimpanzees, we used stem cells grown in a lab. The stem cells were reprogrammed from skin cells by our partners in Germany, the USA and Japan. Then we examined the stem cells that we had developed into brain cells”, explains Johan Jakobsson, professor of neuroscience at Lund University, who led the study.

“The basis for the human brain’s evolution are genetic mechanisms that are probably a lot more complex than previously thought”

Using the stem cells, the researchers specifically grew brain cells from humans and chimpanzees and compared the two cell types. The researchers then found that humans and chimpanzees use a part of their DNA in different ways, which appears to play a considerable role in the development of our brains.

“The part of our DNA identified as different was unexpected. It was a so-called structural variant of DNA that were previously called “junk DNA”, a long repetitive DNA string which has long been deemed to have no function. Previously, researchers have looked for answers in the part of the DNA where the protein-producing genes are – which only makes up about two per cent of our entire DNA – and examined the proteins themselves to find examples of differences.”

Microscope image of neural stem cells
Neural stem cells from chimpanzees (Photo: Johan Jakobsson)

The new findings thus indicate that the differences appear to lie outside the protein-coding genes in what has been labelled as “junk DNA”, which was thought to have no function and which constitutes the majority of our DNA.

“This suggests that the basis for the human brain’s evolution are genetic mechanisms that are probably a lot more complex than previously thought, as it was supposed that the answer was in those two per cent of the genetic DNA. Our results indicate that what has been significant for the brain’s development is instead perhaps hidden in the overlooked 98 per cent, which appears to be important. This is a surprising finding.”

The stem cell technique used by the researchers in Lund is revolutionary and has enabled this type of research. The technique was recognised by the 2012 Nobel Prize in Physiology or Medicine. It was the Japanese researcher Shinya Yamanaka who discovered that specialised cells can be reprogrammed and developed into all types of body tissue. And in the Lund researchers’ case, into brain cells. Without this technique, it would not have been possible to study the differences between humans and chimpanzees using ethically defensible methods.

Why did the researchers want to investigate the difference between humans and chimpanzees?

“I believe that the brain is the key to understanding what it is that makes humans human. How did it come about that humans can use their brain in such a way that they can build societies, educate their children and develop advanced technology? It is fascinating!”

Johan Jakobsson believes that in the future the new findings may also contribute to genetically-based answers to questions about psychiatric disorders, such as schizophrenia, a disorder that appears to be unique to humans.

“But there is a long way to go before we reach that point, as instead of carrying out further research on the two per cent of coded DNA, we may now be forced to delve deeper into all 100 per cent – a considerably more complicated task for research”, he concludes.

Featured image: Mostphotos


Publication:

Link to the article in Cell Stem Cell:

cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development


Provided by Lund University

How Winter Soldier Could Be Able To Withstand Freezing Temperatures? (Superhero / Biology)

James Buchanan “Bucky’’ Barnes is a fictional superhero/supervillain character in the Marvel Cinematic Universe (MCU). Also known as the Winter Soldier, he is able to withstand the biological impairment of cryogenic freezing. But how? Well, Ilja Voets and colleagues now answered this question. Following his super-soldier experimentation, they suggested that, the Winter Soldier’s DNA has been modified to such an extent that he can naturally produce Anti-Freeze Glycoproteins (AF(G)Ps) when his body is subjected to freezing temperatures.

“It is possible that during these treatments the Winter Soldier’s DNA has been adequately modified to allow his body to naturally produce the winter flounder type I AFP.”

— they said.

They got this idea from Arctic and Antarctic fish species. These species produce AF(G)Ps in two different ways which help them to survive in their cold, ice-laden habitats. First, by lowering the freezing temperature of water in comparison to the melting temperature, creating a temperature gap known as the thermal hysteresis (TH) gap. Second, by the ice recrystallization inhibition (IRI) activity, in which these fishes ingest small ice crystals throughout their life span and their AF(G)Ps block further growth of the internalized ice crystals, enabling the fish to survive despite the presence of small ice grains in their blood and in certain vital organs.

“AF(G)Ps would be a more plausible way to improve cryopreservation given that they inhibit ice recrystallization in marine fish.” they said. “It is likely that the Winter Soldier is injected with some sort of serum or medication prior to being brought in cryostatus in the 2014 film Captain America: The Winter Soldier. This serum could contain synthetic cryoprotectants as well as an anaesthetic leading to loss of awareness and external sensation. However, we contend that following his super-soldier experimentation, the Winter Soldier’s DNA has been modified to such an extent that he can naturally produce AF(G)Ps when his body is subjected to freezing temperatures.”

They also hypothesized that, advancement in genetic engineering techniques like CRISPR/Cas9, could be very important for the possible development of genetically advanced humans such as the Winter Soldier in future scientific laboratories. It may be possible to insert the wf-afp gene into human DNA using the CRISPR/Cas9, thus providing the human body with the necessary genetic code to potentially produce the wf-AFP protein. As a result, we would be able to replicate in part the Winter Soldier’s ability to produce proteins to combat ice crystal growth that could arise during cryopreservation.

“However, giving the human body the ability to produce antifreeze proteins when in cryostatus is only part of the story. Unlike the films of the Marvel Cinematic Universe (MCU), scientists in the real world have yet to develop techniques that can resuscitate a person from cryostatus.”

— they concluded.

Reference: Suris-Valls, R., Mehmedbasic, M., & Voets, I. K. (2018). Marine Fish Antifreeze Proteins: The Key Towards Cryopreserving The Winter Soldier. Superhero Science and Technology, 1(1). https://doi.org/10.24413/sst.2018.1.2105


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World Exclusive: CAR-T Cell Therapy Successfully Used Against Autoimmune Disease (Medicine)

20-year-old patient with systemic lupus erythematosus treated with a new therapeutic approach for the first time worldwide

It all started with joint pain and a red facial rash: the then 16-year-old Thu-Thao V had already undergone several medical examinations in three cities when she was diagnosed with systemic lupus erythematosus (SLE) in February 2017 at Universitätsklinikum Erlangen. In the life-threatening autoimmune disease, which mainly affects young women, the immune system attacks its own cells in various organ systems.

After different immunosuppressive therapies failed to improve her symptoms, Thu-Thao V was treated with CAR-T cells by researchers from the German Centre for Immunotherapy (DZI) at Universitätsklinikum Erlangen in March 2021. Almost six months after the cell therapy, her joint pain has now disappeared and the 20-year-old has fully recovered. ‘I can even do normal sports again,’ says Thu-Thao V.

The findings were published in the New England Journal of Medicine.

The immune system usually distinguishes between foreign and endogenous cells, tolerating the body’s cells and attacking foreign cells to protect the organism, for example, from viruses and bacteria. ‘In SLE, parts of the immune system go crazy and form antibodies against their own genetic material, which inevitably leads to severe inflammatory reactions in the organs,’ explains Prof. Dr. med. univ. Georg Schett, Director of the Department of Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen.

During the worst phase of the disease, student Thu-Thao V had to take almost 20 tablets every day so that her body could compensate for the stress of her misguided immune system. ‘The joint pain was also accompanied by water retention due to my renal insufficiency, strong palpitations and hair loss. After an acute episode, the symptoms were particularly severe,’ says Thu-Thao V.

Everything else had failed

‘We were standing with our backs to the wall,’ says Prof. Dr. Gerhard Krönke, senior physician at the department. All therapies aimed at suppressing the patient’s malfunctioning immune system failed. Even at this point, giving up was not an option for the treatment team and researchers decided to bring CAR-T cells into play.

‘CAR stands for chimeric antigen receptor which is an artificial receptor,’ explains Prof. Dr. Andreas Mackensen, Director of the Department of Medicine 5 – Haematology and Oncology. ‘Immune cells, or T cells, from the patient are genetically engineered in the laboratory to add the CAR. The CAR recognises special antigens on the surface of the target cells and destroys them. Cell therapy with CAR-T cells is already being successfully used to treat leukaemia and lymphoma.’

In the case of the young SLE patient, the CAR-T cells were programmed to render harmless the B cells that form antibodies against the body’s own cells.

Rapid improvement thanks to CAR-T cells

Thu-Thao V.
20-year-old Thu-Thao V is doing very well almost six months after CAR-T cell therapy, and the symptoms of SLE have vanished. (Image: Michael Rabenstein/Universitätsklinikum Erlangen)

In March 2021, Thu-Thao V was the world’s first patient treated with SLE CAR-T cells. ‘We were very surprised how quickly her condition improved immediately after the cell infusion,’ reports Prof. Dr. Dimitrios Mougiakakos, senior physician at the Department of Medicine 5. ‘The CAR-T cells have done their job excellently and quickly rendered the B cells causing the disease harmless. All the symptoms of SLE disappeared along with the antibodies that were attacking the body.’

Thu-Thao V was able to discontinue all immunosuppressive drugs including cortisone. She has now been completely free of symptoms for almost six months, so far there are no signs of a recurrence of the disease.

‘I can finally breathe properly and sleep through the night, and I no longer have any water retention, and the redness in my face has disappeared. My hair is also growing much more densely,’ says Thu-Thao V. Her heart function is also back to normal: her heart rate has dropped from an average of 115 to 130 beats per minute to 80 beats per minute.

‘We see this as a milestone in the therapy of autoimmune diseases,’ say the scientists. They are now planning a clinical study with CAR-T cells in patients with autoimmune diseases.

The study on CAR-T cell therapy was published in the New England Journal of Medicine and supported by the German Research Foundation (DFG) Collaborative Research Centres SFB1181 (Switching points for resolving inflammation) and SFB/TRR221 (Controlling graft-versus-host and graft-versus-leukaemia immune reactions after allogenic stem cell transplants)

Systemic lupus erythematosus (SLE)

Lupus erythematosus is a rare chronic inflammatory autoimmune disease that mainly affects young women of childbearing age. The disease is found throughout the world but it is also rare. It occurs in about 50 out of 100,000 people. Two main forms are distinguished: cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). CLE only affects the skin with typical butterfly-shaped skin changes in body parts exposed to the sun, especially around the eyes. SLE also affects internal organs (e.g. kidney inflammation, joint pain, inflammation of the lungs and heart). In some cases, lupus can be fatal. The causes of the disease have not yet been fully identified. Experts assume a genetic predisposition in combination with UV light and hormonal influences.

Featured image: Prof. Dr. Andreas Mackensen (Director/Department of Medicine 5, l.) and Prof. Dr. med. univ. Georg Schett (Director/Department of Medicine 3, right) are pleased that the CAR-T cell therapy has worked so well for their patient Thu-Thao V. (Image: Michael Rabenstein/Universitätsklinikum Erlangen)


Provided by Friedrich-Alexander-Universität Erlangen-Nürnberg 

Discovery of Origin of Oesophageal Cancer Cells Highlights Importance of Screening For Pre-cancerous Barrett’s Oesophagus (Biology)

Abnormal cells that go on develop into oesophageal cancer – cancer that affects the tube connecting the mouth and stomach – start life as cells of the stomach, according to scientists at the University of Cambridge.

The study, published today in Science, found that a particular subtype of oesophageal cancer known as oesophageal adenocarcinoma is always preceded by Barrett’s oesophagus – abnormal cells of the oesophagus – even if these cells are no longer visible at the time of cancer diagnosis. This confirms that screening for Barrett’s is an important approach to oesophageal cancer control.

The techniques we used have shown us the internal processes that happen in the stomach cells when they become Barrett’s. The big question now is: what triggers these genes?

Karol Nowicki-Osuch

Cancer of the oesophagus is the sixth most deadly cancer, and oesophageal adenocarcinoma is on the rise in western countries. Scientists and doctors have known for some time that the development of this cancer is linked with Barrett’s oesophagus, which shows up in endoscopy as a pink ‘patch’ in the surface of oesophagus and affects around one out of every 100 to 200 people in the United Kingdom – and between 3 and 13 people out of 100 with this condition will go on to develop oesophageal adenocarcinoma in their lifetime. However, the question of where these abnormal cells come from has been a mystery that has baffled scientists for decades.

A multidisciplinary group of scientists led by Professor Rebecca Fitzgerald at the Medical Research Council Cancer Unit, University of Cambridge, today provides the most comprehensive explanation to date.

Dr Lizhe Zhuang, joint first author of the study, said: “It’s intriguing that, although Barrett’s oesophagus predominately occurs in the lower part of oesophagus close to stomach, it has so-called ‘goblet cells’ resembling a much more distant organ, the small intestine. Over the past twenty years there have been at least six different hypotheses about the origin of Barrett’s oesophagus. Using the latest techniques, we believe we have arrived at an answer to this mystery.”

The research team analysed tissue samples from patients with Barrett’s oesophagus and from organ donors who have never had the condition. The samples were collected as part of the Cambridge Biorepository for Translational Medicine at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust.

Lead authors Dr Karol Nowicki-Osuch and Dr Lizhe Zhuang established a detailed ‘atlas’ of human cells and tissues from all possible origins of Barrett’s oesophagus, including oesophageal submucosal glands, an elusive tissue structure that acts in a similar way to saliva glands and has never before been isolated from fresh human tissue.

The researchers then compared the maps of cells from healthy tissues, Barrett’s oesophagus and oesophageal adenocarcinoma using a number of state-of-the-art molecular technologies. These included single cell RNA sequencing, a powerful technology that enables researchers to investigate the functions of a large number of individual cells. They also looked at methylation profiles –chemical modifications to the DNA of cells in the tissue – and at genetic linage to trace back where a particular cell type originated.

The results showed a striking similarity between stomach cells and Barrett’s oesophagus, suggesting that the cells at the very top of the stomach can be reprogrammed to adopt a new tissue identity, becoming more like intestine cells, and replace the oesophageal cells. Furthermore, in this new study the team showed that two genes, MYC and HNF4A, are the keys that switch the tissue identity from stomach to intestinal cells.

Dr Karol Nowicki-Osuch, joint first author of the study, said: “The techniques we used have shown us the internal processes that happen in the stomach cells when they become Barrett’s. The big question now is: what triggers these genes? It’s likely to be a complex combination of factors that include bile acid reflux (often felt as heartburn) and other risk factors, such as obesity, age, male sex and Caucasian ethnicity.”

Importantly, the researchers found that all oesophageal adenocarcinoma cells begin as stomach cells before transforming into Barrett’s cells and then into cancer cells.

Professor Fitzgerald added: “Even if the pre-cancerous Barrett’s is not visible at the time of cancer diagnosis, our data suggests the cancer cells will have been through this stage. This has been debated for some time, but our conclusion is important as it means that screening for Barrett’s is an important approach to controlling oesophageal cancer.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said, “Today’s insights into the origin of oesophageal adenocarcinoma could help inform future research efforts into how to diagnose this type of cancer early – which is key for improving patient outcomes.

“This research goes hand in hand with other recent successes in early detection such as Cytosponge, the sponge-on a-string test, which we funded to detect Barrett’s in patients with heartburn symptoms.”

Detecting cancer earlier will be a key focus of the Cambridge Cancer Research Hospital, a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge to build a new specialist cancer hospital. The hospital will combine modern NHS clinical space with two new research institutes, including the National Institute for the Early Detection of Cancer, which will lead the way in helping advance early cancer detection techniques.

The research was largely funded by the Medical Research Council, Wellcome and Cancer Research UK.

Further information on oesophageal cancer and Barrett’s oesophagus is available via Cancer Research UK.


Reference
Nowicki-Osuch, K & Zhuang, L et al. Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition. Science; 13 Aug 2021; DOI: 10.1126/science.abd1449


Provided by University Of Cambridge

People in the Philippines have the most Denisovan DNA (Biology)

Researchers have known from several lines of evidence that the ancient hominins known as the Denisovans interbred with modern humans in the distant past. Now researchers reporting in the journal Current Biology on August 12 have discovered that the Philippine Negrito ethnic group known as the Ayta Magbukon have the highest level of Denisovan ancestry in the world. In fact, they carry considerably more Denisovan DNA than the Papuan Highlanders, who were previously known as the present-day population with the highest level of Denisovan ancestry.

“We made this observation despite the fact that Philippine Negritos were recently admixed with East Asian-related groups—who carry little Denisovan ancestry, and which consequently diluted their levels of Denisovan ancestry,” said Maximilian Larena (@maxlarena) of Uppsala University. “If we account for and masked away the East Asian-related ancestry in Philippine Negritos, their Denisovan ancestry can be up to 46 percent greater than that of Australians and Papuans.”

In the new study, Larena and colleagues, including Mattias Jakobsson, aimed to establish the demographic history of the Philippines. Through a partnership between Uppsala University of Sweden and the National Commission for Culture and the Arts of the Philippines (NCCA), aided by collaboration with indigenous cultural communities, local universities, local government units, non-governmental organizations, and/or regional offices of the National Commission for Indigenous Peoples, they analyzed about 2.3 million genotypes from 118 ethnic groups of the Philippines including diverse self-identified Negrito populations. The sample also included high-coverage genomes of AustraloPapuans and Ayta Magbukon Negritos.

The study shows that Ayta Magbukon possess the highest level of Denisovan ancestry in the world, consistent with an independent admixture event into Negritos from Denisovans. Together with the recent discovery of a small-bodied hominin, called Homo luzonensis, the data suggest that there were multiple archaic species that inhabited the Philippines prior to the arrival of modern humans, and that these archaic groups may have been genetically related.

Altogether, the researchers say that the findings unveil a complex intertwined history of modern and archaic humans in the Asia-Pacific region, where distinct Islander Denisovan populations differentially admixed with incoming Australasians across multiple locations and at various points in time.

“This admixture led to variable levels of Denisovan ancestry in the genomes of Philippine Negritos and Papuans,” Jakobsson said. “In Island Southeast Asia, Philippine Negritos later admixed with East Asian migrants who possess little Denisovan ancestry, which subsequently diluted their archaic ancestry. Some groups, though, such as the Ayta Magbukon, minimally admixed with the more recent incoming migrants. For this reason, the Ayta Magbukon retained most of their inherited archaic tracts and were left with the highest level of Denisovan ancestry in the world.”

“By sequencing more genomes in the future, we will have better resolution in addressing multiple questions, including how the inherited archaic tracts influenced our biology and how it contributed to our adaptation as a species,” Larena said.

This work was supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation.

Current Biology, Larena et al.: “Philippine Ayta possess the highest level of Denisovan ancestry in the world” https://www.cell.com/current-biology/fulltext/S0960-9822(21)00977-5


Provided by Cell Press

Study Reveals Structure Of Receptor Implicated In Type 2 Diabetes And More (Biology)

Researchers from the University of Southern California, Merck & Co., Skoltech, MIPT, UCLA, and the Université de Sherbrooke have determined the structure of the human leukotriene B4 receptor 1, involved in inflammatory, infectious, allergic, and tumorigenic diseases. Published in Nature Communications, the analysis of the structure reveals how the receptor recognizes its binding partners and interacts with them. This opens up avenues for designing better drugs that would target the receptor to treat Type 2 diabetes and other pathologies.

Receptors are the protein-based equipment cells use to receive and transmit signals. A receptor becomes activated when it binds a messenger molecule called an agonist, whereupon it relays the signal, which regulates some biological function. Antagonists, by contrast, shut down the receptor when bound. Agonists and antagonists are collectively known as ligands.

The human leukotriene B4 receptor 1, or hBLT1, regulates inflammation-related processes — such as the recruitment of T cells — as well as the proliferation and migration of smooth muscle cells. That receptor has been associated with diseases, including asthma, influenza, arthritis, atherosclerosis, diabetes, and cancer.

Since its discovery in 1997, there have been a number of attempts to develop hBLT1 ligands for use as drugs, but they had many side effects, low efficacy, and the body took comparatively long to eliminate them. A likely explanation for this is that the hBLT1 ligands used are not specific to that receptor and engage in other unwanted interactions. Learning more about the structure of the receptor and how it binds ligands can allow pharmacologists to design better, more selective drugs.

A recent study by a Russian-U.S.-Canadian collaboration sheds light on the makeup and functioning of hBLT1. Vadim Cherezov, professor of Chemistry at USC and the head of the MIPT Laboratory for Structural Biology of GPCRs, commented: “We have determined the 2.9-angstrom-resolution crystal structure of the hBLT1 receptor in complex with a selective antagonist, MK-D-046, developed by Merck & Co. This structure should help to rationally design better therapeutics to treat type 2 diabetes and other inflammatory conditions.”

Structure determination was complemented by site-directed mutagenesis and docking studies — an experimental and a computational method, respectively. According to Skoltech Assistant Professor Petr Popov, “this made it possible to reveal the key determinants of intermolecular interactions between the receptor and the ligands.”

The analysis of hBLT1 structure reveals how the receptor recognizes and binds ligands, suggesting a putative ligand access channel buried in the receptor’s membrane. More specifically, the findings hint at the possible ways the receptor might bind its endogenous agonists. That is, compounds naturally produced by the body to bind to that receptor and activate it.

By improving our understanding of hBLT1 structure and functioning, the study opens up possibilities for structure-based drug design.

Featured image: Structure and binding site of hBLT1. © Michaelian, N., et al. Nature Communications (https://doi.org/10.1038/s41467-021-23149-1)


Reference: Michaelian, N., Sadybekov, A., Besserer-Offroy, É. et al. Structural insights on ligand recognition at the human leukotriene B4 receptor 1. Nat Commun 12, 2971 (2021). https://doi.org/10.1038/s41467-021-23149-1


Provided by Skoltech

New Technique Illuminates DNA Helix (Biology)

Cornell researchers have identified a new way to measure DNA torsional stiffness – how much resistance the helix offers when twisted – information that can potentially shed light on how cells work.

Understanding DNA is critically important: It stores the information that drives how cells work and is increasingly being used in nano- and biotechnology applications. One key question for DNA researchers has been what role the helical nature of DNA plays in processes that take place on DNA.

As a motor protein moves forward along DNA, it must twist or rotate the DNA, and therefore work against the torsional resistance of the DNA. (These motors can carry out gene expression or DNA replication as they move along DNA.) If a motor protein encounters too much resistance, it may stall. While scientists know that DNA torsional stiffness plays a crucial role in the fundamental processes of DNA, measuring torsional stiffness experimentally has been exceedingly difficult.

In “Torsional Stiffness of Extended and Plectonemic DNA,” published July 7 in Physical Review Letters, researchers report on a new way to measure DNA torsional stiffness by measuring how hard it is to twist the DNA when the DNA end-to-end distance is held constant.

“We figured out a very clever trick to measure the torsional stiffness of DNA,” said senior author Michelle Wang, the James Gilbert White Distinguished Professor in the Physical Sciences in the Department of Physics in the College of Arts and Sciences and investigator of the Howard Hughes Medical Institute.

“Intuitively, it seems that DNA will become extremely easy to twist under an extremely low force,” Wang said. “In fact, many people have made this assumption. We found that this is not the case, both experimentally and theoretically.”

The first author is Xiang Gao, postdoctoral fellow in the Laboratory of Atomic and Solid State Physics.

The technique also offers new opportunities to study twist-induced phase transitions in DNA and their biological implications. “Many colleagues commented to me that they were really excited about this finding as it has broad implications for DNA processes in vivo,” Wang said.

Yifeng Hong, Fan Ye and James T. Inman, Department of Physics, Laboratory of Atomic and Solid State Physics, were co-authors on the paper. The research was supported by funding from the National Institutes of Health and the Howard Hughes Medical Institute.


Provided by Cornell University

Engineers Uncover the Secrets of Fish Fins (Biology)

Peer into any fishbowl, and you’ll see that pet goldfish and guppies have nimble fins. With a few flicks of these appendages, aquarium swimmers can turn in circles, dive deep down or even bob to the surface.

New research led by the University of Colorado Boulder has uncovered the engineering secrets behind what makes fish fins so strong yet flexible. The team’s insights could one day lead to new designs for robotic surgical tools or even airplane wings that change their shape with the push of a button. 

Close up image of a ray in a fish fin in a relaxed, top, and bended, bottom, state.
Close-up image of a ray in a fish fin in a relaxed, top, and bended, bottom, state. (Credit: Fracois Barthelat)

The researchers published their results Aug. 11 in the journal Science Robotics.

Francois Barthelat, senior author of the study, noted that fins are remarkable because they can achieve feats of dexterity even though they don’t contain a single muscle. (Fish move these structures by twitching sets of muscles located at the base of the fins). 

“If you look at a fin, you’ll see that it’s made of many stiff ‘rays,’” said Barthelat, professor in the Paul M. Rady Department of Mechanical Engineering. “Each of those rays can be manipulated individually just like your fingers, but there are 20 or 30 of them in each fin.”

In their latest research, Barthelat and his colleagues drew on a range of approaches, including computer simulations and 3D-printed materials, to dive deep into the biomechanics of these agile structures. They report that the key to fish fins may lie in their unique design. Each ray in a fin is made up of multiple segments of a hard material that stack on top of much softer collagen, making them the perfect balance between bouncy and stiff. 

“You get this dual capability where fins can morph, and yet they’re still quite stiff when they push water,” he said. 

Armor and airplanes

Barthelat is no stranger to looking into aquariums. He previously studied how fish scales can help engineers to design better body armor for humans, and how seashells might inspire tougher glasses.

Fins may be just as useful. When it comes to engineering, Barthelat explained, materials that are both stiff and flexible are a hot commodity. Airplane designers, for example, have long been interested in developing wings that can morph on command, giving planes more ability to maneuver while still keeping them in the air. 

“Airplanes do this now, to some extent, when they drop their flaps,” Barthelat said. “But that’s in a rigid way. A wing made out of morphing materials, in contrast, could change its shape more radically and in a continuous manner, much like a bird.”

To understand how ordinary run-of-the-mill goldfish achieve similar feats every day, take a close look at these structures under the microscope. Each of the rays in a fin has a layered structure, a bit like a bakery éclair: The spikes include two layers of stiff and mineralized materials called hemitrichs that surround an inner layer of spongy collagen. 

But, Barthelat said, those layers of hemitrichs aren’t solid. They’re divided into segments, as if someone had cut up the éclair into bite-sized pieces.

“Until recently, the function of those segments hadn’t been clear,” he said.

Swimming, flying and walking

The engineer and his team decided to use computer simulations to examine the mechanical properties of fins. They discovered that those segments can make all the difference.

Pretend for a moment, Barthelat explained, that fish fins are made up entirely of collagen. They could bend easily, but wouldn’t give fish much traction in the water because hydrodynamic forces would collapse them. Rays made up of solid, non-segmented hemitrichs, in contrast, would have the opposite problem—they’d be way too stiff. 

“All of the segments, essentially, create these tiny hinges along the ray,” Barthelat said. “When you try to compress or pull on those bony layers, they have a very high stiffness. This is critical for the ray to resist and produce hydrodynamic forces that push on water. But if you try to bend individual bony layers, they’re very compliant, and that part is critical for the rays to deform easily from the base muscles.”

The researchers further tested the theory by using a 3D printer to produce model fish fins made from plastic, some with those hinges built in and some without. The idea panned out: The team found that the segmented design provided better combinations of stiffness and morphing capabilities. 

Barthelat added that he and his colleagues have only scratched the surface of the wide diversity of fins in the fish world. Flying fish, for example, deploy their fins to glide above the water, while mudskippers use their fins like legs to walk on land.

“We like to pick up where the biologists and zoologists have left off, using our background in the mechanics of materials to further our understanding of the amazing properties of the natural world,” Barthelat said.

Coauthors of the new study include Floren Hannard at the Catholic University of Louvain in Belgium, Mohammad Mirkhalaf at the University of Sydney in Australia and Abtin Ameri at MIT.


Provided by University of Colorado Boulder