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Visualisation reveals how a protein ‘hunkers down’ to conserve energy

Credit: University of Leeds A visualisation made from nearly 100,000 electron microscope images has revealed the ingenious way a protein

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A visualisation made from nearly 100,000 electron microscope images has revealed the ingenious way a protein involved in muscle activity shuts itself down to conserve energy.

The protein is called myosin and it is known as a molecular motor because of the way it interacts with other proteins and energy molecules to generate force and movement. It is found inside muscle fibres where it forms long myosin filaments made up of hundreds of individual myosin molecules.

When muscle activity ceases, the process of forming the myosin filaments goes into reverse: the filaments decouple and return to the individual myosin molecule state.

The visualisation – developed by scientists from the University of Leeds in the UK and East Carolina University in the US – has revealed how the structure of the molecule changes. It folds up and becomes more compact, meaning it can be moved more easily to where it is next needed in the cell.

Their findings – Structure of the shutdown state of myosin-2 – are published today (Wednesday, 2 December) in the journal Nature.

When the embargo lifts, the paper can be accessed at: https://www.nature.com/articles/s41586-020-2990-5

Structure of myosin

An individual molecule of myosin is large – and is made up of a ‘head’ and a ‘tail’. When in an active state, the tails of the molecules come together to form fibrous myosin filaments. The heads within the filament bind with another protein called actin to produce muscle contraction.

By combing 96,000 electron microscope images, the scientists were able to see how the molecule adopts an inactive form in unprecedented detail. The tail of each molecule wraps itself around the head and is locked in place by key molecular interactions. That process shuts down its activity and makes it easier for the molecule to be recruited to where it is next needed.

Professor Michelle Peckham, from the Astbury Centre for Structural Molecular Biology at Leeds who supervised the research, said: “The analogy here is that the folded myosin is like a Brompton bicycle, kept in a folded state when not needed, and able to be quickly unfolded when it is, by releasing a simple catch.

“The compact folded myosin is also more easily transported through a crowd to where it’s needed.”

Scientists have been aware of the role of myosin in muscle activity for decades. But until now, they were unclear about how this inactive state was formed or how its formation was so highly controlled.

What does the research mean for understanding disease?

There are genetic mutations of myosin linked with certain diseases.

Professor Peckham explained: “Mutations in muscle myosin cause a wide range of muscle diseases. Our research into the structure of myosin and the way it functions help explain how mutations or defects in the protein may be causing disease. That opens the door to the possibility that scientists can develop therapeutic approaches to ensure myosin functions normally.”

The Astbury Centre for Structural Molecular Biology at the University of Leeds is an interdisciplinary research group involving biologists, physicists and chemists to investigate the molecular basis of life. One of the major research themes is to understand the process of protein folding.

The research was funded by the Medical Research Council and Wellcome Trust.

Note to Editors

The image shows, top, a 3D visualisation of the shutdown state of the myosin molecule, where the tail has wrapped around the head; below that is a myosin molecule in its active state and at the bottom, a myosin filament. Picture credit: University of Leeds.

University of Leeds

The University of Leeds is one of the largest higher education institutions in the UK, with more than 38,000 students from more than 150 different countries, and a member of the Russell Group of research-intensive universities. The University plays a significant role in the Turing, Rosalind Franklin and Royce Institutes.??

We are a top ten university for research and impact power in the UK, according to the 2014 Research Excellence Framework, and are in the top 100 of the QS World University Rankings 2020.??

The University was awarded a Gold rating by the Government’s Teaching Excellence Framework in 2017 recognising its ‘consistently outstanding’ teaching and learning provision. Twenty-six of our academics have been awarded National Teaching Fellowships – more than any other institution in England, Northern Ireland and Wales – reflecting the excellence of our teaching. http://www.leeds.ac.uk

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When the embargo lifts, the paper can be accessed at: https://www.nature.com/articles/s41586-020-2990-5

Source: https://bioengineer.org/visualisation-reveals-how-a-protein-hunkers-down-to-conserve-energy/

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Trial of existing antibiotic for treating Staphylococcus aureus Bacteremia begins

NIH-supported trial will test Dalbavancin in hospitalized adultsCredit: NIAID A clinical trial to test the antibiotic dalbavancin for safety and

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A clinical trial to test the antibiotic dalbavancin for safety and efficacy in treating complicated Staphylococcus aureus (S. aureus) bacteremia has begun. The trial will enroll 200 adults hospitalized with complicated S. aureus infection at approximately 20 trial sites around the United States. The trial is being sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

S. aureus is a leading cause of antibiotic-resistant infection. S. aureus infections led to nearly 20,000 deaths in 2017 in the United States, according to the U.S. Centers for Disease Control and Prevention (CDC). This bacterium is of particular concern in healthcare-associated infections. S. aureus bacteremia–an infection of the blood–often requires inserting a central intravenous (IV) catheter to deliver long courses of antibiotics, an invasive procedure that can involve long-term care in healthcare facilities.

“As antibiotic-resistant infections become more widespread, better and easier treatment regimens are needed to ease the burden on both healthcare providers and patients,” said NIAID Director Anthony S. Fauci, M.D. “By investigating existing antibiotics for their action on a broader array of bacterial infections, we may be able to generate new treatment regimens more efficiently.”

The antibiotic dalbavancin has strong activity against gram-positive bacteria, including methicillin-resistant S. aureus, which suggests it could be an effective treatment for S. aureus bacteremia. Dalbavancin is currently FDA-approved in the United States for treating acute bacterial skin and skin structure infections, including those caused by S. aureus. If the two-dose regimen being tested in this trial proves effective, it could lead to a shorter, less invasive treatment for S. aureus bacteremia that does not require an indwelling IV access for daily therapy.

The Phase 2b trial is being conducted by the NIAID-funded Antibacterial Resistance Leadership Group (ARLG) under the leadership of Thomas Holland, M.D., of Duke University (Durham, North Carolina.) It is called the “Dalbavancin as an Option for Treatment of S. aureus Bacteremia (DOTS)” trial. Patients who have stabilized after initial treatment of their bacteremia will be eligible for enrollment in this study.

“Dalbavancin is appealing as a potential option for treatment of these serious S. aureus infections, and we need high quality data to find out if it works,” said Dr. Holland, “This trial will provide clinicians and patients with that data.”

One hundred participants will be randomized to receive the standard of care for complicated infections, including appropriate antibiotics, and 100 participants will receive two doses of dalbavancin intravenously. The doses will be given one week apart. Most participants receiving dalbavancin will be given 1500 milligrams (mg) per dose. Participants with signs of kidney dysfunction will be given 1125 mg per dose. All participants will be followed for approximately 70 days after enrollment, and up to six months if they have vertebral osteomyelitis, an infection of the vertebrae.

At the end of the trial, multiple patient outcomes will be assessed: survival; additional complications (such as relapse) or clinical failures; drug-related adverse events; and overall quality of life. The therapeutic regimen will have met the primary endpoint of the trial if participants who received dalbavancin fare better on these metrics than those who received the current standard of care. This trial could validate a dalbavancin regimen of only one dose a week for two weeks, compared to daily doses administered intravenously for four to six weeks with the current standard of care.

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The ARLG is a clinical research consortium working to reduce the impact of antimicrobial resistance. It is funded through NIH grant UM1AI104681. For more information about this trial, visit ClinicalTrials.gov and search identifiers NCT04775953.

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NIAID conducts and supports research–at NIH, throughout the United States, and worldwide–to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIH…Turning Discovery Into Health®

Source: https://bioengineer.org/trial-of-existing-antibiotic-for-treating-staphylococcus-aureus-bacteremia-begins/

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Metabolite fumarate can reveal cell damage: New method to generate fumarate for MRI

Researchers find new technique for rapid hyperpolarization and purification of fumarate in aqueous solution; obstacles involving the use of parahydrogen

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Researchers find new technique for rapid hyperpolarization and purification of fumarate in aqueous solution; obstacles involving the use of parahydrogen overcome

A promising new concept published by an interdisciplinary research team in “Proceedings of the National Academy of Sciences” (PNAS) paves the way for major advances in the field of magnetic resonance imaging (MRI). Their new technique could significantly simplify hyperpolarized MRI, which developed around 20 years ago for observing metabolic processes in the body. The proposal involves the hyperpolarization of the metabolic product fumarate using parahydrogen and the subsequent purification of the metabolite. “This technique would not only be simpler, but also much cheaper than the previous procedure,” said leader of the project Dr. James Eills, a member of the research team of Professor Dmitry Budker at Johannes Gutenberg University Mainz (JGU) and the Helmholtz Institute Mainz (HIM). Also participating in the project were scientists from the fields of chemistry, biotechnology, and physics at TU Darmstadt, TU Kaiserslautern, the University of California Berkeley in the United States, the University of Turin in Italy, and the University of Southampton in England.

Fumarate is a key biosensor for hyperpolarized imaging

The potential applications of MRI are hindered by its low sensitivity and the technique is essentially limited to observing water molecules in the body. Researchers are therefore constantly working on different ways of improving MRI. A major breakthrough was achieved around 20 years ago when hyperpolarized magnetic resonance imaging was first developed: Because hyperpolarized molecules emit significantly stronger MRI signals, substances that are only present in low concentrations in the body can also be visualized. By hyperpolarizing biomolecules and introducing them in patients, it is possible to track metabolism in real time, thus providing doctors with much more information.

Hyperpolarized fumarate is a promising biosensor for the imaging of metabolic processes. Fumarate is a metabolite of the citric acid cycle that plays an important role in the energy production of living beings. For imaging purposes, the fumarate is tagged with carbon-13 as the atomic nuclei of this isotope can be hyperpolarized. Dynamic nuclear polarization is the current state-of-the-art method for hyperpolarizing fumarate, but this is expensive and relatively slow. The equipment required costs one to two million euros. “Dynamic nuclear polarization is very difficult to use in everyday clinical practice due to the related high costs and technical complexity. Using parahydrogen, we are able to hyperpolarize this important biomolecule in a cost-effective and convenient way,” said Dr. Stephan Knecht of TU Darmstadt, the first author of the published article.

A new method to hyperpolarize and purify fumarate for subsequent use as a biosensor

The research team led by Dr. James Eills has already been working on this concept for some time. “We have made a significant breakthrough as our approach is not only cheap, but also fast and easy to handle,” emphasized Eills. However, parahydrogen-induced polarization, or PHIP for short, also has its disadvantages. The low level of polarization and the large number of unwanted accompanying substances are particularly problematic in the case of this chemistry-based technique. Among other things, transferring the polarization from parahydrogen into fumarate requires a catalyst, which remains in the reaction fluid just like other reaction side-products. “The chemical contaminants must be removed from the solution so it is biocompatible and can be injected in living beings. This is essential if we think about the future clinical translation of this hyperpolarized biosensor,” said Dr. Eleonora Cavallari, a physicist from the Department of Molecular Biotechnology and Health Sciences in Turin.

The solution to this problem is to purify the hyperpolarized fumarate through precipitation. The fumarate then takes the form of a purified solid and can be redissolved at the desired concentration later. “This means we have a product from which all toxic substances have been removed so that it can readily be used in the body,” added Dr. James Eills. In addition, compared to previous experiments with PHIP, the polarization is increased to remarkable 30 to 45 percent. Preclinical studies have already shown that hyperpolarized fumarate imaging is a suitable method of monitoring how tumors respond to therapy as well as for imaging acute kidney injuries or the effects of myocardial infarction. This new way of producing hyperpolarized fumarate should greatly accelerate preclinical studies and bring this technology to more laboratories.

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Hyperpolarized fumarate is a promising biosensor for the imaging of metabolic processes. Fumarate is a metabolite of the citric acid cycle that plays an important role in the energy production of living beings. For imaging purposes, the fumarate is tagged with carbon-13 as the atomic nuclei of this isotope can be hyperpolarized. Dynamic nuclear polarization is the current state-of-the-art method for hyperpolarizing fumarate, but this is expensive and relatively slow. The equipment required costs one to two million euros. “Dynamic nuclear polarization is very difficult to use in everyday clinical practice due to the related high costs and technical complexity. Using parahydrogen, we are able to hyperpolarize this important biomolecule in a cost-effective and convenient way,” said Dr. Stephan Knecht of TU Darmstadt, the first author of the published article.

Source: https://bioengineer.org/metabolite-fumarate-can-reveal-cell-damage-new-method-to-generate-fumarate-for-mri/

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Skoltech researchers propose a new data-driven tool to better understand startups

Credit: Malyy et al., 2021 Skoltech researchers used Google Trends’ Big Data ensuing from human interactions with the Internet to

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Skoltech researchers used Google Trends’ Big Data ensuing from human interactions with the Internet to develop a new methodology – a tool and a data source – for analyzing and researching the growth of startups. A paper reporting these important findings was published in technology management journal, Technological Forecasting and Social Change.

Startups and high-growth technology-based ventures they transform into are regarded as the key drivers of economic development, innovation, and job creation on the national and global level. However, despite their crucial importance for the economy and high interest from researchers and policy-makers, startups display growth patterns that are difficult to analyze. These fragile, early-stage private businesses, which may quickly scale up, do not have time, interest, or obligation to share much data about what they achieved, when, or how. Thus, to outside observers, startups look like “black boxes” whose progress can hardly be assessed due to a lack of objective information.

Maksim Malyy, a PhD student from the Skoltech Center for Entrepreneurship and Innovation (CEI), has been intrigued by this problem since he worked in a startup accelerator in St. Petersburg before joining Skoltech. Looking into theoretical and practical aspects of the problem for the last three years, Maksim, his supervisor, professor Zeljko Tekic, and Skoltech assistant professor Tatiana Podladchikova came up with valuable insights on how to deal with the data scarcity problem in studying startups. Some of their findings were published in the paper.

Maksim explains why this research is so important: We demonstrate that web-search traffic information, in particular Google Trends data, can serve as a valuable source of high-quality data for analyzing the advancement of startups and growth-oriented technology-based new ventures they evolve into. We analyzed a large and transparently selected set of US based companies and showed the existence of a strong correlation between the curves based on Google searches by company name and those depicting valuations achieved through a series of investment rounds.

According to the authors, this correlation enables using Google Trends data as a proxy measure of growth instead of non-public and rarely available measures like sales, employee and market share growth. Google Trends data, which are public, easy to collect and available for almost any company since its inception, can help in building more accurate and even real-time data-driven growth paths for startups. With these evolution curves, one could revisit some old answers, ask new questions, and come up with more solid concepts, theories, and predictions.

Maksim believes that this study has strong implications for start-up research: Our findings suggest that for startups, especially thriving unicorns or B2C digital platforms, the proposed approach may become an equivalent of an X-ray scan, offering a cheap, easy, and non-invasive way to understand the workings of a technology-based new venture.

By way of comment, professor Tekic and professor Podladchikova cite a report by one of the reviewers: “I think this paper will stand the test of time and be useful for many years to come. It truly is a fascinating study.”

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https://www.skoltech.ru/en/2021/04/skoltech-researchers-propose-a-new-data-driven-tool-to-better-understand-startups/

Maksim believes that this study has strong implications for start-up research: Our findings suggest that for startups, especially thriving unicorns or B2C digital platforms, the proposed approach may become an equivalent of an X-ray scan, offering a cheap, easy, and non-invasive way to understand the workings of a technology-based new venture.

Source: https://bioengineer.org/skoltech-researchers-propose-a-new-data-driven-tool-to-better-understand-startups/

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