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First ever ‘pioneer’ factor found in plants enables cells to change their fate

To start the process of unpacking tightly bundled genetic material, plants depend on the LEAFY pioneer protein, according to work

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To start the process of unpacking tightly bundled genetic material, plants depend on the LEAFY pioneer protein, according to work led by biologist Doris Wagner

Cells don’t express all the genes they contain all the time. The portion of our genome that encodes eye color, for example, doesn’t need to be turned on in liver cells. In plants, genes encoding the structure of a flower can be turned off in cells that will form a leaf.

These unneeded genes are kept from becoming active by being stowed in dense chromatin, a tightly packed bundle of genetic material laced with proteins.

In a new study in the journal Nature Communications, biologists from the University of Pennsylvania identify a protein that enables plant cells to reach these otherwise inaccessible genes in order to switch between different identities. Called a “pioneer transcription factor,” the LEAFY protein gets a foothold in particular portions of the chromatin bundle, loosening the structure and recruiting other proteins that eventually allow genes to first be transcribed into RNA and then translated into proteins.

“The programs that are not needed in a given cell or tissue or condition are effectively shut off by various chromatin modifications that make them very inaccessible,” says biologist Doris Wagner of the School of Arts & Sciences, senior author on the work. “The question has always been, How do you go from shut to open? We found that LEAFY, this protein that we already knew was important in reprogramming plant cells, is one of these pioneer transcription factors that get a foot in the door, as it were, to alter the program of cells.”

Pioneer transcription factors were first characterized by Penn faculty member Kenneth Zaret of the Perelman School of Medicine, whose own work has examined these regulatory proteins in animals, such as in the context of liver development. Early in her time at Penn, Wagner heard Zaret give a talk about his work in this area and grew curious about looking for similar factors in plants, given that flexible gene expression is so critical to their survival.

Indeed, plants must switch between expressing whole sets of different genes all the time. In rich soils, they may grow more branches to get bigger, while in a drought they may express more genes associated with developing flowers, so they can set seed and reproduce before they succumb.

How plant cells determine their identity and fate has been a focus of Wagner’s work since the start of her career, and so has LEAFY. During her postdoc days, Wagner showed that LEAFY could reprogram root cells to produce flowers. “That gave us a good clue that LEAFY might have this ‘pioneer’ activity, but we had to look more closely to prove it,” she says.

To do so, Wagner and colleagues first used isolated protein and strands of genetic material to show that LEAFY, though not other transcription factors, bound to nucleosomes, subunits of chromatin where DNA spools on a cluster of proteins called histones. Specifically, the binding occurred at the gene AP1, which is known to be activated by LEAFY to prompt plants to make flowers.

To confirm that this connection was true in a living organism, the researchers took plant roots and applied a compound that causes them to flower spontaneously. When flowering, they found that not only did LEAFY bind strongly to AP1 but that the binding site was also occupied by a histone. “This tells us that the histones and LEAFY are really occupying the same portion of DNA,” Wagner says.

Furthermore, they showed that chromatin structure began to open up at the AP1 region when LEAFY was activated, a key facet of what pioneer transcription factors do. This opening was limited, and full loosening of chromatin took days. What did happen quickly, the researchers found, was that LEAFY displaced a linker histone protein, creating a small local opening that also allowed other transcription factors to nose their way into the DNA.

Though pioneer transcription factors had been proposed to exist in plants, the new work provides the first concrete support backing this conception for LEAFY. And Wagner believes there are others. “If necessary, plants can alter their entire body plan or generate an entire plant from a little piece of leaf,” she says. “We predict setting this in motion will require pioneer transcription factors. So plants may actually have more of these factors than animals.”

In upcoming work, she and her team hope to delve more deeply into the processes that precede and follow this “pioneering” activity of LEAFY: Does anything restrict its activity and how do the other factors that it recruits fully unpack the hidden-away genes? “It would be great to find out both sides of this equation,” Wagner says.

The findings have significance in agriculture and breeding, where LEAFY is already manipulated to encourage earlier flowering, for example. And as more is understood about pioneer transcription factors in plants, Wagner can envision a fine tuning of other aspects of plant growth and activity, which could be leveraged to help crops adapt to new environmental conditions, such as those being ushered in by climate change.

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Doris Wagner is the Robert I. Williams Term Professor of Biology in the University of Pennsylvania School of Arts & Sciences.

Wagner’s coauthors are gradute students Run Jin and Samantha Klasfeld, postdocs Yang Zhu and Jun Xiao, former graduate student Soon-Ki Han, undergraduate Adam Konkol of Penn’s School of Arts & Sciences, and former Zaret lab graduate student Meilin Fernandez Garcia of Penn’s Perlman School of Medicine.

This research was funded by the National Science Foundation Division of Integrated Organismal Systems (grants 1557529 and 1905062).

https://penntoday.upenn.edu/news/first-ever-pioneer-factor-found-plants-enables-cells-change-their-fate

In a new study in the journal Nature Communications, biologists from the University of Pennsylvania identify a protein that enables plant cells to reach these otherwise inaccessible genes in order to switch between different identities. Called a “pioneer transcription factor,” the LEAFY protein gets a foothold in particular portions of the chromatin bundle, loosening the structure and recruiting other proteins that eventually allow genes to first be transcribed into RNA and then translated into proteins.

Source: https://bioengineer.org/first-ever-pioneer-factor-found-in-plants-enables-cells-to-change-their-fate/

first-ever-‘pioneer’-factor-found-in-plants-enables-cells-to-change-their-fate

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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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