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KANAZAWA, Japan, Oct. 3, 2024 /PRNewswire/ -- Researchers at Nano Life Science Institute (WPI-NanoLSI), Kanazawa Universit y, demonstrate how morphogens combined with cell adhesion can generate tissue domains with a sharp boundar y in an in vitro model system. Figure 1 Caption Figure 1: How does the morphogen gradient regulate multicellular patterning? Recent advances that have enabled the growth of tissue cultures into organoids and embryoids have heightened interest as to how tissue growth is controlled during the natural processes of embryo development. It is known that the diffusion of signaling molecules called morphogens directs patterned tissue growth but what has been harder to understand is how the gradient of morphogens from this diffusion can lead to sharply defined domains in the resulting tissue (Fig. 1). Now Satoshi Toda at Kanazawa University NanoLSI (currently Osaka University, Institute for Protein Research), alongside Kosuke Mizuno at NanoLSI and Tsuyoshi Hirashima at the National University of Singapore, demonstrate a simple model system – SYnthetic Morphogen system for Pattern Logic Exploration using 3D spheroids (SYMPLE3D) – that sheds light on the process. Various previous studies have looked at the role of morphogens and cell adhesion during tissue growth separately. However, the researchers noted a couple of recent studies indicating how a morphogen involved in neural tube patterning controls expression of a family of adhesion proteins called cadherins to form sharply defined structures. Prompted by these insights, they devised their model system to investigate the interplay between morphogens and cadherins. They highlight how in vivo morphogens induce numerous changes in cellular properties simultaneously, making it hard to disentangle what is going on. For this reason, as they highlight in the discussion of their report, "SYMPLE3D provides a new synthetic biology approach for mechanistically studying tissue patterning and engineering organoid structures." SYMPLE3D uses two types of cells – one, the GFP secretors, which secrete GFP and express P-cadherin forming what they describe as "GFP-secreting organizer spheroids". The other is a GFP receiver cell, initially engineered to express a synthetic receptor called "synNotch" that recognizes GFP and induces mCherry reporter – "imC cells" (Fig. 2A). The first stage looked at the result of co-culturing the GFP secretors and receiver cells. They found that although the imC cells did capture the secreted GFP resulting in a GFP gradient, the resulting gradient contained ectopically active cells – expression of the high-level mCherry reporter in an inappropriate position of the gradient (Fig. 2B, upper panel). To deal with the issue of ectopically active cells, Mizuno and Toda engineered GFP receiver cells to induce mCherry-fused E-cadherin, a cell adhesion molecule. To their surprise, a uniformly activated tissue domain with sharp boundary emerged instead of a gradient between the secretor and receiver cells (Fig. 2B, lower panel). Figure 2: Caption Figure 2. Tissue domain formation through the coupling of morphogen signals and cell adhesion. (A) SYnthetic Morphogen system for Pattern Logic Exploration using 3D spheroids (SYMPLE3D). (B) mCherry (upper panel) or Ecad-mCherry (lower panel) was induced in response to the GFP gradient. The sharp boundary was also robust to changes in growth conditions. Since the addition of a single factor, E-cadherin, caused a significant change in the pattern, they then focused on the mechanism of the pattern formation process with a combination of molecular gradient and E-cadherin in their model system. By monitoring the real time process of tissue growth, they were able to identify activated GFP receiver cells engineered to induce mCherry-fused E-cadherin were initially scattered but aggregated over the course of time. Ectopically active cells were then gradually absorbed into this active domain resulting in a sharp cut off between the mCherry positive and negative domains. They also note "an intriguing aspect" of their synthetic tissue domain, in that across the active domain the distribution of induced E-cadherin-mCherry was uniformly high, whereas GFP was distributed with a gradient. Here, they revealed a key feature of E-cadherin for the synthetic tissue domain formation. They analyzed the behavior of cells that express various levels of E-cadherin in response to different amounts of GFP and found that the behavior was the same whether the cells induced low or high levels of E-cadherin. Furthermore, they showed that cells that induced more than a certain amount of E-cadherin were able to mix with each other and form a single cell population, regardless of the expression level. Therefore, the mixing of cells that induced different levels of E-cadherin within the GFP gradient allowed the cells to receive GFP uniformly and thus the expression level of E-cadherin became evenly high in the synthetic tissue domain (Fig. 3). A simple mathematical model, developed by Hirashima, based on cell movement governed by differential adhesion energy supported their experimental observations. "Our findings suggest the possibility of programming a new tissue domain with sharp boundaries in organoids by combining synthetic morphogens with cell adhesion control," they conclude in their report. Figure 3: Caption Figure 3. The pattern formation mechanism where morphogen signals and cadherin expression cooperate to generate tissue domains with a sharp boundary. Note about the contributions of Kosuke Mizuno to research at the NanoLSI Kosuke Mizuno, a second-year doctoral student in the Nano Life Science Program, has made notable contributions to NanoLSI research. He was awarded the NanoLSI Transdisciplinary Research Grant for FY2023 and FY2024. Glossary Morphogen A signaling molecule that controls cell fate decision dependently on its local concentration to regulate morphogenesis. Morphogens are secreted from source cells, diffuse within tissues and form a concentration gradient that works as positional information for cell differentiation. Representative morphogens include Wnt, BMP, Shh, and retinoic acid. Cadherins Cadherins are a family of transmembrane proteins that facilitate cell to cell adhesion. Mizuno, Hirashima and Toda use E-cadherin and P-cadherin in the current study, which belong to the classical cadherin family. Cadherins primarily bind to each other via their homophilic extracellular domains. However, cadherins also have an intracellular domain, which binds to adaptor proteins connected to actin cytoskeletons and contributes to tissue compaction and cell sorting. Synthetic Notch receptor (synNotch) Notch is a signal transduction receptor. When the extracellular domain of Notch receptor binds to its ligand Delta, Notch transmembrane region is cleaved, leading to the translocation of Notch intracellular domain into the nucleus to regulate the expression of target genes. The synNotch receptor is a modified version of Notch receptor, in which the extracellular domain of Notch is replaced by an antibody or nanobody and the intracellular domain by an artificial transcription factor. Using synNotch receptors, researchers can design what ligand molecule cells recognize and what target genes cells express in response, which enables manipulation of cell-cell communications. Reference Kosuke Mizuno, Tsuyoshi Hirashima, Satoshi Toda. Robust tissue pattern formation by coupling morphogen signal and cell adhesion EMBO Reports. 2024. DOI：10.1038/s44319-024-00261-z URL： Funding This research was supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan, Japan Science and Technology Agency (JST) PRESTO (JPMJPR2147), Grant-in-Aid for Scientific Research (20K15828, 21H05291, 21H05290), Japan Agency for Medical Research and Development (AMED) (22bm0704048h0003), Senri Life Science Foundation, Kato Memorial Bioscience Foundation, Kao Foundation, Yoshida Scholarship Foundation, and the Mechanobiology Institute, National University of Singapore. Contact Fujiko Imanaga (Ms) Project Planning and Outreach NanoLSI Administration Office, Nano Life Science Institute (WPI-NanoLSI) Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan Email: [email protected] Tel: +81 (76) 234-4555 About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University Understanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms". Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale. About the World Premier International Research Center Initiative (WPI) The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS). See the latest research news from the centers at the WPI News Portal: Main WPI program site: About Kanazawa University As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities. The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas. SOURCE Kanazawa University WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

GREENWICH, Conn., Sept. 12, 2024 /PRNewswire/ -- B.More Inc., a 501(c)(3) non-profit, clinical-stage biopharmaceutical company dedicated to the development of psychedelic medicines for substance abuse disorders, proudly announces that its collaborator, Dr. Michael Bogenschutz, Director of the NYU Langone Center for Psychedelic Medicine, has been awarded a $3.8 million grant from the National Institute of Alcohol Abuse and Alcoholism (NIAAA). This significant grant will: (1) elucidate the brain mechanisms of psilocybin-assisted treatment for alcohol use disorder (AUD), (2) add to the growing body of evidence regarding the safety and efficacy of psilocybin in AUD, and (3) begin to answer the question of logistics for provision of care for psilocybin-assisted treatment in real-world treatment settings. The trial will take place in collaboration with Silver Hill Hospital (SSH), where patients will be recruited and receive residential treatment during the trial. In support of this critical research, B.More Inc. will provide and cover the cost of the cGMP psilocybin to be used in the trial, as well as fund the retention of an independent monitor to ensure high quality data capture acceptable for an eventual New Drug Application (NDA). This trial, in a long-standing substance abuse treatment center, should provide a road map for eventual commercialization, and evidence for cost effective insurance reimbursement. The involvement of NIAAA funding is confirmation of growing interest in the potential of these novel medicines. According to Carey Turnbull, Co-founder, and CEO of B.More Inc., "The awarding of this NIAAA grant is a significant recognition of Dr. Bogenschutz's pioneering work in developing new treatment modalities for alcohol use disorder. Building on the groundbreaking results of his well-publicized Phase 2a study on psilocybin for AUD, this trial has the potential to pave the way for more effective treatments for AUD and other substance use disorders, providing new hope for millions struggling with addiction. We are pleased to partner with Dr. Bogenschutz and his team to support this important work." The double-blind, randomized, placebo-controlled Phase 2 trial aims to explore the therapeutic neural mechanisms of psilocybin in AUD patients using advanced functional magnetic resonance imaging (fMRI). The study will investigate treatment differences between high-dose (30 mg) and inactive placebo, focusing on changes in fMRI metrics, drinking outcomes, and self-reported measures of negative emotionality, craving, and executive function. Additionally, the trial will seek to identify neural predictors of successful treatment outcomes, particularly in response to high-dose psilocybin. In collaboration with SHH, the trial will randomize 120 participants from SHH's 28-day residential treatment program. Primary outcomes will measure changes in neural activation, connectivity, and self-reported alcohol use and related psychological measures. SSH, in New Canaan, Connecticut, is a nationally recognized, not-for-profit hospital for the treatment of psychiatric and addictive disorders, treating over 3,500 patients annually. 'We are pleased to be a part of this crucial trial advancing the care of individuals with alcohol use disorder," said Andrew J. Gerber, MD, PhD, President and Medical Director of Silver Hill and site director for this study. "We are excited to embark on this significant study, which has the potential to help advance the treatment of alcohol use disorder," said Dr. Michael Bogenschutz. "The generous support from the NIAAA underscores the promise of psilocybin as a transformative therapy for substance abuse disorders. We are committed to advancing our understanding of how psilocybin impacts neural mechanisms and contributes to recovery." About B.More Founded in 2017 by Carey and Claudia Turnbull, B.More is a 501(c)(3) non-profit, clinical-stage biopharmaceutical company with a mission to develop better treatment options for those struggling with alcohol use disorder and other substance use disorders. Named after Claudia Turnbull's brother, Brett Moore, who died of a drug overdose 50 years ago, B.More is focused on the development and commercialization of psychedelic medicines that offer the potential to dramatically improve the lives of those for whom current treatment options have not proved effective. With researchers at the NYU Grossman School of Medicine, B.More is advancing clinical research to help these individuals, and their loved ones, live a better tomorrow. For more information, please visit Logo - SOURCE B.More Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Newly developed ultra-low radiation cables reduce background noise for neutrino and dark matter detectors. Imagine trying to tune a radio to a single station but instead encountering static noise and interfering signals from your own equipment. That is the challenge facing research teams searching for evidence of extremely rare events that could help understand the origin and nature of matter in the universe. It turns out that when you are trying to tune into some of the universe's weakest signals, it helps to make your instruments very quiet. Around the world more than a dozen teams are listening for the pops and electronic sizzle that might mean they have finally tuned into the right channel. These scientists and engineers have gone to extraordinary lengths to shield their experiments from false signals created by cosmic radiation. Most such experiments are found in very inaccessible places -- such as a mile underground in a nickel mine in Sudbury, Ontario, Canada, or in an abandoned gold mine in Lead, South Dakota -- to shield them from naturally radioactive elements on Earth. However, one such source of fake signals comes from natural radioactivity in the very electronics that are designed to record potential signals. Radioactive contaminants, even at concentrations as tiny as one part-per-billion, can mimic the elusive signals that scientists are seeking. Now, a research team at the Department of Energy's Pacific Northwest National Laboratory, working with Q-Flex Inc., a small business partner in California, has produced electronic cables with ultra-pure materials. These cables are specially designed and manufactured to have such extremely low levels of the radioactive contaminants that they will not interfere with highly sensitive neutrino and dark matter experiments. The scientists report in the journal EPJ Techniques and Instrumentation that the cables have applications not only in physics experiments, but they may also be useful to reduce the effect of ionizing radiation interfering with future quantum computers. "We have pioneered a technique to produce electronic cabling that is a hundred times lower than current commercially available options," said PNNL principal investigator Richard Saldanha. "This manufacturing approach and product has broad application across any field that is sensitive to the presence of even very low levels of radioactive contaminants." An ultra-quiet choreographed ballet Small amounts of naturally occurring radioactive elements are found everywhere: in rocks, dirt and dust floating in the air. The amount of radiation that they emit is so low that they do not pose any health hazards, but it's still enough to cause problems for next-generation neutrino and dark matter detectors. "We typically need to get a million or sometimes a billion times cleaner than the contamination levels you would find in just a little speck of dirt or dust," said PNNL chemist Isaac Arnquist, who co-authored the research article and led the measurement team. For these experiments, Saldanha, Arnquist, and PNNL colleagues Maria Laura di Vacri, Nicole Rocco and Tyler Schlieder evaluated the amount of uranium, thorium and potassium at each step of the dozen or so processing steps that ultimately produce a detector cable. The team then developed special cleaning and fabrication techniques to reduce the contamination down to insignificant levels. Working in an ultraclean, dust and contaminant-free laboratory, the PNNL researchers meticulously plan out their every move. "I almost think of us as performance athletes because everything, every movement we make, is extremely thought out. It's almost like we're choreographed dancers," said Arnquist. "When we handle a detector sample material, there's no wasted extraneous motion or interaction with the sample because that interaction could impart some contamination that limits how well we can measure the materials." After several years of work and hundreds of measurements, the resulting cables are now so free of contaminants that they will not impact the operation of next-generation dark matter and neutrino experiments such as DAMIC-M, OSCURA, and nEXO. The research team points out in their study that low-radioactivity cables can increase the sensitivity of the experiments and even allow more flexibility in detector design. Getting closer to the a-ha moment So, exactly what are the researchers looking for in these experiments? In the case of both dark matter and neutrinoless double beta decay, they are hoping to record extremely rare events that could solve two key mysteries of the universe. Both of these mysteries pose fundamental questions about why the universe looks the way it does. The galaxies that fill our universe would not have formed without the existence of dark matter. Dark matter makes up around 85 percent of the matter of the universe, and yet, we have never observed dark matter directly, only its gravitational imprint on the universe. Perhaps more intriguing, the question of why there is matter in the universe at all may hinge on a unique property of the smallest known particles of matter -- the neutrino. Unlike all other fundamental particles, neutrinos could possibly interact as both matter and anti-matter. If true, this could result in an extremely rare nuclear decay called neutrinoless double beta decay. Scientists are building large experiments consisting of many tons of sensitive material with the hope of finding the first evidence of neutrinoless double beta decay within the next decade. "Every step we take to eliminate interfering radioactivity gets us closer to finding evidence for dark matter or neutrinoless double beta decay," said Saldanha. "These flexible cables have many conductive pathways, which are needed to read out complicated signals," added Arnquist. "When, say, dark matter interacts with the detector or a neutrinoless double beta decay occurs, it's going to create an event that needs to be accurately recorded -- read out -- to make the discovery. We need to put a complex electronic part that is extremely clean of radioactive elements into the heart of the detector." "Next generation searches for neutrinoless double beta decay will be among the lowest radioactivity experiments ever constructed," said David Moore, a Yale University physicist and PNNL collaborator. "These detectors use such pure materials that even a small amount of normal cabling materials would overwhelm the radioactivity from the entire rest of the detector, so developing ultra-low-background cables to read out such detectors is a major challenge. This recent work from PNNL and Q-Flex is key to enabling these detectors and will reduce the cabling background to a small fraction of what was possible with previous technologies." Planning is already underway to upgrade the highly sensitive DAMIC-M dark matter experiment and the new ultra-pure cables are one of the key improvements scheduled for installation in the detector. "One component that we can't avoid in our detector are the cables that transmit the signals, which must be of very low radioactivity," said Alvaro E Chavarria, a physicist at the University of Washington and a collaborator on the DAMIC-M project. "Prior to this recent PNNL development, the best solution was microcoax cables, which carry too few signals and would have required a significant redesign of our detector. This development is super exciting, since it enables the use of the industry-standard flex-circuit technology for low-background applications." Recent research findings by PNNL scientists and other collaborators indicate that the performance of some quantum computing devices can be affected by the presence of trace radioactive contaminants. While radioactivity is not currently what limits the capabilities of existing quantum computers, it is possible that quantum devices of the future might need low-radioactivity cables to enhance their performance. "We see the potential for these cables to find applications in a wide range of sensitive radiation detectors and perhaps other applications such as quantum computing," Saldanha said. The research was supported by the Department of Energy, Office of Science, under its Early Career Research and Small Business Innovation Research programs.