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Tag: Cell Biology

  • Zymo Research Receives Top Workplaces Awards 2023

    Zymo Research Receives Top Workplaces Awards 2023

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    Newswise — IRVINE, Calif., Dec. 29, 2023 /PRNewswire/ — Zymo Research, a leading provider of innovative life science technologies, has been honored with the Top Workplaces USA 2023 and Culture Excellence 2023 awards. These accolades underscore the company’s commitment to cultivating an exceptional work environment and prioritizing employee engagement.

    The foundation of Zymo Research’s achievements lies with its dedicated team. Their contributions have shaped a collaborative and innovative work culture that emphasizes mutual respect and growth.

    Dr. Larry Jia, Founder and CEO of Zymo Research, stated, “These awards are a testament to our incredible team. Being named the top workplace for consecutive years by our own employees is the highest honor we can receive. Our success is a reflection of our employees’ passion and commitment to our shared vision and values at Zymo Research.”

    The Culture Excellence 2023 awards highlight Zymo Research’s exemplary achievements in eight key areas:

    • Innovation
    • Purpose & Values
    • Leadership
    • Professional Development
    • Compensation & Benefit
    • Work-life Flexibility
    • Employee Well-being
    • Employee Appreciation

    These awards affirm Zymo Research’s comprehensive approach to employee satisfaction, emphasizing not only professional advancement but also the overall well-being and fulfillment of its workforce.

    For those interested in joining Zymo Research, please visit our Careers Page to explore available opportunities.

    For more information on Zymo Research, visit https://www.zymoresearch.com.

    About Zymo Research Corp.

    Zymo Research is a privately owned company that has been serving the scientific and diagnostics community with state-of-the-art molecular biology tools since 1994. “The Beauty of Science is to Make Things Simple” is their motto, which is reflected in all of their products, from epigenetics to DNA/RNA purification technologies. Historically recognized as the leader in epigenetics, Zymo Research is breaking boundaries with novel solutions for sample collection, microbiomic measurements, diagnostic devices, and NGS technologies that are high quality and simple to use.

    Follow Zymo Research on LinkedIn, Instagram, Twitter, and Facebook.

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    Zymo Research Corp

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  • NUS team discovers new method of cultivating human norovirus using zebrafish embryo

    NUS team discovers new method of cultivating human norovirus using zebrafish embryo

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    Food virologists from the National University of Singapore (NUS) have successfully propagated the human norovirus using zebrafish embryos, providing a valuable platform to assess the effectiveness of virus inactivation for the water treatment and food industries.

    Human norovirus (HuNoV) is currently the predominant cause of acute gastroenteritis worldwide, contributing to an estimated 684 million diarrhoea cases, resulting in 212,000 annual fatalities. For a substantial period, the absence of an in vitro culture system has been a major hurdle in norovirus research. The most recently optimised human intestinal enteroid model, designed to support HuNoV replication, relies on human biopsy specimens obtained from surgical or endoscopic procedures, which are typically scarce. Moreover, the maintenance of these cells is both labour and resource intensive.

    A research team led by Assistant Professor Li Dan from the NUS Department of Food Science and Technology, in collaboration with Professor Gong Zhiyuan from the NUS Department of Biological Sciences, serendipitously discovered that zebrafish embryo can be used as a host for cultivating HuNoV. The zebrafish embryo model is easy to handle, robust and has a capacity to efficiently replicate HuNoVs. This study, to the best of their knowledge, represents an inaugural demonstration of the highest fold-increase over the baseline. Most notably, this model enables the continuous passaging of HuNoV within a laboratory setting. With this model, researchers can effectively propagate and sustain the presence of HuNoV over time, enabling them to study in more depth its behaviour, replication, and other properties.

    Asst Prof Li said, “The zebrafish embryo model represents an essential improvement in the HuNoV cultivation method. With its high efficiency and robustness, this tool is able to enhance both the breadth and depth of HuNoV-related research. It is expected that this tool will not only benefit the advancement of epidemiological research on HuNoV but will also be invaluable in establishing HuNoV inactivation parameters. These parameters are highly needed by the water treatment and food industries to develop more effective methods for preventing the spread of the virus.”

    This research was published in the journal Applied and Environmental Microbiology on 21 March 2023.

    In the future, the research team plans to utilise the zebrafish embryo model to investigate inactivation methods for HuNoVs in food products. To date, the successful detection of infectious HuNoV in food products remains an elusive goal. While further refinement and optimisation efforts are still required, the research team’s ongoing work holds great promise in tackling this challenging task.

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    National University of Singapore (NUS)

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  • First-in-human clinical trial of CAR T cell therapy with new binding mechanism shows promising early responses

    First-in-human clinical trial of CAR T cell therapy with new binding mechanism shows promising early responses

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    Newswise — SAN DIEGO – Early results from a Phase I clinical trial of AT101, a new CAR T cell therapy that uses a distinct binding mechanism to target CD19, show a 100 percent complete response (CR) rate at the higher dose levels studied in the trial, according to researchers from the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. The findings were published today in Molecular Cancer and presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 2096).

    CAR T cell therapy has revolutionized treatment for many people with blood cancers who had run out of other treatment options. While some patients experience long-term responses to CAR T cell therapy, it doesn’t work–or the cancer eventually returns–for others. The CD19 CAR T cell therapies that are currently approved all target CD19 through the same epitope (FMC63). To try and make CD19 CAR T cell therapy more effective for more patients, Marco Ruella, MD, an assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program, and his research team, along with the Korean company AbClon Inc, co-developed a CAR T product (AT101), using cells originating from the same patient, that targets CD19 through a different epitope, located closer to the cell membrane, via a novel antibody (h1218). In preclinical studies, the team previously demonstrated that h1218-CART19 had decreased T cell exhaustion and improved control compared to FMC63-CART19.

    The Phase I first-in-human clinical trial (NCT05338931) was conducted in South Korea and enrolled 12 patients with relapsed or refractory B cell non-Hodgkin’s lymphoma (NHL). The study was designed to increase the dose level of AT101 after safety was confirmed in the first six patients. After a median follow-up of 6.5 months, all six patients who received dose level 2 or higher experienced a complete response and their cancer has not relapsed.  

    “We’ve learned that the way you design your CAR really matters. Designing a different CAR might drastically change the way the T cells work, potentially allowing that CAR T cell product to work where other CAR T cell products have failed,” Ruella said. “We were not expecting such a drastic early difference in this study. The CART19 products that are already FDA-approved are very effective, and it’s not easy to do better. While there is not a randomized trial of this product yet, the initial results seem very promising, and we look forward to moving into the planned Phase II portion of the study.”

    The drug was found to be safe, with manageable side effects, including cytokine-release syndrome in four patients and immune-cell-related neurotoxicity syndrome in three patients. One patient experienced grade 3 sepsis that resolved; the same patient later developed fatal neutropenic septic shock outside the dose-limiting toxicity time frame.

    The Phase I study enrolled patients who had not previously received any other CAR19 therapy. In the Phase II expansion, the study will also include patients who have previously received CAR19 therapy.

    Editor’s Note: The study was funded by AbClon Inc; Ruella is a paid consultant for the company and has a Sponsored Research Agreement with them.

    Yunlin Zhang, MS, a research specialist in Ruella’s lab, will present the findings in a poster session on Saturday, Dec. 9, from 5:30 to 7:30 p.m. PT in the San Diego Convention Center Halls G-H.

    ###

    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

    The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

    The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

    Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.

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    Perelman School of Medicine at the University of Pennsylvania

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  • UC Irvine researchers discover a mechanism that controls the identity of stem cells

    UC Irvine researchers discover a mechanism that controls the identity of stem cells

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    Newswise — Irvine, Calif., Dec. 7, 2023 — University of California, Irvine, researchers discovered a mechanism that controls the identity of stem cells. When this mechanism fails, embryonic stem cells revert back in time and become totipotent. When a cell becomes totipotent, this rare change enables the cells the ability to differentiate into hundreds of cell types, and then go on to form every part of our body. This contrasts with pluripotent stem cells which can divide into various cell types but are unable to become an entire organism solely on their own.

    The study, Nuclear RNS catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation, was published Dec. 7, 2023, in Molecular Cell.

    “In a dish of embryonic stem cells, the majority of stem cells are pluripotent. However, one out of 1,000 cells are different from the rest, and are totipotent,” said Ivan Marazzi, PhD, director of the at UCI School of Medicine. “Totipotent cells are the only cells that have unlimited potential and can give rise to all parts of our body. We discovered the mechanism that allows this change from pluripotent to totipotent.”

    The ability to change the identity of stem cells allows researchers to delve into the fundamental aspect of development, specifically what happens when two cells meet and give rise to an embryo. Moreover, many disorders like cancer and neurodegenerative disease are characterized by cells “going back in time,” a process called cellular dedifferentiation.

    “Factors that control this ’reversion’ from stem cell to totipotent cell are mutated in humans with cancer and neurodegenerative disease,” said Marazzi, professor in the Department of Biological Chemistry at UCI School of Medicine.” We think there is a special susceptibility of brain and cancer cells to be vulnerable to this mechanism, which could help us in the future as we treat patients with these conditions.”

    The study was funded by the NIH and UCI.

     

    UCI School of Medicine:

    Each year, the UCI School of Medicine educates more than 400 medical students and nearly 150 PhD and MS students. More than 700 residents and fellows are trained at the UCI Medical Center and affiliated institutions. Multiple MD, PhD and MS degrees are offered. Students are encouraged to pursue an expansive range of interests and options. For medical students, there are numerous concurrent dual degree programs, including an MD/MBA, MD/MPH, or an MD/MS degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Program in Medical Education for Leadership Education to Advance Diversity-African, Black and Caribbean (PRIME LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit medschool.uci.edu.

     

    CITATION:

    Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

    Torre D, Fstkchyan YS, Ho JSY, Cheon Y, Patel RS, Degrace EJ, Mzoughi S, Schwarz M, Mohammed K, Seo JS, Romero-Bueno R, Demircioglu D, Hasson D, Tang W, Mahajani SU, Campisi L, Zheng S, Song WS, Wang YC, Shah H, Francoeur N, Soto J, Salfati Z, Weirauch MT, Warburton P, Beaumont K, Smith ML, Mulder L, Villalta SA, Kessenbrock K, Jang C, Lee D, De Rubeis S, Cobos I, Tam O, Hammell MG, Seldin M, Shi Y, Basu U, Sebastiano V, Byun M, Sebra R, Rosenberg BR, Benner C, Guccione E, Marazzi I.Mol Cell. 2023 Nov 14:S1097-2765(23)00903-6. doi: 10.1016/j.molcel.2023.10.036. Online ahead of print.PMID: 37995687

     

     

    Conflict of Interest Disclosures: Author has no conflict of interest to disclose.

    DOI: doi: 10.1016/j.molcel.2023.10.036.

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    University of California, Irvine

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  • Rubber behavior: Dynamics decoded

    Rubber behavior: Dynamics decoded

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    New device could improve the outcomes of cell-based therapies

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    Northwestern University

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  • Children With Sickle Cell Disease Appear to Suffer Eye Complications at Same Rate as Adults

    Children With Sickle Cell Disease Appear to Suffer Eye Complications at Same Rate as Adults

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    Newswise — SAN FRANCISCO — Sickle cell disease is a rare, inherited disorder in which the red blood cells become hard, sticky, and change shape, resembling the farm tool. People who have it can sometimes develop vision problems when these sickle-shaped cells get trapped in the small blood vessels as the back of the eye. Sickle retinopathy is an age-dependent process, with older people being at substantially higher risk, than younger patients. To learn more about how this condition manifests in children, researchers at the University of Tennessee Health Science Center conducted a large, retrospective review at their institution. What they found surprised them. One in three children had retinopathy, of which 9 percent required treatment, suggesting children need to be screened for vision problems as often as adults with sickle cell disease. The study will be presented today at AAO 2023, the 127th annual meeting of the American Academy of Ophthalmology.

    “Our data underscores the need for patients — including pediatric patients– with sickle cell disease to get routine ophthalmic screenings along with appropriate systemic and ophthalmic treatment,” said lead researcher, Mary Ellen Hoehn, MD, professor of Ophthalmology at University of Tennessee Health Science Center.

    Dr. Hoehn and colleagues also evaluated the effectiveness of different therapies for sickle cell disease. They found that hydroxyurea and chronic transfusions were associated with decreased rates of retinopathy, even when accounting for different genotypes.  

    To conduct the study, they evaluated records for 652 patients, aged 10 to 25 years (median age: 14) who underwent eye exams (2,240 visits) over a 12-year period. They found:

    • 33 percent had nonproliferative retinopathy (NPR)
    • 6 percent had proliferative retinopathy (PR).
    • 33 eyes were treated with panretinal photocoagulation, most commonly for PR stage 3 (43 percent). Intravitreal anti-VEGF therapy was given to five eyes, all with PR.
    • Other complications included retinal detachment and retinal artery occlusion in two patients each.
    • Vision loss (final best corrected visual acuity 20/60) following complications from sickle cell disease was noted in only one patient with a central retinal artery occlusion. 

    “We hope that people will use this information to better care for patients with sickle cell disease, and that more timely ophthalmic screen exams will be performed so that vision-threatening complications from this disease are prevented,” Dr. Hoehn said.

    About the American Academy of Ophthalmology

    The American Academy of Ophthalmology is the world’s largest association of eye physicians and surgeons. A global community of 32,000 medical doctors, we protect sight and empower lives by setting the standards for ophthalmic education and advocating for our patients and the public. We innovate and support research to advance our profession and to ensure the delivery of the highest-quality eye care. Our EyeSmart® program provides the public with the most trusted information about eye health. For more information, visit aao.org.

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    American Academy of Ophthalmology (AAO)

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  • Scientists reveal structures of neurotransmitter transporter

    Scientists reveal structures of neurotransmitter transporter

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    Newswise — (Memphis, Tenn – November 1, 2023) Neurons talk to each other using chemical signals called neurotransmitters. Scientists at St. Jude Children’s Research Hospital have drawn on structural biology expertise to determine structures of vesicular monoamine transporter 2 (VMAT2), a key component of neuronal communication. By visualizing VMAT2 in different states, scientists now better understand how it functions and how the different shapes the protein takes influence drug binding — critical information for drug development to treat hyperkinetic (excess movement) disorders such as Tourette syndrome. The work was published today in Nature.    

    How our neurons talk to each other 

    Chemical compounds called monoamines, which include dopamine, serotonin and adrenaline, play a central role in neuronal communication. These molecules affect how the brain works, controlling our emotions, sleep, movement, breathing, circulation and many other functions. Monoamines are neurotransmitters (signaling molecules) produced and released by neurons, but before they can be released, they must first be packaged into vesicles.  

    Vesicles are cellular compartments that store neurotransmitters before they are released at the synapses (the junction through which chemical signals pass from one neuron to another). Think of vesicles as the cargo ships of the neuronal cell — neurochemicals are packed inside them and taken to where they need to go. VMATs are proteins on the membrane of these vesicles that move monoamines into the space within, acting like loading cranes for the cargo ships.  

    “VMATs are transporters that are required for packing these monoamine neurotransmitters into synaptic vesicles,” explained co-corresponding author Chia-Hsueh Lee, Ph.D., St. Jude Department of Structural Biology.   

    Once the VMAT has packed the vesicle with monoamines, the “cargo ship” moves towards the synaptic gap (the space between neurons), where it releases the chemical compounds.  

    The many faces of monoamine transporters 

    There are two types of VMAT: VMAT1 and VMAT2. VMAT1 is more specialized, found only in neuroendocrine cells, whereas VMAT2 is found throughout the neuronal system and has significant clinical relevance.   

    “We knew that VMAT2 is physiologically very important,” Lee said. “This transporter is a target for pharmacologically relevant drugs used in the treatment of hyperkinetic disorders such as chorea and Tourette Syndrome.” 

    Despite their importance, the structure of VMAT2, which would allow researchers to investigate how it works fully, had remained elusive. Lee and his team used cryo-electron microscopy (cryo-EM) to obtain structures of VMAT2 bound to the monoamine serotonin and the drugs tetrabenazine and reserpine, which are used to treat chorea and hypertension, respectively. This was no easy feat.  

    “VMAT2 is a small membrane protein,” explained co-first author Yaxin Dai, PhD., St. Jude Department of Structural Biology. “This makes it a very challenging target for cryo-EM structure determination.”  

    Despite the difficulty and using some clever tricks, the team captured multiple structures of VMAT2 that allowed them to tease out how the protein functions and investigate how exactly those drugs work. “VMAT transporters adopt multiple conformations [shapes] while transporting their substrate. This is called alternating access transport, where the protein is either “outward” or “inward” facing,” explained co-first author Shabareesh Pidathala, Ph.D., St. Jude Department of Structural Biology. “To completely gain mechanistic understanding at an atomic level, we needed to capture multiple conformations of this transporter.”  

    Answering a 40-year-old question 

    The researchers discovered this dynamic mechanism means multiple opportunities for drugs to bind. They confirmed that reserpine and tetrabenazine bind two different conformations of VMAT2. “30 or 40 years of pharmacological research had suggested that these two drugs bind to the transporter in different ways,” said Pidathala, “but nobody knew the atomic details of how this works. Our structures nicely demonstrate that these two drugs stabilize two different conformations of the transporter to block its activity.” 

    The structure of VMAT2 with serotonin bound allowed the researchers to pinpoint specific amino acids that interact with the neurotransmitter and drive transport. “We believe this is a common mechanism that this transporter uses to engage all the monoamines,” said Lee.  

    While this work offers a huge leap forward in understanding monoamine transport, Lee and his team are delving deeper into its mechanism. For example, the intake of monoamines into vesicles is fueled by protons moving in the other direction. “We identified amino acids that are important for this proton-dependent process,” Lee said, “but we still don’t know how exactly protons drive this transport. Determining this mechanism is our future direction, which will help us to fully appreciate how this transporter works.”  

    Authors and funding 

    The study’s other first author is Shuyun Liao of the School of Life Sciences, Peking University. The study’s co-corresponding author is Zhe Zhang of the School of Life Sciences, Peking University. Other authors include Xiao Li and Chi-Lun Chang of St. Jude, and Changkun Long of the School of Life Sciences, Peking University.  

    The study was supported by grants from National Institutes of Health (R01GM143282), the National Key Research and Development Program of China (2021YFA1302300), the National Natural Science Foundation of China (32171201), the SLS-Qidong innovation fund, the Li Ge-Zhao Ning Life Science Youth Research Foundation, the State Key Laboratory of Membrane Biology of China, and ALSAC, the fundraising and awareness organization of St. Jude. 

     

    St. Jude Children’s Research Hospital  

    St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.   

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    St. Jude Children’s Research Hospital

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  • Hidden way for us to feel touch uncovered by Imperial researchers

    Hidden way for us to feel touch uncovered by Imperial researchers

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    Newswise — Previously, touch was thought to be detected only by nerve endings present within the skin and surrounding hair follicles. This new research from Imperial College London has found that that cells within hair follicles – the structures that surround the hair fibre – are also able to detect the sensation in cell cultures.

    The researchers also found that these hair follicle cells release the neurotransmitters histamine and serotonin in response to touch – findings that might help us in future to understand histamine’s role in inflammatory skin diseases like eczema.

    Lead author of the paper Dr Claire Higgins, from Imperial’s Department of Bioengineering, said: “This is a surprising finding as we don’t yet know why hair follicle cells have this role in processing light touch. Since the follicle contains many sensory nerve endings, we now want to determine if the hair follicle is activating specific types of sensory nerves for an unknown but unique mechanism.”

    A touchy subject

    We feel touch using several mechanisms: sensory nerve endings in the skin detect touch and send signals to the brain; richly innervated hair follicles detect the movement of hair fibres; and sensory nerves known as C-LTMRs, that are only found in hairy skin, process emotional, or ‘feel-good’ touch.

    Now, researchers may have uncovered a new process in hair follicles. To carry out the study, the researchers analysed single cell RNA sequencing data of human skin and hair follicles and found that hair follicle cells contained a higher percentage of touch-sensitive receptors than equivalent cells in the skin. 

    They established co-cultures of human hair follicle cells and sensory nerves, then mechanically stimulated the hair follicle cells, finding that this led to activation of the adjacent sensory nerves.

    They then decided to investigate how the hair follicle cells signalled to the sensory nerves. They adapted a technique known as fast scan cyclic voltammetry to analyse cells in culture and found that the hair follicle cells were releasing the neurotransmitters serotonin and histamine in response to touch.

    When they blocked the receptor for these neurotransmitters on the sensory neurons, the neurons no longer responded to the hair follicle cell stimulation. Similarly, when they blocked synaptic vesicle production by hair follicle cells, they were no longer able to signal to the sensory nerves.

    They therefore concluded that in response to touch, hair follicle cells release that activate nearby sensory neurons.

    The researchers also conducted the same experiments with cells from the skin instead of the hair follicle. The cells responded to light touch by releasing histamine, but they didn’t release serotonin.

    Dr Higgins said: “This is interesting as histamine in the skin contributes to inflammatory skin conditions such as eczema, and it has always been presumed that immune cells release all the histamine. Our work uncovers a new role for skin cells in the release of histamine, with potential applications for eczema research.”

    The researchers note that the research was performed in cell cultures, and will need to be replicated in living organisms to confirm the findings. The researchers also want to determine if the hair follicle is activating specific types of sensory nerves. Since C-LTMRs are only present within hairy skin, they are interested to see if the hair follicle has a unique mechanism to signal to these nerves that we have yet to uncover.

    This work was funded by Engineering and Physical Research Council (EPSRC, part of UKRI), Proctor & Gamble, Wellcome Trust, and Biotechnology and Biological Sciences Research Council (BBSRC, part of UKRI).

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    Imperial College London

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  • Potential source of male fertility issues.

    Potential source of male fertility issues.

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    Newswise — Bonn, 27. October – Mature spermatozoa are characterized by an head, midpiece and a long tail for locomotion. Now, researchers from the University Hospital Bonn (UKB) and the Transdisciplinary Research Unit “Life & Health” at the University of Bonn have found that a loss of the structural protein ACTL7B blocks spermatogenesis in male mice. The cells can no longer develop their characteristic shape and remain in a rather round form. The animals are infertile. The results of the study have now been published in the scientific journal “Development”.

    Male sperm cells are constantly produced in large quantities in the testicles during so-called spermatogenesis. In this process, the typical elongated sperm cells are formed from round germ cells. This enormous change in shape requires the fine tuned reorganization of specialized structural proteins. One of these structural proteins is ACTL7B. “Since it is exclusively made in humans and mice during the maturation of male sperm, it has been postulated that the protein is important for this phase of development,” notes corresponding author Prof. Hubert Schorle from the Institute of Pathology at UKB, who is also a member of the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn.

    To investigate the role of the structural protein in spermiogenesis, Prof. Schorle’s team generated a mouse model with a mutation in the Actl7b gene using gene-editing technology. This results in a complete loss of function of ACTL7B. “Without ACTL7B, development is blocked, the cells often remain in a roundish shape, usually do not form the elongated, typical sperm shape and die to a large extent ,” says first author Gina Esther Merges, a doctoral student in Professor Schorle’s laboratory.

     

    Disruption in the network of proteins

    In this context, the Bonn researchers found that ACTL7B is required for the reorganization of the cytoskeleton of spermatids. Using mass spectrometric analyses, they identified two interaction partners of ACTL7B, DYNLL1 and DYNLL2. “We were able to show that without the structural protein, DYNLL1 and 2 are not correctly localized in the round spermatids. Since it is probably a larger protein complex with further interaction partners, we attribute the above described effect to a loss of temporally and spatially precisely regulated and targeted redistribution of these proteins,” Prof. Schorle notes.

    This explains why the sperm of male mice with a mutated Actl7b gene is not able to develop the characteristic shape. Due to this, the animals are infertile. In addition, according to other research, there is evidence that levels of the protein ACTL7B are reduced in some fertility patients. “Our study shows that mutations in the Actl7b gene could be the cause of male infertility,” says Prof. Schorle.

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    Universitatsklinikum Bonn

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  • Find-and-Replace Genome Editing with CRISPR: A Promising Therapeutic Strategy

    Find-and-Replace Genome Editing with CRISPR: A Promising Therapeutic Strategy

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    Newswise — Severe Combined Immunodeficiencies (SCIDs) are a group of debilitating primary immunodeficiency disorders, primarily caused by genetic mutations that disrupt T-cell development. SCID can also affect B-cell and natural killer cell function and counts. Left untreated, SCID proves fatal within the first year of life. The conventional treatment for SCID patients involves allogeneic hematopoietic stem cell transplantation (HSCT), but the challenges of finding compatible donors and potential complications like graft-versus-host disease (GVHD) pose significant hurdles in this approach.

    A groundbreaking solution has emerged with the advent of genome editing (GE), particularly using CRISPR-Cas9 technology. This cutting-edge gene therapy research offers hope for many genetic disorders such as SCID. The CRISPR-Cas9 system creates site-specific double-strand breaks in the DNA, allowing for precise gene editing. The repair process can either disrupt a specific gene or correct it, potentially targeting nearly any gene in the genome. This development opens the door to therapeutic interventions for a wide range of genomic diseases.

    One promising genome-editing approach, CRISPR-Cas9 Homology-directed repair (HDR)-mediated GE, offers the potential for precise gene insertion. In certain subtypes of SCID, an alternative to HSCT can involve conventional CRISPR-Cas9 HDR-mediated gene insertion, but it carries inherent risks, especially in cases like RAG2-SCID. RAG2 is nuclease involved in DNA cleavage during lymphocyte development, and CRISPR-Cas9 HDR-mediated gene insertion may lead to uncontrolled RAG2 nuclease activity and harmful structural variations.

    In response, researchers from Bar-Ilan University in Israel propose a novel replacement strategy, termed GE x HDR 2.0: Find and Replace. This approach, outlined in a paper published today in Nature Communications, combines CRISPR-Cas9-mediated genome editing with recombinant adeno-associated serotype 6 (rAAV6) DNA donor vectors to precisely replace the RAG2 coding sequence while preserving regulatory elements. This strategy can be applied also to other genes with hot spot regions for disease-causing mutations.

    Dr. Ayal Hendel, of Bar-Ilan University’s Goodman Faculty of Life Sciences, emphasized, “Our innovation hinges on a crucial insight: to efficiently trigger CRISPR-Cas9 HDR-mediated GE for precise coding sequence replacement, it’s essential to separate the distal homology arm from the cleavage site and align it with the sequence immediately downstream of the segment needing replacement. In this process, elongating the distal homology arm length in the donor is of paramount importance. By preserving endogenous regulatory elements and intronic sequences, our approach faithfully reproduces natural gene expression levels, thus reducing the associated risks of unregulated gene expression. This groundbreaking technique, which involves replacing entire coding sequences or exons while retaining critical regulatory elements, brings hope to patients with RAG2-SCID and holds promise for the treatment of various other genetic disorders.”

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    Bar-Ilan University

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  • How mosquito-controlling bacteria might also enhance insect fertility

    How mosquito-controlling bacteria might also enhance insect fertility

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    Newswise — A new study reveals biological mechanisms by which a specific strain of bacteria in the Wolbachia genus might enhance the fertility of the insects it infects—with potentially important implications for mosquito-control strategies. Shelbi Russell of the University of California Santa Cruz, US, and colleagues report these findings in the open access journal PLOS Biology on October 24th.

    Different strains of Wolbachia bacteria naturally infect a number of different animals worldwide, such as mosquitos, butterflies, and fruit flies. Wolbachia can manipulate the fertility of their hosts through a specific biological mechanism that aids the spread of Wolbachia within host populations. In recent years, people have harnessed that mechanism in strategies to deliberately infect mosquitos with a specific Wolbachia strain, reducing targeted mosquito populations and thereby potentially reducing the spread of human viruses carried by mosquitos, such as dengue or Zika.

    Research in fruit flies suggests that that same strain, which is native to fruit flies, may also enhance insect fertility, with potentially important implications for mosquito control. Evidence suggests that biological processes involving the fruit-fly protein meiotic-P26 (“mei-P26″), which is essential for fruit-fly reproduction, may underlie this enhanced fertility. However, these processes have remained unclear.

    To investigate, Russell and colleagues bred fruit flies with various defects affecting mei-P26—resulting in reduced fruit-fly fertility—and examined what happened when they then infected the flies with the fruit-fly-native Wolbachia strain.

    They found that Wolbachia infection restored fertility in fruit flies with various mei-P26 defects, enabling them to produce more offspring than uninfected flies. Further experiments revealed how Wolbachia may restore fertility by mitigating certain perturbing effects of mei-P26 defects on specific genes and proteins, thereby resolving problems with the stem cells that produce fruit fly eggs and sperm.

    In additional experiments, Wolbachia infection also enhanced the fertility of fruit flies without mei-P26 defects, resulting in higher egg lay and hatch rates.

    These findings help to resolve the mystery of how this particular Wolbachia strain enhances fruit-fly fertility. Further research will be needed to better understand these effects and their potential implications for strategies that employ this strain to control mosquito populations.

    Russell adds, “Wolbachia endosymbionts exist at high infection frequencies in many host populations, despite exhibiting weak gene drive systems and unobserved impacts on host fitness. Here, we show that the wMel strain of Wolbachia is able to rescue and reinforce host fertility, demonstrating their capacity to function as a beneficial symbiont.”

    #####

    In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002335

    Press-only preview: https://plos.io/3tudL1r

     

    Image Caption: A mei-P26 mutant Drosophila melanogaster ovariole infected with wMel bacterial symbionts. DNA is stained in red, anti-Vasa protein is stained blue, and anti-Hu-li tai shao ring canal protein is stained cyan.

    Image Credit: Shelbi Russell (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

    Image URL: https://plos.io/459VWBV

    Citation: Russell SL, Castillo JR, Sullivan WT (2023) Wolbachia endosymbionts manipulate the self-renewal and differentiation of germline stem cells to reinforce fertility of their fruit fly host. PLoS Biol 21(10): e3002335. https://doi.org/10.1371/journal.pbio.3002335

    Author Countries: United States

    Funding: This work was supported by the UC Santa Cruz Chancellor’s Postdoctoral Fellowship and the NIH (R00GM135583 to SLR; R35GM139595 to WTS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests: The authors have declared that no competing interests exist.

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  • Magnet manipulation guides muscle fiber alignment in tissue.

    Magnet manipulation guides muscle fiber alignment in tissue.

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    Newswise — Stimulating muscle fibers with magnets causes them to grow in the same direction, aligning muscle cells within tissue, Massachusetts Institute of Technology (MIT) and Boston University investigators report October 20 in the journal Device. The findings offer a simpler, less time-consuming way for medical researchers to program muscle cell alignment, which is strongly tied to healthy muscle function.

    “The ability to make aligned muscle in a lab setting means that we can develop model tissues for understanding muscle in healthy and diseased states and for developing and testing new therapies that combat muscle injury or disease,” says senior author Ritu Raman (@DrRituRaman), an MIT engineer. A better understanding of the rules that govern muscle growth could also have applications in robotics, she adds.

    In a previous investigation, Raman and colleagues found that “exercising” muscle fibers by making them contract in response to electrical stimulation for 30 minutes a day over the course of 10 days made the fibers stronger. This time, the researchers wanted to explore whether mechanically stimulating the muscle fibers over the same time frame (rather than letting them respond on their own) would have the same result. To investigate, they developed a method to mechanically stimulate muscle tissue that differs from typical lab techniques.

    “Generally, when people want to mechanically stimulate tissues in a lab environment, they grasp the tissue at both ends and move it back and forth, stretching and compressing the whole tissue,” said Raman. “But this doesn’t really mimic how cells talk to each other in our bodies. We wanted to spatially control the forces between cells within a tissue, matching native systems.”

    To stimulate the muscle cells in a more true-to-life way, Raman and her team grew cells in a Petri dish on a soft gel that contained magnetic particles. When they would move a magnet back and forth under the gel, the particles moved back and forth, too, which “flexed” the cells. The researchers could precisely control the way the gel moved, and, in turn, the magnitude and direction of the forces the cells within experienced, by changing the strength and orientation of the magnet. To measure the alignment of the muscle fibers within the tissues and whether they contracted in synchrony, the team’s collaborators at Boston University developed a custom software that automatically tracked videos of the muscle and generated graphs of its movement.

    “We were very surprised by the findings of our study,” said Raman. While mechanically stimulating the muscle fibers over the 10-day period did not seem to make them any stronger, it did cause them all to grow in the same direction.

    “Furthermore, we were excited to find that, when we triggered muscle contraction, aligned muscle was beating synchronously, whereas non-aligned muscle was not beating rhythmically,” said Raman. “This confirmed our understanding that the form and function of muscle are intrinsically connected, and that controlling form can help us control function.”

    Raman and colleagues plan to take the study further by investigating how different mechanical stimulation regimens impact both healthy and diseased muscle fibers. Additionally, they plan to study how mechanical stimulation affects other types of cells.

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  • Brain Immune Cell to Neuron Conversion Aids Post-Stroke Mouse Recovery.

    Brain Immune Cell to Neuron Conversion Aids Post-Stroke Mouse Recovery.

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    Newswise — Fukuoka, Japan – Researchers at Kyushu University have discovered that turning brain immune cells into neurons successfully restores brain function after stroke-like injury in mice. These findings, published on October 10 in PNAS, suggest that replenishing neurons from immune cells could be a promising avenue for treating stroke in humans.

    Stroke, and other cerebrovascular diseases, occur when blood flow to the brain is affected, causing damage to neurons. Recovery is often poor, with patients suffering from severe physical disabilities and cognitive problems. Worldwide, it’s one of the most common causes for needing long-term care.

    “When we get a cut or break a bone, our skin and bone cells can replicate to heal our body. But the neurons in our brain cannot easily regenerate, so the damage is often permanent,” says Professor Kinichi Nakashima, from Kyushu University’s Graduate School of Medical Sciences. “We therefore need to find new ways to replace lost neurons.”

    One possible strategy is to convert other cells in the brain into neurons. Here, the researchers focused on microglia, the main immune cells in the central nervous system. Microglia are tasked with removing damaged or dead cells in the brain, so after a stroke, they move towards the site of injury and replicate quickly.

    “Microglia are abundant and exactly in the place we need them, so they are an ideal target for conversion,” says first author, Dr. Takashi Irie from Kyushu University Hospital.

    In prior research, the team demonstrated that they could induce microglia to develop into neurons in the brains of healthy mice. Now, Dr. Irie and Professor Nakashima, along with Lecturer Taito Matsuda and Professor Noriko Isobe from Kyushu University Graduate School of Medical Sciences, showed that this strategy of replacing neurons also works in injured brains and contributes to brain recovery.

    To conduct the study, the researchers caused a stroke-like injury in mice by temporarily blocking the right middle cerebral artery – a major blood vessel in the brain that is commonly associated with stroke in humans. A week later, the researchers examined the mice and found that they had difficulties in motor function and had a marked loss of neurons in a brain region known as the striatum. This part of the brain is involved in decision making, action planning and motor coordination.

    The researchers then used a lentivirus to insert DNA into microglial cells at the site of the injury. The DNA held instructions for producing NeuroD1, a protein that induces neuronal conversion. Over the subsequent weeks, the infected cells began developing into neurons and the areas of the brain with neuron loss decreased. By eight weeks, the new induced neurons had successfully integrated into the brain’s circuits.

    At only three weeks post-infection, the mice showed improved motor function in behavioral tests. These improvements were lost when the researchers removed the new induced neurons, providing strong evidence that the newly converted neurons directly contributed to recovery.

    “These results are very promising. The next step is to test whether NeuroD1 is also effective at converting human microglia into neurons and confirm that our method of inserting genes into the microglial cells is safe,” says Professor Nakashima.

    Furthermore, the treatment was conducted in mice in the acute phase after stroke, when microglia were migrating to and replicating at the site of injury. Therefore, the researchers also plan to see if recovery is also possible in mice at a later, chronic phase.

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  • Newsmakers: Basic Research Findings by Johns Hopkins Scientists Focus on Gene Sequencing, Hearing Loss and a Brain Disorder

    Newsmakers: Basic Research Findings by Johns Hopkins Scientists Focus on Gene Sequencing, Hearing Loss and a Brain Disorder

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    Newswise — Yes, Scientists Have Sequenced the Entire Human Genome, But They’re Not Done Yet

    The human genome, from end to end, has been sequenced, meaning scientists worldwide have identified most of the nearly 20,000 protein-coding genes. However, an international group of scientists notes there’s more work to be done. The scientists point out that even though we have nearly converged on the identities of the 20,000 genes, the genes can be cut and spliced to create approximately 100,000 proteins, and gene experts are far from agreement on what those 100,000 proteins are.

    The group, which convened last fall at Cold Spring Harbor Laboratory in New York, has now published a guide for prioritizing the next steps in the effort to complete the human gene “catalog.”

    “Many scientists have been working on efforts to fully understand the human genome, and it’s much more difficult and complex than we thought,” says Steven Salzberg, Ph.D., Bloomberg Distinguished Professor of Biomedical Engineering, Computer Science, and Biostatistics at The Johns Hopkins University. “We have provided a state of the human gene catalog and a guide on what’s needed to complete it.”

    Salzberg, along with Johns Hopkins biomedical engineer and associate professor Mihaela Pertea, Ph.D., M.S., M.S.E., postdoctoral researcher Ales Varabyou and 19 other scientists, offered perspectives on the human gene catalog Oct. 4 in the journal Nature.

    The scientists say that while the final list of protein coding genes is nearly complete, scientists have not yet fully cataloged the variety of ways that a gene can be cut, or spliced, resulting in “isoforms” of proteins that are slightly different. Some protein isoforms will not affect the protein’s function but some may be different enough to result in increased risk for a particular trait, condition or illness.

    To complete the catalog, the scientists propose a comprehensive look at how each gene is expressed into functional and nonfunctional proteins and the three-dimensional shape of those proteins.

    The scientists also propose a focus on cataloging non-coding RNA genes. RNA is the genetic material that is transcribed by DNA and follows a molecular path to making proteins. Instead of proteins, non-coding RNA genes encode other types of molecular material that performs a cellular function.

    Finally, the international group emphasizes the importance of enhancing commonly used databases of gene variations that cause illness and disease, improving clinical laboratory standards for annotating DNA sequencing results and developing new technology to enable more effective and precise methods to match the wide array of proteins with their gene products.

    When It Comes to Hearing, the Left and Right Sides of the Brain Work Together, Mouse Research Shows

    Johns Hopkins-led research has revealed an extensive network of connections between the right and left sides of the brain when mice are exposed to different sounds. The researchers also found that some areas of the brain are specialized to recognize certain sounds, such as “calls” from the animals. Further, the researchers also found that deaf mice had far fewer right and left brain connections, suggesting that the brain needs to “hear” and process sound during early ages to spur development of left-right brain connections.

    The findings, say the researchers, may eventually help scientists pinpoint the time period when such brain connections and specialization form, and offer potential insights into how to restore hearing loss.

    “The auditory system is a collection of parts, which need to be connected properly,” says Johns Hopkins neuroengineer Patrick Kanold, Ph.D., a professor of biomedical engineering. “Using a novel microscope that enabled us to see both brain hemispheres at the same time, we found that some of those connections are between the right and left brain hemispheres, allowing functional specialization. When the brain does not get the right inputs, for example in hearing loss, these brain connections are missing. This obviously is an issue if we hope to restore hearing at a later age.”

    In efforts to find new ways to restore hearing, Kanold’s team will continue its work to identify the specific time period when brain connections form in response to sound and how to restore abnormal connections. The team is also continuing research to understand how the brain adapts to and modulates sound processing to filter out distracting signals, such as its recent work indicating that the brain’s frontal cortex provides specific signals to the auditory system during behaviors that might help in this filtering process.

    New Mouse Models May Help Scientists Find Therapies for Brain Development Disorder

    For more than 25 years, Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and director of the Solomon H. Snyder Department of Neuroscience, at the Johns Hopkins University School of Medicine, has studied the protein SYNGAP1 that is now known to be linked to a group of neurodevelopmental disorders that are usually diagnosed during early childhood. Working with biotechnology companies to find new therapies for the conditions, his team at Johns Hopkins Medicine reports it has developed new mouse models that more accurately represent genetic mutations in people who have SYNGAP1-related disorders.

    The new collection of mouse models, now available to scientists developing treatments, have several variations in the SYNGAP1 gene, which were discovered to cause conditions marked by seizures, cognitive impairment, social deficits and sleep disturbances.

    The SYNGAP1 gene, found also in humans, makes proteins that regulate synapses, the space between two neurons where they trade chemical and molecular messages. When SYNGAP1 is mutated, as in the case of SYNGAP1-related disorders in people, neurons make less of the protein in the synapse, and learning and memory are impaired.

    In other mouse models, called “knock-out” models, the SYNGAP1 gene is removed entirely. Huganir says both the knock-out models and the new versions — “knock-in” models, which carry a variety of SYNGAP1 mutations linked to the disorders — will be helpful in finding therapies that boost SYNGAP1 protein production.

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  • Remnant of cell division could be responsible for spreading cancer

    Remnant of cell division could be responsible for spreading cancer

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    Newswise — Once thought to be the trash can of the cell, a little bubble of cellular stuff called the midbody remnant is actually packing working genetic material with the power to change the fate of other cells — including turning them into cancer.

    It’s a surprise to many people, according to Ahna Skop, a University of Wisconsin­–Madison genetics professor, that when one cell divides into two, a process called mitosis, the result is not just the two daughter cells.

    “One cell divides into three things: two cells and one midbody remnant, a new signaling organelle,” says Skop. “What surprised us is that the midbody is full of genetic information, RNA, that doesn’t have much to do with cell division at all, but likely functions in cell communication.”

    In a study published today in the journal Developmental Cell, Skop’s lab and collaborators from the Pasteur Institute in Paris, Harvard Medical School, Boston University and the University of Utah analyzed the contents of midbodies — which form between the daughter cells during division — and tracked the interactions of the midbody remnants set free after cell division. Their results point to the midbody as a vehicle for the spread of cancer throughout the body.

    “People thought the midbody was a place where things died or were recycled after cell division,” Skop says. “But one person’s trash is another person’s treasure. A midbody is a little packet of information cells use to communicate.”

    The midbody’s involvement in cell signaling and stimulating cell proliferation has been investigated before, but Skop and her collaborators wanted to look inside the midbody remnants to learn more.

    What the researchers found inside midbodies was RNA — which is a kind of working copy of DNA used to produce the proteins that make things happen in cells — and the cellular machinery necessary to turn that RNA into proteins. The RNA in midbodies tends to be blueprints not for the cell division process but for proteins involved in activities that steer a cell’s purpose, including pluripotency (the ability to develop into any of the body’s many different types of cells) and oncogenesis (the formation of cancerous tumors).

    “A midbody remnant is very small. It’s a micron in size, a millionth of a meter,” Skop says. “But it’s like a little lunar lander. It’s got everything it needs to sustain that working information from the dividing cell. And it can drift away from the site of mitosis, get into your bloodstream and land on another cell far away.”

    Many midbody remnants are reabsorbed by one of the daughter cells that shed them, but those that touch down on a distant surface, like a lunar lander, may instead be absorbed by a third cell. If that cell swallows the midbody, it may mistakenly begin using the enclosed RNA as if it were its own blueprints.

    Previous research showed that cancer cells are more likely than stem cells to have ingested a midbody and its potentially fate-altering cargo. Stem cells, which give rise to new cells and are valuable for their pluripotency, spit a lot of midbodies back out, perhaps to maintain their pluripotency.

    Future research may be able to harness the power of midbody RNA to deliver drugs to cancer cells or to keep them from dividing.

    “We think our findings represent a huge target for cancer detection and therapeutics,” says Skop, whose work is supported by the National Institutes of Health.

    The researchers identified a gene, called Arc, that is key to loading the midbody and midbody remnant with RNA. Taken up long ago from an ancient virus, Arc also plays a role in the way brain cells make memories.

    “Loss of Arc leads to the loss of RNA in the midbody and a loss of the RNA information from getting to recipient cells,” Skop says. “We believe this memory gene is important for all cells to communicate RNA information.”

    Sungjin Park, a senior scientist in Skop’s lab, is the lead author of the new study. Skop and collaborators also have a patent pending on two new methods that make it easier to isolate midbody structures from cell media or blood serum, improving cancer diagnostics.

     

    This research was funded in part by grants from the National Institutes of Health (R01 GM139695-01A1, R01 NS115716, and R01 GM122893 and GM144352) and the French Fondation ARC for cancer research.

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    University of Wisconsin-Madison

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  • Predicting condensate formation by cancer-associated fusion oncoproteins

    Predicting condensate formation by cancer-associated fusion oncoproteins

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    Newswise — (Memphis, Tenn – September 28, 2023) Many cancers are caused by fusion oncoproteins, molecules that aberrantly form when a rearrangement of DNA results in parts of two different proteins being expressed as one. Several fusion oncoproteins spontaneously form condensates inside cells that promote cancer development. New research by St. Jude Children’s Research Hospital established a method to study this biophysical process in cells, then used that information as a launchpad to predict the behavior of other fusion oncoproteins. The findings, which offer insight into fusion oncoprotein-driven cancers, were published today in Nature Communications. 

    While genes define everything about us, they are not immutable. Genes are made of DNA, which is constantly being read and replicated. Errors can occur, and sometimes a piece of DNA can break and reattach at a different location. This can lead to two previously independent genes being glued together, resulting in a fusion protein. These unnatural proteins retain properties of both original components, which can have disastrous consequences for cells.  

    “Fusion proteins have been shown to be oncogenic drivers in upwards of 15% of human cancers,” said Richard Kriwacki, Ph.D., St. Jude Department of Structural Biology. These fusion oncoproteins can interfere with cellular regulatory pathways involved in cell growth and differentiation, leading to uncontrolled cell division and cancer.  

     

    Secrets in the droplets 

    “We hypothesized that gaining the ability to form condensates could be linked with the oncogenic properties of fusion oncoproteins,” Kriwacki explained. Biomolecular condensates can form through a process called liquid-liquid phase separation, in which biomolecules separate from the surrounding local environment and form their own compartment, akin to oil droplets in water. Condensates have been shown to be very powerful tools for a cell to regulate many different processes. However, when a fusion oncoprotein has the ability to form a condensate, it can wreak havoc in our cells. 

    Kriwacki, along with collaborators set out to uncover how interwoven fusion oncoproteins were with the process of phase separation.   

     

    The code of fusion oncoprotein condensate behavior 

    The researchers initially examined 166 fusion oncoproteins in cells to observe if they phase separate. Then they categorized them, which was no small feat, according to co-first author Hazheen Shirnekhi, Ph.D., St. Jude Department of Structural Biology. 

    “The condensates were all different sizes, different shapes, and located in different areas of the cell,” Shirnekhi said. “It was difficult for any computer program to recognize the condensates in an unbiased manner, so we had to do this manually. It took a lot of time.”  

    This effort revealed that 58% of the fusion oncoproteins examined formed condensates, opening the door to additional insights.  

    “We found that a large number of those fusion oncoproteins that form condensates, especially in the nucleus, had functional features associated with regulation of gene expression,” Kriwacki said. “The cytoplasmic fusion oncoproteins forming condensates had functional features associated with regulation of cell signaling.” These observations suggest that the fusion oncoproteins elicit their oncogenic properties by altering gene regulation or cell signaling pathways through formation of condensates. 

     

    Machine learning reveals scope of phenomenon  

    In addition to those links to cellular functions, patterns began to emerge within the protein sequences of the fusion oncoproteins that form condensates. These patterns involve so-called physicochemical features, such as number of polar amino acids, charged groups or disordered regions.  

    “When we looked at the sequences of the condensate-forming fusion oncoproteins, we noticed features that are distinct from the condensate-negative fusion oncoproteins,” explained co-first author Swarnendu Tripathi, Ph.D., St. Jude Department of Structural Biology. “That motivated us to select 25 non-redundant features and use data science to predict whether a fusion oncoprotein forms condensates or not.” 

    This data science aspect allowed the researchers to use their 166-sample groundwork to train a machine-learning algorithm using those 25 features. The computational model was then applied to predict the condensate-forming behavior of ~3,000 additional fusion oncoproteins associated with different cancer types.   

    The model predicted that upwards of 67% of those additional fusion oncoproteins likely form condensates. The condensate-forming predictions were tested for a subset of fusion oncoproteins. “The model was shown to be 80% accurate in independent testing with fusions not used in the training,” Tripathi noted. 

    This research establishes the foundational framework for determining the mechanisms underlying the oncogenic properties of fusion oncoproteins to enable their targeted inhibition through pharmaceutical agents or alternative approaches. “We’re looking to address the relationship between condensate formation, alteration of gene expression and oncogenesis,” Kriwacki explained. “We’re working with collaborators so that we can address this causality question in as rigorous a way as possible.” As Kriwacki highlighted, “By obtaining a grasp of the underlying mechanisms, we are setting the stage for potential innovative therapeutic approaches against fusion oncoprotein-driven cancers.” 

     

    Authors and funding 

    The study’s other co-first author was Scott Gorman, formerly of St. Jude. The study’s other authors include Bappaditya Chandra, David Baggett, Cheon-Gil Park, Ramiz Somjee, Benjamin Lang, Seyed Mohammad Hadi Hosseini, Brittany Pioso, Ilaria Iacobucci, Qingsong Gao, Michael Edmonson, Stephen Rice, Xin Zhou, John Bollinger, Madan Babu, Charles Mullighan and Jinghui Zhang, of St. Jude; Diana Mitrea and Michael White, formerly of St. Jude, Yongsheng Li and Stephen Yi of the University of Texas at Austin; Daniel McGrail of Cleveland Clinic; Daniel Jarosz of Stanford University School of Medicine; and Nidhi Sahni of the University of Texas MD Anderson Cancer Center and Baylor College of Medicine.  

    The study was supported by grants from the National Institutes of Health (R35 GM137836, R35 GM133658), Komen Foundation grants (CCR19609287, PDF17483544), the National Cancer Institute (P30 CA021765, R35 CA197695, R01 CA246125, U54 CA243124, R01 CA216391, T32 CA236748, K99 CA240689), the National Institute of General Medical Sciences (F32 GM143847), a St. Jude Children’s Research Hospital Chromatin Collaborative award, a Neoma Boadway Fellowship from St. Jude Children’s Research Hospital, the Cancer Prevention and Research Institute of Texas (RR160021, RP220292), a SummerPlus Program Fellowship from Rhodes College and ALSAC, the fundraising and awareness organization of St. Jude. 

     

     

    St. Jude Children’s Research Hospital  

    St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch.   

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  • Sperm swimming is caused by the same patterns that are believed to dictate zebra stripes

    Sperm swimming is caused by the same patterns that are believed to dictate zebra stripes

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    BYLINE: Laura Thomas

    Newswise — Patterns of chemical interactions are thought to create patterns in nature such as stripes and spots. This new study shows that the mathematical basis of these patterns also governs how sperm tail moves.

    The findings, published today in Nature Communications, reveal that flagella movement of, for example, sperm tails and cilia, follow the same template for pattern formation that was discovered by the famous mathematician Alan Turing. 

    Flagellar undulations make stripe patterns in space-time, generating waves that travel along the tail to drive the sperm and microbes forward.

    Alan Turing is most well-known for helping to break the enigma code during WWII. However he also developed a theory of pattern formation that predicted that chemical patterns may appear spontaneously with only two ingredients: chemicals spreading out (diffusing) and reacting together. Turing first proposed the so-called reaction-diffusion theory for pattern formation.

    Turing helped to pave the way for a whole new type of enquiry using reaction-diffusion mathematics to understand natural patterns. Today, these chemical patterns first envisioned by Turing are called Turing patterns. Although not yet proven by experimental evidence, these patterns are thought to govern many patterns across nature, such as leopard spots, the whorl of seeds in the head of a sunflower, and patterns of sand on the beach. Turing’s theory can be applied to various fields, from biology and robotics to astrophysics. 

    Mathematician Dr Hermes Gadêlha, head of the Polymaths Lab, and his PhD student James Cass conducted this research in the School of Engineering Mathematics and Technology at the University of Bristol. Gadêlha explained: “Live spontaneous motion of flagella and cilia is observed everywhere in nature, but little is known about how they are orchestrated.

    “They are critical in health and disease, reproduction, evolution, and survivorship of almost every aquatic microorganism in earth.”

    The team was inspired by recent observations in low viscosity fluids that the surrounding environment plays a minor role on the flagellum. They used mathematical modelling, simulations, and data fitting to show that flagellar undulations can arise spontaneously without the influence of their fluid environment.

    Mathematically this is equivalent to Turing’s reaction-diffusion system that was first proposed for chemical patterns.

    In the case of sperm swimming, chemical reactions of molecular motors power the flagellum, and bending movement diffuses along the tail in waves. The level of generality between visual patterns and patterns of movement is striking and unexpected, and shows that only two simple ingredients are needed to achieve highly complex motion.

    Dr Gadêlha added: “We show that this mathematical ‘recipe’ is followed by two very distant species – bull sperm and Chlamydomonas (a green algae that is used as a model organism across science), suggesting that nature replicates similar solutions.

    “Travelling waves emerge spontaneously even when the flagellum is uninfluenced by the surrounding fluid. This means that the flagellum has a fool-proof mechanism to enable swimming in low viscosity environments, which would otherwise be impossible for aquatic species.

    “It is the first time that model simulations compare well with experimental data.

    “We are grateful to the researchers that made their data freely available, without which we would not have been able to proceed with this mathematical study.”

    These findings may be used in future to better understand fertility issues associated with abnormal flagellar motion and other ciliopathies; diseases caused by ineffective cilia in human bodies.

    This could also be further explored for robotic applications, artificial muscles, and animated materials, as the team discovered a simple “mathematical recipe” for making patterns of movement.

    Dr Gadêlha is also a member of the SoftLab at Bristol Robotics Laboratory (BRL), where he uses pattern formation mathematics to innovate the next generation of soft-robots.

    “In 1952, Turing unlocked the reaction-diffusion basis of chemical patterns,” said Dr Gadêlha. “We show that the ‘atom’ of motion in the cellular world, the flagellum, uses Turing’s template to shape, instead, patterns of movement driving tail motion that pushes sperm forwards.

    “Although this is a step closer to mathematically decode spontaneous animation in nature, our reaction-diffusion model is far too simple to fully capture all complexity. Other models may exist, in the space of models, with equal, or even better, fits with experiments, that we simply have no knowledge of their existence yet, and thus substantial more research is still needed!”

    The study was completed using funding from the Engineering and Physical Sciences Research Council (EPSRC) and DTP studentship for James Cass PhD.

    The numerical work was carried out using the computational and data storage facilities of the Advanced Computing Research Centre, at the University of Bristol.

     

    Paper:

    ‘The reaction-diffusion basis of animated patterns in eukaryotic flagella’ by James Cass and Dr Hermes Bloomfield-Gadêlha in Nature Communications.

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  • NCCN Senior Director Evelyn Handel Zapata is Named a ‘40 Under 40 in Cancer: Emerging Leader’ for Milestone Work Improving Safe Use of Chemotherapy

    NCCN Senior Director Evelyn Handel Zapata is Named a ‘40 Under 40 in Cancer: Emerging Leader’ for Milestone Work Improving Safe Use of Chemotherapy

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    Newswise — PLYMOUTH MEETING, PA [September 25, 2023] —Evelyn Handel Zapata, PharmD, BCPS, BCOP, Senior Director of Drugs & Biologics Programs at the National Comprehensive Cancer Network® (NCCN®) was named a 40 Under 40 in Cancer: Emerging Leader at a national reception in Chicago in June. This achievement comes as the NCCN Chemotherapy Order Templates (NCCN Templates®) program celebrates its 15th anniversary and launches new resources for a type of pediatric lymphoma today.

    40 Under 40 in Cancer is an awards initiative that recognizes contributions being made across the field of cancer by rising stars and emerging leaders under the age of 40. The award is sponsored by The Association for Value-Based Cancer Care (AVBCC), The National Community Oncology Dispensing Association (NCODA), Swim Across America, Amplity Health, Servier, Takeda, Jasper Health, BeiGene, and Cumberland Pharmaceuticals.

    “Dr. Handel [Zapata] is an extremely diligent and collaborative pharmacist who [helps] set protocols, standards, templates, and guidance for oncology care providers,” said Eve Segal, PharmD, BCOP, Lead Clinical Pharmacist, Hematology/Oncology at Fred Hutchinson Cancer Center/UW Medicine. “She is also passionate about patient education, and through her leadership within HOPA [the Hematology/Oncology Pharmacy Association], has supported the creation of 70 IV education handouts and over 100 oral chemotherapy handouts that are used by hundreds of oncology practitioners every day. Evelyn’s work at NCCN has helped advance pharmacist involvement and provided pharmacist perspective on important national guidelines.”

    New Resources for Pediatric Oncology

    This year marks the 15th anniversary of the launch of the NCCN Templates® and heralds the publication of the first NCCN Templates for a childhood cancer. The NCCN Templates® contain critical information on dosing, administration, side effects and other monitoring and safety parameters, and are used by clinicians to ensure that they are delivering optimal treatment as recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). The newly launched resources for improving the safe use of systemic therapy when treating pediatric aggressive mature b-cell lymphomas were first published on September 25, 2023.

    There are now 2,531 published NCCN Templates covering 108 unique cancer types across 58 different NCCN Guidelines®, with 328 new templates added in the past year alone. They are licensed for use in a growing number of electronic health record systems, utilization management tools, and clinical decision support tools. In addition to users who access the templates through an HIT licensor, in 2022 more than 10,000 unique subscribers downloaded more than 1.7 million NCCN Templates directly from NCCN.org/templates.

    Dr. Handel Zapata joined NCCN in 2015 and serves as Senior Director of the Drugs & Biologics Programs, where she is involved with management of the NCCN Templates® as well as providing oversight and management for the NCCN Drugs and Biologics Compendium (NCCN Compendium®).

    “Evelyn exemplifies the core values we embrace at NCCN, including passion and innovation to advance high-quality cancer care,” said NCCN CEO Robert W. Carlson, MD. “She leads a team dedicated to providing the best information for the safe and effective use of drugs and biologics in cancer care. The work they do truly makes a difference for people with cancer. I am grateful for Evelyn’s ongoing contributions to NCCN and the field of oncology and congratulate her on this achievement.”

    “It was an honor to see the work that my colleagues and I do to improve the safe use of chemotherapy be recognized in this way,” said Dr. Handel Zapata. “I am grateful to HOPA for nominating me, and grateful to my team for all of their efforts over the years, most recently in the launch of a new pediatric cancer resource. I feel privileged to be part of this work advancing NCCN’s mission to help all people with cancer to live better lives.”

    Dr. Handel Zapata’s team at NCCN includes 12 oncology nurses and pharmacists, including two specializing in pediatric care. She also works with pharmacy directors across NCCN’s Member Institutions as part of the NCCN Pharmacy Directors Forum. In addition to her responsibilities at NCCN, Dr. Handel Zapata also serves as the Chair of the HOPA Patient Education Committee and the President of the International Society of Oncology Pharmacy Practitioners (ISOPP).

    # # #

    About the National Comprehensive Cancer Network

    The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, equitable, and accessible cancer care so all patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing education, global initiatives, policy, and research collaboration and publication in oncology. Visit NCCN.org for more information.

     

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    National Comprehensive Cancer Network(r) (NCCN(r))

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  • Single Cell Protein: an alternative eco-friendly protein source derived from microorganisms

    Single Cell Protein: an alternative eco-friendly protein source derived from microorganisms

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    Newswise — Researchers and businesses are increasingly drawn to alternative protein sources as they grapple with the challenge of meeting the growing global demand for protein. Among the unconventional sources, microorganisms stand out for their remarkable protein content.

    Dry microorganism cells have been described as “single cell protein” (SCP) or “microbial protein”. SCP is primarily sourced from microorganisms such as yeasts, fungi, bacteria and algae. They serve as an environmentally friendly alternative to animal-derived proteins. Furthermore, microorganisms exhibit the capacity to thrive on a diverse range of substrates for their growth, including waste materials. Leveraging renewable resources derived from different waste streams within the food and agricultural sector, such as dairy waste, crop residues, sugar industry byproducts, and fruit waste, has the potential to greatly enhance SCP production from a standpoint of socio-economic and environmental sustainability.

    “Particularly when SCP production is integrated into biorefinery frameworks, it can significantly advance circular bio-economy concepts, fostering the continued growth of the SCP market for applications in animal feed, innovative food formulations, and bioactive food packaging,” explains Danai Ioanna Koukoumaki, first author of a recent review on the topic published in Carbon Resources Conversion.

    “It’s true that the use of microorganisms for protein production holds promise, but it is nonetheless crucial to study consumer perceptions of this alternative protein source,” adds Koukoumaki, who is a PhD candidate at the Department of Food Science and Nutrition, University of the Aegean.

    For instance, in a research study examining the attitudes of older adults towards alternative protein sources such as single-cell protein and plant-based protein, it was observed that gender and country of residence had a notable impact on acceptance levels.

    Overall, the review provides a clear insight of the micro-organisms, agro-industrial wastes, functional properties, as well as current applications of single-cell protein.

    “Utilizing renewable feedstock in SCP production has the potential to address both modern society’s challenges of food waste management and protein shortages. However, to effectively commercialize this alternative, efforts must be made to enhance consumer acceptance,” concludes corresponding author Dimitris Sarris.

    ###

    References

    DOI

    10.1016/j.crcon.2023.07.004

    Original Source URL

    https://doi.org/10.1016/j.crcon.2023.07.004

    Funding information

    This research was funded by the project “Infrastructure of Microbiome Applications in Food Systems-FOODBIOMES” (MIS 5047291), which is implemented under the Action “Regional Excellence in R&D Infrastructures”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union (European Regional Development Fund).

    Journal

    Carbon Resources Conversion

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    Chinese Academy of Sciences

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  • New method to study microRNA activity in single cells

    New method to study microRNA activity in single cells

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    Newswise — MicroRNAs are small molecules that regulate gene activity by binding to and destroying RNAs produced by the genes. More than 60% of all human genes are estimated to be regulated by microRNAs, therefore it is not surprising that these small molecules are involved in many biological processes including diseases such as cancer. To discover the function of a microRNA, it is necessary to find out exactly which RNAs are targeted by it. While such methods exist, they require a lot of material typically in order of millions of cells, to work.

    Now researchers at Stockholm University and SciLifeLab have developed a new method to detect microRNA targets at the level of single cells. Such cells are each around one-hundredth millimeter in diameter and weigh less than a billionth gram, and comprise the basic building blocks of living organisms. With their new sensitive method, the researchers can follow microRNA targeting of thousands of RNAs during biological processes such as the cell cycle or differentiation into red blood cells. In these processes, the researchers find that microRNAs – surprisingly – perform quite different tasks in each cell. In the future, it will be possible to also apply this method to study microRNA targeting in whole tissues, to find out exactly what is happening in each of the many cell types that comprise complex organs such as brains.

    Marc Friedländer, associate professor at Stockholm University, says: “In our research team, we want to understand and ultimately make mathematical models of gene regulation at the level of the single cell. Our new method is a huge leap towards making this possible”.

    The work was spearheaded by Dr. Inna Biryukova, who took a leading role in developing the laboratory method, and by PhD student Vaishnovi Sekar, who performed the bulk of the advanced computational analyses. Vaishnovi Sekar highlights the challenges of the project: “In terms of complexity of the computational work, this is uncharted territory, and we lacked reference points and thresholds. We had to explore a myriad of approaches to devise a methodology that not only works but also yields biologically meaningful observations.”

    The study was supported by ERC and Vetenskapsrådet and has been published in the journal Nature Biotechnology.

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    Stockholm University

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