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Victor Ambros:
Welcome, everyone, and thank you for joining me in this fascinating series of imaginary conversations about one of the most transformative discoveries in modern biology: microRNAs. When Gary Ruvkun and I first stumbled upon these tiny molecules, we could never have foreseen how profoundly they would shape our understanding of life. MicroRNAs, though small, are mighty—they orchestrate the regulation of genes with a precision and elegance that continues to inspire awe and drive innovation in biology.
Today, we’re embarking on an intellectual journey to explore the impact of microRNAs across five critical areas. These conversations, though fictional, are enriched by the perspectives of some of the brightest minds in science. Joining us are pioneers like Gary Ruvkun, my collaborator and friend, whose insights into evolutionary conservation have been foundational; Craig Venter, who spearheaded the Human Genome Project and redefined genomics; Jennifer Doudna and Emmanuelle Charpentier, who revolutionized gene editing with CRISPR; and Francis Collins, whose leadership at the NIH bridged basic science and transformative medicine. We’re also imagining the presence of legendary figures like Sydney Brenner, who would undoubtedly have marveled at the subtleties of microRNA biology, and Svante Pääbo, whose work on ancient DNA connects our discoveries to the broader story of evolution.
Together, we’ll explore five interconnected topics: First, we’ll dive into how microRNAs have transformed our understanding of gene regulation, adding layers of complexity to how life is controlled and expressed. Next, we’ll examine their roles in development and cellular processes, where they guide cells through intricate pathways of differentiation and repair. Then, we’ll discuss their implications in human health, from diagnostics to therapeutics, where they are becoming key tools in fighting diseases. Moving further, we’ll delve into their evolutionary and epigenetic significance, uncovering how these molecules have shaped life over millennia. Finally, we’ll look to the future—imagining the many ways microRNAs will continue to drive breakthroughs in biotechnology, precision medicine, and synthetic biology.
These discussions are, of course, imagined, but they are rooted in the genuine brilliance and contributions of the people involved. Together, we’ll celebrate how far we’ve come and look ahead to the extraordinary possibilities still waiting to be realized. Thank you for joining me, and let’s begin this exciting journey into the world of microRNAs.

MicroRNAs: Transforming Our Understanding of Gene Regulation
Victor Ambros:
Thank you all for being here to discuss how microRNAs have transformed our understanding of gene regulation. Gary, it’s only fair to begin with you. We discovered microRNAs together—how do you reflect on their significance today?
Gary Ruvkun:
Victor, I think what amazes me most is how microRNAs reveal the interconnectedness of biology. These tiny molecules are like the conductors of a genetic orchestra, ensuring everything plays in harmony. The fact that microRNAs are conserved across species—from worms to humans—still gives me goosebumps. It tells us that their role is not just critical, but ancient and universal.
Victor Ambros:
Beautifully put. Craig, from the perspective of genomics, how did the discovery of microRNAs change the game for you?
Craig Venter:
When we were sequencing the genome, we thought we were identifying the "instructions manual" for life. Then along came microRNAs, which showed us the manual has hidden annotations and post-it notes everywhere! They’re not just regulators; they’re the unsung heroes making sure those instructions are executed properly. Gary and Victor’s work forced us to rethink what we considered functional in the genome.
Victor Ambros:
Jennifer, as someone at the forefront of genome editing, how do microRNAs fit into your vision of the future?
Jennifer Doudna:
MicroRNAs have tremendous potential in gene editing. While CRISPR is great for editing specific DNA sequences, microRNAs offer a more nuanced approach to regulate gene expression post-transcriptionally. Imagine combining the precision of CRISPR with the fine-tuning of microRNAs—we could create dynamic therapies that adjust to the body’s needs in real time.
Gary Ruvkun:
That’s a great point, Jennifer. What excites me is how microRNAs act like natural error correctors. They suppress unwanted noise in gene expression, which is invaluable for maintaining cellular balance. If we can harness that natural mechanism therapeutically, the possibilities are endless.
Victor Ambros:
Sydney, as someone who witnessed the evolution of molecular biology, what strikes you about microRNAs?
Sydney Brenner:
(Laughing) You know, Victor and Gary, if I were still working in the lab, I’d probably be kicking myself for not spotting these molecules sooner. MicroRNAs are elegant—they're like the punctuation marks in the language of the genome, controlling the rhythm and clarity of gene expression. It’s a discovery that reminds us biology is as much about subtlety as it is about power.
Victor Ambros:
Craig, you mentioned hidden annotations earlier. What questions about microRNAs are still left unanswered in your view?
Craig Venter:
There’s so much we don’t know. For instance, how do microRNAs coordinate across entire gene networks? What’s the evolutionary logic behind their specific targets? And how do environmental factors influence microRNA expression? These are questions that could redefine medicine and biology.
Victor Ambros:
Gary, how do you see the unanswered questions shaping future research?
Gary Ruvkun:
I think we’re at the tip of the iceberg. We’ve uncovered many microRNAs, but their full regulatory networks remain largely unexplored. Another exciting frontier is their role in intercellular communication—how microRNAs travel between cells and tissues to coordinate responses. That could open entirely new fields in diagnostics and therapy.
Jennifer Doudna:
I agree. If we can decode these networks, we might even predict and preempt diseases at the molecular level, years before symptoms appear.
Victor Ambros:
Sydney, would you say microRNAs also highlight the limits of our current understanding?
Sydney Brenner:
Certainly. MicroRNAs reveal just how intricate biology is—our reductionist approach can only take us so far. They’re a reminder that we must think holistically, considering not just genes but their regulators and environments.
Victor Ambros:
As we wrap up, let’s go around: What excites you most about the future of microRNA research? Gary?
Gary Ruvkun:
For me, it’s their therapeutic potential. I dream of a day when we can engineer microRNAs to suppress diseases like cancer or neurodegeneration at their root.
Craig Venter:
I’m most excited about personalized medicine—using microRNA profiles to create bespoke treatments for individuals.
Jennifer Doudna:
I’m inspired by their potential in synthetic biology, creating self-regulating systems in cells for everything from drug production to tissue repair.
Sydney Brenner:
For me, it’s philosophical. MicroRNAs remind us that life is beautifully intricate, and there’s always more to learn. They’re a testament to nature’s ingenuity.
Victor Ambros:
Thank you, everyone. This conversation highlights that microRNAs, though small, have sparked a revolution in how we understand and approach biology. The journey has only just begun.
MicroRNAs in Development and Cellular Processes
Victor Ambros:
Welcome, everyone. Today, we’ll explore the role of microRNAs in development and cellular processes. Let’s start with Shinya. Your work on induced pluripotent stem cells revolutionized regenerative medicine. How do you see microRNAs influencing stem cell research?
Shinya Yamanaka:
Thank you, Victor. MicroRNAs are critical for controlling cell identity and differentiation. When reprogramming somatic cells into pluripotent stem cells, microRNAs can act as both barriers and facilitators. They regulate gene networks that determine whether a cell stays differentiated or returns to a pluripotent state. Harnessing microRNAs could make the reprogramming process more efficient and precise.
Victor Ambros:
Fascinating. Elizabeth, you’ve studied telomeres and cellular aging. Do you see a connection between microRNAs and aging-related processes?
Elizabeth Blackburn:
Absolutely, Victor. MicroRNAs regulate many genes involved in cell senescence and telomere maintenance. For instance, some microRNAs suppress pathways that protect telomeres, accelerating cellular aging, while others promote repair mechanisms. Understanding these dynamics could lead to interventions that slow aging or extend cellular health spans.
Gary Ruvkun:
That’s an exciting area, Elizabeth. I’d add that microRNAs act as guardians of cellular stability. They help cells respond to stress by regulating apoptosis, repair, and metabolic pathways. In aging tissues, their dysregulation could be a key driver of degeneration.
Victor Ambros:
Eve, your research focuses on neuronal networks. How do microRNAs impact brain development and function?
Eve Marder:
MicroRNAs are essential in the nervous system. During brain development, they help neurons differentiate, migrate, and form connections. In adulthood, they fine-tune synaptic plasticity, which is crucial for learning and memory. Dysregulated microRNAs have been linked to neurological disorders like autism, Alzheimer’s, and schizophrenia. Studying them could reveal new therapeutic targets for these conditions.
Shinya Yamanaka:
Eve, I completely agree. One exciting possibility is using microRNAs to guide the differentiation of stem cells into specific neuron types for treating neurodegenerative diseases.
Victor Ambros:
That’s an intriguing synergy. Gary, you’ve studied the evolutionary conservation of microRNAs. How does that conservation relate to their role in development?
Gary Ruvkun:
It’s remarkable, Victor. MicroRNAs involved in development are highly conserved across species, suggesting their roles are fundamental. They likely emerged as evolutionary solutions to controlling complex gene networks. For instance, the same microRNAs that regulate timing in worms also play roles in human development. It’s a testament to their universality.
Victor Ambros:
Elizabeth, does this universality extend to cellular aging processes?
Elizabeth Blackburn:
Yes, and it underscores the importance of balance. MicroRNAs fine-tune pathways involved in both cell division and repair. Too much or too little activity can lead to issues like cancer or accelerated aging. The key lies in understanding how to restore equilibrium.
Eve Marder:
Balance is critical in the brain as well. MicroRNAs often regulate multiple genes simultaneously, which is essential for maintaining neuronal homeostasis. A single dysregulated microRNA can disrupt an entire network.
Victor Ambros:
Shinya, how does this concept of balance influence your work in regenerative medicine?
Shinya Yamanaka:
Balance is everything. For example, microRNAs control the transitions between stem cell states. If we can precisely manipulate these molecules, we can guide cells to regenerate damaged tissues without forming tumors or other complications.
Victor Ambros:
As we wrap up, let’s share a final thought: What’s the most exciting future application of microRNAs in development and cellular processes? Eve?
Eve Marder:
For me, it’s their potential in treating brain disorders by restoring balance in neuronal networks.
Elizabeth Blackburn:
I’m excited about using microRNAs to combat aging by preserving telomere health and reducing cellular senescence.
Shinya Yamanaka:
I envision microRNAs as tools for perfecting regenerative therapies, making them safer and more efficient.
Gary Ruvkun:
I’d say understanding how microRNAs evolve could unlock universal principles of cellular and developmental biology.
Victor Ambros:
Thank you, everyone. This discussion highlights how microRNAs are not just regulators but architects of life’s complexity, offering immense potential for research and innovation.
MicroRNAs and Human Disease: Diagnostics and Therapeutics

Victor Ambros:
Thank you all for joining this discussion on microRNAs and their potential in diagnosing and treating human diseases. Gary, since your early work laid the foundation, how do you view the role of microRNAs in understanding diseases today?
Gary Ruvkun:
Victor, it’s incredible how far we’ve come. MicroRNAs are like molecular sentinels—when they’re dysregulated, it’s often a sign of disease. They’re implicated in cancer, neurodegeneration, and even metabolic disorders. What excites me most is their dual role: as biomarkers for early detection and as therapeutic targets.
Victor Ambros:
That’s a great point. Harold, as a pioneer in cancer research, how do you see microRNAs contributing to advances in oncology?
Harold Varmus:
MicroRNAs are pivotal in cancer biology. They regulate genes involved in cell proliferation, apoptosis, and metastasis. Dysregulated microRNAs often act like switches, either promoting or suppressing tumor growth. For instance, some microRNAs function as tumor suppressors, while others act as oncogenes. Therapeutically, targeting these microRNAs could give us a new way to stop cancer at its root.
Victor Ambros:
Feng, your work on CRISPR has revolutionized gene editing. How does that intersect with microRNA research in therapy?
Feng Zhang:
MicroRNAs and CRISPR complement each other beautifully. With CRISPR, we can edit or delete genes. But microRNAs allow for dynamic control of gene expression. Combining the two, we could design systems where microRNAs regulate the timing and intensity of therapeutic gene activity. It’s a way to mimic natural processes while correcting diseases.
Katalin Karikó:
That’s a fascinating idea, Feng. I see microRNAs as natural allies for RNA-based therapeutics. In mRNA vaccines, we’ve focused on creating proteins to fight disease. MicroRNA therapies, on the other hand, could silence harmful genes or enhance beneficial pathways. The two approaches could work hand-in-hand to tackle a wide range of conditions.
Victor Ambros:
Katalin, you mentioned RNA therapeutics. Can you elaborate on how microRNAs could be integrated into this field?
Katalin Karikó:
Certainly. One approach is designing synthetic microRNAs to mimic natural ones and restore balance in diseased cells. Alternatively, we can use inhibitors, called antagomiRs, to block harmful microRNAs. For instance, in cancers driven by overactive oncogenic microRNAs, antagomiRs could suppress their activity and slow tumor progression.
Gary Ruvkun:
Exactly, Katalin. I think the beauty of microRNA-based therapies is their specificity. Unlike traditional drugs, which can have off-target effects, microRNAs are precise. They act directly on messenger RNAs, minimizing collateral damage.
Victor Ambros:
Harold, precision is crucial in cancer therapy. How close are we to seeing microRNAs in clinical use?
Harold Varmus:
We’re making progress, but challenges remain. Delivery is a major hurdle—getting microRNAs or their inhibitors to the right tissues at the right time. That said, clinical trials using microRNA-based therapies for liver cancer and fibrosis are already underway. It’s only a matter of time before these approaches become mainstream.
Victor Ambros:
Feng, does CRISPR offer solutions to the delivery problem?
Feng Zhang:
Potentially, yes. We’re developing delivery systems like lipid nanoparticles and viral vectors that could transport CRISPR tools and microRNA therapeutics together. These hybrid approaches might overcome the barriers and improve targeting.
Victor Ambros:
Let’s wrap up with a forward-looking question: What’s the most promising future application of microRNAs in disease treatment? Katalin?
Katalin Karikó:
For me, it’s using microRNAs to create tailored therapies for rare genetic diseases, where current treatments are limited or nonexistent.
Feng Zhang:
I’m excited about integrating microRNAs into CRISPR-based platforms to treat complex diseases like cancer and neurodegeneration.
Harold Varmus:
I see microRNAs as a game-changer for precision oncology—targeting the unique molecular profile of each tumor.
Gary Ruvkun:
I’d say the biggest promise lies in early detection. If we can identify microRNA signatures in blood or other fluids, we could diagnose diseases long before symptoms appear.
Victor Ambros:
Thank you all for such insightful contributions. MicroRNAs clearly hold transformative potential for diagnosing and treating diseases, and it’s thrilling to see the progress being made.
MicroRNAs in Evolution and Epigenetics
Victor Ambros:
Welcome, everyone. Today, we’ll discuss microRNAs in the context of evolution and epigenetics. To begin, Svante, as someone who has explored ancient DNA, how do you view the evolutionary significance of microRNAs?
Svante Pääbo:
Thank you, Victor. MicroRNAs are fascinating because they’re highly conserved across species, from simple organisms like worms to humans. This conservation suggests that microRNAs have been crucial in fine-tuning gene expression during evolution. They likely allowed organisms to adapt to changing environments without needing large-scale genomic changes.
Victor Ambros:
That’s a profound observation. Eric, during the Human Genome Project, how did discoveries like microRNAs change our perspective on the genome?
Eric Lander:
MicroRNAs were a revelation. Initially, we focused on protein-coding genes, but the discovery of microRNAs showed us that the majority of the genome’s function lies outside of coding regions. They add a regulatory layer, allowing the same genes to be expressed differently in different contexts—across species, tissues, and developmental stages. It’s evolution’s way of getting more complexity from the same genetic toolkit.
Gary Ruvkun:
Exactly, Eric. What I find amazing is how microRNAs provide a form of "evolutionary plasticity." They can suppress or activate gene networks in response to environmental pressures, giving organisms a competitive edge without requiring new genes.
Victor Ambros:
Barbara, your work on chromosomal epigenetics highlights another layer of gene regulation. How do microRNAs interact with epigenetic mechanisms?
Barbara Meyer:
Victor, microRNAs are deeply intertwined with epigenetics. They influence and are influenced by DNA methylation, histone modifications, and chromatin structure. For instance, microRNAs can target enzymes responsible for these modifications, altering the epigenetic landscape. Conversely, epigenetic changes can regulate microRNA expression. It’s a bidirectional relationship that adds incredible complexity to gene regulation.
Svante Pääbo:
Barbara’s point ties back to evolution. Epigenetic modifications driven by microRNAs could explain how organisms adapt to new environments within a single generation, while genetic changes take longer.
Eric Lander:
Absolutely, Svante. This adaptability may have played a key role in human evolution. For example, subtle changes in microRNA regulation could have shaped traits like brain development or immune responses, giving humans an evolutionary advantage.
Victor Ambros:
Gary, does this evolutionary adaptability make microRNAs unique compared to other regulators?
Gary Ruvkun:
In many ways, yes. MicroRNAs can coordinate responses across entire gene networks, enabling rapid yet precise adaptations. They act like switches, fine-tuning gene activity without requiring structural changes to the DNA. This makes them incredibly efficient evolutionary tools.
Victor Ambros:
Svante, does studying ancient DNA reveal microRNA-related insights into human evolution?
Svante Pääbo:
Definitely. By comparing microRNAs in Neanderthals and modern humans, we can identify differences that might explain unique traits, such as cognitive abilities. MicroRNAs likely played a role in the small but critical changes that define us as a species.
Victor Ambros:
Barbara, how does this evolutionary perspective connect to your work on chromosomal stability?
Barbara Meyer:
It’s all about balance. MicroRNAs help maintain stability by preventing overexpression or suppression of genes. In evolutionary terms, this balance allows species to explore new traits without jeopardizing survival. It’s a remarkable system of checks and balances.
Victor Ambros:
Eric, as we push the boundaries of genomics, how do you see microRNAs shaping future research?
Eric Lander:
I think microRNAs will guide us toward understanding how complex traits evolve. They’re like the genome’s "adaptive layer," helping us decode how regulatory changes drive diversity in form and function across species.
Victor Ambros:
Let’s close with a forward-looking question: What excites you most about the role of microRNAs in evolution and epigenetics? Gary?
Gary Ruvkun:
For me, it’s understanding how microRNAs orchestrate gene networks to drive adaptation and resilience in changing environments.
Svante Pääbo:
I’m excited about using microRNAs to uncover subtle but powerful changes that define human evolution.
Barbara Meyer:
I’m fascinated by their ability to bridge epigenetics and evolution, revealing new mechanisms of gene regulation.
Eric Lander:
I’m looking forward to mapping the interplay between microRNAs and other regulatory elements to better understand the origins of complex traits.
Victor Ambros:
Thank you, everyone. This discussion highlights how microRNAs are at the intersection of evolution, epigenetics, and adaptability, shaping the story of life itself.
Future Applications of MicroRNA Research
Victor Ambros:
Welcome, everyone. Today, we’ll discuss the future applications of microRNA research. To start, George, your work in synthetic biology has reimagined what’s possible in gene regulation. How do you envision microRNAs shaping this field?
George Church:
Thanks, Victor. MicroRNAs are incredibly elegant tools. In synthetic biology, we aim to design regulatory systems that mimic natural processes, and microRNAs are ideal for that. They allow precise, multi-gene control with minimal interference. I foresee using synthetic microRNAs to create "smart" cells that can adapt to environmental changes or produce therapeutics in real time.
Victor Ambros:
That’s fascinating. Emmanuelle, your development of CRISPR has revolutionized genome editing. How do you see microRNAs complementing tools like CRISPR?
Emmanuelle Charpentier:
CRISPR excels at making permanent changes to the genome, but microRNAs offer dynamic, reversible regulation. Combining the two could allow us to fine-tune gene expression after editing. For instance, we could design systems where CRISPR makes structural changes, and microRNAs adjust gene activity based on environmental cues or therapeutic needs.
Victor Ambros:
Gary, as someone who pioneered microRNA research, what do you think about these futuristic applications?
Gary Ruvkun:
It’s incredibly exciting. MicroRNAs are nature’s regulators, and understanding their networks can help us create bioengineered systems that respond to complex signals. For example, we could program microRNA-based therapies that adjust in real time to disease progression, offering a level of precision we’ve never had before.
Victor Ambros:
Francis, you’ve always championed translational research. How do you see microRNAs bridging basic science and clinical applications?
Francis Collins:
Victor, I believe microRNAs could be transformative. Their role in regulating entire gene networks makes them powerful tools for tackling complex diseases like cancer, diabetes, and neurodegenerative disorders. For diagnostics, microRNA profiles could act as disease signatures, enabling early detection. For therapeutics, targeted microRNAs could correct dysregulated pathways with unprecedented precision.
George Church:
I’d add that microRNAs also have enormous potential in regenerative medicine. We could use them to guide stem cells in repairing damaged tissues or even regrowing organs. Their ability to control multiple genes simultaneously is a game-changer.
Victor Ambros:
Emmanuelle, do you see microRNAs playing a role in global health challenges?
Emmanuelle Charpentier:
Absolutely. MicroRNA-based diagnostics could be used in resource-limited settings because they require minimal infrastructure. For example, we could design portable microRNA detection kits for infectious diseases, allowing rapid and accurate diagnoses. On the therapeutic side, microRNAs could help combat antimicrobial resistance by targeting bacterial regulatory networks.
Victor Ambros:
Gary, we’ve discussed many applications. Which area do you find the most promising?
Gary Ruvkun:
It’s hard to choose, but I’m particularly intrigued by intercellular communication. MicroRNAs can travel between cells, even between organisms, via extracellular vesicles. Understanding this could open new avenues in treating systemic diseases or even influencing microbiomes for better health.
Victor Ambros:
Francis, what about the challenges? What hurdles do we need to overcome before these applications become a reality?
Francis Collins:
The biggest challenge is delivery—how do we ensure microRNAs or their inhibitors reach the right cells without side effects? Advances in nanotechnology, like lipid nanoparticles, are promising, but we need more work. Another challenge is understanding off-target effects and how to minimize them.
Victor Ambros:
George, do you see synthetic biology contributing to these solutions?
George Church:
Definitely. We can design delivery systems that use microRNAs as part of a larger synthetic circuit, ensuring they act only in targeted tissues. For example, synthetic cells could deliver microRNAs locally at a tumor site or within a damaged organ.
Victor Ambros:
As we wrap up, let’s share your most exciting vision for the future of microRNA research. Gary?
Gary Ruvkun:
I’m excited about using microRNAs to map and control entire gene networks, allowing us to treat diseases at their root causes.
George Church:
For me, it’s creating self-regulating systems in synthetic biology that mimic the adaptability of living organisms.
Emmanuelle Charpentier:
I envision microRNA-based solutions for global health, from diagnostics to antimicrobial therapies, improving lives worldwide.
Francis Collins:
I’m thrilled by the potential of microRNAs to revolutionize precision medicine, tailoring treatments to individual patients with unparalleled specificity.
Victor Ambros:
Thank you all for your inspiring insights. MicroRNAs are not just tools for understanding biology—they are the key to shaping the future of medicine, biotechnology, and global health.
Short Bios:
Victor Ambros:
A molecular biologist and co-discoverer of microRNAs, whose groundbreaking work revealed how these small molecules regulate gene expression.
Gary Ruvkun:
A geneticist celebrated for uncovering the evolutionary conservation of microRNAs and their role in developmental timing.
Craig Venter:
A genomic researcher and entrepreneur who led the sequencing of the human genome, revolutionizing genetic research and innovation.
Jennifer Doudna:
A biochemist who co-developed CRISPR-Cas9, a revolutionary genome-editing technology that allows precise manipulation of DNA.
Emmanuelle Charpentier:
A biochemist who co-developed CRISPR-Cas9, transforming the field of genetics and enabling targeted gene modifications.
Sydney Brenner:
A Nobel laureate and pioneer in molecular biology, who decoded the genetic code and contributed foundational research on C. elegans.
Svante Pääbo:
A Nobel laureate known for sequencing ancient DNA, uncovering evolutionary links between modern humans and extinct hominins.
Francis Collins:
A physician-geneticist who led the Human Genome Project and directed the NIH, bridging basic science and medical innovation.
George Church:
A visionary in synthetic biology, exploring the creation of biological systems with novel functions and applications.
Harold Varmus:
A Nobel laureate who discovered the genetic basis of cancer, advancing our understanding of oncogenes and tumor development.
Katalin Karikó:
A scientist who advanced RNA therapeutics and played a pivotal role in developing mRNA vaccines for global health.
Elizabeth Blackburn:
A Nobel laureate and biologist who discovered the role of telomeres in aging and their implications for cellular health.
Barbara Meyer:
A geneticist known for her work on epigenetics and chromosome regulation, providing insights into genetic stability and function.
Eve Marder:
A neuroscientist specializing in neuronal circuits and their plasticity, contributing to our understanding of brain adaptability.
Feng Zhang:
A molecular biologist whose work in CRISPR and optogenetics has opened new frontiers in genome editing and neuroscience.
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