Introduction – Company Background

GuangXin Industrial Co., Ltd. is a specialized manufacturer dedicated to the development and production of high-quality insoles.

With a strong foundation in material science and footwear ergonomics, we serve as a trusted partner for global brands seeking reliable insole solutions that combine comfort, functionality, and design.

With years of experience in insole production and OEM/ODM services, GuangXin has successfully supported a wide range of clients across various industries—including sportswear, health & wellness, orthopedic care, and daily footwear.

From initial prototyping to mass production, we provide comprehensive support tailored to each client’s market and application needs.

At GuangXin, we are committed to quality, innovation, and sustainable development. Every insole we produce reflects our dedication to precision craftsmanship, forward-thinking design, and ESG-driven practices.

By integrating eco-friendly materials, clean production processes, and responsible sourcing, we help our partners meet both market demand and environmental goals.

Core Strengths in Insole Manufacturing

At GuangXin Industrial, our core strength lies in our deep expertise and versatility in insole and pillow manufacturing. We specialize in working with a wide range of materials, including PU (polyurethane), natural latex, and advanced graphene composites, to develop insoles and pillows that meet diverse performance, comfort, and health-support needs.

Whether it's cushioning, support, breathability, or antibacterial function, we tailor material selection to the exact requirements of each project-whether for foot wellness or ergonomic sleep products.

We provide end-to-end manufacturing capabilities under one roof—covering every stage from material sourcing and foaming, to precision molding, lamination, cutting, sewing, and strict quality control. This full-process control not only ensures product consistency and durability, but also allows for faster lead times and better customization flexibility.

With our flexible production capacity, we accommodate both small batch custom orders and high-volume mass production with equal efficiency. Whether you're a startup launching your first insole or pillow line, or a global brand scaling up to meet market demand, GuangXin is equipped to deliver reliable OEM/ODM solutions that grow with your business.

Customization & OEM/ODM Flexibility

GuangXin offers exceptional flexibility in customization and OEM/ODM services, empowering our partners to create insole products that truly align with their brand identity and target market. We develop insoles tailored to specific foot shapes, end-user needs, and regional market preferences, ensuring optimal fit and functionality.

Our team supports comprehensive branding solutions, including logo printing, custom packaging, and product integration support for marketing campaigns. Whether you're launching a new product line or upgrading an existing one, we help your vision come to life with attention to detail and consistent brand presentation.

With fast prototyping services and efficient lead times, GuangXin helps reduce your time-to-market and respond quickly to evolving trends or seasonal demands. From concept to final production, we offer agile support that keeps you ahead of the competition.

Quality Assurance & Certifications

Quality is at the heart of everything we do. GuangXin implements a rigorous quality control system at every stage of production—ensuring that each insole meets the highest standards of consistency, comfort, and durability.

We provide a variety of in-house and third-party testing options, including antibacterial performance, odor control, durability testing, and eco-safety verification, to meet the specific needs of our clients and markets.

Our products are fully compliant with international safety and environmental standards, such as REACH, RoHS, and other applicable export regulations. This ensures seamless entry into global markets while supporting your ESG and product safety commitments.

ESG-Oriented Sustainable Production

At GuangXin Industrial, we are committed to integrating ESG (Environmental, Social, and Governance) values into every step of our manufacturing process. We actively pursue eco-conscious practices by utilizing eco-friendly materials and adopting low-carbon production methods to reduce environmental impact.

To support circular economy goals, we offer recycled and upcycled material options, including innovative applications such as recycled glass and repurposed LCD panel glass. These materials are processed using advanced techniques to retain performance while reducing waste—contributing to a more sustainable supply chain.

We also work closely with our partners to support their ESG compliance and sustainability reporting needs, providing documentation, traceability, and material data upon request. Whether you're aiming to meet corporate sustainability targets or align with global green regulations, GuangXin is your trusted manufacturing ally in building a better, greener future.

Let’s Build Your Next Insole Success Together

Looking for a reliable insole manufacturing partner that understands customization, quality, and flexibility? GuangXin Industrial Co., Ltd. specializes in high-performance insole production, offering tailored solutions for brands across the globe. Whether you're launching a new insole collection or expanding your existing product line, we provide OEM/ODM services built around your unique design and performance goals.

From small-batch custom orders to full-scale mass production, our flexible insole manufacturing capabilities adapt to your business needs. With expertise in PU, latex, and graphene insole materials, we turn ideas into functional, comfortable, and market-ready insoles that deliver value.

Contact us today to discuss your next insole project. Let GuangXin help you create custom insoles that stand out, perform better, and reflect your brand’s commitment to comfort, quality, and sustainability.

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Orthopedic pillow OEM solutions Indonesia

Are you looking for a trusted and experienced manufacturing partner that can bring your comfort-focused product ideas to life? GuangXin Industrial Co., Ltd. is your ideal OEM/ODM supplier, specializing in insole production, pillow manufacturing, and advanced graphene product design.

With decades of experience in insole OEM/ODM, we provide full-service manufacturing—from PU and latex to cutting-edge graphene-infused insoles—customized to meet your performance, support, and breathability requirements. Our production process is vertically integrated, covering everything from material sourcing and foaming to molding, cutting, and strict quality control.Taiwan anti-bacterial pillow ODM production factory

Beyond insoles, GuangXin also offers pillow OEM/ODM services with a focus on ergonomic comfort and functional innovation. Whether you need memory foam, latex, or smart material integration for neck and sleep support, we deliver tailor-made solutions that reflect your brand’s values.

We are especially proud to lead the way in ESG-driven insole development. Through the use of recycled materials—such as repurposed LCD glass—and low-carbon production processes, we help our partners meet sustainability goals without compromising product quality. Our ESG insole solutions are designed not only for comfort but also for compliance with global environmental standards.Smart pillow ODM manufacturer Taiwan

At GuangXin, we don’t just manufacture products—we create long-term value for your brand. Whether you're developing your first product line or scaling up globally, our flexible production capabilities and collaborative approach will help you go further, faster.Graphene-infused pillow ODM Indonesia

📩 Contact us today to learn how our insole OEM, pillow ODM, and graphene product design services can elevate your product offering—while aligning with the sustainability expectations of modern consumers.Flexible manufacturing OEM & ODM factory Taiwan

Algae bloom in Baltic Sea, where extreme blooms are a significant problem. Captured June 2016, by the European Space Agency Sentinel-3A satellite, which helps monitor, for example, concentrations of algae, suspended matter and chlorophyll in seawater, useful to predict harmful algal blooms, The health and vulnerability of marine ecosystems is fundamental to our knowledge of ocean productivity and, in turn, fish stocks. Credit: European Space Agency UNESCO IOC delivers 1st global assessment report after 7 years’ work by 109 experts in 35 countries, creating a baseline to detect and gauge the changing distribution, frequency, and intensity of harmful — often poisonous — algal blooms. An unprecedented analysis of almost 10,000 Harmful Algal Bloom (HAB) events worldwide over the past 33 years was launched today by UNESCO’s Intergovernmental Oceanographic Commission. The first-ever global statistical analysis examined ~9,500 HABs events over 33 years and found that the harm caused by HABs rises in step with growth of the aquaculture industry and marine exploitation and calls for more research on linkages. Conducted over seven years by 109 scientists in 35 countries, the study found that reported HAB events have increased in some regions and decreased or held steady in others. A widely-stated view that HABs are on the rise throughout the world, perhaps due to climate change, isn’t confirmed. However, the study, “Perceived global increase in algal blooms is attributable to intensified monitoring and emerging bloom impacts,” published in the Nature journal Communications Earth & Environment, creates the world’s first baseline against which to track future shifts in the location, frequency, and impacts of HABs, which differ depending on which of the 250 harmful marine algae species is involved and where, requiring assessment on a species-by-species and site-by-site basis. Databases mined The scientists mined both the global Harmful Algae Event Database (HAEDAT), consisting of 9,503 events with one or more impacts on human society, and the Ocean Biodiversity Information System (OBIS) database, containing 7 million microalgal observation records, including 289,668 toxic algal species occurrences. The study found that regionally-recorded HAB events, after being corrected for higher levels of monitoring effort, have Increased: Central America/Caribbean South America Mediterranean North Asia Decreased: West Coast America Australia/New Zealand No significant change: East Coast America South East Asia Europe The 9,503 events’ impacts on humans break down as follows: 48% involved seafood toxins 43% high phytoplankton counts and/or water discolorations with a socio-economic impact 7% mass animal or plant mortalities 2% caused other impacts (including foam and mucilage production) (As well, in 11% of events, a single incident had multiple impacts, e.g. both water discoloration and mass mortality) Of the event records linked to seafood toxins: 35% were Paralytic Shellfish Toxins (PST) 30% Diarrhetic Shellfish Toxins (DST) 9% Ciguatera Poisoning (CP) 9% marine and brackish water cyanobacterial toxins 7% Amnesic Shellfish Toxins (AST) 10% others, including Neurotoxic Shellfish Toxins (NST), Azaspiracid Shellfish Toxins (AZA), and toxic aerosols By region, the largest number of records came from, in order: Europe North Asia Mediterranean The east and west coasts of North America Caribbean Pacific/Oceania Southeast Asia With more limited data sets for South America, and Australia/New Zealand All geographic regions were impacted by multiple HAB types, but in varying proportions. 50% of regional HAEDAT records in the Caribbean, Benguela, Mediterranean Sea, North and South East Asia related to high phytoplankton density problems. Seafood toxins and fish kill impacts dominated in all other regions Among toxin-related impacts: Paralytic Shellfish Toxins (PST) prevailed in North America, the Caribbean, South America, South East Asia, and North Asia Diarrhetic Shellfish Toxins (DST) were the most frequently recorded in Europe and the Mediterranean (and are an emerging threat in the USA) Neurotoxic Shellfish Toxins (NST) were confined to the US State of Florida, with a single outbreak also reported from New Zealand Human poisonings from Ciguatera were prominent in the tropical Pacific, the Indian Ocean, Australia, and the Caribbean. For the most part, however, the impacts were confined to shellfish harvesting area closures; rarely to human poisonings. The exception: Ciguatera event records are almost exclusively based on medical reports of human poisonings. HAB events over time Eight of nine regions used in the study showed increases in reports logged via HAEDAT of harmful events per year, of which six were statistically significant. The OBIS dataset, meanwhile, generally showed an increase in sampling effort in five of the nine regions. When all the information was combined, the researchers could find no statistically significant global trend overall. They also found, however, that aquaculture production increased 16-fold from a global total of 11.35 million tonnes of seafood in 1985 to 178.5 million tonnes in 2018, with the largest increases occurring in Southeast Asia and South America/Caribbean and Central America, with North America and Europe stabilizing. The number of recorded harmful algal bloom events over time was strongly correlated with intensified aquaculture production in all regions with data suitable for the study. However, says lead author Gustaaf M. Hallegraeff of the University of Tasmania: Intensified aquaculture clearly drives an increase in HAB monitoring efforts essential to sustaining the industry and protecting human health. “And, just as clearly, a secondary effect of aquaculture is nutrient pollution. But a major data gap exists here. Conducting a meta-analysis of HABs vs aquaculture we had data on HAB monitoring efforts using OBIS records as a proxy but data on nutrient pollution is inadequate. The relationship between aquaculture-related nutrients and HABs therefore represents an important direction for further research.” Greater monitoring efforts The study revealed A 4-fold increase from 1985 to 2018 in observations of organisms mainly responsible for Diarrhetic Shellfish Poisoning (84,392 OBIS records) A 7-fold increase in observations of organisms mainly responsible for Amnesic Shellfish Poisoning (128,282 OBIS records) A 6-fold increase in observations of organisms mainly responsible for Paralytic Shellfish Poisoning (9,887 OBIS records) (Note: Some observations may include non-toxic species or strains.) In each case, the clear increase in the number of observations of problematic organisms paralleled an increase in records of associated toxic syndrome impacts. They also found that the presence of toxic HAB species doesn’t always accurately predict cases of human shellfish poisonings, which the study credits to the food safety risk management strategies in many affected countries. Some 11,000 non-fatal events related to Diarrhetic Shellfish Poisoning were reported worldwide, mostly from Europe, South America, and Japan, with impacts consisting mostly of shellfish harvesting area closures. Also, the study says, despite widespread distribution of the responsible algal species, there have been no human fatalities from Amnesic Shellfish Poisoning since the original 1987 incident in Prince Edward Island, Canada (150 illnesses, three fatalities). But ASP-associated mortalities of important marine mammals are of growing concern in Alaska and other parts of western North America, and ASP toxins have been linked to marine mammal calf mortalities in Argentina. Of the world’s 3,800 human Paralytic Shellfish Poisonings from 1985 to 2018, the largest number (2,555 from 1983 to 2013, including 165 fatalities) occurred in the Philippines, which depends strongly on aquaculture for human food protein. DNA and other advanced detection methods have improved knowledge of the global distribution of ciguatera-causing organisms. Ciguatera poisonings, rarely fatal but annually affecting 10,000 to 50,000 people, have been decreasing in Hawaii and remained stable in French Polynesia and the Caribbean but constitute a new phenomenon in the Canary Islands. Farmed fish killed by algal blooms: Largely a human-generated problem. Aquacultured finfish mortalities account for much greater economic damage than HAB-contaminated seafood. Notes the study: wild marine finfish can simply swim away from blooms but those held captive in intensive aquaculture operations are vulnerable. Recorded losses include US $71 million in Japan in 1972, $70 million in Korea in 1995, $290 million in China in 2012, and $100 million in Norway in 2019. A 2016 Chilean salmon mortality event caused a record $800 million loss, causing major social unrest. Again, the presence of fish-killing HAB species doesn’t accurately predict economic losses, the study shows. For example, Heterosigma blooms occur on the west and east coasts of Canada and the US, but fish mortalities are mostly confined to the west coast. In large part, the difference reflects the differences between sites where blooms occur and the relative location and size of aquaculture operations. A harmful algae species that caused no problems in Australian lagoons killed 50,000 caged fish in Malaysia in 2014. It is now also known in Japan and the Philippines. The authors note that some troublesome algal species may thrive, others decline, as ocean waters warm and acidify. Commentary “There has been a widely-stated contention that HABs worldwide are increasing in distribution, frequency or intensity, so a quantitative global assessment is long overdue,” says lead author Prof. Hallegraeff of the Institute for Marine and Antarctic Studies, University of Tasmania. “While some of the HAB literature over the past 30 years has handpicked selected examples to claim a global increase and expansion in HABs, this new big data approach shows a much more nuanced trend,” he adds. “Our study concludes that the health and economic damages caused by harmful microalgae — seafood poisoning, water discoloration that blights tourism, and the death of finfish in aquaculture operations, for example — differ between regions.” Adds co-author Adriana Zingone: “We also found that overexploitation acts as a natural multiplier of the effects of HABs, leading to an increase in impacts independent of an actual trend in HABs.” “It should be noted that over the last 40 years capacity and monitoring efforts to detect harmful species and harmful events have also increased, thus increasing the reporting of harmful events across the world’s seas,” she says. “The absence of events and decreasing trends, like all negative results, are rarely published. Whether or not HABs are increasing globally, however, their impacts are a growing concern all around the globe.” Says co-author Henrik Oksfeldt Enevoldsen: “As the human population continues to increase in tandem with resource demands, HABs will predictably constitute a serious threat in terms of seafood safety and security, a hindrance to recreational uses of the sea, and a problem for the tourism industry.” “Occurrences of harmful species over time and their human impacts can be expected to change locally, regionally and globally alongside the effects that climate, hydrography and human pressure impose on the coastal environment.” “Understanding the trends and distribution patterns of harmful species and events at multiple spatial and temporal scales will help predict whether, where and when to expect HABs, their frequency and intensity. This knowledge is fundamental for effective management of HABs and to optimize the uses and values of the maritime space in coastal areas.” Johan Hanssens, Secretary-General of Flanders Department of Economy, Science and Innovation, a sponsor of this report, concluded: “This status report is a very timely reminder, at the start of the UN Decade of Ocean Science for Sustainable Development, that a thorough understanding of natural and ecological processes in the ocean is crucial for the development of the blue economy, now that many coastal countries are turning to the sea for additional resources, including food provisioning. International scientific collaboration is essential and most efficient to address the associated challenges.” Reference: “Perceived global increase in algal blooms is attributable to intensified monitoring and emerging bloom impacts” by Gustaaf M. Hallegraeff, Donald M. Anderson, Catherine Belin, Marie-Yasmine Dechraoui Bottein, Eileen Bresnan, Mireille Chinain, Henrik Enevoldsen, Mitsunori Iwataki, Bengt Karlson, Cynthia H. McKenzie, Inés Sunesen, Grant C. Pitcher, Pieter Provoost, Anthony Richardson, Laura Schweibold, Patricia A. Tester, Vera L. Trainer, Aletta T. Yñiguez and Adriana Zingone, 8 June 2021, Communications Earth & Environment. DOI: 10.1038/s43247-021-00178-8 New interactive portal At a new interactive portal (https://data.hais.ioc-unesco.org), also launched today, concerned citizens and scientists can extract data and knowledge about HABs occurrences over time at every scale, from local to global. Key public databases used The Harmful Algal Event Database (HAEDAT) The only existing database of information about harmful algal events from around the world, summarized into ‘events’ associated with a management action or negative economic / ecological impact. Includes cases of non-toxic water discolorations, mucilage, anoxia or other damage to fish. Link: http://haedat.iode.org HABMAP-OBIS: Database on the geographic range of Harmful Species The Database provides biogeographic information, as referenced maps, of the microalgal species that are listed in the IOC-UNESCO Taxonomic Reference List of Harmful Microalgae. Because entries concern these taxa regardless of the intraspecific variability in toxicity and impacts, the database provides a worldwide map of potential risks related to the occurrence of toxic species. Link: https://obis.org The IOC-UNESCO Taxonomic Reference List of Harmful Microalgae Includes formally accepted names of 150+ planktonic or benthic microalgae that have been proven to produce toxins. The number of species in the list has doubled over the years. Link: http://marinespecies.org/hab These datasets will help address three main questions in future: The distribution of HAB species, HAB events, and toxins globally How the geographic distribution, characteristic, frequency and intensity of HABs are changing and if these changes attributable to global change How climate change alters impacts from HABs on human health, ecosystems, economics, food and water security Background Algae are essential for life on Earth and for fisheries. But when some species “bloom” they can cause harm in various ways. Some 5,000 species of microalgae form the foundation of aquatic food chains, help control atmospheric CO2 levels, and produce roughly half of the world’s oxygen. The troublemakers are approximately 250 species that can produce potent toxins or cause harm through their sheer biomass. A harmful algal event is broadly defined as “any event where humans, animals or other organisms are negatively affected by algae.” These include: A bioaccumulation of toxins in seafood reaching levels unsafe for human consumption, or a ban on harvesting wild or farmed shellfish or other seafood. An abundance of harmful algae causing the closure of e.g. a beach or desalination plant A bloom of toxic or non-toxic microalgae causing discoloured water, scum or foam causing damage to tourism The Global Harmful Algal Bloom Status Report (GHSR) initiative is funded by the Flanders Government through the DIPS-4-Ocean Assessments project (link) as part of the UNESCO/Flanders Fund-in-Trust for the support of UNESCO’s activities in the field of Science (FUST). Principal authors: 19 principal authors from 15 countries (including two from Australia, two from France, three from the USA) Gustaaf M. Hallegraeff, University of Tasmania, Australia Donald M. Anderson, Woods Hole Oceanographic Institution, USA Catherine Belin, IFREMER, France Marie-Yasmine Bottein, Ecotoxicology and Sustainable Development Expertise, France Eileen Bresnan, Marine Scotland, UK Mireille Chinain, Institut Louis Malardé-UMR241, Tahiti Henrik Enevoldsen, Intergovernmental Oceanographic Commission of UNESCO, University of Copenhagen, Denmark Mitsunori Iwataki, University of Tokyo, Japan Bengt Karlson, Swedish Meteorological and Hydrological Institute, Oceanographic Research, Sweden Cynthia H. McKenzie, Fisheries and Oceans Canada, Canada Inés Sunesen, CONICET – UNLP, Argentina Grant C. Pitcher, University of Cape Town, South Africa Pieter Provoost, Intergovernmental Oceanographic Commission of UNESCO, Oostende, Belgium Anthony Richardson, CSIRO Oceans and Atmosphere, and University of Queensland, Australia Laura Schweibold, Institut Universitaire Européen de la Mer, France Patricia A. Tester, Ocean Tester, USA Vera L. Trainer, National Oceanic and Atmospheric Administration, USA Aletta T. Yñiguez, University of the Philippines, Philippines Adriana Zingone, Stazione Zoologica Anton Dohrn, Italy About the HAB Program: The Intergovernmental Panel on Harmful Algal Blooms (IOC-IPHAB), part of the Intergovernmental Oceanographic Commission of UNESCO, initiated the development of the Global HAB Status Report in Paris in April 2013, developed with the support of the Government of Flanders within the IOC International Oceanographic Data and Information Exchange (IODE) Program, which manages both the Harmful Algae Event Data Base (HAEDAT) and the Ocean Biodiversity Information System (OBIS). Partners include the International Council for the Exploration of the Sea (ICES), The North Pacific Marine Science Organization (PICES) and the International Atomic Energy Agency (IAEA). OBIS focuses on the global distribution of all marine species including those HAB species that are toxic to humans and fish as covered by the IOC-UNESCO Taxonomic Reference list of Harmful MicroAlgae (a subset of the World Register of Marine Species), while HAEDAT holds information specifically on the HAB events that have adversely impact on human society, whether by high biomass (clogging of fishing nets, beach closures), aquaculture fish kills, or seafood toxin events leading to shellfish farm closures, human poisonings or even death.

Life reconstruction of the early tetrapod Pederpes showing the forelimb bones beneath the skin. Credit: Image copyright 2021, Julia Molnar From Fins to Limbs: A Defining Moment in Evolution When tetrapods (four-limbed vertebrates) began to move from water to land roughly 390 million years ago it set in motion the rise of lizards, birds, mammals, and all land animals that exist today, including humans and some aquatic vertebrates such as whales and dolphins. The earliest tetrapods originated from their fish ancestors in the Devonian period and are more than twice as old as the oldest dinosaur fossils. They resembled a cross between a giant salamander and a crocodile and were about 1-2 meters long, had gills, webbed feet and tail fins, and were still heavily tied to water. Their short arms and legs had up to eight digits on each hand and foot and they were probably ambush predators, lurking in shallow water waiting for prey to come near. Scientists know how the fins of fish transformed into the limbs of tetrapods, but controversies remain about where and how the earliest tetrapods used their limbs. And, while many hypotheses have been proposed, very few studies have rigorously tested them using the fossil record. Modeling Ancient Movement with Modern Tools In a paper published on January 22, 2021, in Science Advances an international team of researchers examined three-dimensional digital models of the bones, joints, and muscles of the fins and limbs of two extinct early tetrapods and a closely related fossil fish to reveal how the function of the forelimb changed as fins evolved into limbs. The research led by Julia Molnar, Assistant Professor at New York Institute of Technology College of Osteopathic Medicine, and Stephanie Pierce, Thomas D. Cabot Associate Professor of Organismic and Evolutionary Biology at Harvard University, discovered three distinct functional stages in the transition from fins to limbs, and that these early tetrapods had a very distinct pattern of muscle leverage that didn’t look like a fish fin or modern tetrapod limbs. Virtual skeleton of the early tetrapod Pederpes from micro-CT scanned fossil and musculoskeletal reconstruction of its forelimb. Credit: Copyright 2021, Julia Molnar Reconstructing Muscles That Fossils Don’t Preserve To reconstruct how limbs of the earliest known tetrapods functioned, Molnar, Pierce and co-authors John Hutchinson (Royal Veterinary College), Rui Diogo (Howard University), and Jennifer Clack (University of Cambridge) first needed to figure out what muscles were present in the fossil animals. A challenging task as muscles are not preserved in fossils, and the muscles of modern fish fins are completely different from those of tetrapod limbs. The team spent several years trying to answer the question, how exactly did the few simple muscles of a fin become dozens of muscles that perform all sorts of functions in a tetrapod limb? “Determining what muscles were present in a 360-million-year-old fossil took many years of work just to get to the point where we could begin to build very complicated musculoskeletal models,” said Pierce. “We needed to know how many muscles were present in the fossil animals and where they attached to on the bones so we could test how they functioned.” They built three-dimensional musculoskeletal models of the pectoral fin in Eusthenopteron (a fish closely related to tetrapods that lived during the Late Devonian period about 385 million years ago) and the forelimbs of two early tetrapods, Acanthostega (365 million years old living towards the end of the Late Devonian period) and Pederpes (348-347 million years old living during the early Carboniferous period). For comparison, they also built similar models of the pectoral fins of living fishes (coelacanth, lungfish) and forelimbs of living tetrapods (salamander, lizard). To determine how the fins and limbs worked, the researchers used computational software originally developed to study human locomotion. This technique had been used recently to study locomotion in the ancestors of humans and also dinosaurs like T. rex, but never in something as old as an early tetrapod. Manipulating the models in the software, the team were able to measure two functional traits: the joint’s maximum range of motion and the muscles’ ability to move the fin or limb joints. The two measurements would reveal trade-offs in the locomotor system and allow the researchers to test hypotheses of function in extinct animals. Three Functional Stages in Tetrapod Evolution The team found the forelimbs of all terrestrial tetrapods passed through three distinct functional stages: a “benthic fish” stage that resembled modern lungfish, an “early tetrapod” stage unlike any extinct animal, and a “crown tetrapod” stage with characteristics of both lizards and salamanders. “The fin from Eusthenopteron had a pattern that was reminiscent of the lungfish, which is one of the closest living relatives of tetrapods,” said Pierce. “But the early tetrapod limbs showed more similarities to each other than either fish or modern tetrapods.” “That was perhaps the most surprising,” said Molnar. “I thought Pederpes, and possibly Acanthostega, would fall pretty well within the range of modern tetrapods. But they formed their own distinct cluster that didn’t look like a modern tetrapod limb or a fish fin. They were not smack dab in the middle but had their own collection of characteristics that probably reflected their unique environment and behaviors.” Early Limbs Were Built for Swimming, Not Walking The results showed that early tetrapod limbs were more adapted for propulsion rather than weight bearing. In the water, animals use their limbs for propulsion to move themselves forward or backward allowing the water to support their body weight. Moving on land, however, requires the animal act against gravity and push downward with their limbs to support their body mass. This doesn’t mean that early tetrapods were incapable of moving on land, but rather they didn’t move like a modern-day living tetrapod. Their means of locomotion were probably unique to these animals that were still very much tied to the water, but were also venturing onto land, where there were many opportunities for vertebrate animals but little competition or fear from predators. Confirming Past Findings and Charting New Directions “These results are exciting as they independently support a study I published last year using completely different fossils and methods,” said Pierce. “That study, which focused on the upper arm bone, indicated that early tetrapods had some capacity for land movement but that they may not have been very good at it.” The researchers are closer to reconstructing the evolution of terrestrial locomotion, but more work is needed. They plan to next model the hind limb to investigate how all four limbs work together. It has been suggested that early tetrapods were using their forelimbs for propulsion, but modern tetrapods get most of their propulsive power from the hind limb. “We plan to look for any evidence of a shift from forelimb driven locomotion toward hind limb driving locomotion, like modern tetrapods,” said Molnar. Looking at the forelimb and hind limb together could reveal more about the transition from water to land and how tetrapods eventually came to dominate the terrestrial realm. Reference: “Evolution of forelimb musculoskeletal function across the fish-to-tetrapod transition” by J. L. Molnar, J. R. Hutchinson, R. Diogo, J. A. Clack and S. E. Pierce, 22 January 2021, Science Advances. DOI: 10.1126/sciadv.abd7457

Lifelong production of sperm is made possible by a newly discovered stem cell regulator. According to research conducted by the University of Pennsylvania, the enzyme DOT1L, a stem cell self-renewal factor, is necessary for mice to continue producing sperm throughout adulthood. Men may continue to generate sperm throughout their adult life, in contrast to women who are born with all the eggs they will ever have. To do so, they must constantly renew the spermatogonial stem cells that give birth to sperm. According to research by Jeremy Wang of the University of Pennsylvania School of Veterinary Medicine and colleagues, this stem cell renewal is dependent on a recently identified stem cell self-renewal factor known as DOT1L. The scientists demonstrated that animals lacking DOT1L are unable to retain spermatogonial stem cells, which affects their ability to constantly make sperm. The finding, which was reported in the journal Genes and Development, adds another entity to the handful of stem cell renewal factors that have already been identified by scientists. “This novel factor was only able to be identified by finding this unusual phenotype: the fact that mice lacking DOT1L were not able to continue to produce sperm,” says Wang, the Ralph L. Brinster President’s Distinguished Professor at Penn Vet and a corresponding author on the paper. “Identifying this essential factor not only helps us understand the biology of adult germline stem cells but could also allow us to one day reprogram somatic cells, like a type of skin cell called fibroblasts, to become germline stem cells, essentially creating a gamete in a petri dish. That is the next frontier for fertility treatment.” When the enzyme DOT1L is not functional, spermatogonial stem cells become exhausted, leading to a failure of sperm cell development. This crucial role for DOT1L places it in rarefied company as one of just a handful of known stem cell self-renewal factors, a Penn Vet team found. Credit: Jeremy Wang The Role of DOT1L in Sperm Production The function of DOT1L in stem cell self-renewal was accidentally discovered by the researchers. The gene is widely expressed; mice with a mutant form of DOT1L in every cell do not survive beyond the embryonic stage. However, Wang and colleagues hypothesized that DOT1L could be involved in meiosis, the process of cell division that results in sperm and eggs, based on the genetic expression patterns of DOT1L. So they made the decision to investigate what would happen if they mutated the gene only in these germ cells. “When we did this, the animals lived and appeared healthy,” Wang says. “When we looked closer, however, we found that the mice with the mutant DOT1L in their germ cells could complete an initial round of sperm production, but then the stem cells became exhausted and the mice lost all germ cells.” This drop-off in sperm production could arise due to other problems. But various lines of evidence supported the link between DOT1L and a failure of stem cell self-renewal. In particular, the researchers found that the mice experienced a sequential loss of the various stages of sperm development, first failing to make spermatogonia and then spermatocytes, followed by round spermatids, and then elongated spermatids. In a further experiment, the researchers observed what happened when DOT1L was inactivated in germ cells not from birth, but during adulthood. As soon as Wang and colleagues triggered the DOT1L loss, they observed the same sequential loss of sperm development they had seen in the mice born without DOT1L in their germ cells. Previously, other scientific groups have studied DOT1L in the context of leukemia. Overexpression of the gene in the progenitors of blood cells can lead to malignancy. From that line of investigation, it was known that DOT1L acts as a histone methyltransferase, an enzyme that adds a methyl group to histones to influence gene expression. DOT1L’s Mechanism: Histone Methylation and Gene Regulation To see whether the same mechanism was responsible for the results Wang and his team had observed in sperm development, the researchers treated spermatogonial stem cells with a chemical that blocks the methyltransferase activity of DOT1L. When they did so, the stem cells’ ability to give rise to spermatogonia was significantly reduced. The treatment also impaired the ability of stem cells to tag histones with a methyl group. And when these treated stem cells were transplanted into otherwise healthy mice, the animals’ spermatogonial stem cell activity was cut in half. The team found that DOT1L appeared to be regulating a gene family known as Hoxc, transcription factors that play significant roles in regulating the expression of a host of other genes. “We think that DOT1L promotes the expression of these Hoxc genes by methylating them,” says Wang. “These transcription factors probably contribute to the stem cell self-renewal process. Finding out the details of that is a future direction for our work.” A longer-term goal is to use factors like DOT1L and others involved in germline stem cell self-renewal to help people who have fertility challenges. The concept is to create germ cells from the ground up. “That’s the future of this field: in vitro gametogenesis,” Wang says. “Reprogramming somatic cells to become spermatogonial stem cells is one of the steps. And then we’d have to figure out how to have those cells undergo meiosis. We’re in the early stages of envisioning how to accomplish this multi-step process, but identifying this self-renewal factor brings us one step closer.” Reference: “Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells” by Huijuan Lin, Keren Cheng, Hiroshi Kubota, Yemin Lan, Simone S. Riedel, Kazue Kakiuchi, Kotaro Sasaki, Kathrin M. Bernt, Marisa S. Bartolomei, Mengcheng Luo and P. Jeremy Wang, 23 June 2022, Genes & Development. DOI: 10.1101/gad.349550.122 The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Natural Science Foundation of China, the China Scholarship Council, and the Japan Society for the Promotion of Science.

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