nature based tourism grant

• Funding Database

Nature-based Solutions Funding Database

National Wildlife Federation’s interactive database for communities interested in pursuing federal funding and/or technical assistance for nature-based solutions. Use the filters below to search for nature-based solutions funding and technical assistance resources that fit your needs. For additional information on search filters, see our Glossary page.

Promoting Resilient Operations for Transformative, Efficient, and Cost-Saving Transportation (PROTECT) Discretionary Grants Program

The Bipartisan Infrastructure Law established both the PROTECT Formula and Discretionary Grant Programs. The PROTECT Discretionary Grants Program funds projects on a competitive basis that address the climate crisis by … Read more

Promoting Resilient Operations for Transformative, Efficient, and Cost-Saving Transportation (PROTECT) Formula Program

The Bipartisan Infrastructure Law established both the PROTECT Formula and Discretionary Grant Programs (described separately). The PROTECT Program helps increase surface transportation resilience to natural hazards, like flooding, through planning … Read more

Climate Resilience Regional Challenge

Through funding from the Inflation Reduction Act (IRA), this one-time program supports projects that build the resilience of coastal communities facing extreme weather, like hurricanes and storm surge, and other … Read more

National Fish Passage Program

The National Fish Passage Program provides funding and direct technical assistance to restore rivers and conserve our nation’s aquatic resources by removing or bypassing barriers. The resulting infrastructure is more … Read more

WaterSMART Aquatic Ecosystem Restoration Projects

The Aquatic Ecosystem Restoration Projects (AERP) is a new, competitive grant program that will provide funding for the study, design, and construction of aquatic ecosystem restoration and protection projects in … Read more

WaterSMART Environmental Water Resources Projects

The Environmental Water Resources Projects is a competitive grant program that received new funding from the Bipartisan Infrastructure Law to design, implement, and monitor conservation outcomes of habitat restoration projects … Read more

WaterSMART Cooperative Watershed Management Program

The Cooperative Watershed Management Program provides funding to watershed groups to encourage diverse stakeholders to form local solutions to address their water management needs through two phases: 1) Watershed Group … Read more

Climate Change Technical Assistance for Territories

The Climate Change Technical Assistance for Territories is a newly established program under the Inflation Reduction act and aims to provide technical assistance to the U.S. Insular Areas for climate … Read more

Land and Water Conservation Fund – State and Local Assistance Program

The LWCF is funded by revenues from offshore oil and gas leases and uses funding to conserve resources, like parks, wildlife refuges, forests, open spaces, trails and wildlife habitat. The … Read more

Climate and Environmental Justice Block Grants

Climate and Environmental Justice Block Grants provide $3 billion in competitive, 3-year grants to states, Tribes, and municipalities and community-based nonprofit organizations for financial and technical assistance to address clean … Read more

Environmental Justice Government-to-Government Program

The Environmental Justice Government-to-Government (EJG2G) Program provides funding for community-based organizations to engage in model activities that achieve measurable environmental impacts in communities who disproportionately bear the burden of pollution. … Read more

Environmental Justice Collaborative Problem-Solving Cooperative Agreement Program

The Environmental Justice Collaborative Problem-Solving (EJCPS) Cooperative Agreement Program provides financial assistance to organizations working to address local environmental or public health issues in their communities.  The program assists recipients … Read more

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Traveling for Good: How Nature-Based Tourism & Regenerative Travel Can Drive Development

Travel has long been a means of escape, adventure, and relaxation, giving us rich and unique perspectives. It can also help us save the world.

As we face unprecedented environmental challenges, the way we explore and experience destinations must evolve. In recent years, as travelers have become more interested in reducing their negative impact on the environment, two significant travel trends have emerged: nature-based tourism and regenerative travel. Interestingly, as visitors form a deeper connection with their surroundings through these tourism modalities, they are further inspired to support conservation efforts and responsible practices.

Nature-based tourism allows travelers to experience the raw beauty of destinations. By understanding the fragility of ecosystems, a focus on sustainability, conservation, and responsible stewardship emerges. This results in visitors making more conscious travel choices, opting for environmentally-friendly accommodations, selecting hotels that strive for green certifications that seek to protect the environment, and engaging in activities that support conservation.

Nature-based tourism spans a broad spectrum of subcategories like wildlife-watching, adventure tourism, community-based tourism, and stargazing, to name a few. They all attract a wide amplitude of demand segments, and this interest only continues to grow. In fact, according to a UN analysis, by 2050, around 70% of the population is expected to live in cities , underlining the need to maintain a connection with nature and seek nature-based experiences.

The United Nations Environment Programme has found that for every US$1 spent on nature restoration, an astounding US$9 in economic benefits is obtained . For investors, this is a golden opportunity to generate exponential impact by aligning their portfolios with genuinely responsible tourism practices, to obtain profitability while contributing to positive environmental impact.

As the largest potential source of investment in climate change mitigation and adaptation measures, with the ability to effect positive change across entire value chains, the private sector has a crucial role in these endeavors, as recognized by the Global Biodiversity Framework. The appeal combines financial returns and a desire to help fight the climate crisis, creating a circular investment thesis.

Likewise, regenerative travel is driven by travelers placing a premium on authenticity and seeking genuine environmental, social, and governance (ESG) practices. These travelers, who tend to be environmentally-conscious, are more apt to recognize meaningful ESG initiatives and reject superficial greenwashing attempts. This approach sets the stage for understanding the importance of the regenerative living method, which actively involves travelers in revitalizing the environment and communities. It emphasizes the restoration of ecosystems through myriad activities like reforestation and habitat restoration, inviting travelers to actively participate in these conservation efforts.

For investors, this goes beyond taking simple steps toward better practices such as removing straws from restaurants, eliminating single-use plastics from bathrooms, or fostering the re-use of towels. This is about asking them to do a deep dive on the needs of a destination or community and become part of the solution, thereby creating development impact through a circular effect.

As such, engagement with community members and sponsors is key to building resilience. The regenerative living method becomes even more powerful when travelers understand their role in contributing to a circular economy by embracing efficient resource use, waste reduction and the support of products designed for recycling and reusability.

In Latin America, Costa Rica represents a beacon for nature-based tourism and regenerative travel with over 25% of its land protected, as well as 30% of its waters. Benefitting from a thriving sustainable tourism sector, the country offers fertile ground for impactful development projects. Its extensive network of national parks and commitment to conservation and community engagement have made it a global leader in ecotourism, with over 400 certified sustainable tourism companies, providing appealing prospects for impact-driven investors.

Opportunities abound there to support projects with high environmental sensitivity and collaborate closely with the local community to create direct and indirect quality jobs and generate long-term economic prosperity. This has created an ideal environment for domestic and international investors who seek an impact investing agenda to find attractive opportunities in the country.

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Moreover, Costa Rica's commitment to nature-based tourism has safeguarded its biodiversity and boosted the economic activity of local communities. Nicoya’s Blue Zone, highlighted in the Netflix documentary “Live to 100: Secrets of the Blue Zones” , showcases the residents' longevity, a testament to sustainable tourism's positive impact on community well-being for decades now. Investors and financial institutions keen to support ventures that balance profit and societal benefits can find ample opportunities in Costa Rica's sustainable tourism landscape, where financial growth aligns with environmental and social well-being.

This development impact mandate aligns well with IDB Invest's principles and core mission, resulting in support not only through resources, but also through the introduction of innovative financial solutions and the provision of advisory services. The latter is key, as technical assistance is often required to provide guidance on implementing tailored solutions and grant resources to magnify certain initiatives to make them more impactful and demonstrative.

Furthermore, through the effective use of Blended Finance, financial incentives can be provided subject to the achievement of certain sustainability performance indicators. In fact, potent trends are emerging around the integration of the local value chain, especially by engaging small and medium-sized enterprises. This ultimately has a multiplier effect.

Nature-based tourism and regenerative travel are more than buzzwords. However, there needs to be an evolution from traditional philanthropic conservation models to develop new business propositions that actively monetize sustainability. Ultimately, developing these types of platforms will create the necessary project-level scale to obtain profitability on a sustained basis.

The journey is challenging and worth taking. It’s where the common interests of every stakeholder intersect: a genuine desire to pursue meaningful sustainability principles in the context of profitable tourism projects.

• climate change
• sustainability
• sustainable tourism

Rogerio Basso

Rogerio is the Head of Tourism for IDB Invest and has over two decades of real estate and hospitality experience. He is responsible for executing t

Andrés García Bernal

Andres is an Investment Consultant at BID Invest's Tourism team since 2021. His role involves analyzing new business opportunities and the portfolio s

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JHAPPI TIME

Growing Wildlife-Based Tourism Sustainably: A New Report and Q&A

Copyright: Sanjayda, Shutterstock.com

STORY HIGHLIGHTS

• While wildlife and biodiversity are increasingly threatened by habitat loss, poaching, and a lack of funding for protection, nature-based tourism is on the rise and could help provide solutions for these issues.
• The publication Supporting Sustainable Livelihoods through Wildlife Tourism highlights successful wildlife tourism programs in seven countries in Africa and Asia that can be used as models to promote conservation and boost economies.
• World Bank lead economist Richard Damania answers questions on the drivers, innovations and challenges for wildlife tourism, and why the World Bank Group and governments should support sustainable tourism strategies.

Wildlife tourism is a powerful tool countries can leverage to grow and diversify their economies while protecting their biodiversity and meeting several Sustainable Development Goals. It is also a way to engage tourists in wildlife conservation and inject money into local communities living closest to wildlife. Success stories and lessons learned from nature-based tourism are emerging from across the globe.

“Here is a way of squaring the circle: provide jobs and save the environment,” said World Bank lead economist Richard Damania, who has extensive experience in understanding the link between tourism and the economy . In 2016, travel and tourism contributed $7.6 trillion, or 10.2%, to total GDP, and the industry provided jobs to one in 10 people, according to the World Travel & Tourism Council .

While nature-based tourism, which includes wildlife tourism, has been expanding rapidly in the last decade or so due to increased demand and opportunities, wildlife and biodiversity are increasingly threatened by habitat loss, poaching, and a lack of funding for protection.

Which is why more than ever countries need to look to concrete examples of well-planned, sustainably-run tourism operations that have led to increased investments in protected areas and reserves, a reduction in poaching, an increase in the non-consumptive value of wildlife through viewing , and opportunities for rural communities to improve their livelihoods through tourism-related jobs, revenue-sharing arrangements, and co-management of natural resources.

A recently-released publication— Supporting Sustainable Livelihoods through Wildlife Tourism —developed by the World Bank Group and the Global Wildlife Program , funded by the Global Environment Facility , showcases sustainable wildlife tourism models that can be applied to developing countries, and offers solutions and case studies to bring insight into this sector as a mechanism for inclusive poverty reduction and global conservation.

The Global Wildlife Program spoke with Damania to learn more about the growth, challenges, and innovations in wildlife-based tourism.

Copyright: Wandel Guides, Shutterstock.com

Why should the World Bank support conservation endeavors, and how does wildlife tourism help support our mission?

Enlightened self-interest is one obvious reason why we need to promote wildlife tourism.  It provides the most obvious way to reconcile the interests of nature with the imperative for development and growth. Tourism simultaneously creates jobs while, when done well, protects natural habitats.

Prudence and precaution are another reason why investments in nature-based tourism ought to be promoted. The science of “ planetary boundaries ” warns us that many fragile natural environments and ecosystems are reaching their limits and in some cases, the hypothesized safe boundaries have been crossed. Further damage will imply that we lose important ecosystem services such as watershed and soil protection with damaging consequences for development.

But, in my mind, perhaps the most important reason is humanity’s moral and ethical imperative as stewards of global ecosystems. Simply because humanity has the ability to destroy or convert ecosystems and drive species to extinction does not make it ethically justifiable. There needs to be an ethical balance and that is where ecotourism comes in. We need jobs and economic growth, but here is a way to get jobs and growth in ways that meet our moral and ethical obligation.

What have been the drivers behind a burgeoning nature-based/wildlife-based tourism sector?  

I think there are two things that drive it: as habitats diminish there is more scarcity and their value goes up. Everyone wants to see the last remaining habitats of wild gorillas for instance, or the few remaining wild tigers in India. In sum scarcity confers economic value. 

Another force driving demand is the internet and rising lifestyles—you can learn about animals and habitats you might not have known existed, and more people have the ability to visit them. So, you have supply diminishing on one hand, and demand rising on the other hand which creates an opportunity for economic progress together with conservation.

What is your advice to governments and others who are developing or expanding on a nature or wildlife-based tourism strategy?

Tourism benefits need to be shared better . There is a lack of balance with too many tourists in some places, and none elsewhere. Some destinations face gross overcrowding, such as South Africa’s Krueger National Park or the Masai Mara in Kenya where you have tourists looking at other tourists, instead of at lions. We need to be able to distribute the demand for tourists more equally. The Bank has a role to play in developing the right kind of tourism infrastructure.

Those living closest to nature and wildlife must also benefit .   The local inhabitants that live in the national parks or at their periphery are usually extremely poor. Having tourism operations that can benefit them is extremely important for social corporate reasons, but also for sustainability reasons. If the benefits of tourism flow to the local communities, they will value the parks much more.

We also need to be mindful of   wildlife corridors . We know that dispersion and migration are fundamental biological determinants of species survival. Closed systems where animals cannot move to breed are not sustainable in the long run. As we break off the corridors because of infrastructure and increasing human populations we are putting the ecosystems on life support.

There are some who believe we can manage these closed ecosystems, but it takes an immense amount of self assurance in science to suggest this with confidence, and it is unclear that one can manage ecosystems that we do not adequately understand. A measure of caution and humility is needed when we are stretching the bounds of what is known to science.

What are some of the innovative partnerships that are helping the wildlife-based tourism businesses in developing countries? 

One very successful model that has combined wildlife conservation and management and community benefits and welfare is the  Ruaha Carnivore Project  in Tanzania, part of Oxford University’s Wildlife Conservation Research Unite ( WildCRU ). They use a payment for ecosystem services (PES) scheme and do all the right things.

Another example are the community conservancies in Namibia. The community manages the land for wildlife and there are a variety of profit sharing commercial tourism arrangements—although not everything always works fairly or perfectly. Incentives matter deeply and communities need to be guided and need technical assistance in setting up commercial arrangements.

The Bank needs to understand these better and find ways of scaling those up. The IFC has a very good role to play here as well. 

To learn more and to explore numerous examples of community involvement in wildlife tourism from Botswana, India, Kenya, Malawi, Namibia, South Africa and Uganda, read the report  Supporting Sustainable Livelihoods through Wildlife Tourism   or find a one-page fact sheet here .

The Global Wildlife Program (GWP) is led by the World Bank and funded by a $131 million grant from the Global Environment Facility (GEF). The program is working with 19 countries across Africa and Asia to promote wildlife conservation and sustainable development by combatting illicit trafficking in wildlife, and investing in wildlife-based tourism. 

• Full Report: Supporting Sustainable Livelihoods through Wildlife Tourism
• Fact Sheet on Key Messages
• Report: Twenty Reasons Sustainable Tourism Counts for Development
• Report: Women and Tourism: Designing for Inclusion
• Blog: Africa can Benefit from Nature-based Tourism in a Sustainable Manner
• Feature: Ramping up Nature-Based Tourism to Protect Biodiversity and Boost Livelihoods
• Website: Global Wildlife Program
• Website: Environment
• Website: Competitiveness
• Global Environment Facility

Cultural Tourism Funding Opportunities

AIANTA collects funding opportunities that may be of interest to Indigenous or Native American tourism & hospitality enterprises looking to grow their tourism, culture, heritage, arts, agritourism or other culture and heritage programming.

Open Funding Opportunities

DOT/FHWA: Development Deployment of Innovative Technologies for Concrete Pavements     

Deadline: May 20, 2024

Tourism Tip:  Use innovative technologies relating to the design, production, testing, control, construction, investigation, operation and impacts of concrete pavements.

MAP Round 2 2024 Request for Proposals (RFP)

Tourism Tip:   Create lasting change to activities on National Forest System lands or adjacent public lands.

Rural Development Broadband ReConnect Program

Deadline: May 21, 2024

Tourism Tip:  Use loans or grant funds for costs of construction, improvement or acquisition of facilities and equipment needed to provide broadband service.

National Endowment for the Humanities: Cultural and Community Resilience

Deadline: May 22, 2024

Tourism Tip:   Address the impacts of climate change by safeguarding cultural resources and fostering cultural resilience through identifying, documenting and/or collecting cultural heritage and community experiences. 

First Nations Development Institute Advancing Tribal Nature-Based Solutions

Deadline: May, 22, 2024

Tourism Tip:   to support climate action through nature-based solutions based on Native knowledge.

  Western SARE: Research and Education Invitation for Proposal

Deadline: May 23, 2024

Tourism Tip : Develop a project incorporating research and education that brings together a team of researchers, students, ag professionals and producers. 

Natural Resources Conservation Service Grazing Lands Conservation Initiative

Deadline: May 26, 2024

Tourism Tip : Develop a more strategic and comprehensive approach to support grazing systems, reach underserved producers and address climate change.

NPS Historic Preservation Fund Tribal Historic Preservation Office Grants

Deadline: May 30, 2024

Tourism Tip : Preserve historic properties and cultural traditions through the designation of a Tribal Historic Preservation Office or annual THPO grant funding.

Clean Energy Technology Deployment on Tribal Lands 

Tourism Tip : Install clean energy technology and/or energy efficiency measures on Tribal lands.

  Newman’s Own Foundation: Food Justice for Kids Prize – Indigenous Food Justice

Tourism Tip : Reclaim traditional food practices and systems to enable Indigenous children to learn about, grow, gather and cook Native foods. 

USDA Rural Cooperative Development Grants

Deadline: May 31, 2024

Tourism Tip :   S tart, improve or expand rural cooperatives and other mutually-owned businesses to help improve economic conditions in rural areas.

Union Pacific Foundation Community Ties Giving Program: Local Grants

Tourism Tip : Create, sustain or expand artistic and cultural experiences, provide recreational opportunities or preserve and restore nature along the UP footprint.

NEH Public Impact Projects at Smaller Organizations (PIPSO)

Deadline: June 12, 2024 (anticipated)

Tourism Tip:  Use interpretive strategies to advance your public programming , strengthen interpretive skill sets or enhance community engagement.

DOE Clean Energy to Communities 

Deadline: June 14, 2024 (anticipated)

Tourism Tip:  Help your  community understand different institutional contexts, resources, challenges, opportunities and ambitions to implement clean energy.

USFS Tribal Wildlife Grant Program

Deadline: June 21, 2024

Tourism Tip :  Use for planning or managing programs to benefit wildlife and their habitat, especially those with cultural or traditional importance. Funding can also be used for mapping, surveys and public education.

National Forest Foundation Matching Awards Program

Tourism Tip : Provide o pportunities for your community to benefit from activities on National Forest System lands or adjacent public lands. 

Bank of America Charitable Foundation

Tourism Tip : Focus on economic mobility in small businesses and support for community arts and cultural institutions.

USDA Rural   Energy for America Renewable Energy Systems & Energy Efficiency Improvement   Loans & Grants

Deadlines: June 30, and September 30, 2024

Tourism Tip:  Use guaranteed loan financing or grant funding for renewable energy systems or to make energy efficiency improvements.

National Credit Union Administration Community Development Revolving Loan Fund

Deadline: July 1, 2024

Tourism Tip:  Use  loans and technical assistance grants to help your credit union support the communities and tourism enterprises they operate.  

NEA Grants for Arts – Part II

Deadline: July 11, 2024

Tourism Tip: Use the funds to assist with art projects that tell the story of your place and culture. Grants are available for arts projects in a variety of artistic disciplines.

National Forest Foundation’s Collaborative Capacity Program for Forests & Communities

Tourism Tip: Support collaboration-based activities to benefit forests and grasslands currently managed by the US Forest Service through the National Forest System.  

NPS Cultural Resources Management Services

Deadline: July 15, 2024

Tourism Tip:   Work in partnership with the NPS to conduct various activities, including, but not limited to, studies outlined in the NPS Cultural Resource Management Guidelines.

VIA Art Fund Artistic Production Grants

Deadline: July 18, 2024

Tourism Tip:   Awards to individual artists, nonprofit organizations or institutions to support new artistic commissions outside museum or gallery walls, within the public realm or in nontraditional exhibition environments.

O’Reilly Automotive Foundation Inc.

Deadline: July 31, 2024

Tourism Tip:   In communities with O’Reilly Auto Parts companies, create a project that addresses economic stability in your tourism programs.

NEA Our Town Grants

Deadline: August 1, 2024

Tourism Tip:   Develop a placemaking project that integrates arts, culture, and design activities to strengthen communities over the long term. 

America Walks: Community Change Grants   

Deadline: October 17, 2024

Tourism Tip:  Use funds to create change and walking opportunities within your community.

NDN Collective Community Action Fund

Deadline: October 31, 2024

Tourism Tip : Support climate disaster response efforts to climate disasters such as flooding, fires and earthquakes.  

Western SARE Professional Development Program

Deadline: November 1, 2024

Tourism Tip:  Engage professionals to conduct educational programs and activities that incorporate environmental, economic and social dimensions of agriculture. 

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Guides & Publications

USDA Resource Guide for American Indians and Alaska Natives

The USDA recently published a Resource Guide for American Indians and Alaska Natives (AI/AN) to provide tribal leaders and tribal citizens, 1994 Land-Grant Tribal Colleges and Universities, AI/AN businesses and non-governmental organizations serving AI/AN communities with a tool for navigating USDA resources. This guide provides readers with a comprehensive summary of USDA Programs.  

Recreation Economy at USDA Economic Development Resources for Rural Communities

USDA’s Forest Service (FS), Rural Development (RD) and the National Institute for Food and Agriculture (NIFA) developed this resource guide for rural communities to identify resources that develop the recreation economy. The report forecasts that interest in outdoor recreation will continue over the next 30 years.

Resources for Rural Entrepreneurs: A Guide to Planning, Adapting, and Growing Your Business

In 2022, in collaboration with a network of federal partners, the USDA Resources for Rural Entrepreneurs guide provides resources for start-ups and already-established rural businesses. RD offers more than 40 loan, grant, and technical assistance programs to help improve the economy and quality of life in rural America. Many of these programs can also support community-based entrepreneurial planning and growth. USDA partners with community leaders and developers, local, state and Tribal governments, cooperatives, nonprofits, private organizations and a nationwide network of participating lenders skilled at building local economies.

Stronger Together, Federal funding and planning strategies designed to promote sustainable economic development in rural America

In 2022, the U.S. Department of Commerce Economic Development Administration (EDA) and the U.S. Department of Agriculture Rural Development (USDA RD) published Stronger Together a joint planning resource guide to help community organizations access USDA and EDA resources to build strategies to boost economic development in rural America. The guide is separated into four key focus areas: Planning and technical assistance, Infrastructure and broadband expansion, Entrepreneurship and business assistance and Workforce development and livability.

Federal Resources for Native Arts & Cultural Activities

In 2020, the National Endowment for the Arts published the Federal Resources for Native Arts & Cultural Activities, a guide providing information to connect Native communities to resources that can sustain and invigorate arts and cultural heritage initiatives. It is a consolidation of opportunities offered by federal agencies for organizations looking for funding and other resources to support Native arts and culture activities.

Grants.gov provides a unified site for interaction between grant applicants and the U.S. federal agencies that manage grant funds. The site allows applicants to search for funds by agency.

Federal Agencies

• U.S. Department of Commerce
• Economic Development Administration (EDA) 
• Small Business Administration 
• Regional Innovation Strategies 
• Minority Business Development Agency 

U.S. Department of Interior

• Bureau of Indian Affairs 
• National Park Service 
• Fish and Wildlife Service 
• Bureau of Land Management 
• Bureau of Reclamation 

Bureau of Indian Affairs (U.S. Department of Interior)

• Office of Indian Energy and Economic Development
• Division of Transportation 
• Division of Economic Development 

National Park Service (Department of Interior)

• Grants & Financial Assistance
• Tourism Program 
• Tribal Preservation Program 
• National Historic Landmarks 
• National Register of Historic Places 
• Rivers, Trails and Conservation Assistance Program 
• Conservation and Outdoor Recreation Division 
• Cultural Resources 

U.S. Department of Housing and Urban Development (HUD) www.hud.gov/program_offices/public_indian_housing/ih

• Office of Economic Development 
• Indian Community Development Block Grant 

U.S. Department of Health and Human Services

• Administration for Native Americans (ANA)
• Social and Economic Development Strategies (SEDS)
• Sustainable Employment and Economic Development Strategies (SEEDS)
• Native Youth Initiative for Leadership, Empowerment, and Development (I-LEAD)

U.S. Department of Agriculture (USDA)

• Business & Industry Loan Guarantees 
• Community Connect Grants 
• Rural Business Investment Program 
• Rural Economic Development Loan & Grant Program 
• Rural Microentrepreneur Assistance Program 
• Socially-Disadvantaged Groups Grant 
• Strategic Economic and Community Development 
• Value-Added Producer Grants 
• U.S. Forest Service (trail construction, archaeology)

National Endowment for the Arts (NEA)

• Our Town ($25,000 – $200,000) 
• Challenge America ($10,000 underserved populations)
• Art Works ($10,000 – $100,000)

National Endowment for the Humanities (NEH)

• Division of Preservation and Access 
• Documenting Endangered Languages
• Sustaining Cultural Heritage Collections
• Preservation Assistance Grants for Smaller Institutions 
• Office of Challenge Programs

Institute of Museum and Library Sciences (IMLS)

• Native American Library Services: Basic Grants 
• Native American Library Services: Enhancement Grants 
• Native Hawaiian Library Services Grants 
• Museums for America 
• Inspire! Grants for Small Museums 
• Museums Empowered 
• National Leadership Grants for Museums
• Laura Bush 21st Century Librarian Program
• Museum Assessment Program 
• Accelerating Promising Practices for Small Libraries 

U.S. Department of Transportation www.transportation.gov/grants

• Office of Infrastructure Finance and Innovation 
• National Scenic Byways Program 
• Office of Tribal Transportation 

Environmental Protection Agency (EPA)

• Building Blocks for Sustainable Communities 

State Tourism, Arts & Economic Development Agencies

Arts.gov State and Regional Arts Councils arts.gov/partners/state-regional

California Arts Council arts.ca.gov/grants

California Governor’s Office of Business & Economic  Development business.ca.gov

Montana Tourism Office marketmt.com

Nevada Arts Council: Folklife Community Grant nvartscouncil.org/grants

New Mexico Tourism Office newmexico.org/industry/work-together/grants

Oregon Tourrism traveloregon.com/grants

Additional Resources

Community Foundations www.cof.org/community-foundation-locator The Council on Foundations, founded in 1949, is a nonprofit leadership association of grantmaking foundations and corporations. Use their search tool to find local funding resources.

The Grantsmanship Center www.tgci.com The Grantsmanship Center offers training, publications and consulting to help organizations find funding. The Center provides free access to its Funding State-by-State database listing each state’s top grantmaking foundations, community foundations, corporate giving programs and State website homepages.

Candid (formerly the Foundation Center and GuideStar) candid.org/

Candid is an online source for grants available through private foundations, corporate foundations, and other nonprofits that accept grant proposals. It also provides research on nonprofits and guides, like the 990 Finder.

Bureau of Indian Affairs

Juan Bautista de Anza National Historic Trail

Native American Agriculture Fund

Lewis & Clark National Historic Trail

Bureau of Land Management

National Endowment of the Arts

National Park Service

United States Forest Service

Mississippi-Alabama Sea Grant Consortium

Team to develop online training for nature-based tourism recognition program, by: melissa schneider / published: aug 11, 2021.

A team with the Mississippi State University (MSU) Extension Service and the Mississippi-Alabama Sea Grant Consortium will create online training modules for the Gulf Coast Outpost Program , making the certification program more accessible to nature-based tourism businesses.

The program, administered by Mississippi Gulf Coast National Heritage Area ( MSCoastNHA ), is part of the Nature-Based Tourism Plan for Coastal Mississippi and recognizes businesses whose owners and operators are knowledgeable about the coast’s natural environment and work to foster environmental and cultural understanding, appreciation and conservation of its resources.

The training development team will produce course content, including video instruction and tests, through MSU's online education platform, which will allow for self-paced learning with online interaction with instructors. The course design and implementation project will be funded through a grant from MSCoastNHA.

Team members include Eric Sparks, Marcus Drymon and Renee Collini, who are extension specialists with MSU and the Mississippi-Alabama Sea Grant Consortium.

“A recognized barrier to entry into the program has been the availability and accessibility of training resources for certification requirements,” Sparks said. “This course design will allow business owners and operators to complete the course when their schedules allow.”

To create the training modules, the team will draw from several of its existing programs, including Mississippi Master Naturalist , Student Naturalist , Mississippi Coastal Cleanup , Mississippi Inland Cleanup , MSU Coastal Conservation and Restoration , MSU Marine Fisheries Ecology , Program for Local Adaptation to Climate Effects: Sea-Level Rise ( PLACE:SLR ) and Plastic Free Gulf Coast .

“The Mississippi Gulf Coast National Heritage Area is continuously looking for opportunities to support and grow our nature-based tourism industry along the Gulf Coast, and we are thrilled to partner with MSU and Mississippi-Alabama Sea Grant in that effort,” Rhonda Price, the MSCoastNHA director, said. “This collaboration will provide a much-needed opportunity for nature-based businesses to receive training and work toward their Gulf Coast Outpost certification.”

Businesses in the six coastal counties qualify for the program if 50% or more of their primary business line focuses on nature-based activities. Eco tours, locally owned outfitters, charter boat operators, tour guides, eco-lodges and agritourism entities are some examples of businesses that qualify.

After completing the program and becoming certified as a Gulf Coast Outpost, businesses gain access to a resource toolkit, which includes marketing tools, such as the Gulf Coast Outpost seal of approval and window decals. The businesses also gain recognition as a leader in sustainability, and they receive notifications of training opportunities to support sustainable business practices and prepare their employees for careers in nature-based tourism.

Certified businesses also become eligible to apply for the MSCoastNHA Community Grants Program.

The one-year course design project is set to begin soon, and the online course is expected to be available in early 2022.

The Mississippi Gulf Coast National Heritage Area is funded by the National Park Service and was Congressionally designated as a Heritage Area in 2004. The Heritage Area is managed by the Mississippi Department of Marine Resources (DMR) and helps to fulfill the DMR's mission to enhance, protect and conserve the cultural and natural resources of the Mississippi Gulf Coast.

For more information about the Gulf Coast Outpost Program, go to https://gulfcoastoutpost.com/ .

Eric is the assistant director for outreach and a coastal ecology specialist.

His work focuses on...

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You can submit an application for a Nature-Based Visitor Experience Development Grant  of between $100,000 and $250,000, in matched dollar-for-dollar funding, for the creation of new nature-based tourism attractions or experiences.

Applications must be received by 11.59pm AEST on Monday, 22 May 2023

To be considered for funding, please  register  (or  login  if you have already registered) and complete the online form.

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USDA Forest Service Urban and Community Forestry Ten-Year Action Plan

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The Illinois Department of Natural Resources facilitates planting of native plants in schoolyards. Applications are typically due in January.

The Office of Resource Conservation’s Division of Wildlife Resources administers four special grant programs that are funded by Illinois sportsmen through the purchase of Habitat Stamps and Migratory Waterfowl Stamps. These are the Illinois Habitat Fund, State Pheasant Fund, State Furbearer Fund, and the Migratory Waterfowl Stamp Fund. Together, these programs are designed to protect, acquire, enhance, or manage wildlife habitat and to support limited research and educational programs to further advance this mission.

Periodically, the Illinois Department of Natural Resources awards funding to public landowners to conduct urban forestry practices. This includes inventories, planting, management plans, and ordinances. Contact Colette Copic at [email protected] for more information.

The IFDC periodically has small grants available for projects that support forestry practices and improvement of forests in the state of Illinois.

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Funding for this grant program is derived from the Illinois Natural Areas Acquisition Fund (NAAF) and must be used by the Department of Natural Resources for the acquisition, protection, and stewardship of natural areas, including habitats for endangered and threatened species (Open Space Lands Acquisition and Development Act, 525 ILCS 35/14). The Illinois Natural Areas Stewardship Grant Program was established to make grants to conservation land trusts for the purpose of promoting stewardship actions on eligible lands.

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Houses of worship are required to conduct outreach within their own congregation and into surrounding communities through workshops, garden tours, native plant sales, and other forms of education. These efforts contribute to the development of networks of faith communities and community partners working together to build healthy habitats and communities.

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The Illinois Department of Natural Resources provides funding assistance to local government agencies for acquisition and/or development of land for public parks and open space.

The Illinois Department of Natural Resources helps public museums in Illinois expand and upgrade facilities and create new exhibits and other physical facilities to enhance public museums’ abilities to meet their mission.​

The Illinois Environmental Protection Agency provides funds to assist groups that have established a recurring stream or lakeshore cleanup

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The National Fish and Wildlife Foundation (NFWF) provides funding on a competitive basis to projects that sustain, restore and enhance our nation’s fish, wildlife and plants, and their habitats. Browse NFWF’s conservation programs and learn how to apply for a grant.

Through the TD Green Space Grants program, municipalities in the United States and Canada are eligible to receive grants in support of local forestry projects in the areas of great need within a community.

The TREE Fund provides a wide range of grants to fund forestry related education programs.

The TREE Fund provides a wide range of research grants on forestry and arboriculture.

The U.S. Department of Agriculture (USDA), Forest Service, State, Private & Tribal Forestry, is requesting applications for the Community Forest and Open Space Conservation Program (Community Forest Program or CFP). The purpose of the program is to establish community forests by protecting forestland from conversion to non-forest uses and provide community benefits including public recreation, environmental and economic benefits, and forest-based educational programs. Public access is required for all projects. To apply, interested local government and nonprofit applicants must submit applications to the State Forester where the property is located. Tribal applicants must submit applications to equivalent Tribal government officials. All applications must be received by State Foresters or Tribal governments by January 12, 2024.

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• Open access
• Published: 11 June 2024

Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction

• Keith Siew   ORCID: orcid.org/0000-0002-6502-5095 1 ,
• Kevin A. Nestler 2 ,
• Charlotte Nelson   ORCID: orcid.org/0000-0002-3687-1102 3 ,
• Viola D’Ambrosio 1 , 4 ,
• Chutong Zhong 1 ,
• Zhongwang Li 1 , 5 , 6 ,
• Alessandra Grillo   ORCID: orcid.org/0000-0001-6482-8796 1 ,
• Elizabeth R. Wan 1 ,
• Vaksha Patel 7 ,
• Eliah Overbey   ORCID: orcid.org/0000-0002-2866-8294 8 ,
• JangKeun Kim   ORCID: orcid.org/0000-0002-8733-9925 8 ,
• Sanghee Yun   ORCID: orcid.org/0000-0001-7505-0836 9 , 10 ,
• Michael B. Vaughan   ORCID: orcid.org/0000-0002-9979-1265 11 , 12 , 13 ,
• Chris Cheshire 14 ,
• Laura Cubitt   ORCID: orcid.org/0000-0003-1948-6795 15 ,
• Jessica Broni-Tabi 16 ,
• Maneera Yousef Al-Jaber   ORCID: orcid.org/0000-0002-5051-7345 17 ,
• Valery Boyko   ORCID: orcid.org/0000-0002-3724-9294 18 ,
• Cem Meydan   ORCID: orcid.org/0000-0002-0663-6216 8 ,
• Peter Barker 19 ,
• Shehbeel Arif 20 , 21 ,
• Fatemeh Afsari 22 ,
• Noah Allen   ORCID: orcid.org/0000-0003-0998-8337 23 ,
• Mohammed Al-Maadheed 17 , 24 ,
• Selin Altinok 25 ,
• Nourdine Bah 15 ,
• Samuel Border 22 ,
• Amanda L. Brown 26 ,
• Keith Burling 19 ,
• Margareth Cheng-Campbell 23 , 27 ,
• Lorianna M. Colón 28 ,
• Lovorka Degoricija 29 ,
• Nichola Figg 30 ,
• Rebecca Finch 31 ,
• Jonathan Foox 32 , 33 ,
• Pouya Faridi 34 ,
• Alison French 18 ,
• Samrawit Gebre 18 ,
• Peter Gordon 16 ,
• Nadia Houerbi 35 ,
• Hossein Valipour Kahrood   ORCID: orcid.org/0000-0003-4166-0382 34 , 36 ,
• Frederico C. Kiffer   ORCID: orcid.org/0000-0001-5269-3951 10 ,
• Aleksandra S. Klosinska 37 ,
• Angela Kubik 23 ,
• Han-Chung Lee 34 ,
• Yinghui Li   ORCID: orcid.org/0000-0002-9294-4652 38 ,
• Nicholas Lucarelli 22 ,
• Anthony L. Marullo   ORCID: orcid.org/0000-0002-1460-7167 11 ,
• Irina Matei   ORCID: orcid.org/0000-0002-5712-8430 39 , 40 ,
• Colleen M. McCann 26 ,
• Sayat Mimar 22 ,
• Ahmed Naglah 22 ,
• Jérôme Nicod   ORCID: orcid.org/0000-0003-2459-3480 41 ,
• Kevin M. O’Shaughnessy   ORCID: orcid.org/0000-0002-1476-7566 37 ,
• Lorraine Christine De Oliveira 27 , 42 ,
• Leah Oswalt   ORCID: orcid.org/0000-0001-7097-0801 26 ,
• Laura Ioana Patras 43 ,
• San-huei Lai Polo   ORCID: orcid.org/0000-0003-1460-6647 29 ,
• María Rodríguez-Lopez   ORCID: orcid.org/0000-0002-2066-0589 41 ,
• Candice Roufosse   ORCID: orcid.org/0000-0002-6490-4290 44 ,
• Omid Sadeghi-Alavijeh 7 ,
• Rebekah Sanchez-Hodge 26 ,
• Anindya S. Paul 22 ,
• Ralf Bernd Schittenhelm   ORCID: orcid.org/0000-0001-8738-1878 34 ,
• Annalise Schweickart   ORCID: orcid.org/0000-0001-9691-3741 8 , 45 ,
• Ryan T. Scott   ORCID: orcid.org/0000-0003-0654-5661 29 ,
• Terry Chin Choy Lim Kam Sian   ORCID: orcid.org/0000-0001-7038-1214 34 ,
• Willian A. da Silveira 31 , 46 ,
• Hubert Slawinski   ORCID: orcid.org/0000-0002-8996-8477 41 ,
• Daniel Snell   ORCID: orcid.org/0000-0002-0105-8437 41 ,
• Julio Sosa   ORCID: orcid.org/0000-0001-5516-5724 47 ,
• Amanda M. Saravia-Butler 29 ,
• Marshall Tabetah   ORCID: orcid.org/0000-0002-1651-7659 48 ,
• Erwin Tanuwidjaya 34 ,
• Simon Walker-Samuel   ORCID: orcid.org/0000-0003-3530-9166 5 , 6 ,
• Xiaoping Yang 49 ,
• Yasmin 37 ,
• Haijian Zhang 34 ,
• Jasminka Godovac-Zimmermann   ORCID: orcid.org/0000-0002-6820-4128 7 ,
• Pinaki Sarder 50 , 51 ,
• Lauren M. Sanders   ORCID: orcid.org/0000-0001-9393-0861 18 , 27 ,
• Sylvain V. Costes   ORCID: orcid.org/0000-0002-8542-2389 18 ,
• Robert A. A. Campbell 16 ,
• Fathi Karouia   ORCID: orcid.org/0000-0002-1142-9684 27 , 52 , 53 ,
• Vidya Mohamed-Alis 17 , 24 ,
• Samuel Rodriques 15 ,
• Steven Lynham 49 ,
• Joel Ricky Steele   ORCID: orcid.org/0000-0002-3070-9761 34 ,
• Sergio Baranzini   ORCID: orcid.org/0000-0003-0067-194X 3 ,
• Hossein Fazelinia 54 ,
• Zhongquan Dai 38 ,
• Akira Uruno   ORCID: orcid.org/0000-0002-9224-0161 55 ,
• Dai Shiba   ORCID: orcid.org/0000-0003-3808-5428 56 , 57 ,
• Masayuki Yamamoto 55 , 58 ,
• Eduardo A.C.Almeida 18 ,
• Elizabeth Blaber 23 , 59 , 60 ,
• Jonathan C. Schisler   ORCID: orcid.org/0000-0001-7382-2783 26 ,
• Amelia J. Eisch   ORCID: orcid.org/0000-0001-6476-5385 10 , 61 ,
• Masafumi Muratani   ORCID: orcid.org/0000-0002-0276-8000 62 ,
• Sara R. Zwart   ORCID: orcid.org/0000-0001-8694-0180 63 ,
• Scott M. Smith   ORCID: orcid.org/0000-0001-9313-7900 64 ,
• Jonathan M. Galazka   ORCID: orcid.org/0000-0002-4153-0249 18 ,
• Christopher E. Mason   ORCID: orcid.org/0000-0002-1850-1642 32 , 33 , 65 , 66 ,
• Afshin Beheshti   ORCID: orcid.org/0000-0003-4643-531X 29 , 67 , 68 &
• Stephen B. Walsh   ORCID: orcid.org/0000-0002-8693-1353 1  

Nature Communications volume  15 , Article number:  4923 ( 2024 ) Cite this article

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• Mass spectrometry
• Renal calculi
• Thrombotic microangiopathies

Missions into Deep Space are planned this decade. Yet the health consequences of exposure to microgravity and galactic cosmic radiation (GCR) over years-long missions on indispensable visceral organs such as the kidney are largely unexplored. We performed biomolecular (epigenomic, transcriptomic, proteomic, epiproteomic, metabolomic, metagenomic), clinical chemistry (electrolytes, endocrinology, biochemistry) and morphometry (histology, 3D imaging, miRNA-ISH, tissue weights) analyses using samples and datasets available from 11 spaceflight-exposed mouse and 5 human, 1 simulated microgravity rat and 4 simulated GCR-exposed mouse missions. We found that spaceflight induces: 1) renal transporter dephosphorylation which may indicate astronauts’ increased risk of nephrolithiasis is in part a primary renal phenomenon rather than solely a secondary consequence of bone loss; 2) remodelling of the nephron that results in expansion of distal convoluted tubule size but loss of overall tubule density; 3) renal damage and dysfunction when exposed to a Mars roundtrip dose-equivalent of simulated GCR.

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Introduction.

The renewed zeitgeist for space travel, ushered in by the advent of commercial spaceflight and tourism, has spurred on state-funded agencies to embark on even more ambitious exploratory ‘Deep Space’ missions. The first of these, namely the Artemis Program, Lunar Gateway space station and later the Deep Space Transport/Mars Missions, will for the first-time place humans outside of Earth’s protective magnetic field exposed to significant quantities of unmitigated space radiation and weightlessness for many months to years at a time.

The health effects of low Earth orbit (LEO) spaceflight (e.g. the International Space Station) are multiple, with much of the research communities’ intense focus centred on the musculoskeletal, neurological, ocular and cardiovascular degeneration that can manifest as early as a few weeks into a mission. Notably, the effects of LEO spaceflight on many other organ systems are less clear, with indispensable organs such as the kidneys receiving relatively little attention in the absence of overt symptoms. However, in the face of extended periods of deep space travel health issues may only present with late onset due to cloaked subclinical pathophysiology and chronic damage eating into the extensive functional reserves of such organs.

The kidneys are critical in regulating blood pressure, by controlling both the renin/angiotensin/aldosterone system (RAAS) and the reabsorption of sodium chloride and water from the urine. In microgravity, the cephalad redistribution of blood volume with the concomitant decrease in the pressure gradient should reduce kidney perfusion. In turn, a lower perfusion pressure within the renal artery should lead to a greater release of renin and activation of the RAAS. However, studies show a marked reduction of diuresis and natriuresis in space with the RAAS, and antidiuretic hormone (ADH) increasing through unknown mechanisms 1 , 2 , 3 . These unexplained effects, be they mediated through known homeostatic mechanisms, or more theoretical ones, such as tensegrity 4 , are germane to kidney stone formation (i.e. nephrolithiasis). Astronauts have an unusually high rate of kidney stone formation, with 1-year post-flight astronauts experiencing incidence rates of 2–7 times that of pre-flight estimates, and in-flight risk estimated to be double that again 5 . This is of mission critical significance, one Soviet in-flight renal stone episode nearly caused a mission termination due to the severe symptoms, but was relieved by spontaneous stone passage by the cosmonaut just before an urgent deorbit was initiated 6 . It has been demonstrated that spaceflight associated changes in urinary biochemistry favour kidney stone formation 7 , 8 , 9 . Microgravity may have a direct effect on the crystallisation and nucleation of nascent kidney stones 10 , but this is dwarfed by the net biochemical urinary changes historically attributed to the microgravity-induced bone demineralisation observed in spaceflight. A school of thought that has led to a paucity of research into other pathophysiological phenomena that may be contributing to the unusually high incidence of nephrolithiasis.

The kidney is a plastic organ, and is capable of dynamically remodelling the architecture of the nephron in response to changes in blood pressure or dietary potassium. An 18 day potassium-free diet resulted in a 31% increase in rat kidney weight, which was mainly seen in the medullary collecting duct 11 . Changes in the size of nephron segments in wild type mice have been observed using advanced imaging techniques in a period as short as three days 12 . So, it is plausible that spaceflight-induced shifts in fluid and electrolyte handling could precipitate maladaptive remodelling events that contribute to the underlying pathophysiology.

In addition to the well-studied environmental stressor of microgravity, deep space missions beyond the protection of the geomagnetosphere (the Van Allen belts) are exposed to space radiation. Space radiation comprises both intermittent events (e.g. Solar Particle Events or Solar Proton Events) with the most energetic being a Coronal Mass Ejection and Solar Wind and Galactic Cosmic Radiation (GCR), with GCR having the most significant health impacts.

There is concern regarding the carcinogenic effect of GCR exposure in the planned Mars Missions. However, the kidney is an exquisitely radiation sensitive organ; it is the dose limiting organ in abdominal radiotherapy 13 . Chronic kidney dysfunction can occur with acute low linear energy transfer (LET) γ-radiation doses as low as <0.5 Gy 14 , the LET dose expected on a Mars Mission. However, GCR comprises low-LET x- and γ-rays with protons and high energy ‘HZE’ ions of heavier elements (e.g. silicon, titanium, iron). It has been established that exposure to HZE ions results in mitochondrial damage 15 , 16 . The renal proximal tubule is heavily dependent on mitochondrial respiration 17 and is one of the main tubular segments in which damage is associated with kidney failure 18 . Indeed, proximal tubular injury is a prominent histological feature in medical (low-LET) radiation nephropathy 19 . Due to their dependence on mitochondrial aerobic respiration, proximal tubular cells are extremely vulnerable to mitochondrial damage that we would expect from HZE exposure in addition to low-LET radiation damage.

We hypothesised that the biochemical urinary changes seen in spaceflight might reflect functional and morphological changes detectable in the kidney secondary to microgravity, possibly due to abnormal renal perfusion.

Further, we hypothesised that GCR exposure will cause mitochondrial and therefore proximal tubular dysfunction, leading to tissue damage and potentially irreversible loss of renal function, in addition to the known micro and macrovascular damage caused by GCR.

In order to explore these questions, we took a pan-omics approach incorporating anatomical and physiological parameters from 20 independent human and rodent spaceflight missions/simulations that had extant data and/or samples from which we could generate novel data (Fig.  1 ).

a Infographic representation of the study design. (Created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license). b Details of spaceflight missions and simulations included in the project. R return, L launch, PE post-exposure, P plasma, U urine, K kidney; F faecal. a , b N numbers correspond to the number of experimental individuals that were exposed to spaceflight or a simulated spaceflight condition, and to control condition individuals were omitted from the presented counts to ensure paired and unpaired experiments were comparable.

Primary changes in kidney function increase the risk of spaceflight-induced nephrolithiasis

We analysed urinary and plasma parameters of interest for nephrolithiasis in 66 astronauts that stayed on the International Space Station (ISS) for up to 180 days. Values were analysed across time, including before, during and after flight. Our data showed an increased urinary excretion of metabolites and electrolytes that are considered risk factors for nephrolithiasis (Fig.  2 ). In the figure, urinary excretion of calcium is expressed as fractional excretion (FE Ca ). In the absence of plasma calcium abnormalities FE Ca should be < 1%; in astronauts, FE Ca increases significantly during flight. This urinary abnormality normalises on return to Earth (Fig.  2 ). A less significant increase was seen in oxalate, phosphate, uric acid urinary excretion during spaceflight, all rapidly decreasing at return with some parameters transiently overcorrecting. Urinary citrate did not significantly change and remained within the normal range. There was also a decrease in urinary volume during spaceflight and an increase in urinary osmolality (Fig.  2 ). Urinary electrolytes (chloride, sodium and potassium) remained stable during spaceflight compared to pre-flight with the exception of magnesium that, although within the normal range, significantly increased (Fig.  2 ; Supplementary Fig.  1A ). Calculated values including estimated glomerular filtration rate (eGFR), aldosterone:renin ratio, FE for urinary electrolytes and water, transtubular potassium gradient (TTKG) and the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR can be found in Fig.  2 and Supplementary Fig.  1A, B . In addition, Supplementary Fig.  1C shows plasma values from the SpaceX Inspiration4 mission. Although these astronauts only spent 3 days in space, there was a degree of eGFR instability detected several months after returning to Earth.

a Urinary chemistries and b blood plasma endocrine profiles from NASA astronauts ( n  = 66) exposed to spaceflight up to 180 days measured pre-flight, during (FD flight day) and after returning (R). Dashed lines represent upper and lower normal clinical values, or upper limit where only a single line is present. Data are presented as mean ± SD. Boxed P -values report the repeated measure one-way ANOVA result; all timepoints were compared to pre-flight by pairwise multiple comparison Bonferroni corrected post-hoc tests (* p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001) (For exact P -values see Supplementary Table  1 ). FE Ca Fraction Excretion of Calcium. TmP/GFR ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate. 1,25-dihydroxyvitamin D3 calcitriol. PTH parathyroid hormone. FGF-23 fibroblast growth factor-23.

Although, most of the metabolite changes support the emergence of pro-lithogenic profile during spaceflight, they do not entirely explain the increased risk of nephrolithiasis in astronauts, suggesting that there might be other previously unidentified mechanisms underpinning this phenomenon.

To investigate this, we initially explored RR-10 spaceflight mouse kidney tissue epiproteomic data to infer functional changes. Post-translational modifications of channels, transporters and pumps can alter their activity, and chief among these is phosphorylation status for which we noted several thousand significantly altered phosphosites (Fig.  3a ; Supplementary Data  1 ), suggesting a general increase in phosphatase and decrease in kinase activities (Fig.  3b ). In particular, two of the most dramatically dephosphorylated proteins were the thiazide-sensitive Na-Cl cotransporter (NCC), encoded by SLC12A3 , expressed in the distal convoluted tubule (and validated by phospho-specific antibody staining in Fig.  3c ) and furosemide-sensitive Na-K-Cl cotransporter (NKCC2), encoded by SLC12A1 , expressed in the thick ascending limb of the loop of Henle (Fig.  3a ). These transporters requires phosphorylation of key residues at their N-terminus for activation 20 , and NKCC2 is regulated by the calcium-sensing receptor (CaSR) and genetic (i.e., Bartter syndrome) or pharmacological (e.g., furosemide) impairment of NKCC2 leads to hypercalciuria, and is associated with nephrolithiasis. Whereas changes in NCC activity can lead to alterations in calcium handling and bone mineral density.

a Volcano plot of differentially phosphorylated amino acid residues detected in phosphopeptide-enriched kidney protein extract from RR-10 spaceflight-exposed mice (28 days). Regulatory phosphosites in transporters and channels related to the thick ascending limb of the loop of Henle and distal convoluted tubule are highlighted. Green indicates a statistically significant increase in peptide phosphorylation, magenta indicates a decrease, and grey represents no significant change. An unadjusted two-tailed -Log 10 (Adjusted P -value) of 1.3 was considered statistically significant (indicated by the dashed line intersecting the x-axis). Kir4.1 ( KCNJ10 ); Kir5.1 ( KCNJ16 ); NKCC2 ( SLC12A1) ; NCC ( SLC12A3 ); KCC4 ( SLC12A7 ); pT, phospho-threonine; pS, phospho-serine. b Kinase-Substrate Enrichment Analysis (KSEA) was performed using the Robust Inference of Kinase Activity (RoKAI) App v2.2.1 to predict kinase and phosphatase activity levels using phosphoproteomics from RR-10 spaceflight-exposed mice (28 days) kidney tissue. Bars in blue represent downregulated activity and those in red represent upregulated activity. An adjusted P -value of < 0.05 was considered significant. Data are mean SEM. An FDR of 5% was used as a cutoff. N  = 10 biologically independent animals per group (flight vs ground control). 4257 single-site phosphopeptides (Ser/Thr/Tyr) were used as initial input, 495 of which were matched to known kinase/phosphatase targets, that were then used to calculate respective predicted kinase/phosphatase activities. Input and results files for this can be found at OSD 466. c Representative confocal images of RR-10 spaceflight-exposed mice (28 days) kidney sections [ n  = 7 spaceflight / n  = 10 ground control) stained with an anti-NCC pT44, pT48 & pT53 antibody (green; pNCC) and a total NCC antibody (magenta; tNCC) to visualise NCC phosphorylation-dependent activation (green and magenta overlap will appear as white); 50 µm scale bar.

To look for corroborating evidence of primary changes in renal function, we analysed plasma and kidney tissue multi-omic data from human and mouse samples (Fig.  4a ; Supplementary Fig.  2 ; Supplementary Data  2 ) for disease ontologies related to kidney stone formation. The nephrolithiasis and related ontologies were heavily represented across different datasets, providing orthogonal confirmation of real changes in the gene products comprising this ontology for spaceflight conditions vs controls. For example, α-tubulin ( TUB1A1 ) is known to protect against cell-crystal adhesion 21 but is decreased across multiple kidney datasets in our study (Fig.  5 ; Supplementary Data  3 ). In contrast, hypercalciuria and hyperoxaluria ontologies were scantily represented, implying that standard terrestrial causes of dysregulated urinary calcium and oxalate were not particularly enriched and therefore not strongly implicated in kidney stone formation.

a Multi-omic over-representation analysis of DisGeNET gene-disease associations related to nephrolithiasis. To integrate datasets from different omics modalities, species, missions and tissues, all biomolecules (e.g. phosphopeptides, proteins, transcripts and methylated DNA) were converted to the human orthologs where necessary and linked back to their HGNC gene symbol, aggregated and collapsed to single genes (e.g. multiple phosphosites, isoforms, CpG sites). An unadjusted, two-tailed -Log 10 ( P -value) of 2 was considered significant for ontological term enrichment. b Categorical heatmap of differential abundance directionality in nephrolithiasis-related faecal microbial taxa after spaceflight. An unadjusted, two-tailed -Log 10 ( P -value) of 1.3 was considered significant. c Over-representation analysis of KEGG module metabolic pathways with replication in at least two datasets. An unadjusted, two-tailed -Log 10 ( P -value) of 1.3 was considered significant for ontological term enrichment. a , c Enrichment ratio; the number of differentially regulated hits in a dataset that belong to a given ontological term, normalised to the total number of statistically significant hits in the respective dataset.

Categorical heatmap of a , upregulated and b , downregulated gene products in exposure groups (e.g. spaceflight, GCRsim) compared to control groups (e.g. ground control, sham). To integrate datasets from different omics modalities, species, missions and tissues, all biomolecules (e.g. phosphopeptides, proteins, transcripts and methylated DNA) were converted to the human orthologs where necessary and linked back to their HGNC gene symbol, aggregated and collapsed to single genes (e.g. multiple phosphosites, isoforms, CpG sites). These differentially regulated gene products (DRGP) were ranked and represented in descending order using the following rules: (1) only DRGPs with a P -value < 0.05 by Wald test were counted as significant and plotted; (2) Each DRGP was assigned a score of +1 each time it was upregulated or −1 each time it was downregulated; (3) only DRGPs observed in proteome and transcriptome kidney-specific datasets were used for the calculation of the ranking score to avoid confounders, although additional datasets (epiproteome, epigenome and those from plasma/exosomes sources) were plotted for visualisation comparison purposes; (4) The resulting sum of scores for each DRGP was then calculated and multiplied by the number of times the DRGP was observed in the kidney-specific proteome and transcriptome datasets; (5) To increase confidence only DRGPs with a product score of absolute value 9 or higher (but excluding a score of 12) were plotted as these will have a directionality consensus of at least 3 datasets above the number of disagreeing datasets.

The directional changes in nephrolithiasis-related faecal microbiome abundances between spaceflight and ground controls are illustrated in ( Fig.  4b ; Supplementary Data  4 ). Overall, these microbiota changes paint a mixed picture with some changes expected to confer a protective profile against nephrolithiasis and others tending to contribute to increased risk, implying that the increased urinary oxalate excretion is unlikely to be primarily diet or microbiota-dependent. Nevertheless, whole faecal microbiome KEGG analysis shows some enrichment of glyoxalate (a precursor to oxalate) and arginine metabolism (Supplementary Fig.  3 ).

Pathway analysis of novel plasma metabolomic data from humans and rodents under spaceflight conditions (Fig.  4c ; Supplementary Data  5 ) shows a striking over-representation of Aminoacyl-tRNA biosynthesis and arginine biosynthesis metabolic pathways.

Aminoacyl-tRNA biosynthesis is the ubiquitous housekeeping process of charging amino acids to their cognate tRNAs and providing the substrates for global protein synthesis. In addition to this canonical function, it has become clear that aminoacyl-tRNA synthetases are involved in a variety of physiological and pathophysiological processes including angiogenesis, inflammation, translational control and post translational modification 22 , 23 , 24 .

Arginine metabolism has been implicated in toxic nephrolithiasis 25 and glycerophospholipids are the main lipid component of cell membranes and pathway enrichment is compatible with remodelling events (reviewed by Han 26 ). Citric Acid Cycle pathway is common to many metabolomic analyses of oxalosis.

Structural remodelling of the nephron occurs within a month of spaceflight exposure

To investigate whether renal remodelling was occurring in spaceflight, we performed Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis across 24 datasets obtained from 2 human and 13 rodent spaceflight missions and 2 rodent GCR simulation experiments. The datasets were epigenomic, transcriptomic, proteomic and phosphoproteomic. GO pathways (Fig.  6a ; Supplementary Data  6 ) that are repeatedly significantly enriched across the datasets are compatible with remodelling events occurring in the kidney, these include regulation of cell adhesion, actin filament organisation, epithelial tube morphogenesis and renal system development pathways.

a A curated list of multi-omic over-representation analysis of GO—biological process ontological terms related to remodelling. b A curated list of multi-omic over-representation analysis of KEGG pathway ontological terms related to remodelling. a , b To integrate datasets from different omics modalities, species, missions and tissues, all biomolecules (e.g. phosphopeptides, proteins, transcripts and methylated DNA) were converted to the human orthologs where necessary and linked back to their HGNC gene symbol, aggregated and collapsed to single genes (e.g. multiple phosphosites, isoforms, CpG sites). An unadjusted, two-tailed -Log 10 ( P -value) of 2 was considered significant for ontological term enrichment. Enrichment ratio; the number of differentially regulated hits in a dataset that belong to a given ontological term, normalised to the total number of statistically significant hits in the respective dataset. c STRING protein-protein interaction network of previously absent inflammation-associated and collagen I-associated ECM proteins that appeared in cosmonauts’ urine ( n  = 10) after 166–199 days of spaceflight exposure.

Enriched KEGG pathways (Fig.  6b ; Supplementary Data  7 likewise include focal adhesion, tight junction, gap junction, sphingolipids, actin and cell cycle pathways, again consistent with remodelling.

Proteomic analysis of urine from the Russian Roscosmos human spaceflight mission (Fig.  6c ) shows extracellular matrix (ECM) and lipid-turnover related proteins that were enriched 7 days after spaceflight compared to baseline. These include Fibronectin ( FN1 ; involved in the organisation of the ECM), Cathepsin B ( CTSB ; maintains turnover of glomerular basement membrane 27 ), Apolipoprotein H ( APOH ; which binds to cell surface phospholipids) and Proactivator Polypeptide ( PSAP ; involved in the lysosomal degradation of sphingolipids). Notable among these are Nidogen-1 ( NID1 ; a key part of the nephron basement membrane) and Podocalyxin ( PODXL ; a major constituent of the glycocalyx of podocytes in the glomerulus) which are two of the most frequently downregulated gene products across kidney datasets in our study (Fig.  5 ; Supplementary Data  3 ).

To determine the extent of any potential structural remodelling, we looked for macroscopic changes in GCR and/or microgravity exposed rodent kidneys. Much like Elger and co-workers 11 , who found an increase in kidney weight of 30% in chronically potassium depleted animals, we found that microgravity (simulated) and microgravity+GCR (real and simulated) exposed animals had significantly greater kidney weights (relative to bodyweight) than control animals (Fig.  7a ).

a Morphometry of kidney mass was assessed by wet weights in 1 G, the weight of both left and right kidneys were averaged, and the kidney weights were normalised against bodyweight (BW) for the same animal and expressed as a percentage. All ground control and sham animals that received no exposure treatment were grouped into control. Animals that only received either full or simplified galactic cosmic radiation (GCR) simulations were grouped into GCR. Animals that only underwent hindlimb unloading microgravity simulation were grouped into microgravity (MG). Animals that underwent a combination of GCR and MG, or were exposed to spaceflight, were grouped into GCR + MG. Data are presented as mean ± SD. One-way ANOVA with pairwise Dunnett’s multiple comparison post-hoc tests (* p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001). N numbers are control = 48, GCR = 30, MG = 28, MG + GCR = 39 biologically independent animals per group. b Representative confocal images showing the annotations of cortex regions (magenta borders) and distal convoluted tubules (DCT, green) in RR-10 spaceflight-exposed mice (28 days) from whole slide images of kidney sections immunolabelled with tNCC/pNCC as DCT markers. 200 µm scale bar. c Morphometric analysis of DCTs assessed the average area per tubule (top Y-axis), the density of no. of tubules per unit area of cortex (middle Y-axis), and the total summed area of all DCTs as percentage of cortex area. Data are mean ± SD. P -value of  0.05 by students t-test was considered significant. N  = 10 biologically independent animals per group. Source data are provided as a Source Data file.

To establish that these changes weren’t merely due to alterations in extracellular fluid content, quantitative and qualitative histomorphometry was performed on mouse kidneys from the RR-10 spaceflight mission. Samples were stained for the canonical distal convoluted tubule marker Na-Cl cotransporter (NCC; encoded by SLC12A3 ), as this segment is known to be the most plastic in the nephron. Our data suggest that RR-10 mice have chronic dephosphorylation of NCC in addition to potentially altered basolateral potassium handling via Kir4.1/5.1 and KCC4, both of which are known to induce distal convoluted tubule remodelling 12 , 28 (Fig.  3a, c ; Supplementary Data  1 ).

Qualitative assessment of 3D images of optically cleared tissues revealed no obvious lesions or anatomical abnormalities (See videos in Supplementary Movie  1 & 2 ). However, quantitative analysis of distal convoluted tubules revealed that spaceflight led to a reduction in tubule density, but that these retained tubules had a larger average size, demonstrating tubular segment remodelling (Fig.  7b, c ).

Multi-omic analyses reveal convergent disease pathways induced by spaceflight

To understand the common processes occurring across the multiple human and rodent, spaceflight and GCR exposed missions, omics data were analysed against DisGeNET, KEGG and GO databases. Significantly enriched kidney-relevant disease ontologies that were reproduced in our diverse cohort of datasets were plotted in Fig.  8 for DisGeNET (Supplementary Fig.  2 ; Supplementary Data  2 ).

A curated list of enriched gene-disease associations are presented for DisGeNET ontological terms relevant to kidney health. These were ranked and represented in descending order using the following rules: 1) No. of mission datasets it replicated in; 2) most significant P -value; 3) greatest enrichment. To integrate datasets from different omics modalities, species, missions and tissues, all biomolecules (e.g. phosphopeptides, proteins, transcripts and methylated DNA) were converted to the human orthologs where necessary and linked back to their HGNC gene symbol, aggregated and collapsed to single genes (e.g. multiple phosphosites, isoforms, CpG sites). An unadjusted, two-tailed Log 10 ( P -value) of 2 was considered significant for ontological term enrichment. Enrichment ratio; the number of differentially regulated hits in a dataset that belong to a given ontological term, normalised to the total number of statistically significant hits in the respective dataset.

Many of the same ontologies are represented in both the spaceflight and simulated GCR experiments. Ontologies that are particularly enriched include amyloidosis, nephrotic syndrome, and membranous glomerulonephritis, reflecting the presence of acute phase and inflammatory gene products in addition to the profibrotic and cell death gene products represented in the chronic kidney disease (CKD) stage 5, renal fibrosis and renal insufficiency ontologies. The heavily enriched peripheral vascular disease and endothelial damage ontologies reflect the known endothelial and microvascular damage marker gene products enriched across the multiple GCR and spaceflight datasets.

Mitochondrial diseases are enriched in the proteomics datasets of kidney tissues (Fig.  8 ) and is further supported by the enrichment of ontologies relating to mitochondrial suborganellular structures, oxidative phosphorylation, oxidative stress, reactive oxygen species, apoptosis, cellular senescence, HIF-1 and TNFα signalling in GO (Supplementary Fig.  4 ; Supplementary Data  6 ) and KEGG (Supplementary Fig.  5 ; Supplementary Data  7 ) over-representation analyses. Mitochondria may also be showing signs of stress-induced fusion (Supplementary Fig.  6 ), although future studies would be needed to specifically address changes in mitochondria morphology.

As a final step we used the Scalable Precision Medicine Open Knowledge Engine (SPOKE) 29 knowledge graph tool which is capable of integrating heterogeneous datasets from various biological levels, assay modalities, tissue types, organisms and experimental conditions to validate our findings (Supplementary Fig.  7 ).

A GCR exposure with a dose-equivalent to a Mars roundtrip induces renal damage and dysfunction

LEO spaceflight mission participants are exposed to comparatively low doses of GCR due to the protection provided by Earth’s magnetic field. Therefore, to disentangle the impacts of GCR from microgravity and evaluate the consequence of unmitigated GCR exposure, we examined tissues that had only been exposed to simulated GCR. To do this we utilised NASA’s ground-based GCR simulator at Brookhaven National Laboratory, where animals either had an acute exposure to a ~ 1.5-year dose-equivalent (0.5 Gy) in the simplified 6-beam/5-ion GCR simulator followed by rapid 24 h sacrifice (BNL experiments) or were given an acute exposure to a ~ 2.5-year dose-equivalent (0.75 Gy) in the full 33-beam/7-ion GCR simulator with sacrifice at 6 months post-exposure (NSRL-22A experiment).

Pathogenic serum miRNA species have been previously implicated to mediate tissue damage in spaceflight 30 , and GCR is a plausible pathogenic factor. Weighted correlation network analysis (WGCNA) of plasma miRNAs revealed three clusters that generally trended downward in BNL-1 (Supplementary Fig.  8 ). However, investigation of miRNA predicted mRNA targets and DisGeNET analysis of these targets suggested that these circulating miRNAs would be minor players in the context of renal damage in the acute setting (Supplementary Data  8 ).

Retaining biomolecular information within the gross and micro-anatomical context is important, especially when highly heterogenous tissues like the kidney (Fig.  9a ). So, we next performed in situ hybridisation (RNAScope) and quantitative whole slide imaging to ascertain the presence and density of these pathogenic miRNAs in kidney tissues of BNL-3 mice. miR-125b was significantly increased in the inner stripe of the outer medulla (ISOM) (Fig.  9b ), particularly in the vascular compartment (arrows) which corresponds to the thick ascending limb of the loop of Henle, the thin descending limb of the loop and the medullary collecting duct. miR-16 has a similar pattern of distribution and differential expression but fails to reach significance (Supplementary Fig.  9 ) . These miRNA species are implicated in vascular damage and the ISOM is also the site of the vascular bundle 31 , a complex structure which is the bottleneck of all blood flow to and from the inner medulla. Additionally, mRNA target prediction, KEGG and DisGeNET analysis of miR-125b and miR-16 suggest that these may mediate cell senescence, apoptosis, TGFβ signalling and oncogenesis (Supplementary Fig.  9 ).

a Schematic representation of an axial cross section of mouse kidney hemisected at through the hilum as shown. Annotations of gross anatomical regions of the kidney used for spatial RNA expression analyses. b Representative images of miR-125b staining (small red dots) in the outer medulla of haematoxylin-stained kidney sections from BNL-3 simGCRsim-exposed mice (~ 1.5-year-dose equivalent) harvested ~ 24 h post-exposure. White arrows indicate concentrations of miR-125b staining around capillaries in the interstitium; 50 µm scale bar. Data are mean ± SD. A P -value of < 0.05 by students t -test was considered significant. Average; the simple arithmetic mean of the four anatomical regions, n  = 6 biologically independent animals per group c Gross anatomical and microanatomy features annotated on exemplar slide-seq pucks of BNL-1 simGCRsim-exposed mice (~ 1.5-year-dose equivalent) harvested ~ 24 h post-exposure. Samples for pucks were taken to maximise the anatomical coverage from the approximate regions shown in the green (autofluorescence) axial section of mouse kidney. Beads are assigned identities according to their highest probable cell type classification. For scale, each dot represents a 10 µm bead. d The table shows the differentially regulated mRNA transcripts from c, captured by different cell typed beads after exposure to GCR. An adjusted P -value of < 0.05 by students t -test was considered significant. Abbreviations: OSOM outer stripe of outer medulla. ISOM inner stripe of outer medulla. IM Inner medulla. DCT distal convoluted tubule. Early PT or PTS1 early proximal tubule S1. Endo; endothelial cell. IC; intercalated cell. CTAL/MTAL or LOH; (cortical or medullary) thick ascending limb of the loop of Henle. Macro; macrophage. Neutro neutrophil. NP nephron progenitor cell. PC principal cell. PCT or PTS1/2 proximal convoluted tubule S1 + S2; Podo podocyte. PST or PTS3 proximal straight tubule S3. G glomerulus. DTL descending thin limb of the loop of Henle. ATL ascending thin limb of the loop of Henle. MD macula densa. CNT connecting tubule. CCD cortical collecting duct. OMCD outer medullary collecting duct. IMCD inner medullary collecting duct. Endo endothelial cell. IC intercalated cell. Macro macrophage. Neutro neutrophil. NP nephron progenitor cel.; Podo podocyte. The schematic map of a whole kidney’s cross section and the visualisation by actin filament fluorescent were published in The FEBS Journal 287 (2020) 1176–1194 [doi:10.1111/febs.15088] © 2019 Kumaran et al. and is licensed under CC BY 4.0. Source data are provided as a Source Data file.

To further understand the effect of simulated GCR on the segment-specific cell types of the kidney’s nephron (Fig.  9a ), we performed 2D spatial transcriptomics (Slide-seq 32 ) on BNL-1 GCR-exposed renal tissue. Cell types were inferred using a published renal cell atlas 33 , which were mapped onto individual data points which accurately reproduced anatomy (Fig.  9c ). Individual significant transcriptional changes in specific cell types were then examined and top hits were analysed by KEGG and DisGeNET (Fig.  9d ; Supplementary Data  10 ). Interestingly, immunoglobulin components were among the hits overexpressed by loop of Henle cells, presumably reflecting increased B-cell activity in the interstitium as supported by enrichment of the KEGG pathway for “leukocyte transendothelial migration” (Supplementary Data  10 ). SGK1 transcriptional activity was decreased in proximal convoluted and straight tubule cells (Fig.  9d ). SGK1 is a master regulator of multiple epithelial membrane transporters, including canonical segment specific transporters. The data also support disruption of circadian rhythm in several tubule segments via Cytochrome-1 and Nuclear Receptor Subfamily 1 Group D Member 1 (also known as Rev-Erbɑ; encoded by NR1D1 ) 34 (Fig.  9d ), and hits on KEGG and DisGeNET (Supplementary Data  10 ). When it comes to damage markers, again the proximal straight tubule and thick ascending limb of the loop of Henle appear to be the most impacted, with decrease in ALAS1 , and increases in ANGPT2 and KRT18 all prognostically poor for renal outcomes 35 , 36 , 37 (Fig.  9d ).

From a radiobiological perspective, the kidney is considered a late-responding tissue, and studies spanning at least 1-2 years may be required to appreciate the full impact of chronic GCR exposure on kidney health 38 . Although, some features of radiation-induced nephropathy and sub-clinical manifestations can emerge in < 6 months post-irradiation. To investigate this, serial tissue sections from NSRL-22A mice were histochemically stained for routine examination of potential kidney damage (haematoxylin and eosin, Masson’s trichrome stain, Martius Scarlet Blue) were examined by a blinded expert histopathologist (Fig.  10a ).

a Representative images of haematoxylin and eosin (H&E), Masson’s trichrome, Martius scarlet blue (MSB), Periodic acid–Schiff (PAS), Picrosirius red, and Von Kossa stained kidney sections from NSRL22A GCRsim-exposed mice (~ 2.5-year dose-equivalent) harvested ~ 6 months post-exposure. Arrows indicate microthrombi in the glomerular capillary tufts visible in H&E, Masson, MSB and PAS stains. Scale bar: 50 µm (left panel) and 100 µm (right). b Urine (Protein:Cr, Glucose:Cr, Magnesium:Cr, FE Na , FE Ca , FE Mg (Corr), FE PO4 ) and plasma (sodium, chloride) physiological measurements from NSRL22A GCRsim-exposed mice ( ~ 2.5-year dose-equivalent) harvested ~ 6 months post-exposure that were normalised to sham controls for illustrative purposes. Boxed P-values report the two-way ANOVA treatment group factor result. Data are mean ± SD. A P -value of < 0.05 was considered significant. Cr Creatinine, FE Fraction Excretion, Corr corrected for albumin, Ca calcium, Na sodium, Mg magnesium, P O4 phosphate, N  = 12 biologically independent animals per sex per group. ‘Source data are provided as a Source Data file.

No histological evidence of differences in interstitial fibrosis or tissue calcifications were observed between Sham and GCR exposed tissues stained with PAS, Picrosirius Red and Von Kossa (Fig.  10a ). To confirm this, we quantitated the fractional interstitial area in the PAS stains which showed no difference between groups (mean 6.10% ± 2.10 vs 6.16% ± 2.27. p  = 0.9623). As previously reported, first signs of fibrosis or calcifications may not present until after 6 months 38 , and therefore NSRL-22A may be too short a period to observe these disease features, despite significant enrichment of fibrosis-related DisGeNET ontologies in the kidney proteomics from the same animals (Supplementary Fig.  2 ; Supplementary Data  2 ). However, consistent with radiation-induced nephropathy, overt thrombotic microangiopathy was detected in GCR exposed tissues from 27% (3/11) female animals, and 0% (0/12) male animals. None was seen in tissue from sham exposed animals (Fig.  10a ).

Given the biomolecular and histopathological signs of renal injury, we then looked for functional evidence of glomerular, proximal tubular and distal tubular dysfunction. Urinary and plasma biochemical analyses (Fig.  10b ; Supplementary Fig.  10 ) showed significantly greater urinary protein excretion in GCR vs sham animals, consistent with a glomerular lesion or proximal tubule dysfunction, the latter supported by the reduction in the endocytic receptor megalin ( LRP2 ) which normally reabsorbs proteins that escape into the ultrafiltrate (Fig.  5 ). There was a slight increase in urinary glucose, which is a highly specific, but not very sensitive marker of proximal tubular dysfunction in non-diabetic animals. While this did not reach significance ( p  = 0.1198), there was significant downregulation of sodium-glucose linked transporter, SGLT1 ( SLC5A1 ) (Fig.  5 ), that would be consistent with proximal tubule dysfunction. Finally, there was significantly greater magnesiuria in GCR exposed animals, consistent with downregulated magnesium reabsorption in the loop of Henle or the distal convoluted tubule.

We have presented a large volume of data encompassing both human and rodent data, extant and novel multi-omics datasets, historical and extant clinical chemistry and novel imaging data from 16 spaceflight missions and 4 GCR exposures to examine the effect of spaceflight on kidney function.

Tubular remodelling, by which we mean structural and functional adaptation of the tubular nephron to environmental stimuli, is a well described yet underappreciated phenomenon. Tubular remodelling occurs not only in response to genetic modification of signal pathways 39 , but also chronic diuretic exposure 40 , kidney injury 41 , and both chronic 11 and acute 42 hypokalaemia. These changes occur rapidly, within 3 days of diet induced hypokalaemia 12 .

Our data robustly and orthogonally supports tubular remodelling occurring in microgravity with and without GCR. This is highly likely to have functional consequences, as tubular remodelling does in other scenarios 39 .

Renal remodelling in microgravity (possibly related to the cephalad fluid shift) may therefore be a primary event that causes subsequent dysregulation of serum and urine electrolyte homeostasis. This is supported by the prompt return to baseline of humans on return to terrestrial gravity.

Changes in urinary biochemistry are known to be critical in the pathogenesis of kidney stone formation; a condition that occurs disproportionally commonly in astronauts, and that is potentially mission critical.

The increased risk for nephrolithiasis in space has been historically attributed to the negative impact of microgravity on bone mineral density that leads to increased resorption of bone, release of calcium salts in the bloodstream, increased renal load and therefore increased urinary excretion of calcium and phosphate 6 , 8 . Our historical data (from 66 astronauts) confirms hypercalciuria, and the phosphoproteomic data shows decreased phosphorylation of NKCC2 ( SLC12A1 ), which will cause decreased paracellular reabsorption of divalent cations in the loop of Henle, and thus renal calcium and magnesium wasting. Hypocitraturia was not observed; this is in line with previous observations by Pietryzk et al. of an approximate rate of 14% of hypocitraturia during spaceflight 6 , and Whitson et al. who found no significant hypocitraturia 8 .

Hyperoxaluria also occurs during spaceflight. Oxalate is freely filtered by the glomerulus and almost entirely excreted in the urine. Increased urinary oxalate reflects increased plasma oxalate load that could come from either increased endogenous liver production or increased absorption by the gut. The latter could be caused by several conditions such as increased dietary oxalate, malabsorptive conditions or altered microbiome. Dietary data were not available, and we assumed an absence of malabsorptive conditions. However, we do know that spaceflight affects the gut microbiome 43 . Metagenomic analysis of the microbiome showed that in the highest quality faecal microbiome dataset (namely RR-23) Oxalobacter sp., the bacterium primarily responsible for oxalate metabolism 44 , increases during spaceflight. Bacteroides, a bacterium that was found to be increased in stone formers 45 , and Bifidobacterium, a pro-biotic able to metabolise oxalate in the gut 46 , were enriched and depleted in spaceflight respectively. It is difficult, based on low replicability of data to ascribe a primary, or even secondary microbiome-related aetiology for increased stone formation in spaceflight.

Proposed interventions to prevent potential mission critical kidney stone formation in spaceflight include increasing urine output by maximising oral fluid intake 47 , oral potassium citrate 48 (or potassium magnesium citrate 49 ) supplementation and inflight management, including ureteral stenting 50 and lithotripsy 51 . While these are sensible and may indeed be effective, none deal with the hypercalciuria that has been consistently shown in human space travellers. Oral or parenteral bisphosphonates have been used with some success 52 . Further, thiazide diuretics reduce urinary calcium excretion 53 (possibly by ECV contraction causing increased proximal tubular calcium reabsorption 54 ) and reduce age related bone mineral density loss 55 , and could represent a “two birds with one stone” therapeutic option.

Could the dephosphorylation of NKCC2 guide us toward a therapeutic target to reduce spaceflight induced hypercalciuria? NKCC2 activity is modulated by the calcium sensing receptor (CaSR) via phosphorylation 56 , and calcilytics (CaSR antagonists), well tolerated but disappointing agents in their utility for treating terrestrial osteoporosis 57 , might be one potential avenue to manipulate NKCC2 activity to ameliorate spaceflight induced hypercalciuria.

Abnormal water homeostasis has been noted in astronauts since the early days of spaceflight, with a marked reduction in both diuresis and natriuresis with vasopressin dysregulation via unknown mechanisms 1 , 2 , 3 . In fact, the reduced NKCC2 activity would conversely be anticipated to enhance diuresis, much like a loop diuretic. In this context, downregulation of prostaglandin transporters (PGT; encoded by SLCO2A1 ), a result seen in multiple of our proteomic and transcriptomic datasets (Fig.  5 ), is intriguing and may offer a way to reconcile this paradox. As carriers of a gain-of-function mutation of SLCO2A1 58 , see a reduction in PGT activity in the proximal straight tubule and the cortical collecting duct which colocalises with Aquaporin-2 ( AQP2 ). Loss of PGT-mediated reabsorption by collecting duct principal cells, causes a subsequent build-up in the luminal concentration of the prostaglandin PGE 2 , which stimulates apical prostaglandin E 2 receptor 4 (EP 4 ) receptors to activate Aquaporin-2 and inappropriate water reabsorption. In our study the loss of NKCC2 activity through dephosphorylation and reduction of PGT abundance can offset each other.

Tubular remodelling in spaceflight raises another, interesting question; is the hypercalciuria seen in spaceflight a consequence or cause of spaceflight related loss of bone mineral density (BMD)? We know that primary renal phenomena associated with tubular remodelling (e.g. genetic inactivation of SLC12A1 in Bartter syndrome 59 or chronic furosemide exposure 60 ) can cause a loss of BMD as a consequence of the primary hypercalciuria. This implies that renally targeted therapies (e.g. thiazides, calcilytics) will be effective. There does appear to be a synergistic effect of microgravity and GCR on BMD loss; GCR does have primary bone effects, increasing osteoclastogenesis and bone loss in rodents 16 , so bone targeted countermeasures will still be relevant.

The kidney is a key microvascular end-organ and microvascular disease appears to be one of the main consequences of GCR exposure 30 . We concur with this view: vascular disease and endothelial dysfunction disease ontologies were highly enriched across omics datasets (Fig.  8 ). Consistent with this, the arginine biosynthesis pathway was highly enriched across our human and mouse datasets (Fig.  4c ), there was a significantly increased amount of pathogenic miR-125b in the highly vascular ISOM (Fig.  9b ) and as a likely consequence of this microvascular pathology, we observed incidences of thrombotic microangiopathy on histopathological examination (Fig.  10a ).

In addition to this, pathophysiological macrovascular changes are a well-documented consequence of microgravity, with 6 months in space shown to induce ~ 20 years of vascular ageing through arterial stiffening 61 . The resultant loss of vascular elasticity, and thus buffering capacity, leads to elevated transmission of blood flow and pressure pulsatility to the microvasculature. Long-term, this can cause barotrauma or oxidative stress to renal microvasculature due to suboptimal perfusion, especially as the myogenic response of the afferent arteriole is to vasoconstrict and provide resistance (and thus reduce flow) in the face of excessive pulsatile pressure 62 . Indeed arterial stiffness and CKD are strongly associated, and it is thought that one begets the other in a positive feedback loop 63 . Taken together with the general drop in blood pressure experienced by astronauts 64 , exposure to spaceflight long-term places the kidney in an impossible position whereby it must choose whether to defend renal perfusion or the health of its microvasculature. If the arterioles dilate to enhance blood flow, they leave the microvasculature open to damage from unbuffered pressure waves on top of the radiation damage caused by GCR. Whereas if they constrict to provide protection to the microvasculature, they reduce blood flow and therefore oxygen supply to the renal tubules, which further compounds and exacerbates the chronic oxidative stress and mitochondrial dysfunction from GCR bombardment.

This study is the largest to ever look at the effect of spaceflight on kidney function. We have demonstrated that there is renal structural and functional remodelling likely caused by microgravity, probably synergistically with GCR. We have shown that this remodelling is a potential driver of kidney stone formation and many of the changes in the urinary biochemistry of humans and animals experienced by those exposed to LEO spaceflight. We have also shown that acute exposure to simulated GCR causes both acute and chronic tubular epithelial and vascular damage that appears both progressive and irreversible.

However, our study has several limitations. We have necessarily relied on human (mostly male) and animal (mostly female) data from missions which were exposed to microgravity for relatively short periods of time compared to the projected length of a Mars mission, and only in LEO, which also limited the amount of GCR and other space radiation that they were exposed to. Additionally, our simulated GCR experiments only looked at acute unfractionated dosing, which may not accurately model the chronic cumulative exposure that would happen on a Mars mission.

Therefore, in the absence of experiments that can more accurately model the long-term simultaneous exposure to full GCR and microgravity over several years, and the plausible synergistic impact of these insults, our results should be taken a conservative glimpse into the potential dire health consequences of long-term deep space travel. Much more intensive study of the health impacts of spaceflight on the kidneys and other visceral organs that have received little attention is of the utmost importance if we are to develop mitigation strategies and send humans to other planets and beyond.

Human studies ethical approval

All crews from the Inspiration4, NASA, JAXA spaceflights provided informed written consent prior to their participation.

Inspiration4 subjects were consented at an informed consent briefing (ICB) at SpaceX (Hawthorne, CA), and samples were collected and processed under the approval of the Institutional Review Board (IRB) at Weill Cornell Medicine, under Protocol 21-05023569. All crew members have consented for data and sample sharing. Tissue samples were provided by SpaceX Inspiration4 crew members after consent for research use of the biopsies, swabs, and biological materials.

The procedure followed guidelines set by the Health Insurance Portability and Accountability Act (HIPAA) and operated under Institutional Review Board (IRB) approved protocols. Experiments were conducted in accordance with local regulations and with the approval of the IRB at Weill Cornell Medicine (IRB #21-05023569). NASA IRB (CSA defers to NASA’s IRB), ESA IRB, JAXA IRB for their respective crewmembers from Biochemical Profile (NASA IRB Pro0797) and Nutritional Status Assessment: SMO 016E (pro0326) projects. All crews provided informed written consent prior to participation.

The JAXA human spaceflight study was proposed to and supported by the 2014 International Life Sciences Research Announcements, JAXA, and NASA. Ethics committee approvals were obtained at the University of Tsukuba (No. 251, Nov. 27, 2015), JAXA (JX-IRBA-20-071, Aug. 30, 2016), NASA (Pro1995, Feb. 28, 2017), ESA (2017_04_09, Apr. 20, 2017). Informed consent was obtained by the personal information manager of the study, and de-identified samples were made available to researchers who performed sample processing and data analysis.

Cosmonaut data were obtained from previously published data [ https://link.springer.com/article/10.1007/s10517-013-2310-2 ].

Animal Studies ethical approval

For all animal data coming from NASA Genelab Open Science Data Repository (see detailed citations for all missions in the supplementary methods section) the ethical oversight information and protocol number can be found in the Protocol section (e.g. https://osdr.nasa.gov/bio/repo/data/studies/OSD-102 ).

For BNL-1/2/3—Brookhaven National Laboratory IACUC Protocol 506 “miRNA Signature Detection and Countermeasures Against HZE Radiation Exposure for Tissue Degeneration”.

For NSRL-22A—All care and procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at BNL and CHOP and were in accordance with the AAALAC and National Institute of Health (NIH) guidelines for the care and use of laboratory animals.

For RR-10- NASA John F. Kennedy Space Center Institutional Animal Care and Use Committee (IACUC) Research Protocol Review IACUC Protocol #: FLT-20-133 “The Role of CDKN1a/p21Pathway in Microgravity-Induced Bone Tissue Regenerative Arrest—A Spaceflight Study of Transgenic CDKN1a/p21-Null Mice in Microgravity (SpaceX-21)”

Sex differences

For the human studies: NASA historical data is pooled and anonymised for ethical reasons.

Cosmonaut and JAXA data is all male. SpaceX data involves both sexes, but this cannot be disaggregated for ethical reasons of anonymity.

For the animal studies: The findings apply mostly female animals (roughly two thirds of animal missions were female). As we were collecting data from previously conducted experiments, we did not have the ability to alter this sex disparity. Only one study had both males and females, which enabled us to perform sex difference analyses for parameters such as blood and urine electrolytes.

Sample sizes

Due to the nature of our study we used samples from animals that had been in spaceflight (usually as part of the ‘Rodent Research’ missions to the International Space Station) or had been taken from costly experiments using the Galactic Cosmic Radiation Simulator at Brookhaven national laboratories. We also used samples and/or data from humans who had undergone spaceflight (in historical NASA missions, Roscosmos missions, and JAXA missions to the ISS or modern commercial missions with SpaceX such as inspiration4). Our sample numbers were therefore limited to the number of samples made available to us in the original experimental designs or mission parameter limitations (restricted by practical considerations of weight to launch, available space and resource consumption). In all cases, we endeavoured to use the maximum number of biological replicates available to us to maximise experimental power.

Statistics and reproducibility

Omics studies.

This study encompassed 2 epigenomic (Whole-genome bisulfite sequencing), 9 transcriptomic (8 Bulk RNA sequencing, 1 Bulk small RNA sequencing), 7 proteomic (3 Quantitative fractionated TMT-labelled DDA LC-MS/MS, 2 Quantitative label-free SEER DIA LC-MS/MS, 1 Plasma Slow Off-Rate Modified Aptamers, 1 Shotgun LC-MS/MS), 1 epiproteomic (Quantitative fractionated TMT-labelled DDA LC-MS/MS of phospho-enriched peptides), 3 metabolomic (Quantitative label-free UHPLC-MS/MS) and 6 metagenomic (4 Whole metagenome shotgun sequencing, 2 16S rRNA gene amplicon sequencing) studies on both humans and animals. Full details of the experimental, processing and analytical methodologies and locations of publicly available raw data are given in the supplementary methods.

Sample collection and processing

Urine collection was performed in awake mice to obtain spontaneous and uncontaminated samples. Mice were gently handled over a sheet of Saran® wrap or Parafilm® to facilitate micturition. Upon collection, each urine sample was carefully divided into two aliquots. One aliquot was immediately acidified with HNO3 to achieve a final concentration of 1% v/v, preventing precipitation of electrolytes and maintaining sample integrity. Both aliquots were then promptly stored at − 80 °C to preserve their biochemical constituents until further analysis. For blood collection, mice were subjected to terminal anaesthesia to minimise distress and ensure compliance with ethical guidelines. Blood samples were drawn from the vena cava using a fine needle and syringe. Plasma was separated by transferring the blood into Microvette® CB 300 LH (Sarstedt) tubes and centrifuging at 2000  g for 5 min. The resulting plasma supernatant was carefully aspirated and stored at − 80 °C for future analysis. Both plasma and non-acidified urine samples were analysed for creatinine levels by employing either the standard Jaffe reaction or the enzymatic method, depending on the investigator’s preference and laboratory resources. Electrolyte levels, biochemistries and biomarkers were assessed using the Siemens Dimension RxL Max Integrated Chemistry System, at the Core Biochemical Assay Laboratory at Addenbrooke’s Hospital, Cambridge, UK.

Inspiration4

Plasma samples collected from astronauts at timepoints L-92d, L-44d and L-3d were grouped and averaged into “pre-flight” for comparison against individual post-flight timepoints R + 1d, R + 45d, R + 82d and R + 194d. These samples were analysed by Quest Diagnostics using the Comprehensive metabolic panel [CMP; CPT code 80053].

A historical collection of archived astronaut frozen plasma and urine aliquots were collected and stored at − 80 °C over many years. Clinical chemistries, endocrine profiles and biomarkers were obtained at the Nutritional Biochemistry Laboratory at NASA Johnson Space Center. Timepoints L-180d and L-45d were grouped and averaged as “pre-flight” for comparison to individual timepoints L + 15d, L + 30d, L + 60d, L + 120d, L + 180d, R + 0d and R + 30d.

Functional calculations

Functional calculations used in the data analysis are fully detailed in the supplementary methods.

Sample fixation and processing

Mouse kidney samples were harvested and fixed through immersion in freshly prepared 4% (w/v) formaldehyde-PBS solution (pH 6.9) for 16 h at 37 °C. Subsequently, the samples were washed three times with PBS with 0.02% Na-Azide and stored at 4 °C until they were embedded in paraffin.

Histopathology and Brightfield WSI

2-3 µm FFPE sections from NSRL-22A kidneys were prepared, deparaffinised using Histoclear (National Diagnostics), and rehydrated through a series of graded methanol steps. These were then stained for either Haematoxylin and Eosin (#ab245880, Abcam) or Masson’s Trichrome (#ab150686, Abcam) according to the manufacturers guidelines.

Sections underwent brightfield whole slide imaging with 20X objective tiled and stitched focus stacks taken for each section on a Zeiss Axio Scan.Z1 slide scanner. The resultant images were viewed in QuPath (v0.4.3) and semi-quantitatively scored for any histopathological findings.

Immunostaining and confocal WSI

5 µm FFPE sections from RR-10 kidneys were prepared, deparaffinised using Histoclear (National Diagnostics), and rehydrated through a series of graded methanol steps. Antigen retrieval was performed using [1X] R-Universal buffer (AP0530) in a 2100 antigen retriever for a single heat-pressure cycle (Aptum Biologics). Sections were then permeabilized with 0.05% (v/v) Triton X-100-PBS solution for 20 minutes and incubated with Section Block ‘ready-to-use’ (AP0471; Aptum Biologics) for 30 mins at RT. Primary antibodies were incubated overnight at 4 °C for 16 hours at specified concentrations (see supplementary methods), diluted in Antibody Diluent ‘FF/PE Sections’ (AP0472; Aptum Biologics). For phospho-specific antibodies, 10 μg/ml of the non-phospho peptide used to raise the antibody was added per 2 μg/ml of the antibody used. Negative control samples omitted the primary antibody and were processed simultaneously. Following incubation, slides were washed by dipping slides 50x times in 0.05% (v/v) Triton X-100-PBS for 3 rounds, and incubated with secondary antibodies for 1 hour at RT. Pre-absorbed fluorochrome conjugated secondary antibodies were utilised at specified concentrations (concentrations (see supplementary methods), diluted in Antibody Diluent ‘FF/PE Sections’ (AP0472; Aptum Biologics). After washing, slides were mounted using Prolong Gold antifade (#P36930, Life Technologies), permitted to cure for 48-72hrs, sealed with CoverGrip Coverslip Sealant (#23005; Biotium) and protected from light exposure.

Immunofluorescent images were captured using either a Zeiss LSM700 LED laser-scanning confocal microscope or Leica SP8 white-light laser-scanning confocal microscope using 488-nm, 555-nm and 639-nm laser lines, employing a 10X/0.3NA (Zeiss) or 10X/0.5NA (Leica) objective. Zeiss acquisition parameters included single field of view, 8-bit resolution, 1844 x 1844 pixels, 1x digital zoom, 3.85µs pixel dwell time, 4-line Kalman filtering, sequential (by line) channel imaging, and a 4-slice z-stack with a 6 µm thickness to account for chromatic aberration.

Leica acquisition parameters included tile scanning with a 10% overlap, 8-bit resolution, 1024 × 1024 pixels, 0.75x digital zoom, 600 Hz scan speed, 6-line Kalman filtering, sequential (by line) channel imaging, and a 3-slice z-stack with a 5 µm thickness to account for chromatic aberration.

Images were processed using FIJI image analysis software (v.1.53p). Fluorescent z-stacks underwent background subtraction (200 px radius rolling ball) and maximum intensity z-projection. Brightness and contrast adjustments were made using linear histogram stretching to enhance visibility.

miRNA in situ hybridisation and brightfield WSI

FFPE blocks for BNL-3 kidneys were trimmed to remove tissue exposed to air, and fresh 5 µm sections were taken. These were not baked onto the slide and stored with desiccant instead. Samples were then processed using the miRNAscope™ HD RED assay (#324531 and #324500, ACD-Biotechne) with the FFPE tissue section workflow according to the manufacturers guidelines. miRNAscope™ Probes against the following were used: mmu-miR-125b-5p (#1082311-S1), mmu-let-7a-5p (#727761-S1) and mmu-miR-16-5p (729031-S1).

Sections underwent brightfield whole slide imaging with 20X objective tiled and stitched focus stacks (with extended depth of focus) taken for each section on a Zeiss Axio Scan.Z1 slide scanner. Using QuPath (v0.4.3) the cortex, outer stripe of the outer medulla, inner stripe of the outer medulla and inner medulla were manually annotated with the aid of a Wacom cintiq pro 32 to create a segmentation mask of the anatomical regions for area calculation. Ilastik (v1.4.0) 65 automated (supervised) pixel-level classification was then trained to identify positive miRNAscope probe staining. A custom in-house python script was then used to count all positive staining and calculate the area of all anatomical regions, so that the density of each miRNA per unit area of each region could be determined for each kidney section.

Optical clearing and 3D imaging

Tissue transformation, delipidation and refractive index matching

Quartered formaldehyde-fixed kidneys from RR-10 mice were tissue transformed using the SHIELD protocol 66 and reagents from Lifecanvas technologies (MA, USA) based on (10.1038/nbt.4281). SHIELD-transformed kidneys were delipidated (Lifecanvas Technologies; Full Passive Pipeline Protocol v4.06) for approximately 10–14 days at 37 °C in 40 mL of passive delipidation buffer with gentle agitation in EasyClear device. Following delipidation, tissues were washed in several rounds of PBS at 37˚C overnight to remove any delipidation buffer. Before imaging tissues were immersed in Incubated in EasyIndex RI 1.53 refractive index matching solution as per protocol. Tissues were then embedded in 2% w/v ultra-low melting point agarose (Sigma A5030) blocks made up with EasyIndex solution to immobilise the samples. These were then stored in EasyIndex in airtight containers shielded from light prior to imaging.

MesoSPIM imaging

Samples were mounted in quartz cuvettes and immersion oil with refractive indices matching that of EasyIndex, and then suspended and aligned for light-sheet fluorescence imaging with a MesoSPIM 67 . Images were captured at 16-bit for 1-channel dual laser lightsheet illumination (488 nm excitations) to obtain autofluorescence emissions at 2048 x 2048 pixels in the XY, with a Z depth range of 700-1200 pixels, giving a pixel resolution of 3.26 μm (XY) and 4.0 μm (Z).

Image analysis

To evaluate any qualitative changes in gross morphology images were imported into Syglass 68 (v.1.7.2-79; https://www.syglass.io/ ; RRID: SCR_017961) for visual investigation by nephrologists and histopathologists in 3D virtual space using Meta Quest 2 VR headsets. Images were also imported into Imaris 69 (v10.0) for visualisation on a Wacom cintiq pro 32” 4 K touchscreen monitor. 3D video renders were later generated with Syglass (v.2.0.0) and Z-slice video created with FIJI (ImageJ; v.1.54 h).

Morphometry

Normalised kidney weights.

PI and NASA GeneLab records for all animals included in the study were examined for bodyweight and kidney wet weight measurements. Only BNL-1, BNL-2, BNL-3 and RR-23 missions had complete kidney and body weight information available. Where available, the weights of both left and right kidneys were averaged, and the kidney weights were normalised against bodyweight for the same animal and expressed as a percentage. All ground control and sham animals that received no exposure treatment were grouped into control for pairwise comparisons against GCR (animals that only received either full or simplified galactic cosmic radiation simulations) or MG (animals that only underwent hindlimb unloading microgravity simulation) or GCR + MG (animals that underwent a combination of GCR and MG or were exposed to spaceflight).

Histomorphometry

Whole slide images of tiled immunofluorescent confocal images taken from RR-10 were used for analysis. Using QuPath (v0.4.3) the cortex was manually annotated with the aid of a Wacom cintiq pro 32 to create a segmentation mask of the anatomical region for area calculation. Similarly distal convoluted tubules (DCT) labelled with antibodies against total NCC / phospho-NCC (see supplementary methods for details), the canonical DCT marker, were annotated. Initially, only a handful of tubules were annotated from each slide, and these were then used to train Ilastik (v1.4.0) 65 for automated (supervised) pixel-level classification of DCTs. These were then further manually refined to remove/include any false-positive/negatives. A custom in-house python script was then used to compute the number of discrete tubules positive for DCT markers, the corresponding area of each of these as well as the total cortex area, such that average tubule area and DCT density per area of cortex could be determined for each kidney section.

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

Figure  1 a, b Aggregated from NASA OSDR Fig.  2 . a, b and Supplementary Fig.  1 A, B. The data included in these figures are available under restricted access and deidentified in order to preserve participants anonymity, access can be obtained by contacting Scott Smith ([email protected]). Figure  3a, b, c ; Fig.  7b, c ; Supplementary Fig.  6 ; Supplementary Data  1 ,Supplementary Movie  1 , 2 ) underlying data from NASA OSDR : OSD-462 ( https://doi.org/10.26030/8g1a-3041 ) Fig.  4a ; Fig.  5 ; Fig.  6a, b ; Fig.  8 ; Supplementary Figs.  2 , 4 , 5 , 7 ; Supplementary Data  2 , 3 , 6 , 7 ) underlying datasets from NASA OSDR : OSD-102 ( https://doi.org/10.26030/yn9m-2d19 ), 163 ( https://doi.org/10.26030/q8vt-7p92 ), 253 ( https://doi.org/10.26030/4mx6-5x80 ), 336 ( https://doi.org/10.26030/qasa-rr29 ), 342 ( https://doi.org/10.26030/v2ak-0y21 ), 462 ( https://doi.org/10.26030/8g1a-3041 ), 513 ( https://doi.org/10.26030/pprb-6227 ), 457 ( https://doi.org/10.26030/yyce-8y73 ), 530 ( https://doi.org/10.26030/r2xr-h714 ), 532 ( https://doi.org/10.26030/j15f-vj38 ), 571 ( https://doi.org/10.26030/h3p5-tc29 ), 708 ( https://doi.org/10.26030/r4pv-hw21 ), 709 ( https://doi.org/10.26030/fhs1-z519 ) Fig.  4b ; Supplementary Fig.  3 , 7 ; Supplementary data  4 ) underlying datasets from NASA OSDR : OSD-72 ( https://doi.org/10.26030/qyw7-qn34 ), 212 ( https://doi.org/10.26030/8vac-wb94 ), 249 ( https://doi.org/10.26030/h713-bd02 ), 250 ( https://doi.org/10.26030/rj1y-dq03 ), 465 ( https://doi.org/10.26030/vqhs-qq63 ), 466 ( https://doi.org/10.26030/6axn-0058 ). Figure  4c ; Supplementary Fig.  7 ; Supplementary Data  5 ) Rat data at request of CNSA authors ( https://doi.org/10.3389/fphys.2020.00939 ), MHU-3 data at request from authors ( https://ibsls.megabank.tohoku.ac.jp/metabolite-list ) 70 , 71 , NASA OSDR : OSD-571 ( https://doi.org/10.26030/h3p5-tc29 ) Fig.  6c ) data available from Peptide Atlas ( https://peptideatlas.org/ ). Dataset identifier: PASS00239 Fig.  7a ) kidney and bodyweight data are available on request to [email protected] for BNL-11213 mice and to [email protected] and NASA OSDR : OSD-513 ( https://doi.org/10.26030/pprb-6227 ), 462 ( https://doi.org/10.26030/8g1a-3041 ), 710 ( https://doi.org/10.26030/r1hh-ev67 ), 712 ( https://doi.org/10.26030/f6b9-4093 ), 709 ( https://doi.org/10.26030/fhs1-z519 ) Fig.  9b ; Supplementary Fig.  9 ) underlying datasets from NASA OSDR : OSD-710 ( https://doi.org/10.26030/r1hh-ev67 ) Fig.  9d ; Fig.  10A ; Supplementary Data  10 ) underlying datasets from NASA OSDR : OSD-708 ( https://doi.org/10.26030/r4pv-hw21 ) Fig.  10b ) underlying datasets from NASA OSDR : OSD- 706 ( https://doi.org/10.26030/rrwe-h429 ), 707 ( https://doi.org/10.26030/bcnk-5z50 ) Supplementary Fig.  1C ) underlying datasets from NASA OSDR : O5D-575 ( https://doi.org/10.26030/mc5d-p710 ) Supplementary Fig.  7 Comprises all of the other data sets listed here. Supplementary Fig.  8 ; Supplementary Data  8 , 9 ) underlying datasets from NASA OSDR : OSD-336 ( https://doi.org/10.26030/qasa-rr29 ) For further information see Supplementary Information.  Source data are provided with this paper.

Code availability

Scripts used for the analysis in this manuscript can be found at the following GitHub sites: https://github.com/nestlerk/Kidney_Spaceflight , https://github.com/luslab/spatial-space-kidney and at https://github.com/ZWL-S/Cosmic-Kidney-Disease_LTC .

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Acknowledgements

S.B.W. and K.S. acknowledges this work was partially funded by the UK Space Agency through a grant [ST/X000036/1] administered by the Science and Technology Facilities Council (STFC). S.B.W. is supported by Kidney Research UK grant [RP_017_20190306] and St Peters Trust. K.S. acknowledges this research was funded in part by the Wellcome Trust [Grant number 110282/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A.G . is supported by Kidney Research UK (RP_017_20190306). E.R.W. is supported by Kidney Research UK, TF_007_20191202. J.K. thanks MOGAM Science Foundation. J.K. was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00241586). S.Y. received 2021 NASA HERO grant 80NSSC21K0814 and Augmentation award, 2019 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation, 2020 PENN Undergraduate Research Foundation grant; MH076690, and by NIH DK135871 (PI Zderic), R01 NS088555 (PI: AM Stowe), R15 MH117628 (PI: K. Lambert). M.B.V. received Eli Lilly Doctoral Scholarship. L.C . received funding support from the Francis Crick Institute (CC2168). J.B.T., P.G. and R.A.A.C . are supported by the Sainsbury Wellcome Centre’s core provided by Wellcome (219627/Z/19/Z) and the Gatsby Charitable Foundation (GAT3755). L.M.C . received Penn Provost/CHOP Postdoctoral Fellowship for Academic Diversity, Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program. S.G. and S.L.P . are supported by the GeneLab Project at NASA Ames Research Center, through NASA’s Biological and Physical Sciences (BPS) Division in the Science Mission Directorate (SMD). F.C.K . is supported by Translational Research Institute for Space Health (TRISH) through NASA cooperative agreement NNX16AO69A, Penn Provost/CHOP Postdoctoral Fellowship for Academic Diversity. A.L.M . is funded by Science Foundation Ireland SFI/19/6628 INSPIRE DMD. C.R. is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.S.A. is funded by an MRC Clinical Research Training Fellowship (MR/S021329/1). Y. is supported by a project grant from the British Heart Foundation (PG/20/10270). J.G.Z . is supported by United Kingdom Space Agency—ST/X000036/1 (Walsh). P.S. ’s work was funded by NIH—NIDDK grants R01 DK114485, R01 DK129541, and R01 AR080668. S.R . is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (CC2168), the UK Medical Research Council (CC2168), and the Wellcome Trust (CC2168), and by the Harold J Newman Brain Mapping Foundation. S.B . received NIH OT2TR003450 (SEB, Co-PI), NSF 2033569 (SEB, PI), NSF 2333819 (SEB, PI). A.U . received Grant number 23K10820 from Japan Society for the Promotion of Science (JSPS). M.Y . is supported by space rodent research study for JAXA feasibility experiments using ISS/ Kibo 2015 and 2018 [No grant number]. Grants- in-Aid for Scientific Research from JSPS [grant numbers JSPS 19H05649] and JAXA biorepository multi-omics data program [No grant number]. Almeida, ECA ’s NASA Rodent Research 10 Spaceflight experiment supported by a NASA Space Biology Grant NNH14ZTT001N14-14SF. J.C.S . received NIH-R01AG066710 and NIH-R01AG061188. A.J.E . received NIH R01 MH129970 (PI); NIH T32 NS007413 (co-PI); NIH R01 DK135871 (PI: SA Zderic), R01 NS088555 (PI: AM Stowe), R01 NS126279 (PI: Ahrens-Nicklas), R15 MH117628 (PI: K Lambert). S.M.S . and S.R.Z . belong to Biochemical Profile and Nutritional Status Assessment projects and were funded by the NASA Human Research Program’s human Health Countermeasures Element. J.M.G . is supported by the NASA Space Biology Program C.E.M. thanks the Scientific Computing Unit (SCU) at WCM, the WorldQuant and GI Research Foundation, NASA (NNX14AH50G, NNX17AB26G, NNH18ZTT001N-FG2, 80NSSC22K0254, 80NSSC23K0832, the Translational Research Institute through NASA Cooperative Agreement NNX16AO69A), the National Institutes of Health (R01MH117406), and the LLS (MCL7001-18, LLS 9238-16, 7029-23) The NASA Biological & Physical Sciences (BPS) Open Science Data Repository (OSDR) team (S.V.C., L.M.S., S.L.P., R.T.S., L.D., S.G., A.F., A.S.B., V.B., J.M.G.) is primarily funded by the BPS Space Biology Program within the NASA Science Mission Directorate and receive some support from the NASA Human Research Program (HRP). S.V.C. is also funded by NASA HRP grant NNJ16HP24I (P.I. Costes). The OSDR Sample Processing Team (INITIAL) was instrumental generating open science data for numerous tissues from spaceflight missions RR-1, RR-3, RR-7, RR-10, and RR-23. The data supporting this paper can be accessed publicly at osdr.nasa.gov/bio. We would also like to acknowledge the significant role played by the OSDR Analysis Working Groups (AWG) in establishing omics pipeline standards over the past five years. Their collaborative efforts in refining OSDR and analysing multiple datasets have been instrumental in unravelling crucial biological processes occurring in space. Biospecimens utilised in this research were collected by the NASA Space Biology Biospecimen Sharing Program at NASA Ames Research Center (Moffett Field, CA), and awarded to K.S. through the NASA Biological Institutional Scientific Collection (NBISC).

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K.S., S.B.W. conceived the study and were responsible for project management. A.J.E., A.B., J.M.G., R.T.S., K.S., S.B.W., V.P., M.M., C.E.M. were involved in conceptualisation of the study. M.Y.A.J., V.M.A., F.K., L.C.D.O., L.M.S., H.F., I.M., S.M.S., C.R., S.L., X.Y., E.T., H.C.L., H.V.K., H.Z., J.R.S., P.F., R.B.S., T.C.C.L.K.S., A.B., A.F., J.M.G., L.D., R.T.S., S.G., S.L.P., S.V.C., V.B., A.S.B., R.F., W.A.D.S., C.C., D.S., H.S., J.N., L.C., M.R.L., N.B., S.R., K.A.N., J.C.S., V.D.A., M.B.V., A.G., C.Z., E.R.W., J.B.T., J.G.Z., K.S., M.A.M., P.G., R.A.A.C., S.B.W., S.W.S., V.P., J.S., C.N., S.B., K.B., K.M.O., N.F., P.B., Y., A.N., F.A., N.L., P.S., S.B.2., S.M., A.S., S.R.Z., M.M., A.S.2, C.E.M., C.M., E.O., J.F., J.K., L.I.P., N.H. developed the methodology. L.M.S., A.J.E., F.C.K., L.M.C., D.Z., Y.L., I.M., S.M.S., D.S.2., S.L., X.Y., A.B., A.F., J.M.G., L.D., R.T.S., S.G., S.L.P., S.V.C., V.B., A.S.B., E.A.C.A., A.K., M.C.C., D.S., H.S., J.N., L.C., M.R.L., S.R., J.C.S., A.L.B., C.M.M., L.O., R.S.H., S.A., A.U., M.Y., V.D.A., E.B., A.G., C.Z., E.R.W., J.B.T., K.S., .P.G., R.A.A.C., V.P., Z.L., A.S.K., K.B., N.F., P.B., Y., S.Y., S.R.Z., M.M., A.S.2., C.E.M., C.M., E.O., J.F., J.K., L.I.P., N.H. carried out the experiments and investigation of the samples. M.Y.A.J., V.M.A., F.K., L.C.D.O., L.M.S., S.A.2, H.F., I.M., S.M.S., C.R., D.S.2, S.L., X.Y., E.T., H.C.L., H.V.K., H.Z., J.R.S., P.F., R.B.S., T.C.C.L.K.S., A.B., A.F., J.M.G, L.D., R.T.S., S.G., S.L.P., S.V.C., V.B., A.S.B., M.T., R.F., W.A.D.S., C.C., L.C., N.B., S.R., K.A.N., J.C.S., A.L.B., C.M.M., R.S.H., A.U., M.Y., V.D.A., A.L.M., M.B.V., A.G., C.Z., E.R.W., M.A.M., O.S.A., S.W.S., V.P., C.N., S.B., K.M.O., Y., S.R.Z., M.M., A.S.2., C.E.M., C.M., E.O., J.F., J.K., L.I.P, N.H. contributed to the analysis and interpretation of the results. L.M.S., A.E., F.C.K., L.M.C., D.Z., Y.L., IM, SMS, DS2, A.B., A.F., J.M.G., L.D., R.T.S., S.G., S.L.P., S.V.C., V.B., A.S.B., E.A.C.A., A.K,. M.C.C., J.C.S., L.O., R.S.H., S.A., A.U., M.Y., E.B., S.Y., S.R.Z., M.M., A.S.2., C.E.M., C.M., E.O., J.F., J.K., L.I.P., N.H. provided the study resources. V.D.A., A.G., C.Z., E.R.W., K.S., S.B.W., V.P., Z.L. contributed to the original drafting of the manuscript. M.Y.A.J., V.M.A., F.K., L.C.D.O., L.M.S., A.J.E, F.C.K., S.A.2, H.F., L.M.C., D.Z., Y.L., I.M., S.M.S., C.R., D.S.2., S.L., X.Y., E.T., H.C.L., H.V.K., H.Z., J.R.S., P.F., R.B.S., T.C.C.L.K.S., A.B., A.F., J.M.G., L.D., R.T.S., S.G., S.L.P., S.V.C., V.B., A.S.B., E.A.C.A., M.T., A.K., M.C.C., R.F., W.A.D.S., C.C., D.S., H.S., J.N., L.C., M.R.L., N.B., S.R., K.A.N., J.C.S., L.O., R.S.H., S.A., A.U., M.Y., V.D.A., E.B., A.L.M., M.B.V., A.G., C.Z., E.R.W., J.B.T., J.G.Z., K.S., M.A.M., O.S.A., P.G., R.A.A.C., S.B.W., S.W.S., V.P., Z.L., J.S., C.N., S.B., A.S.K., K.B., K.M.O., N.F., P.B., Y., A.N., F.A., N.L., P.S., S.B.2, S.M., A.S., S.Y., S.R.Z., M.M., A.S.2, C.E.M., C.M., E.O., J.F., J.K., L.I.P., NH provided critical feedback and helped shape the study and edit the manuscript. M.Y.A.J., S.A.2, C.C., K.A.N., J.C.S., V.D.A., M.B.V., A.G., C.Z., E.R.W., K.S., S.B.W., Z.L., C.N., S.B. planned and designed the figures and visualisation of results. V.M.A., F.K., L.M.S., A.J.E., D.Z., S.M.S., D.S.2, S.L., J.R.S., A.B., J.M.G., R.T.S., S.G., S.V.C., A.S.B., W.A.D.S., C.C., J.N., L.C., S.R., J.C.S., M.Y., E.B., M.B.V., K.S., M.A.M., R.A.A.C., S.B.W., S.W.S., V.P., S.B., K.B., P.B., Y., P.S., S.Y., S.R.Z., M.M., C.E.M., E.O., J.K. supervised this project.

Corresponding authors

Correspondence to Keith Siew or Stephen B. Walsh .

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Competing interests.

C.A.N. and S.E.B. are cofounders and hold shares in MATE Bioservices, a company that commercialises uses of SPOKE knowledge graph. V.D.A. received consultancy fees from Allena Pharmaceuticals. C.M. is compensated by Thorne HealthTech. C.R. received Consultancy from Novartis. External Committee member in the Banff Foundation for Allograft Pathology, the Renal Pathology Society, the Royal College of Pathologists. P.S. is an equity holder in DigPath Inc, and currently he serves on the advisory board of the same incorporation. S.R. is an active shareholder in Curio Bio, which commercialises Slide-seq. C.E.M. is a co-Founder of Onegevity All other authors declare no competing interests.

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Siew, K., Nestler, K.A., Nelson, C. et al. Cosmic kidney disease: an integrated pan-omic, physiological and morphological study into spaceflight-induced renal dysfunction. Nat Commun 15 , 4923 (2024). https://doi.org/10.1038/s41467-024-49212-1

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ChatGPT: Everything you need to know about the AI-powered chatbot

ChatGPT, OpenAI’s text-generating AI chatbot, has taken the world by storm since its launch in November 2022. What started as a tool to hyper-charge productivity through writing essays and code with short text prompts has evolved into a behemoth used by more than 92% of Fortune 500 companies .

That growth has propelled OpenAI itself into becoming one of the most-hyped companies in recent memory. And its latest partnership with Apple for its upcoming generative AI offering, Apple Intelligence, has given the company another significant bump in the AI race.

2024 also saw the release of GPT-4o, OpenAI’s new flagship omni model for ChatGPT. GPT-4o is now the default free model, complete with voice and vision capabilities. But after demoing GPT-4o, OpenAI paused one of its voices , Sky, after allegations that it was mimicking Scarlett Johansson’s voice in “Her.”

OpenAI is facing internal drama, including the sizable exit of co-founder and longtime chief scientist Ilya Sutskever as the company dissolved its Superalignment team. OpenAI is also facing a lawsuit from Alden Global Capital-owned newspapers , including the New York Daily News and the Chicago Tribune, for alleged copyright infringement, following a similar suit filed by The New York Times last year.

Here’s a timeline of ChatGPT product updates and releases, starting with the latest, which we’ve been updating throughout the year. And if you have any other questions, check out our ChatGPT FAQ here.

Timeline of the most recent ChatGPT updates

February 2024, january 2024.

• ChatGPT FAQs

Apple brings ChatGPT to its apps, including Siri

Apple announced at WWDC 2024 that it is bringing ChatGPT to Siri and other first-party apps and capabilities across its operating systems. The ChatGPT integrations, powered by GPT-4o, will arrive on iOS 18, iPadOS 18 and macOS Sequoia later this year, and will be free without the need to create a ChatGPT or OpenAI account. Features exclusive to paying ChatGPT users will also be available through Apple devices .

Apple is bringing ChatGPT to Siri and other first-party apps and capabilities across its operating systems #WWDC24 Read more: https://t.co/0NJipSNJoS pic.twitter.com/EjQdPBuyy4 — TechCrunch (@TechCrunch) June 10, 2024

House Oversight subcommittee invites Scarlett Johansson to testify about ‘Sky’ controversy

Scarlett Johansson has been invited to testify about the controversy surrounding OpenAI’s Sky voice at a hearing for the House Oversight Subcommittee on Cybersecurity, Information Technology, and Government Innovation. In a letter, Rep. Nancy Mace said Johansson’s testimony could “provide a platform” for concerns around deepfakes.

ChatGPT experiences two outages in a single day

ChatGPT was down twice in one day: one multi-hour outage in the early hours of the morning Tuesday and another outage later in the day that is still ongoing. Anthropic’s Claude and Perplexity also experienced some issues.

You're not alone, ChatGPT is down once again. pic.twitter.com/Ydk2vNOOK6 — TechCrunch (@TechCrunch) June 4, 2024

The Atlantic and Vox Media ink content deals with OpenAI

The Atlantic and Vox Media have announced licensing and product partnerships with OpenAI . Both agreements allow OpenAI to use the publishers’ current content to generate responses in ChatGPT, which will feature citations to relevant articles. Vox Media says it will use OpenAI’s technology to build “audience-facing and internal applications,” while The Atlantic will build a new experimental product called Atlantic Labs .

I am delighted that @theatlantic now has a strategic content & product partnership with @openai . Our stories will be discoverable in their new products and we'll be working with them to figure out new ways that AI can help serious, independent media : https://t.co/nfSVXW9KpB — nxthompson (@nxthompson) May 29, 2024

OpenAI signs 100K PwC workers to ChatGPT’s enterprise tier

OpenAI announced a new deal with management consulting giant PwC . The company will become OpenAI’s biggest customer to date, covering 100,000 users, and will become OpenAI’s first partner for selling its enterprise offerings to other businesses.

OpenAI says it is training its GPT-4 successor

OpenAI announced in a blog post that it has recently begun training its next flagship model to succeed GPT-4. The news came in an announcement of its new safety and security committee, which is responsible for informing safety and security decisions across OpenAI’s products.

Former OpenAI director claims the board found out about ChatGPT on Twitter

On the The TED AI Show podcast, former OpenAI board member Helen Toner revealed that the board did not know about ChatGPT until its launch in November 2022. Toner also said that Sam Altman gave the board inaccurate information about the safety processes the company had in place and that he didn’t disclose his involvement in the OpenAI Startup Fund.

Sharing this, recorded a few weeks ago. Most of the episode is about AI policy more broadly, but this was my first longform interview since the OpenAI investigation closed, so we also talked a bit about November. Thanks to @bilawalsidhu for a fun conversation! https://t.co/h0PtK06T0K — Helen Toner (@hlntnr) May 28, 2024

ChatGPT’s mobile app revenue saw biggest spike yet following GPT-4o launch

The launch of GPT-4o has driven the company’s biggest-ever spike in revenue on mobile , despite the model being freely available on the web. Mobile users are being pushed to upgrade to its $19.99 monthly subscription, ChatGPT Plus, if they want to experiment with OpenAI’s most recent launch.

OpenAI to remove ChatGPT’s Scarlett Johansson-like voice

After demoing its new GPT-4o model last week, OpenAI announced it is pausing one of its voices , Sky, after users found that it sounded similar to Scarlett Johansson in “Her.”

OpenAI explained in a blog post that Sky’s voice is “not an imitation” of the actress and that AI voices should not intentionally mimic the voice of a celebrity. The blog post went on to explain how the company chose its voices: Breeze, Cove, Ember, Juniper and Sky.

We’ve heard questions about how we chose the voices in ChatGPT, especially Sky. We are working to pause the use of Sky while we address them. Read more about how we chose these voices: https://t.co/R8wwZjU36L — OpenAI (@OpenAI) May 20, 2024

ChatGPT lets you add files from Google Drive and Microsoft OneDrive

OpenAI announced new updates for easier data analysis within ChatGPT . Users can now upload files directly from Google Drive and Microsoft OneDrive, interact with tables and charts, and export customized charts for presentations. The company says these improvements will be added to GPT-4o in the coming weeks.

We're rolling out interactive tables and charts along with the ability to add files directly from Google Drive and Microsoft OneDrive into ChatGPT. Available to ChatGPT Plus, Team, and Enterprise users over the coming weeks. https://t.co/Fu2bgMChXt pic.twitter.com/M9AHLx5BKr — OpenAI (@OpenAI) May 16, 2024

OpenAI inks deal to train AI on Reddit data

OpenAI announced a partnership with Reddit that will give the company access to “real-time, structured and unique content” from the social network. Content from Reddit will be incorporated into ChatGPT, and the companies will work together to bring new AI-powered features to Reddit users and moderators.

We’re partnering with Reddit to bring its content to ChatGPT and new products: https://t.co/xHgBZ8ptOE — OpenAI (@OpenAI) May 16, 2024

OpenAI debuts GPT-4o “omni” model now powering ChatGPT

OpenAI’s spring update event saw the reveal of its new omni model, GPT-4o, which has a black hole-like interface , as well as voice and vision capabilities that feel eerily like something out of “Her.” GPT-4o is set to roll out “iteratively” across its developer and consumer-facing products over the next few weeks.

OpenAI demos real-time language translation with its latest GPT-4o model. pic.twitter.com/pXtHQ9mKGc — TechCrunch (@TechCrunch) May 13, 2024

OpenAI to build a tool that lets content creators opt out of AI training

The company announced it’s building a tool, Media Manager, that will allow creators to better control how their content is being used to train generative AI models — and give them an option to opt out. The goal is to have the new tool in place and ready to use by 2025.

OpenAI explores allowing AI porn

In a new peek behind the curtain of its AI’s secret instructions , OpenAI also released a new NSFW policy . Though it’s intended to start a conversation about how it might allow explicit images and text in its AI products, it raises questions about whether OpenAI — or any generative AI vendor — can be trusted to handle sensitive content ethically.

OpenAI and Stack Overflow announce partnership

In a new partnership, OpenAI will get access to developer platform Stack Overflow’s API and will get feedback from developers to improve the performance of their AI models. In return, OpenAI will include attributions to Stack Overflow in ChatGPT. However, the deal was not favorable to some Stack Overflow users — leading to some sabotaging their answer in protest .

U.S. newspapers file copyright lawsuit against OpenAI and Microsoft

Alden Global Capital-owned newspapers, including the New York Daily News, the Chicago Tribune, and the Denver Post, are suing OpenAI and Microsoft for copyright infringement. The lawsuit alleges that the companies stole millions of copyrighted articles “without permission and without payment” to bolster ChatGPT and Copilot.

OpenAI inks content licensing deal with Financial Times

OpenAI has partnered with another news publisher in Europe, London’s Financial Times , that the company will be paying for content access. “Through the partnership, ChatGPT users will be able to see select attributed summaries, quotes and rich links to FT journalism in response to relevant queries,” the FT wrote in a press release.

OpenAI opens Tokyo hub, adds GPT-4 model optimized for Japanese

OpenAI is opening a new office in Tokyo and has plans for a GPT-4 model optimized specifically for the Japanese language. The move underscores how OpenAI will likely need to localize its technology to different languages as it expands.

Sam Altman pitches ChatGPT Enterprise to Fortune 500 companies

According to Reuters, OpenAI’s Sam Altman hosted hundreds of executives from Fortune 500 companies across several cities in April, pitching versions of its AI services intended for corporate use.

OpenAI releases “more direct, less verbose” version of GPT-4 Turbo

Premium ChatGPT users — customers paying for ChatGPT Plus, Team or Enterprise — can now use an updated and enhanced version of GPT-4 Turbo . The new model brings with it improvements in writing, math, logical reasoning and coding, OpenAI claims, as well as a more up-to-date knowledge base.

Our new GPT-4 Turbo is now available to paid ChatGPT users. We’ve improved capabilities in writing, math, logical reasoning, and coding. Source: https://t.co/fjoXDCOnPr pic.twitter.com/I4fg4aDq1T — OpenAI (@OpenAI) April 12, 2024

ChatGPT no longer requires an account — but there’s a catch

You can now use ChatGPT without signing up for an account , but it won’t be quite the same experience. You won’t be able to save or share chats, use custom instructions, or other features associated with a persistent account. This version of ChatGPT will have “slightly more restrictive content policies,” according to OpenAI. When TechCrunch asked for more details, however, the response was unclear:

“The signed out experience will benefit from the existing safety mitigations that are already built into the model, such as refusing to generate harmful content. In addition to these existing mitigations, we are also implementing additional safeguards specifically designed to address other forms of content that may be inappropriate for a signed out experience,” a spokesperson said.

OpenAI’s chatbot store is filling up with spam

TechCrunch found that the OpenAI’s GPT Store is flooded with bizarre, potentially copyright-infringing GPTs . A cursory search pulls up GPTs that claim to generate art in the style of Disney and Marvel properties, but serve as little more than funnels to third-party paid services and advertise themselves as being able to bypass AI content detection tools.

The New York Times responds to OpenAI’s claims that it “hacked” ChatGPT for its copyright lawsuit

In a court filing opposing OpenAI’s motion to dismiss The New York Times’ lawsuit alleging copyright infringement, the newspaper asserted that “OpenAI’s attention-grabbing claim that The Times ‘hacked’ its products is as irrelevant as it is false.” The New York Times also claimed that some users of ChatGPT used the tool to bypass its paywalls.

OpenAI VP doesn’t say whether artists should be paid for training data

At a SXSW 2024 panel, Peter Deng, OpenAI’s VP of consumer product dodged a question on whether artists whose work was used to train generative AI models should be compensated . While OpenAI lets artists “opt out” of and remove their work from the datasets that the company uses to train its image-generating models, some artists have described the tool as onerous.

A new report estimates that ChatGPT uses more than half a million kilowatt-hours of electricity per day

ChatGPT’s environmental impact appears to be massive. According to a report from The New Yorker , ChatGPT uses an estimated 17,000 times the amount of electricity than the average U.S. household to respond to roughly 200 million requests each day.

ChatGPT can now read its answers aloud

OpenAI released a new Read Aloud feature for the web version of ChatGPT as well as the iOS and Android apps. The feature allows ChatGPT to read its responses to queries in one of five voice options and can speak 37 languages, according to the company. Read aloud is available on both GPT-4 and GPT-3.5 models.

ChatGPT can now read responses to you. On iOS or Android, tap and hold the message and then tap “Read Aloud”. We’ve also started rolling on web – click the "Read Aloud" button below the message. pic.twitter.com/KevIkgAFbG — OpenAI (@OpenAI) March 4, 2024

OpenAI partners with Dublin City Council to use GPT-4 for tourism

As part of a new partnership with OpenAI, the Dublin City Council will use GPT-4 to craft personalized itineraries for travelers, including recommendations of unique and cultural destinations, in an effort to support tourism across Europe.

A law firm used ChatGPT to justify a six-figure bill for legal services

New York-based law firm Cuddy Law was criticized by a judge for using ChatGPT to calculate their hourly billing rate . The firm submitted a $113,500 bill to the court, which was then halved by District Judge Paul Engelmayer, who called the figure “well above” reasonable demands.

ChatGPT experienced a bizarre bug for several hours

ChatGPT users found that ChatGPT was giving nonsensical answers for several hours , prompting OpenAI to investigate the issue. Incidents varied from repetitive phrases to confusing and incorrect answers to queries. The issue was resolved by OpenAI the following morning.

Match Group announced deal with OpenAI with a press release co-written by ChatGPT

The dating app giant home to Tinder, Match and OkCupid announced an enterprise agreement with OpenAI in an enthusiastic press release written with the help of ChatGPT . The AI tech will be used to help employees with work-related tasks and come as part of Match’s $20 million-plus bet on AI in 2024.

ChatGPT will now remember — and forget — things you tell it to

As part of a test, OpenAI began rolling out new “memory” controls for a small portion of ChatGPT free and paid users, with a broader rollout to follow. The controls let you tell ChatGPT explicitly to remember something, see what it remembers or turn off its memory altogether. Note that deleting a chat from chat history won’t erase ChatGPT’s or a custom GPT’s memories — you must delete the memory itself.

We’re testing ChatGPT's ability to remember things you discuss to make future chats more helpful. This feature is being rolled out to a small portion of Free and Plus users, and it's easy to turn on or off. https://t.co/1Tv355oa7V pic.twitter.com/BsFinBSTbs — OpenAI (@OpenAI) February 13, 2024

OpenAI begins rolling out “Temporary Chat” feature

Initially limited to a small subset of free and subscription users, Temporary Chat lets you have a dialogue with a blank slate. With Temporary Chat, ChatGPT won’t be aware of previous conversations or access memories but will follow custom instructions if they’re enabled.

But, OpenAI says it may keep a copy of Temporary Chat conversations for up to 30 days for “safety reasons.”

Use temporary chat for conversations in which you don’t want to use memory or appear in history. pic.twitter.com/H1U82zoXyC — OpenAI (@OpenAI) February 13, 2024

ChatGPT users can now invoke GPTs directly in chats

Paid users of ChatGPT can now bring GPTs into a conversation by typing “@” and selecting a GPT from the list. The chosen GPT will have an understanding of the full conversation, and different GPTs can be “tagged in” for different use cases and needs.

You can now bring GPTs into any conversation in ChatGPT – simply type @ and select the GPT. This allows you to add relevant GPTs with the full context of the conversation. pic.twitter.com/Pjn5uIy9NF — OpenAI (@OpenAI) January 30, 2024

ChatGPT is reportedly leaking usernames and passwords from users’ private conversations

Screenshots provided to Ars Technica found that ChatGPT is potentially leaking unpublished research papers, login credentials and private information from its users. An OpenAI representative told Ars Technica that the company was investigating the report.

ChatGPT is violating Europe’s privacy laws, Italian DPA tells OpenAI

OpenAI has been told it’s suspected of violating European Union privacy , following a multi-month investigation of ChatGPT by Italy’s data protection authority. Details of the draft findings haven’t been disclosed, but in a response, OpenAI said: “We want our AI to learn about the world, not about private individuals.”

OpenAI partners with Common Sense Media to collaborate on AI guidelines

In an effort to win the trust of parents and policymakers, OpenAI announced it’s partnering with Common Sense Media to collaborate on AI guidelines and education materials for parents, educators and young adults. The organization works to identify and minimize tech harms to young people and previously flagged ChatGPT as lacking in transparency and privacy .

OpenAI responds to Congressional Black Caucus about lack of diversity on its board

After a letter from the Congressional Black Caucus questioned the lack of diversity in OpenAI’s board, the company responded . The response, signed by CEO Sam Altman and Chairman of the Board Bret Taylor, said building a complete and diverse board was one of the company’s top priorities and that it was working with an executive search firm to assist it in finding talent. 

OpenAI drops prices and fixes ‘lazy’ GPT-4 that refused to work

In a blog post , OpenAI announced price drops for GPT-3.5’s API, with input prices dropping to 50% and output by 25%, to $0.0005 per thousand tokens in, and $0.0015 per thousand tokens out. GPT-4 Turbo also got a new preview model for API use, which includes an interesting fix that aims to reduce “laziness” that users have experienced.

Expanding the platform for @OpenAIDevs : new generation of embedding models, updated GPT-4 Turbo, and lower pricing on GPT-3.5 Turbo. https://t.co/7wzCLwB1ax — OpenAI (@OpenAI) January 25, 2024

OpenAI bans developer of a bot impersonating a presidential candidate

OpenAI has suspended AI startup Delphi, which developed a bot impersonating Rep. Dean Phillips (D-Minn.) to help bolster his presidential campaign. The ban comes just weeks after OpenAI published a plan to combat election misinformation, which listed “chatbots impersonating candidates” as against its policy.

OpenAI announces partnership with Arizona State University

Beginning in February, Arizona State University will have full access to ChatGPT’s Enterprise tier , which the university plans to use to build a personalized AI tutor, develop AI avatars, bolster their prompt engineering course and more. It marks OpenAI’s first partnership with a higher education institution.

Winner of a literary prize reveals around 5% her novel was written by ChatGPT

After receiving the prestigious Akutagawa Prize for her novel The Tokyo Tower of Sympathy, author Rie Kudan admitted that around 5% of the book quoted ChatGPT-generated sentences “verbatim.” Interestingly enough, the novel revolves around a futuristic world with a pervasive presence of AI.

Sam Altman teases video capabilities for ChatGPT and the release of GPT-5

In a conversation with Bill Gates on the Unconfuse Me podcast, Sam Altman confirmed an upcoming release of GPT-5 that will be “fully multimodal with speech, image, code, and video support.” Altman said users can expect to see GPT-5 drop sometime in 2024.

OpenAI announces team to build ‘crowdsourced’ governance ideas into its models

OpenAI is forming a Collective Alignment team of researchers and engineers to create a system for collecting and “encoding” public input on its models’ behaviors into OpenAI products and services. This comes as a part of OpenAI’s public program to award grants to fund experiments in setting up a “democratic process” for determining the rules AI systems follow.

OpenAI unveils plan to combat election misinformation

In a blog post, OpenAI announced users will not be allowed to build applications for political campaigning and lobbying until the company works out how effective their tools are for “personalized persuasion.”

Users will also be banned from creating chatbots that impersonate candidates or government institutions, and from using OpenAI tools to misrepresent the voting process or otherwise discourage voting.

The company is also testing out a tool that detects DALL-E generated images and will incorporate access to real-time news, with attribution, in ChatGPT.

Snapshot of how we’re preparing for 2024’s worldwide elections: • Working to prevent abuse, including misleading deepfakes • Providing transparency on AI-generated content • Improving access to authoritative voting information https://t.co/qsysYy5l0L — OpenAI (@OpenAI) January 15, 2024

OpenAI changes policy to allow military applications

In an unannounced update to its usage policy , OpenAI removed language previously prohibiting the use of its products for the purposes of “military and warfare.” In an additional statement, OpenAI confirmed that the language was changed in order to accommodate military customers and projects that do not violate their ban on efforts to use their tools to “harm people, develop weapons, for communications surveillance, or to injure others or destroy property.”

ChatGPT subscription aimed at small teams debuts

Aptly called ChatGPT Team , the new plan provides a dedicated workspace for teams of up to 149 people using ChatGPT as well as admin tools for team management. In addition to gaining access to GPT-4, GPT-4 with Vision and DALL-E3, ChatGPT Team lets teams build and share GPTs for their business needs.

OpenAI’s GPT store officially launches

After some back and forth over the last few months, OpenAI’s GPT Store is finally here . The feature lives in a new tab in the ChatGPT web client, and includes a range of GPTs developed both by OpenAI’s partners and the wider dev community.

To access the GPT Store, users must be subscribed to one of OpenAI’s premium ChatGPT plans — ChatGPT Plus, ChatGPT Enterprise or the newly launched ChatGPT Team.

the GPT store is live! https://t.co/AKg1mjlvo2 fun speculation last night about which GPTs will be doing the best by the end of today. — Sam Altman (@sama) January 10, 2024

Developing AI models would be “impossible” without copyrighted materials, OpenAI claims

Following a proposed ban on using news publications and books to train AI chatbots in the U.K., OpenAI submitted a plea to the House of Lords communications and digital committee. OpenAI argued that it would be “impossible” to train AI models without using copyrighted materials, and that they believe copyright law “does not forbid training.”

OpenAI claims The New York Times’ copyright lawsuit is without merit

OpenAI published a public response to The New York Times’s lawsuit against them and Microsoft for allegedly violating copyright law, claiming that the case is without merit.

In the response , OpenAI reiterates its view that training AI models using publicly available data from the web is fair use. It also makes the case that regurgitation is less likely to occur with training data from a single source and places the onus on users to “act responsibly.”

We build AI to empower people, including journalists. Our position on the @nytimes lawsuit: • Training is fair use, but we provide an opt-out • "Regurgitation" is a rare bug we're driving to zero • The New York Times is not telling the full story https://t.co/S6fSaDsfKb — OpenAI (@OpenAI) January 8, 2024

OpenAI’s app store for GPTs planned to launch next week

After being delayed in December , OpenAI plans to launch its GPT Store sometime in the coming week, according to an email viewed by TechCrunch. OpenAI says developers building GPTs will have to review the company’s updated usage policies and GPT brand guidelines to ensure their GPTs are compliant before they’re eligible for listing in the GPT Store. OpenAI’s update notably didn’t include any information on the expected monetization opportunities for developers listing their apps on the storefront.

GPT Store launching next week – OpenAI pic.twitter.com/I6mkZKtgZG — Manish Singh (@refsrc) January 4, 2024

OpenAI moves to shrink regulatory risk in EU around data privacy

In an email, OpenAI detailed an incoming update to its terms, including changing the OpenAI entity providing services to EEA and Swiss residents to OpenAI Ireland Limited. The move appears to be intended to shrink its regulatory risk in the European Union, where the company has been under scrutiny over ChatGPT’s impact on people’s privacy.

What is ChatGPT? How does it work?

ChatGPT is a general-purpose chatbot that uses artificial intelligence to generate text after a user enters a prompt, developed by tech startup OpenAI . The chatbot uses GPT-4, a large language model that uses deep learning to produce human-like text.

When did ChatGPT get released?

November 30, 2022 is when ChatGPT was released for public use.

What is the latest version of ChatGPT?

Both the free version of ChatGPT and the paid ChatGPT Plus are regularly updated with new GPT models. The most recent model is GPT-4o .

Can I use ChatGPT for free?

There is a free version of ChatGPT that only requires a sign-in in addition to the paid version, ChatGPT Plus .

Who uses ChatGPT?

Anyone can use ChatGPT! More and more tech companies and search engines are utilizing the chatbot to automate text or quickly answer user questions/concerns.

What companies use ChatGPT?

Multiple enterprises utilize ChatGPT, although others may limit the use of the AI-powered tool .

Most recently, Microsoft announced at it’s 2023 Build conference that it is integrating it ChatGPT-based Bing experience into Windows 11. A Brooklyn-based 3D display startup Looking Glass utilizes ChatGPT to produce holograms you can communicate with by using ChatGPT.  And nonprofit organization Solana officially integrated the chatbot into its network with a ChatGPT plug-in geared toward end users to help onboard into the web3 space.

What does GPT mean in ChatGPT?

GPT stands for Generative Pre-Trained Transformer.

What is the difference between ChatGPT and a chatbot?

A chatbot can be any software/system that holds dialogue with you/a person but doesn’t necessarily have to be AI-powered. For example, there are chatbots that are rules-based in the sense that they’ll give canned responses to questions.

ChatGPT is AI-powered and utilizes LLM technology to generate text after a prompt.

Can ChatGPT write essays?

Can chatgpt commit libel.

Due to the nature of how these models work , they don’t know or care whether something is true, only that it looks true. That’s a problem when you’re using it to do your homework, sure, but when it accuses you of a crime you didn’t commit, that may well at this point be libel.

We will see how handling troubling statements produced by ChatGPT will play out over the next few months as tech and legal experts attempt to tackle the fastest moving target in the industry.

Does ChatGPT have an app?

Yes, there is a free ChatGPT mobile app for iOS and Android users.

What is the ChatGPT character limit?

It’s not documented anywhere that ChatGPT has a character limit. However, users have noted that there are some character limitations after around 500 words.

Does ChatGPT have an API?

Yes, it was released March 1, 2023.

What are some sample everyday uses for ChatGPT?

Everyday examples include programing, scripts, email replies, listicles, blog ideas, summarization, etc.

What are some advanced uses for ChatGPT?

Advanced use examples include debugging code, programming languages, scientific concepts, complex problem solving, etc.

How good is ChatGPT at writing code?

It depends on the nature of the program. While ChatGPT can write workable Python code, it can’t necessarily program an entire app’s worth of code. That’s because ChatGPT lacks context awareness — in other words, the generated code isn’t always appropriate for the specific context in which it’s being used.

Can you save a ChatGPT chat?

Yes. OpenAI allows users to save chats in the ChatGPT interface, stored in the sidebar of the screen. There are no built-in sharing features yet.

Are there alternatives to ChatGPT?

Yes. There are multiple AI-powered chatbot competitors such as Together , Google’s Gemini and Anthropic’s Claude , and developers are creating open source alternatives .

How does ChatGPT handle data privacy?

OpenAI has said that individuals in “certain jurisdictions” (such as the EU) can object to the processing of their personal information by its AI models by filling out  this form . This includes the ability to make requests for deletion of AI-generated references about you. Although OpenAI notes it may not grant every request since it must balance privacy requests against freedom of expression “in accordance with applicable laws”.

The web form for making a deletion of data about you request is entitled “ OpenAI Personal Data Removal Request ”.

In its privacy policy, the ChatGPT maker makes a passing acknowledgement of the objection requirements attached to relying on “legitimate interest” (LI), pointing users towards more information about requesting an opt out — when it writes: “See here  for instructions on how you can opt out of our use of your information to train our models.”

What controversies have surrounded ChatGPT?

Recently, Discord announced that it had integrated OpenAI’s technology into its bot named Clyde where two users tricked Clyde into providing them with instructions for making the illegal drug methamphetamine (meth) and the incendiary mixture napalm.

An Australian mayor has publicly announced he may sue OpenAI for defamation due to ChatGPT’s false claims that he had served time in prison for bribery. This would be the first defamation lawsuit against the text-generating service.

CNET found itself in the midst of controversy after Futurism reported the publication was publishing articles under a mysterious byline completely generated by AI. The private equity company that owns CNET, Red Ventures, was accused of using ChatGPT for SEO farming, even if the information was incorrect.

Several major school systems and colleges, including New York City Public Schools , have banned ChatGPT from their networks and devices. They claim that the AI impedes the learning process by promoting plagiarism and misinformation, a claim that not every educator agrees with .

There have also been cases of ChatGPT accusing individuals of false crimes .

Where can I find examples of ChatGPT prompts?

Several marketplaces host and provide ChatGPT prompts, either for free or for a nominal fee. One is PromptBase . Another is ChatX . More launch every day.

Can ChatGPT be detected?

Poorly. Several tools claim to detect ChatGPT-generated text, but in our tests , they’re inconsistent at best.

Are ChatGPT chats public?

No. But OpenAI recently disclosed a bug, since fixed, that exposed the titles of some users’ conversations to other people on the service.

What lawsuits are there surrounding ChatGPT?

None specifically targeting ChatGPT. But OpenAI is involved in at least one lawsuit that has implications for AI systems trained on publicly available data, which would touch on ChatGPT.

Are there issues regarding plagiarism with ChatGPT?

Yes. Text-generating AI models like ChatGPT have a tendency to regurgitate content from their training data.

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