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Enrich your students’ educational experience with case-based teaching

The NCCSTS Case Collection, created and curated by the National Center for Case Study Teaching in Science, on behalf of the University at Buffalo, contains over a thousand peer-reviewed case studies on a variety of topics in all areas of science.

Cases (only) are freely accessible; subscription is required for access to teaching notes and answer keys.

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Latest Case Studies

Development of the NCCSTS Case Collection was originally funded by major grants to the University at Buffalo from the National Science Foundation , The Pew Charitable Trusts , and the U.S. Department of Education .

Interactive Case Study for Natural Selection in an Outbreak

• Pathogens & Disease
• Natural Selection

Resource Type

• Interactive Videos

Description

This interactive video explores how two scientists tracked the 2013 Ebola outbreak in West Africa. 

Geneticist Pardis Sabeti investigated the evolution of the virus over time, whereas epidemiologist Lina Moses investigated the societal factors that contributed to the outbreak. Their experiences illustrate some of the factors that can cause an outbreak to occur and why it is important to curb the spread of infection as rapidly as possible. As students watch the video, they are prompted to answer questions that require them to predict steps in the research process and interpret data. Students also make connections to their own experiences with infectious diseases.

The “Student Worksheet” lists the questions embedded in the video. The “Educator Materials” document provides implementation tips from educators who have used interactive case studies in their classroom. It also provides additional discussion questions and guidance on assessing students’ responses.

The “Resource Google Folder” link directs to a Google Drive folder of resource documents in the Google Docs format. Not all downloadable documents for the resource may be available in this format. The Google Drive folder is set as “View Only”; to save a copy of a document in this folder to your Google Drive, open that document, then select File → “Make a copy.” These documents can be copied, modified, and distributed online following the Terms of Use listed in the “Details” section below, including crediting BioInteractive.

Student Learning Targets

• Identify some of the factors that can fuel an infectious disease outbreak in humans.
• Explain how viruses evolve by natural selection during an epidemic.
• Describe how the evolution of viruses can be studied using their genetic information.
• Explain why outbreaks should be stopped as early as possible.

Estimated Time

Ebola, epidemic, epidemiology, health profession, healthcare, infection, spillover, zoonotic disease 

Primary Literature

Gire, Stephen K., Augustine Goba, Kristian G. Andersen, Rachel S. G. Sealfon, Daniel J. Park, Lansana Kanneh, Simbirie Jalloh, et al. “Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak.” Science 345, 6202 (2014): 1369–1371. https://www.science.org/doi/10.1126/science.1259657 .

Terms of Use

Please see the Terms of Use for information on how this resource can be used.

Accessibility Level (WCAG compliance)

Version history, curriculum connections.

HS-LS3-2, HS-LS4-4; SEP1, SEP6, SEP8

AP Biology 2019

SYI-3.A, IST-1.K, IST-1.O, IST-4.B, EVO-1.D, EVO-1.M, ENE-3.D; SP1, SP6

IB Biology 2016

5.2, 6.3, B.5

Vision and Change 2009

Explore related content, other resources about epidemiology.

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Case Study: Cystic Fibrosis - CER

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• Page ID 26446

This page is a draft and is under active development. 

Part I: A​ ​Case​ ​of​ ​Cystic​ ​Fibrosis

Dr. Weyland examined a six month old infant that had been admitted to University Hospital earlier in the day. The baby's parents had brought young Zoey to the emergency room because she had been suffering from a chronic cough. In addition, they said that Zoey sometimes would "wheeze" a lot more than they thought was normal for a child with a cold. Upon arriving at the emergency room, the attending pediatrician noted that salt crystals were present on Zoey's skin and called Dr. Weyland, a pediatric pulmonologist. Dr. Weyland suspects that baby Zoey may be suffering from cystic fibrosis.

CF affects more than 30,000 kids and young adults in the United States. It disrupts the normal function of epithelial cells — cells that make up the sweat glands in the skin and that also line passageways inside the lungs, pancreas, and digestive and reproductive systems.

The inherited CF gene directs the body's epithelial cells to produce a defective form of a protein called CFTR (or cystic fibrosis transmembrane conductance regulator) found in cells that line the lungs, digestive tract, sweat glands, and genitourinary system.

When the CFTR protein is defective, epithelial cells can't regulate the way that chloride ions pass across cell membranes. This disrupts the balance of salt and water needed to maintain a normal thin coating of mucus inside the lungs and other passageways. The mucus becomes thick, sticky, and hard to move, and can result in infections from bacterial colonization.

• "Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon will die" This is an old saying from the eighteenth century and describes one of the symptoms of CF (salty skin). Why do you think babies in the modern age have a better chance of survival than babies in the 18th century?
• What symptoms lead Dr. Weyland to his initial diagnosis?
• Consider the graph of infections, which organism stays relatively constant in numbers over a lifetime. What organism is most likely affecting baby Zoey?
• What do you think is the most dangerous time period for a patient with CF? Justify your answer.

Part​ ​II:​ ​ ​CF​ ​is​ ​a​ ​disorder​ ​of​ ​the​ ​cell​ ​membrane.

Imagine a door with key and combination locks on both sides, back and front. Now imagine trying to unlock that door blind-folded. This is the challenge faced by David Gadsby, Ph.D., who for years struggled to understand the highly intricate and unusual cystic fibrosis chloride channel – a cellular doorway for salt ions that is defective in people with cystic fibrosis.

His findings, reported in a series of three recent papers in the Journal of General Physiology, detail the type and order of molecular events required to open and close the gates of the cystic fibrosis chloride channel, or as scientists call it, the cystic fibrosis transmembrane conductance regulator (CFTR).

Ultimately, the research may have medical applications, though ironically not likely for most cystic fibrosis patients. Because two-thirds of cystic fibrosis patients fail to produce the cystic fibrosis channel altogether, a cure for most is expected to result from research focused on replacing the lost channel.

5. Suggest a molecular fix for a mutated CFTR channel. How would you correct it if you had the ability to tinker with it on a molecular level?

6. Why would treatment that targets the CFTR channel not be effective for 2⁄3 of those with cystic fibrosis?

7. Sweat glands cool the body by releasing perspiration (sweat) from the lower layers of the skin onto the surface. Sodium and chloride (salt) help carry water to the skin's surface and are then reabsorbed into the body. Why does a person with cystic fibrosis have salty tasting skin?

Part​ ​III:​ ​No​ ​cell​ ​is​ ​an​ ​island

Like people, cells need to communicate and interact with their environment to survive. One way they go about this is through pores in their outer membranes, called ion channels, which provide charged ions, such as chloride or potassium, with their own personalized cellular doorways. But, ion channels are not like open doors; instead, they are more like gateways with high-security locks that are opened and closed to carefully control the passage of their respective ions.

In the case of CFTR, chloride ions travel in and out of the cell through the channel’s guarded pore as a means to control the flow of water in and out of cells. In cystic fibrosis patients, this delicate salt/water balance is disturbed, most prominently in the lungs, resulting in thick coats of mucus that eventually spur life-threatening infections. Shown below are several mutations linked to CFTR:

8. Which mutation do you think would be easiest to correct. Justify your answer. 9. Consider what you know about proteins, why does the “folding” of the protein matter?

Part​ ​IV:​ ​Open​ ​sesame

Among the numerous ion channels in cell membranes, there are two principal types: voltage-gated and ligand-gated. Voltage-gated channels are triggered to open and shut their doors by changes in the electric potential difference across the membrane. Ligand-gated channels, in contrast, require a special “key” to unlock their doors, which usually comes in the form of a small molecule.

CFTR is a ligand-gated channel, but it’s an unusual one. Its “key” is ATP, a small molecule that plays a critical role in the storage and release of energy within cells in the body. In addition to binding the ATP, the CFTR channel must snip a phosphate group – one of three “P’s” – off the ATP molecule to function. But when, where and how often this crucial event takes place has remains obscure.

10. Compare the action of the ligand-gated channel to how an enzyme works.

11. Consider the model of the membrane channel, What could go wrong to prevent the channel from opening?

12. Where is ATP generated in the cell? How might ATP production affect the symptoms of cystic fibrosis?

13. Label the image below to show how the ligand-gated channel for CFTR works. Include a summary.

Part​ ​V:​ Can​ ​a​ ​Drug​ ​Treat​ ​Zoey’s​ ​Condition?

Dr. Weyland confirmed that Zoey does have cystic fibrosis and called the parents in to talk about potential treatments. “Good news, there are two experimental drugs that have shown promise in CF patients. These drugs can help Zoey clear the mucus from his lungs. Unfortunately, the drugs do not work in all cases.” The doctor gave the parents literature about the drugs and asked them to consider signing Zoey up for trials.

The​ ​Experimental​ ​Drugs

Ivacaftor TM is a potentiator that increases CFTR channel opening time. We know from the cell culture studies that this increases chloride transport by as much as 50% from baseline and restores it closer to what we would expect to observe in wild type CFTR. Basically, the drug increases CFTR activity by unlocking the gate that allows for the normal flow of salt and fluids.

In early trials, 144 patients all of whom were age over the age of 12 were treated with 150 mg of Ivacaftor twice daily. The total length of treatment was 48 weeks. Graph A shows changes in FEV (forced expiratory volume) with individuals using the drug versus a placebo. Graph B shows concentrations of chloride in patient’s sweat.

14. What is FEV? Describe a way that a doctor could take a measurement of FEV.

15. Why do you think it was important to have placebos in both of these studies?

16. Which graph do you think provides the most compelling evidence for the effectiveness of Ivacafor? Defend your choice.

17. Take a look at the mutations that can occur in the cell membrane proteins from Part III. For which mutation do you think Ivacaftor will be most effective? Justify your answer.

18. Would you sign Zoey up for clinical trials based on the evidence? What concerns would a parent have before considering an experimental drug?

Part​ ​VI:​ ​Zoey’s​ ​Mutation

Dr. Weyland calls a week later to inform the parents that genetic tests show that Zoey chromosomes show that she has two copies of the F508del mutation. This mutation, while the most common type of CF mutation, is also one that is difficult to treat with just Ivacaftor. There are still some options for treatment.

In people with the most common CF mutation, F508del, a series of problems prevents the CFTR protein from taking its correct shape and reaching its proper place on the cell surface. The cell recognizes the protein as not normal and targets it for degradation before it makes it to the cell surface. In order to treat this problem, we need to do two things: first, an agent to get the protein to the surface, and then ivacaftor (VX-770) to open up the channel and increase chloride transport. VX-809 has been identified as a way to help with the trafficking of the protein to the cell surface. When added VX-809 is added to ivacaftor (now called Lumacaftor,) the protein gets to the surface and also increases in chloride transport by increasing channel opening time.

In early trials, experiments were done in-vitro, where studies were done on cell cultures to see if the drugs would affect the proteins made by the cell. General observations can be made from the cells, but drugs may not work on an individual’s phenotype. A new type of research uses ex-vivo experiments, where rectal organoids (mini-guts) were grown from rectal biopsies of the patient that would be treated with the drug. Ex-vivo experiments are personalized medicine, each person may have different correctors and potentiators evaluated using their own rectal organoids. The graph below shows how each drug works for 8 different patients (#1-#8)

19. Compare ex-vivo trials to in-vitro trials.

20. One the graph, label the group that represents Ivacaftor and Lumacaftor. What is the difference between these two drugs?

21. Complete a CER Chart. If the profile labeled #7 is Zoey, rank the possible drug treatments in order of their effectiveness for her mutation. This is your CLAIM. Provide EVIDENCE​ to support your claim. Provide REASONING​ that explains why this treatment would be more effective than other treatments and why what works for Zoey may not work for other patients. This is where you tie the graph above to everything you have learned in this case. Attach a page.

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Structural Biology: The Science Behind Creating Vaccines

Published on: May 2, 2024

Vaccine technology has been a hot topic over the past several years, particularly during the COVID-19 global pandemic, when it was clear that an effective vaccine would be needed to curb the spread of the virus. At the heart of modern vaccine technology is structural biology, a branch of science that lays the groundwork for new vaccine development. Those passionate about universal vaccine research and public health immunization may find that this is the ideal specialization to pursue within the larger field of biology.

Understanding Structural Biology

Structural biology is a specialization within the field of biology that focuses on molecular structure. Advancements within the field of structural biology and improvements in structural biology techniques have transformed the vaccine formulation process.

What Is Structural Biology?

Nature Portfolio  defines structural biology as the study of both molecular structures as well as the dynamics of biological macromolecules, including nucleic acids and proteins. Structural biologists rely on advanced structural biology techniques to change the structure of those molecular structures and evaluate how those alterations impact their overall function.

Those who study structural biology need to have an advanced understanding of:

• Biochemistry
• Molecular biology

The Techniques of Structural Biology

Structural biologists rely on several key techniques to expedite vaccine research and improve the vaccine formulation process. According to  Technology Networks , the primary structural biology techniques include:

• X-Ray crystallography – Known for being the best structural biology technique for achieving high-resolution results, this technique is ideal for those looking to analyze a wide range of molecules. It is also one of the more affordable structural biology techniques.
• Nuclear magnetic resonance spectroscopy – This technique is primarily used for studying macromolecular dynamics, characterizing the interaction that occurs between molecules and analyzing the structural elucidation of macromolecules.
• Cryogenic electron microscopy – Often referred to as Cryo-EM, this technique requires a biologist to cryogenically freeze a molecule prior to analysis, and it is often used to study proteins.

These primary techniques can often be complemented by additional, more specialized structural biology techniques. This includes small angle X-ray scattering, neutron diffraction, cross-linking mass spectrometry and circular dichroism.

The Role of Structural Biology in Vaccinology

Defined as both a science and engineering field, vaccinology is the study of vaccine development to prevent serious infectious diseases. Vaccinology has been a growing field for the past several centuries, with work picking up at a rapid pace during the 19th and early 20th centuries. While the vaccine formulation process once heavily relied on working with past or dead viral samples, structural biology now serves as the foundation for advancements in vaccinology.

Identifying Targets for Vaccine Development

Structural biology techniques are often used to identify targets for vaccine development. Vaccine research relies heavily on discovering the right targets, as this is the best way to focus the research and quickly develop a safe and effective vaccine.

Science Direct states identifying the right vaccine target is a critical step in the development process, and it can be incredibly difficult to complete. The trick is to identify the unique component of a microorganism that can produce an immune response that will offer some degree of protection from a serious illness.

Understanding Virus Mechanisms

As structural biologists work to identify the right techniques required for vaccine development, they also must have an in-depth understanding of pathogenesis, which is the process that occurs when a virus infects the body and results in disease. Per an article published in  Medical Microbiology , common virus mechanisms include:

• Implantation of the virus.
• Replication of the virus.
• Viral spread to specific disease sites in the body, such as organs.
• Shedding the virus to other host sites.

By understanding the viral mechanisms that take place with a specific virus, structural biologists can identify the best techniques to use to alter the structure of a molecule and produce an immune response.

Case Studies: Vaccines and Structural Biology

In recent years, the world watched vaccine development play out in real time, as people around the globe anxiously awaited the arrival of a safe and effective COVID-19 vaccine. However, the COVID-19 vaccine is not the only recent vaccine development that relied heavily on structural biology techniques. Many of the most advanced and effective vaccines of our era would not have been possible without this important vaccine development science. While vaccine regulatory approval varies from country to country, most medical experts agree that structural biology has been the key to unlocking advancements in vaccinology.

COVID-19 Vaccine Development

For plenty of people, the development of the COVID-19 vaccine felt incredibly fast — and that’s because it was. The COVID-19 vaccine was rapidly developed within the first year of the global pandemic, exceeding the expectations of anxious people who were ready to resume their normal lives. Yet, it still made some weary about how quickly it was produced.

The key to this rapid development was structural biology. The foundation for the rapid development of new MRNA vaccines had been built over the past several decades, giving scientists an ideal opportunity to create a vaccine in real-time and provide the world with a solution as quickly as possible.

The original COVID-19 vaccine was developed based on the variant that was circulating at the onset of the pandemic. Today, scientists and biologists continue to work to refine the vaccine based on the most recent variants circulating. It is also widely assumed that medical experts will continue to recommend an updated COVID-19 vaccine each year to offer adults and children the best protection from this highly contagious virus.

Other Success Stories

When it comes to vaccine development, almost everyone immediately thinks of the COVID-19 vaccine. Yet, structural biology has played a crucial role in the successful development of other, equally significant vaccines. A malaria vaccine is currently being distributed in parts of Africa, and it is significantly reducing the impact of the deadly virus that often infects children.

Challenges in Vaccine Development

As is true in any type of science, the road to vaccine development is not always easy. In fact, structural biologists and vaccinologists often encounter hurdles and challenges along the way. Many of these can be devastating when they think they are within reach of having an effective and safe vaccine that will provide people around the world with a higher quality of life. Some of the most common vaccinology challenges include:

• Rising cost for development
• Vaccine hesitancy
• Additional vaccine regulatory approval requirements
• Increasing requirements for single-dose efficacy
• Effective antigen identification

Complexities of Viral Structures

Vaccinologists and structural biologists must be able to rely on structural biology techniques to analyze the increasingly complex structures of the viruses they are working with. For example, they must be able to evaluate the viral envelope structure to better understand the virus and how it infects its host. However, not all viruses have these protective envelopes, which can complicate the path toward vaccine development.

Evolving Pathogens

The frustration of evolving pathogens took center stage during the COVID-19 pandemic, when the COVID-19 virus evolved and mutated into a new variant before the original vaccine had even been released. While the vaccine still proved effective in lessening the severity of the disease, it was no longer as efficacious as it was against the original variant. This trend continues to be true today as viruses mutate more quickly and effectively, and vaccines struggle to protect against the most recent variant.

Future Directions in Vaccine Development

Medical experts, scientists and citizens from around the world learned a great deal from the devastating COVID-19 pandemic. Today, vaccinologists and structural biologists are taking the lessons learned from those harrowing moments and creating a brighter future for vaccine development. As universal vaccine research continues, scientists are working to develop more ways to create safe and effective vaccines as quickly as possible.

Advancements in Structural Biology Techniques

The science of structural biology is constantly changing, thanks in large part to advancements in technology and further research that has revealed unique ways to improve structural biology techniques. These advancements will allow scientists to continue to create vaccines not only for the viruses circulating around the world today, but for the pathogens that may infect us in the future.

The Potential for Universal Vaccines

Structural biologists may hold the key to universal vaccines, which are largely considered to be the gold standard of future vaccine development. The need for universal vaccines has never been greater, particularly in light of the COVID-19 pandemic. The hope is that advanced structural biology technologies will be able to create universal vaccines that can offer broad and lasting protection from a wide range of viruses.

Explore Your Passion for Vaccine Development Science with a Biology Degree From Park University

At Park University, we offer a  Bachelor of Science in Biology  that provides you with a foundational understanding of all aspects of this science, including structural biology, microbiology, genetics, zoology, physiology and cell biology. By emphasizing the importance of research and providing you with a skills-based education, this degree program allows you to launch a dynamic career in science.

Request more information  about our online degree programs today.

Park University is accredited  by the  Higher Learning Commission .

Park University is a private, non-profit, institution of higher learning since 1875.

First-of-its-kind study definitively shows that conservation actions are effective at halting and reversing biodiversity loss

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A new study published online today, April 25, in the scientific journal Science provides the strongest evidence to date that not only is nature conservation successful, but that scaling conservation interventions up would be transformational for halting and reversing biodiversity loss—a crisis that can lead to ecosystem collapses and a planet less able to support life—and reducing the effects of climate change.

The findings of this first-ever comprehensive meta-analysis of the impact of conservation action are crucial as more than 44,000 species are documented as being at risk of extinction , with tremendous consequences for the ecosystems that stabilize the climate and that provide billions of people around the world with clean water, livelihoods, homes, and cultural preservation, among other ecosystem services. Governments recently adopted new global targets to halt and reverse biodiversity loss, making it even more critical to understand whether conservation interventions are working.

“If you look only at the trend of species declines, it would be easy to think that we’re failing to protect biodiversity, but you would not be looking at the full picture,” said Penny Langhammer, lead author of the study and executive vice president of Re:wild. “What we show with this paper is that conservation is, in fact, working to halt and reverse biodiversity loss. It is clear that conservation must be prioritized and receive significant additional resources and political support globally, while we simultaneously address the systemic drivers of biodiversity loss, such as unsustainable consumption and production.”

Although many studies look at individual conservation projects and interventions and their impact compared with no action taken, these papers have never been pulled into a single analysis to see how and whether conservation action is working overall. The co-authors conducted the first-ever meta-analysis of 186 studies, including 665 trials, that looked at the impact of a wide range of conservation interventions globally, and over time, compared to what would have happened without those interventions. The studies covered over a century of conservation action and evaluated actions targeting different levels of biodiversity—species, ecosystems, and genetic diversity.

The meta-analysis found that conservation actions—including the establishment and management of protected areas, the eradication and control of invasive species, the sustainable management of ecosystems, habitat loss reduction, and restoration—improved the state of biodiversity or slowed its decline in the majority of cases (66%) compared with no action taken at all. And when conservation interventions work, the paper’s co-authors found that they are highly effective .

For example:

• Management of invasive and problematic native predators on two of Florida’s barrier islands, Cayo Costa and North Captiva, resulted in an immediate and substantial improvement in nesting success by loggerhead turtles and least terns, especially compared with other barrier islands where no predator management was applied.
• In the Congo Basin, deforestation was 74% lower in logging concessions under a Forest Management Plan (FMP) compared with concessions without an FMP.
• Protected areas and Indigenous lands were shown to significantly reduce both deforestation rate and fire density in the Brazilian Amazon. Deforestation was 1.7 to 20 times higher and human-caused fires occurred four to nine times more frequently outside the reserve perimeters compared with inside.
• Captive breeding and release boosted the natural population of Chinook salmon in the Salmon River basin of central Idaho with minimal negative impacts on the wild population. On average, fish taken into the hatchery produced 4.7 times more adult offspring and 1.3 times more adult second generation offspring than naturally reproducing fish.

“Our study shows that when conservation actions work, they really work. In other words, they often lead to outcomes for biodiversity that are not just a little bit better than doing nothing at all, but many times greater,” said Jake Bicknell, co-author of the paper and a conservation scientist at DICE, University of Kent. “For instance, putting measures in place to boost the population size of an endangered species has often seen their numbers increase substantially. This effect has been mirrored across a large proportion of the case studies we looked at.”

Even in the minority of cases where conservation actions did not succeed in recovering or slowing the decline of the species or ecosystems that they were targeting compared with taking no action, conservationists benefited from the knowledge gained and were able to refine their methods. For example, in India the physical removal of invasive algae caused the spread of the algae elsewhere because the process broke the algae into many pieces, enabling their dispersal. Conservationists could now implement a different strategy to remove the algae that is more likely to be successful.

This might also explain why the co-authors found a correlation between more recent conservation interventions and positive outcomes for biodiversity— conservation is likely getting more effective over time . Other potential reasons for this correlation include an increase in funding and more targeted interventions.

In some other cases where the conservation action did not succeed in benefiting the target biodiversity compared with no action at all, other native species benefitted unintentionally instead. For example, seahorse abundance was lower in protected sites because marine protected areas increase the abundance of seahorse predators, including octopus.

“It would be too easy to lose any sense of optimism in the face of ongoing biodiversity declines,” said study co-author and Associate Professor Joseph Bull , from the University of Oxford’s Department of Biology. “However, our results clearly show that there is room for hope. Conservation interventions seemed to be an improvement on inaction most of the time; and when they were not, the losses were comparatively limited."

More than half of the world’s GDP, almost $44 trillion , is moderately or highly dependent on nature. According to previous studies, a comprehensive global conservation program would require an investment of between US$178 billion and US$524 billion , focused primarily in countries with particularly high levels of biodiversity. To put this in perspective, in 2022, global fossil fuel handouts--which are destructive to nature—were US$7 trillion . This is 13 times the highest amount needed annually to protect and restore the planet. Today more than US$121 billion is invested annually into conservation worldwide , and previous studies have found the cost-benefit ratio of an effective global program for the conservation of the wild is at least 1:100 .

“Conservation action works—this is what the science clearly shows us,” said Claude Gascon, co-author and director of strategy and operations at the Global Environment Facility. “It is also evident that to ensure that positive effects last, we need to invest more in nature and continue doing so in a sustained way. This study comes at a critical time where the world has agreed on ambitious and needed global biodiversity targets that will require conservation action at an entirely new scale. Achieving this is not only possible, it is well within our grasp as long as it is appropriately prioritized.”

The paper also argues that there must be more investment specifically in the effective management of protected areas, which remain the cornerstone for many conservation actions. Consistent with other studies, this study finds that protected areas work very well on the whole . And what other studies have shown is that when protected areas are not working, it is typically the result of a lack of effective management and adequate resourcing. Protected areas will be even more effective at reducing biodiversity loss if they are well-resourced and well-managed.

Moving forward, the study’s co-authors call for more and rigorous studies that look at the impact of conservation action versus inaction for a wider range of conservation interventions, such as those that look at the effectiveness of pollution control, climate change adaptation, and the sustainable use of species, and in more countries.

“For more than 75 years, IUCN has advanced the importance of sharing conservation practice globally,” said Grethel Aguilar, IUCN director general. “This paper has analyzed conservation outcomes at a level as rigorous as in applied disciplines like medicine and engineering—showing genuine impact and thus guiding the transformative change needed to safeguard nature at scale around the world. It shows that nature conservation truly works, from the species to the ecosystem levels across all continents. This analysis, led by Re:wild in collaboration with many IUCN Members, Commission experts, and staff, stands to usher in a new era in conservation practice.”

This work was conceived and funded through the International Union for Conservation of Nature (IUCN) by the Global Environment Facility.

Lindsay Renick Mayer

[email protected]

+1 512-686-6225

Devin Murphy

+1 512-686-6188

The paper ‘The positive impact of conservation action’ has been published in Science:  https://www.science.org/doi/full/10.1126/science.adj6598  

Additional quotes

Thomas Brooks, co-author and chief scientist, IUCN

“This paper is not only extremely important in providing robust evidence of the impact of

conservation actions. It is also extremely timely in informing crucial international policy processes, including the establishment of a 20-year vision for IUCN, the development of an IPBES assessment of biodiversity monitoring, and the delivery of the action targets toward the outcome goals of the new Kunming-Montreal Global Biodiversity Framework.”

Stuart Butchart, co-author and chief scientist, BirdLife International

“Recognising that the loss and degradation of nature is having consequences for societies worldwide, governments recently adopted a suite of goals and targets for biodiversity conservation. This new analysis is the best evidence to date that conservation interventions make a difference, slowing the loss of species’ populations and habitats and enabling them to recover. It provides strong support for scaling up investments in nature in order to meet the commitments that countries have signed up to.”

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• Published: 03 April 2024

Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development

• Neha Pincha Shroff   ORCID: orcid.org/0000-0002-5043-8639 1   na1 ,
• Pengfei Xu 1   na1 ,
• Sangwoo Kim 2 , 3 ,
• Elijah R. Shelton 2 ,
• Ben J. Gross 2 ,
• Yucen Liu 2 ,
• Carlos O. Gomez 4 ,
• Qianlin Ye 5 , 6 ,
• Tingsheng Yu Drennon 1 ,
• Jimmy K. Hu 5 , 6 ,
• Jeremy B. A. Green   ORCID: orcid.org/0000-0002-6102-2620 7 ,
• Otger Campàs   ORCID: orcid.org/0000-0002-9642-8030 2 , 4 , 8 , 9 , 10 &
• Ophir D. Klein   ORCID: orcid.org/0000-0002-6254-7082 1 , 11  

Nature Cell Biology volume  26 ,  pages 519–529 ( 2024 ) Cite this article

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• Developmental biology
• Organogenesis

Localized sources of morphogens, called signalling centres, play a fundamental role in coordinating tissue growth and cell fate specification during organogenesis. However, how these signalling centres are established in tissues during embryonic development is still unclear. Here we show that the main signalling centre orchestrating development of rodent incisors, the enamel knot (EK), is specified by a cell proliferation-driven buildup in compressive stresses (mechanical pressure) in the tissue. Direct mechanical measurements indicate that the stresses generated by cell proliferation are resisted by the surrounding tissue, creating a circular pattern of mechanical anisotropy with a region of high compressive stress at its centre that becomes the EK. Pharmacological inhibition of proliferation reduces stresses and suppresses EK formation, and application of external pressure in proliferation-inhibited conditions rescues the formation of the EK. Mechanical information is relayed intracellularly through YAP protein localization, which is cytoplasmic in the region of compressive stress that establishes the EK and nuclear in the stretched anisotropic cells that resist the pressure buildup around the EK. Together, our data identify a new role for proliferation-driven mechanical compression in the specification of a model signalling centre during mammalian organ development.

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Data availability.

The data supporting the findings of this study are all available within the article. All other data supporting the findings of this study are available from the corresponding authors. Source data are provided with this paper.

Code availability

The 3D images of oil microdroplet injected tooth buds were processed using the STRESS code developed at the Campas lab 27 ( https://github.com/campaslab/STRESS ). No other custom codes were used.

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Acknowledgements

We thank D. Cuylear, P. Marangoni, A. Rathnayake, B. Hoehn and A. Cortez for technical support, E. Sletten (University of California Los Angeles) for sharing custom-made fluorinated rhodamine dyes and Klein and Campas laboratory members for helpful discussions. We acknowledge the staff within the Biological Imaging Development CoLab at UCSF Parnassus Heights, especially K. Marchuk and J. Eichorst, for their training and support in using the Nikon A1r and the NIS Elements software. We also thank the Laboratory Animal Resource Center, UCSF for assistance with animal care. Funding has been obtained from the National Institute of Dental and Craniofacial Research grant R01-DE027620 (O.D.K. and O.C.), R35-DE026602 (O.D.K.) and the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy – EXC 2068 – 390729961– Cluster of Excellence Physics of Life of TU Dresden (O.C.).

Author information

These authors contributed equally: Neha Pincha Shroff, Pengfei Xu.

Authors and Affiliations

Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, CA, USA

Neha Pincha Shroff, Pengfei Xu, Tingsheng Yu Drennon & Ophir D. Klein

Department of Mechanical Engineering, University of California, Santa Barbara, CA, USA

Sangwoo Kim, Elijah R. Shelton, Ben J. Gross, Yucen Liu & Otger Campàs

Institute of Mechanical Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Sangwoo Kim

Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA

Carlos O. Gomez & Otger Campàs

School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA

Qianlin Ye & Jimmy K. Hu

Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA

Centre for Craniofacial Regeneration and Biology, King’s College London, London, UK

Jeremy B. A. Green

Cluster of Excellence Physics of Life, TU Dresden, Dresden, Germany

Otger Campàs

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Center for Systems Biology Dresden, Dresden, Germany

Department of Pediatrics, Cedars-Sinai Guerin Children’s, Los Angeles, CA, USA

Ophir D. Klein

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Contributions

O.C., O.D.K., N.P.S. and P.X. designed the experiments. N.P.S. and P.X. performed all experiments. S.K. performed the analysis of tissue anisotropy. E.R.S. and B.J.G. adapted the STRESS code to analyse stresses. Q.Y. collected the Piezo mutant embryos. Y.L. prepared and calibrated the oil droplets. T.Y.D. and C.O.G. helped in training and initial trials. C.O.G. did the Imaris analysis. J.K.H. participated in conceptualization of the project. J.B.A.G. and J.K.H. provided critical feedback and helped design experiments. N.P.S., P.X., O.C. and O.D.K. wrote the paper, with input from J.K.H. and J.B.A.G. O.C. and O.D.K. supervised the project. All authors edited the paper.

Corresponding authors

Correspondence to Otger Campàs or Ophir D. Klein .

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The authors declare no competing interests.

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Nature Cell Biology thanks Thomas Diekwisch, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended data fig. 1 a concentric cellular arrangement develops around the ek in the embryonic mouse incisor..

( a ) Analysis of 2.5D nuclear orientation in representative images using OrientationJ in 3 confocal slices 15 µm apart in Z from a E13.5 incisor. (n = 1) ( b ) 3D analysis of nuclear orientation in representative images using Imaris nuclear segmentation of top, middle and bottom planes of a 52 µm thick Z-stack from a E13 incisor. (n = 1) ( c ) Average quantification of nuclear anisotropy in E11.5 through E14.5 incisor epithelia as shown in Fig. 1f using OrientationJ analysis (n = 4; Methods ). ( d ) Average quantification of cytoskeletal anisotropy in E12.5 and E14.5 incisor epithelia as shown in Fig. 1g using OrientationJ analysis (n = 3). ( e ) Representative tissue anisotropy analysis (anisotropy in actin spatial distribution) of E13.5 Phalloidin stained bud and the overlay of the E13.5 Shh RNAscope image (from Fig. 1d ) on the map. Scale bar, 25 µm. Data are represented as mean ± s.e.m. n represents number of embryos; one incisor measured per embryo.

Extended Data Fig. 2 OrientationJ and Epyseg analysis of incisors in 2D.

( a - b ) OrientationJ and Epyseg analysis of representative (a) E12 and (b) E13.5 K14 Cre ;R26 mTmG/mTmG incisors with the spatial averaging of the Epyseg analysis on the right (n = 1 per stage). White arrows indicate the low coherence region. Representative 2D central plane shown. Scale bar, 25 µm. n represents number of embryos; one incisor measured per embryo.

Extended Data Fig. 3 Inhibition of acto-myosin activity does not interfere with anisotropic stress mediated development of EK formation.

( a ) Schematic depicting the dissection, agarose embedding, injection of oil microdroplets, and imaging of the incisor. The image of the embryo and the microscope have been obtained from Biorender.com . ( b ) Outline of E13.5 incisor with reference points 1–3 illustrating the marker locations on the border and point 4 illustrating the oil droplet for vector field and microdroplet orientation analysis. ( c ) Anisotropy analysis of the live E12 and E13.5 murine incisor. (E12: n = 6 and E13.5: n = 6). ( d ) Representative E14.5 incisor epithelium separated from the mesenchyme after 45 mins dispase treatment. (n = 3) ( e ) EdU and E-Cad immunostaining after a 1 h EdU pulse chase in E12 murine incisors cultured with DMSO or blebbistatin for 40 h. Quantification of total EdU positive cells in each field per condition for all incisors. (Control: n = 7; Blebbistatin: n = 7) ( f ) Whole mount in situ of Shh and E-Cad immunostaining in E12 incisors cultured for 40 h with DMSO or Y27632 (ROCK inhibitor). (DMSO: n = 5; Y27632 : n = 5). Scale bar, 25 µm. Dashed line outlines the incisor. Representative 2D central plane shown in all images. Data are represented as mean ± s.e.m. Statistical analysis was done using the unpaired two-tailed Student’s T test (assuming unequal variance) with Welch’s correction for e. n represents number of embryos; one incisor measured per embryo.

Source data

Extended data fig. 4 inhibiting cell proliferation in the embryonic murine incisor interferes with incisor growth and anisotropic stress development..

( a ) Measured proliferation profiles from the centre in the epithelium at E11.5, 12.5, 14.5 and 15.5. (Mean values plotted from n = 3 per stage). ( b ) EdU and eGFP or BrdU and E-Cad immunostaining after a 1 h EdU or BrdU pulse chase in E12 murine incisors cultured with DMSO or Aphidicolin for 7 h (Top panel) and 40 h (Bottom panel). (n = 6 per condition) ( c ) Morphology of E12 incisors at 0 h and 40 h after culture with DMSO or aphidicolin. Dashed line outlines the incisor in (b, c). (Ctrl: n = 4, 6 and Aphi: n = 4, 6 for 0 and 40 hours respectively) ( d ) Quantification of the epithelial area (outlined in yellow dotted line) from all the buds represented in c. (n values in c). ( e, f ) Anisotropy analysis of the live E12 murine incisors cultured for (e) 7 h or (f) 30 h with DMSO or aphidicolin. (7 h – n = 5; 30 h - n = 3) ( g ) Representation of droplet orientation and cell anisotropy (orientation) maps (reproduced from Fig. 3c, c’ ) and quantification of droplet orientation with reference to the regional cell orientation in live 7 h DMSO or aphidicolin treated incisors. Compilation of average data from 3–6 h after injection. Orientation angle values for DMSO treated incisors reproduced from Fig. 2f E12 data. (Ctrl: n = 15 in LC and n = 14 in HC; Aphi: n = 13 in LC and n = 15 in HC) LC, low coherence region; HC, high coherence region. ( h ) Quantification of the tissue stress anisotropy measured by the oil droplets in the LC region of E12 incisors cultured for 7 hours with DMSO or aphidicolin (Ctrl: n = 15 from 2 h; Aphi: n = 13). Dashed line outlines the incisor. Scale bars, 25 µm. epi, epithelium; mes, mesenchyme. Representative 2D central plane shown in all images. Data are represented as mean ± s.e.m. Statistical analysis was done using 2 way ANOVA for d, unpaired two-tailed Student’s T test (assuming unequal variance) with Welch’s correction for g and 2 tailed Mann-Whitney test for h. Source data are available for all plots. n represents number of embryos; one incisor measured per embryo.

Extended Data Fig. 5 Cell proliferation increases compressive stress and area of the embryonic murine incisor.

( a ) Whole mount in situ of Shh and E-Cad immunostaining in E12 incisors cultured for 40 h with DMSO or Mitomycin C. (n = 4 per condition) ( b ) BrdU-EdU double labelling in the E13.5 murine incisor after sequential pulse chase with EdU (1 h) – BrdU (15 mins). (n = 5) ( c ) Morphology of E12 incisors at 40 h after culture in DMSO or aphidicolin or aphidicolin washed out after 16 h. (Ctrl: n = 6; Aphi: n = 4; Aphi wash: n = 6) ( d ) Quantification of the area from all the buds represented in (a). ( e ) Whole mount in situ of Shh and E-Cad immunostaining in E13 incisors cultured for 40 h with DMSO or aphidicolin. (n = 3 per condition). Dashed line outlines the incisor. Scale bar, 25 µm. epi, epithelium; mes, mesenchyme. Representative 2D central plane shown in all images. Data are represented as mean ± s.e.m. Statistical analysis was done using the 2 tailed Mann-Whitney test for d. n represents number of embryos; one incisor measured per embryo.

Extended Data Fig. 6 Dextran-induced compression regulates incisor area and EK localization.

( a ) Images showing the morphology of E12 incisor buds treated with DMSO or aphidicolin for 40 h with varying concentrations of dextran (30 mg/ml and 60 mg/ml). ( b ) Quantification of the area (outlined in yellow dashed lines) from all the buds represented in (a) (Ctrl: n = 3, 5 and 4 and Aphi: n = 5, 5 and 5 for Dextran 0, 30 and 60 mg/ml respectively). ( c ) EdU and E-Cad immunostaining after a 2 hour EdU chase in E12 incisors cultured for 40 h with DMSO or dextran (30 mg/ml). Quantification of EdU positive cells from these and incisors cultured in DMSO, or 30, 60, 80 mg/ml dextran. (n = 6, 5, 4 and 4 respectively) ( d ) Representative images of E12 mandible explants cultured for 40 h with DMSO or aphidicolin + dextran (30 mg/ml) (n = 6 and 5 respectively). Explants are outlined in red with the center marked by a red dot. Quantification of the relative distance of the EK from the center of the tissue in E12 incisors cultured with DMSO or aphidicolin with 30 or 60 mg/ml dextran. (n = 6, 5, 5 and 5 respectively) ( e ) Quantification of relative area of Shh expression to incisor area in E12 incisors cultured with DMSO or aphidicolin with 30 or 60 mg/ml dextran. (n = 7, 6, 6 and 5 respectively). Dashed line outlines the incisor. epi, epithelium; mes, mesenchyme. Scale bar, 25 µm. Representative 2D central plane shown in all images. Data are represented as mean ± s.e.m. Statistical analysis was done using the 2 tailed Mann-Whitney test for b and 1 way ANOVA with Bonferroni’s correction for multiple comparisons for c, d and e. n represents number of embryos; one incisor measured per embryo.

Extended Data Fig. 7 The expression patterns of EK markers Bmp4 and Wnt10a are affected by compressive stress.

( a, b, c ) RNAscope for (a) Pax9 , (b) Bmp4 and (c) Wnt10a in E12 incisors after 40 h culture with DMSO, aphidicolin throughout, aphidicolin washed out after 16 h (Aphi wash) or aphidicolin + 30 mg/ml dextran throughout (Dxt 30 mg/ml + Aphi) (n = 3). Dashed line outlines the incisor. epi, epithelium; mes, mesenchyme. Representative 2D central plane shown in all images. Scale bar, 25 mm. n represents number of embryos; one incisor measured per embryo.

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Combined single statistical source data excel file for all plots in the manuscript main and extended data figures with clearly named tabs for each figure/extended data figure item.

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Shroff, N.P., Xu, P., Kim, S. et al. Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development. Nat Cell Biol 26 , 519–529 (2024). https://doi.org/10.1038/s41556-024-01380-4

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DOI : https://doi.org/10.1038/s41556-024-01380-4

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Study: Airway hillocks challenge our understanding of lung biology

by Tufts University

Airway hillocks are mysterious, flat-topped structures that were only recently identified within regular lung tissue, and their role in airway biology and pathology has previously been unknown.

A research team from Tufts University School of Medicine and Massachusetts General Hospital is now reporting evidence that hillocks and their stem cells are physiologically distinct from other cells within the lung and consist of a stratified outer layer of scale-like squamous cells that protect an underlying layer of rapidly expanding basal stem cells that are capable of restoring airway tissue after injury.

The results are published in a study appearing May 1 in the journal Nature .

"This study links previous research describing seemingly disparate phenomena to an unappreciated reservoir of injury-resistant cells," says Brian Lin, GSB17, a research assistant professor of developmental, molecular and chemical biology at the School of Medicine, and a co-first, co-corresponding author on the paper.

"By doing a whole organ stain, structures popped out that aren't easily seen when looking at the tissue in slices."

Lin was among the group of scientists who, in 2019, first described the cells called hillocks, so named because of how they resemble mounds on the surface of lung tissue.

"The identification of hillocks explains a whole host of findings about airway regeneration," adds Jayaraj Rajagopal, MD, the senior author of the study and an investigator in the Center for Regenerative Medicine at Mass General. "It is remarkable to think these structures were missed for decades. They have implications for regenerative medicine and cancer alike."

In this new study, Lin and team generated a genetic mouse model that made it possible to fluorescently label hillocks and their progeny in the lungs.

They found that hillock-derived stem cells (the basal cells underlying the layers of scaly or squamous cells on top) could rapidly regenerate airway lining after injury and capable of creating all six component cell types of the pseudostratified airway epithelium.

The researchers also demonstrated that the stratified, tightly interlocking layers of squamous cells on the top of hillocks were resistant to a broad spectrum of insults, ranging from physical injury to acid injury to infection to toxins related to smoking.

Viral Shah, member of the Rajagopal Lab and one of the co-first authors, searched for hillocks in human airways by dissecting and staining human lung tissue and found that humans also have hillocks that mirror the structure and function of those in mice.

These findings establish that the presence of a stratified squamous epithelium, long thought to be a metaplastic (precancerous) response to damage is characteristic of an uninjured airway .

Dissections of hillocks revealed specific genes not expressed by other lung cell types which produce a hard protein in the keratin family similar to those used to form hair and nails.

Despite being so hardy, Lin says one of the study's most surprising findings is how quickly hillock cells replace themselves, hinting that part of their function is to be disposable. For example, in response to physical injury to the trachea, hillocks dramatically proliferate and migrate to spread stem cells to the impacted area in order to regenerate it.

Cells that divide so quickly are prone to mutation, and so a short life span for these cells is likely to prevent hillock cells from building up errors.

The research team plans to continue their characterization of hillocks, work that could alter our understanding of the progression of lung cancer, the physiology of conditions like asthma, and how the body combats viral infections and drug interactions. "I think we've cracked open the door, but there's so much more to do," Lin says.

Journal information: Nature

Provided by Tufts University

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Study: Hillocks Challenge Our Understanding of Lung Biology

By Joseph Caputo

Airway hillocks are mysterious, flat-topped structures that were only recently identified within regular lung tissue, and their role in airway biology and pathology has previously been unknown.

A research team from Tufts University School of Medicine and Massachusetts General Hospital is now reporting evidence that hillocks and their stem cells are physiologically distinct from other cells within the lung and consist of a stratified outer layer of scale-like squamous cells that protect an underlying layer of rapidly expanding basal stem cells that are capable of restoring airway tissue after injury.

The results are published in a study appearing May 1 in the journal Nature .

“This study links previous research describing seemingly disparate phenomena to an unappreciated reservoir of injury-resistant cells,” says Brian Lin , GSB17, a research assistant professor of developmental, molecular and chemical biology at the School of Medicine, and a co-first, co-corresponding author on the paper. “By doing a whole organ stain, structures popped out that aren’t easily seen when looking at the tissue in slices.”

Lin was among the group of scientists who, in 2019, first described the cells called hillocks, so named because of how they resemble mounds on the surface of lung tissue.

“The identification of hillocks explains a whole host of findings about airway regeneration,” adds Jayaraj Rajagopal, MD, the senior author of the study and an investigator in the Center for Regenerative Medicine at Mass General. “It is remarkable to think these structures were missed for decades. They have implications for regenerative medicine and cancer alike.”

In this new study, Lin and team generated a genetic mouse model that made it possible to fluorescently label hillocks and their progeny in the lungs.

They found that hillock-derived stem cells (the basal cells underlying the layers of scaly or squamous cells on top) could rapidly regenerate airway lining after injury and capable of creating all six component cell types of the pseudostratified airway epithelium.

The researchers also demonstrated that the stratified, tightly interlocking layers of squamous cells on the top of hillocks were resistant to a broad spectrum of insults, ranging from physical injury to acid injury to infection to toxins related to smoking.

Viral Shah, member of the Rajagopal Lab and one of the co-first authors, searched for hillocks in human airways by dissecting and staining human lung tissue and found that humans also have hillocks that mirror the structure and function of those in mice.

These findings establish that the presence of a stratified squamous epithelium, long thought to be a metaplastic (precancerous) response to damage is characteristic of an uninjured airway.

Dissections of hillocks revealed specific genes not expressed by other lung cell types which produce a hard protein in the keratin family similar to those used to form hair and nails.

Despite being so hardy, Lin says one of the study’s most surprising findings is how quickly hillock cells replace themselves, hinting that part of their function is to be disposable.

For example, in response to physical injury to the trachea, hillocks dramatically proliferate and migrate to spread stem cells to the impacted area in order to regenerate it.

Cells that divide so quickly are prone to mutation, and so a short life span for these cells is likely to prevent hillock cells from building up errors.

The research team plans to continue their characterization of hillocks, work that could alter our understanding of the progression of lung cancer, the physiology of conditions like asthma, and how the body combats viral infections and drug interactions. “I think we’ve cracked open the door, but there’s so much more to do,” Lin says.

Citation: Viral Shah and Chaim Chernoff from the Rajagopal Lab are co-first authors. This study was supported by grants from the National Institutes of Health, Bernard and Mildred Kayden Endowed MGH Research Institute Chair and Cystic Fibrosis Foundation. Complete information on authors, methodology, funders, and conflicts of interest is available in the published paper.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

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Case Study – A Tiny Heart (old version)

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This case study focuses on a baby boy who was born with a problem with his heart.  The story is based on a real scenario, though some of the names have been changed, and the parents gave permission to include photos of the infant.

Students will read about symptoms that occur when a baby is born with stenosis, or a narrowing of the artery.   Students consider treatment options and compare the circulation of a fetus to that of an adult.   Finally, the Ross Procedure is described where a valve from the pulmonary artery is moved to the aorta.

This case study was made for a high school anatomy class, and may not be appropriate for younger audiences.  Students should have already completed the chapter on the circulatory system and have a strong foundation in how the circulatory system works.  Case studies are designed to be completed in small groups so that students can have discussions and help each other with difficult vocabulary.

HS-LS1-2 Develop and use a model to illustrate the hierarchical organization of interacting systems that provide specific functions within multicellular organisms

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