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Immunology

Nature Publishes New Research from Vir Biotechnology Demonstrating the Capacity of Enhanced Monoclonal Antibodies to Induce Protective Adaptive…

SAN FRANCISCO, Oct. 09, 2020 (GLOBE NEWSWIRE) -- Vir Biotechnology Inc. (Nasdaq: VIR) today announced the publication of preclinical research in an influenza animal model highlighting a new mechanism for enhancing the efficacy of monoclonal antibodies to treat viral infection and induce a protective response. Data demonstrate that selective engagement of an activating Fc receptor on dendritic cells by antiviral monoclonal antibodies induced protective CD8+ T cell adaptive responses. The paper, entitled Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection, was published in the October 8, 2020 online edition of Nature.

In the past several years, we've gained a better understanding of how integral Fc mediated effector functions of monoclonal antibodies are for their therapeutic efficacy in pre-clinical models of neoplastic, infectious and inflammatory diseases, said Jeffrey V. Ravetch, M.D., Ph.D., study senior author and Theresa and Eugene M. Lang Professor and Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller University. These approaches have been successfully applied to anti-tumor therapeutics and have resulted in improved clinical outcomes in a variety of oncologic diseases. Our present studies have uncovered a significant new mechanism by which antibodies, through their Fc region, can not only engage innate immune responses but activate adaptive T cell responses, thereby stimulating protective anti-viral immunity in these models.

The research published in Nature focuses on the role of the Fc domain of monoclonal antibodies, regions with the capacity to bind to other immune cells through a family of receptors (the Fc receptors). By engineering antibodies with modified Fc domains to enhance binding to specific Fc receptors on innate immune cells, investigators observed an enhanced protective immune response. Certain modifications (GAALIE variants) were associated with activation of dendritic cells, as well as antiviral effector T-cells, indicating induction of the adaptive arm of the immune system, which is responsible for long-term immunity. Based on this research, monoclonal antibodies programmed with improved effector function represent a potential new approach in the design of therapeutic antibodies for both the prevention and treatment of infectious diseases.

By observing and learning from our bodys powerful natural defenses, we have discovered how to maximize the capacity of antibodies through the amplification of key characteristics that may enable more effective treatments for viral diseases, said Herbert Skip Virgin, M.D., Ph.D., study co-author and executive vice president, research, and chief scientific officer of Vir. These data may have significant implications across a wide range of infectious diseases, and we look forward to exploring the vaccinal potential of the GAALIE-engineered antibodies we are advancing through clinical development VIR-3434 for chronic hepatitis B and VIR-7832 for SARS-CoV-2.

The preclinical study was conducted by Dr. Ravetch and Stylianos Bournazos, Ph.D., of the Laboratory of Molecular Genetics and Immunology at The Rockefeller University, in collaboration with Dr. Virgin and Davide Corti, Ph.D., senior vice president of antibody research at Virs subsidiary Humabs BioMed SA.

This type of exceptional collaborative partnership between cutting-edge science and clinical application has the potential to significantly improve our ability to address infectious diseases, stated Dr. Virgin.

Vir is currently evaluating several monoclonal antibodies that have been Fc engineered to include the XX2 vaccinal mutation (or GAALIE variant) for which Vir has licensed exclusive rights for all infectious diseases.

About VIR-3434VIR-3434 is a subcutaneously administered HBV-neutralizing monoclonal antibody designed to block entry of all 10 genotypes of HBV into hepatocytes and also to reduce the level of virions and subviral particles in the blood. VIR-3434 has been engineered to have an extended half-life as well as to potentially function as a T cell vaccine against HBV in infected patients.

About VIR-7832VIR-7832 is a monoclonal antibody that has shown the ability to neutralize SARS-CoV-2 live virus in vitro. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as SARS), indicating that the epitope is highly conserved, which may make it more difficult for escape mutants to develop. VIR-7832 has been engineered with the potential to enhance lung bioavailability, have an extended half-life, and function as a therapeutic and/or prophylactic T cell vaccine. VIR-7832 is being developed by Vir and its partner GlaxoSmithKline plc(LSE/NYSE: GSK) as part of their broader collaboration to research and develop solutions for coronaviruses, including SARS-CoV-2.

About Vir BiotechnologyVir Biotechnology is a clinical-stage immunology company focused on combining immunologic insights with cutting-edge technologies to treat and prevent serious infectious diseases. Vir has assembled four technology platforms that are designed to stimulate and enhance the immune system by exploiting critical observations of natural immune processes. Its current development pipeline consists of product candidates targeting hepatitis B virus, influenza A, SARS-CoV-2, human immunodeficiency virus and tuberculosis. For more information, please visitwww.vir.bio.

Vir Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as potential, may, will, could, expect, plan, anticipate, believe, estimate, goal, intend, candidate, continuing, developing and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Virs expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding the ability of enhanced Fc mediated effector functions in enhancing the efficacy of monoclonal antibodies to treat viral infections and inducing a protective response in animal models, using an oncological therapeutic approach and enhanced effector function in the treatment of infectious diseases, the vaccinal potential of specifically engineered antibodies in the treatment of chronic hepatitis B and SARS-CoV-2, and statements around the companys plans to explore the vaccinal potential of engineered antibodies as it advances through clinical development of VIR-3434 for the treatment of chronic hepatitis B and VIR-7832 for SARS-CoV-2. Many factors may cause differences between current expectations and actual results including unexpected safety or efficacy data observed during preclinical or clinical studies, challenges in treating chronic hepatitis B and neutralizing SARS-CoV-2, difficulty in collaborating with other companies or government agencies, and challenges in accessing manufacturing capacity. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Virs filings with theU.S. Securities and Exchange Commission, including the section titled Risk Factors contained therein. Except as required by law, Vir assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

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Nature Publishes New Research from Vir Biotechnology Demonstrating the Capacity of Enhanced Monoclonal Antibodies to Induce Protective Adaptive...

Biochemistry

CCM Professor’s Research to Assist with Finding Drugs to Combat Coronavirus Providing Maps of Virus Proteins for the World’s Scientific Community -…

RANDOLPH, NJ Professor Brian Olson, of the Department of Biology and Chemistry at County College of Morris (CCM), recently had his research on coronavirus targets published in the peer-reviewed Journal of Computer-Aided Molecular Design to assist with the development of drugs to combat the virus.

Olson, the lead author on the paper, worked with Dr. Tom Kurtzman of Lehman College to put together a team of researchers this past March when he realized how extensive the COVID-19 pandemic would become. In the paper,An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets, the researchers provide maps of water moleculeson the virus proteins that also are known as solvation maps. Olson explains that knowing which water molecules need to be displaced, and which do not, provides essential information to guide the development of drugs to treat COVID-19. The first step toward determining that is mapping where the water molecules are located on the proteins.

In March, Olson, who had been tracking the coronavirus on several databases, was certain COVID-19 would turn into a pandemic.

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We were seeing clusters on multiple continents and were unable to trace the sources of infection. It was clear this was going to be an immediate and international public health issue, he says. That compelled me to do something.

Utilizing the computational tool, GIST, developed by Kurtzman, the researchers worked from their homes during the pandemic. Prior to being published in the Journal of Computer-Aided Molecular Design, the research was posted by the team on Chemrxiv so it could be accessed early while the peer-review process was taking place.

Now that solvation maps of the COVID-19 virus are available, Olson and his team plan to use that information to search for new drugs. Making the information public and free also will aid others in their search for new and effective pharmaceuticals to defeat the coronavirus. According to Altmetrics Attention Score, which measures the online attention and activity of research papers, the work conducted by the Olson team ranks in the top 25 percent. Given that ranking, based on more than 2,200 views and over 300 downloads of the paper, Olson is encouraged about the development of drugs to fight the coronavirus.

I have never seen the international scientific community come together the way it has now to find some answers, says Olson. There is international collaboration and the sharing of information that previously would not have been shared.

Olson, who teaches forensic science at CCM, joined the colleges faculty in 2018. At CCM, he and several other professors, developed the colleges first virtual reality class to teach students forensic science skills by analyzing murder scenes. Along with his work on the coronavirus, he is researching the development of pain killers to replace opiates.

Olson earned his associate degree in science from the Borough of Manhattan Community College, his bachelors in biochemistry from Hunter College, his masters in biochemistry from the City University of New York (CUNY) Graduate Center, and is working on his doctorate in biochemistry from CUNY Graduate Center.

He is a strong advocate for community colleges, and CCM in particular. Community colleges place a high value on quality teaching, he says. I am so fortunate. I have fun researching tiny molecules and on top of that I get paid to talk to students about narcotics, murders and other fascinating topics. I cant imagine having a better job.

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CCM Professor's Research to Assist with Finding Drugs to Combat Coronavirus Providing Maps of Virus Proteins for the World's Scientific Community -...

Biochemistry

Scientists zoom in on HIV inside a test tube, find critical steps in infection – Live Science

Scientists have finally recreated the initial steps of HIV infection in a test tube, offering an incredibly zoomed-in view of the virus in action.

The amazing images show a cone-shaped shell of geometric tiles, called the capsid, that sits at the virus's center and contains its genetic material, known as RNA. Before infiltrating a cell, the capsid is surrounded by an envelope of fatty molecules; this envelope fuses to the host cell to let the capsid inside, where it then carries the RNA to the cell's nucleus. On the way, the RNA replicates, and once inside the nucleus, it invades the host's DNA.

By granting a closer look at this replication process, the new study highlights that the capsid itself plays a critical role in infection and that specific criteria must be met for the virus to interweave its genome with the host cell's.

Knowing how to recreate the initial steps of HIV infection "means we have many more tools for dissecting the process of replication," said study author Wesley Sundquist, a distinguished professor of biochemistry at University of Utah Health. In particular, the study, published Oct. 8 in the journal Science, describes a cell-free system that can be used to study how HIV invades the host genome such a system could "revolutionize HIV experiments in many labs," Leo James, a group leader at the MRC Laboratory of Molecular Biology, who was not involved in the study, told Live Science in an email.

"To have accomplished all this is a real tour de force," James said. Beyond basic research, the system could also help explain how experimental drugs that target the capsid work to limit HIV replication, Sundquist said in a statement.

Related: 12 amazing images in medicine

Although the test tube experiments capture aspects of HIV infection in superb detail, they cannot recreate every step in the process, Sundquist noted. Infection typically starts when the outer membrane of the virus fuses with the membrane of a host cell, allowing the capsid and its innards to sneak inside. But with a cell-free system, the authors had to bypass this initial step.

They instead used a compound found in bee venom, called melittin, to "permeabilize" the viral membrane and release the capsid held within.

The HIV capsid has tiny pores in it, and normally, as a virus particle floats through a human cell's cytoplasm, it picks up the cellular building blocks of DNA, called deoxynucleotide triphosphates, that are already there, according to a 2017 report in the journal Nature. As it travels to the nucleus, the virus particle uses those building blocks to make copies of full strands of DNA, thanks to a special enzyme housed inside the capsid. This is how the virus copies its genetic material to later insert into the host genome. How the virus "knows" when to start this so-called reverse transcription is still somewhat mysterious, but studies hint that biochemical properties of the host cell act as cues for the reaction to begin.

But a test tube doesn't automatically have DNA building blocks in solution, so to jumpstart reverse transcription, the authors added them. "This method has been around for a while, but it's tricky to get the reaction to go until completion," James noted. But the study authors managed to get reverse transcription running smoothly; to do so, they learned that the capsid must stay mostly intact throughout the process.

Related: Going viral: 6 new findings about viruses

"The capsid has to be largely intact, and it has to be of the proper stability or flexibility, to support reverse transcription," meaning the capsid must be bound tightly enough to not fall apart during reverse transcription, but able to open up when the capsid enters the nucleus, in order to unleash its copied DNA, Sundquist said. Fortunately, scientists recently discovered a way to keep the capsid just stable enough.

Study author Owen Pornillos, an associate professor of molecular physiology and biological physics at the University of Virginia, and his colleagues found that a compound called IP6 binds to the capsid's tiled surface, they reported in 2018 in the journal Nature. IP6 carries a negative charge, while each tile carries a positive charge on the side that points in toward the center of the capsid; since opposites attract, when IP6 binds to the capsid, it helps pull the tiles into a tighter, more stable arrangement.

"Before the discovery of IP6, someone would remove the [viral] envelope in vitro and everything would fall apart and they could not see anything," said Joo Mamede, an assistant professor in the Department of Microbial Pathogens and Immunity at Rush University, who was not involved in the study.

IP6 is "quite abundant" in cells, so in their test tube experiments, the authors added similar concentrations of the compound as would be found in cells, Sundquist said. "That was really the trick," he added. "Until we knew it, we were working with capsids that were far too unstable."

Using computer models of molecules and an electron microscope, the authors could literally see that the 240 tiles making up the capsid held their lattice-like structure stable throughout reverse transcription. As the DNA strands grew larger, their ends sometimes poked through tiny gaps in the lattice weave, the authors noted, and sometimes singular tiles could be seen dislodging while the rest of the capsid stayed intact.

The capsid may need to stay stable to keep the RNA and transcribing enzyme close to each other, said Christopher Aiken, a professor of pathology, microbiology and immunology at Vanderbilt University, who was not involved in the study. The enzyme tends to fall off the RNA during transcription, so "by keeping the enzyme contained, it can rebind the template and continue DNA synthesis," Aiken told Live Science in an email.

With reverse transcription complete, the authors then moved on to the next step in infection: integration, where the viral DNA infiltrates the host genome. They introduced DNA strands known as plasmids into their test tubes, to serve as proxies for the DNA in a human nucleus, but integration would not begin without an additional ingredient. Only "whole cell extracts," a mix of proteins and molecules drawn from cells, would allow the viral DNA to pervade the plasmids.

In the future, the team hopes to pinpoint precisely which ingredients in the cell extracts trigger integration, Sundquist said. "It's likely to be more than one thing," he noted. One challenge is that, in test tube experiments, "it's always difficult to know if you're missing something," he said.

Related: The 12 deadliest viruses on Earth

One limitation of the study is that it can't perfectly recreate cellular conditions, James said.

"Any in vitro system, however powerful, can only be used to test the components we know about and can add into the reaction," James said. For instance, in actual cells, the capsid must travel to the cell nucleus, where the DNA is held, and then slip through portals known as the nuclear pores. There may be unknown factors that alter the capsid during this journey, Sundquist noted.

That said, the new cell-free system could help reveal the identity of those unknown factors, Mamede added. Scientists can now make observations in a cell-free environment and then check to see if the same behavior appears in actual cells, he said.

In addition, the system could be useful in drug development. "You can test [new drugs] more readily with one of these simplified systems than with a cell," Mamede told Live Science. "This way, you can see mechanistically what it's really doing to the virus."

The pharmaceutical company Gilead Sciences currently has a new drug in human trials that targets the HIV capsid specifically, according to ClinicalTrials.gov. Based on early data, the drug appears to alter the capsid at various points of infection, including during reverse transcription. Sundquist said that the cell-free study underscores that the capsid is a "critical component" of HIV infection, and that corrupting the capsid can limit the virus's ability to multiply.

Originally published on Live Science.

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Scientists zoom in on HIV inside a test tube, find critical steps in infection - Live Science

Biochemistry

Scientists recreate initial steps of HIV infection in a test tube – News-Medical.Net

Reviewed by Emily Henderson, B.Sc.Oct 9 2020

Accomplishing a feat that had been a pipe dream for decades, scientists have recreated in a test tube the first steps of infection by HIV (human immunodeficiency virus), the virus that causes AIDS (acquired immunodeficiency syndrome).

Doing so has provided up-close access to the virus-;which is otherwise obstructed from view deep within the cell-;and enabled identification of essential components that HIV needs to replicate within its human host.

Specifically, the scientists were able to monitor the virus as it replicated its genome and inserted it into target DNA, mirroring steps that ordinarily take place within the host. Published in Science on October 9, these advances yield a new understanding of how HIV works, the authors say, allowing for explorations of early stages of the virus life cycle in unprecedented detail.

Such knowledge could lead to improved treatments for AIDS, a lifelong disease that can only be kept under control with a continuous medication regimen.

"This is teaching us how HIV infects," says Wesley I. Sundquist, Ph.D., distinguished professor of biochemistry at University of Utah Health. He is co-senior author of the study with his former trainee, Owen Pornillos, Ph.D., now an associate professor at the University of Virginia.

The co-first authors are Devin Christensen, Ph.D., and Barbie Ganser-Pornillos, Ph.D. "We are learning new things about one of the most significant pathogens that humans have ever encountered, and that is important."

For all its danger, HIV is deceptively simple in appearance. The virus resembles a rounded ice cream cone, where an outer shell encapsulates the virus' genetic material inside. Previously, it had been thought that the main role of the shell, called the capsid, was to protect its precious cargo. But the investigations by Sundquist and Pornillos' team show that the capsid also plays an active role in infection.

Carrying out initial steps of infection in a test tube allowed the research team to precisely manipulate HIV in ways that had not been possible before.

They found that when they used genetic and biochemical methods to destabilize the capsid, HIV could not effectively replicate its genetic material. It was the first direct demonstration that, rather than serving merely as packaging, the capsid is an essential component of the HIV infection process itself.

If seeing is believing, then watching the HIV molecule in action gave credence to the experimental finding. Recent advances in cryo-electron microscopy and molecular modeling have made it possible to see the virus-;which, at 130nm, is about 60 times smaller than a red blood cell-;in exquisite detail.

Using these techniques, the team visualized each of the 240 tiny protein "tiles" that fit together to make the cone-shaped outer shell. With the up-close view, the scientists could literally see that the capsid remained largely intact throughout the replication process, called reverse transcription.

This is different than in the textbooks. Our data indicate that the viral capsid plays an active and indispensable role in supporting efficient reverse transcription."

Wesley I. Sundquist, Ph.D., Distinguished Professor Department of Biochemistry, University of Utah Health

Sundquist says that the discovery may help explain why an investigative HIV drug developed by Gilead, the first to target the capsid, is a potent inhibitor of the virus. Previous work by Sundquist, Pornillos, and others elucidating the structure and function of the HIV capsid informed the design of the drug, which has performed well in phase 1 clinical trials. Additional insights gained through the test tube system could improve drug design even further.

Advances in microscope technology, coupled with dogged persistence, led to the new view of HIV, which was first discovered as the cause of AIDS more than 35 years ago.

It took years of trial and error to determine the minimum components required for recapitulating the process in a test tube, outside the cell. Now that the simplified system is up and running, Pornillos says, it opens doors to learning more fundamental truths about a familiar foe.

"For me, there is both the fundamental knowledge aspect of it, but also the translational aspect that could help us come up with better ways to stop HIV," Pornillos says. "That's why it's great research."

Source:

Journal reference:

Christensen, D. E., et al. (2020) Reconstitution and visualization of HIV-1 capsiddependent replication and integration in vitro. Science. doi.org/10.1126/science.abc8420

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Scientists recreate initial steps of HIV infection in a test tube - News-Medical.Net

Biochemistry

Take-home labs and virtual dissections: How the science courses are adjusting – The Scout

Labs have gone hybrid as classes are in person or remote. Photo by Morgan Patrick.

One of the biggest shifts as college and the COVID-19 pandemic collided may have been in the sciences, where a hands-on curriculum plays a big role in student academics.

This past summer, a team of about 40 professors from all departments across campus had meetings to discuss virtual learning and to determine how much face-to-face interaction would be necessary.

In biology, all the labs were kept in-person except for the anatomy labs and major level genetics labs. These labs involve dissections, which could prove difficult to continue if the university decided to shut down all in-person classes. Hence, professors deemed it best to keep these labs virtual instead of shifting back and forth, given the uncertain possibilities.

We discovered very quickly that the virtual dissections that are now available are of high quality and were not even available five years ago, said Kelly McConnaughay, biology professor and acting dean of the College of Liberal Arts and Sciences.

Students have responded positively to these online labs.

My lab professor gives us an informative walk through the experiment outlines as we identify the three-dimensional structures of proteins, genetic mutations, etc., said Dainaly Campuzeno, a senior biomedical science and psychology major. Its been a pretty good experience so far, but it definitely does not beat hands-on experience.

Some other labs, like the Science 101 series, provided remote learners with kits to work on experiments from the comfort of their own homes while being challenged to come up with hypotheses and discover ways to either accept or reject them.

In our department, we have never given students cookbook labs, like Mix this with this and pour this, then write this number down, said Sherri Morris, chair and professor of biology and co-director of Bradleys Center of STEM Education. We encourage them to make observations and challenge themselves to have a certain level of engagement.

In the biochemistry department, all senior-level students are taking their labs in-person due to smaller class numbers and lack of remote learners.

The associate professor and chair of the chemistry and biochemistry department, Michelle Fry, said that students who had to quarantine could even make up missed labs after the quarantine period.

The psychology department is offering the behavioral neuroscience lab this semester, both virtually and in-person. The lab includes the dissection of sheep brains. Students learn about the biological basis of behaviors in animals by locating important structures in the brain that are responsible for daily functions. The lab is offered in-person and virtually.Even though our intent this summer was to be face-to-face during the fall, I dont think we fully grasped the challenges that came with it, like wearing masks and classroom sizes, said Timothy Koeltzow, associate professor and chair of the psychology department.

For virtual learners, a document camera is used to show the dissections while students in the classroom do the brain dissecting themselves in the labs.

There are other internship opportunities through community partnerships offered this semester in the psychology department, which were impacted by the pandemic. Most of the training for those partnerships had to be moved online to reduce contact, as much as possible.

Something good about all of this is that we will be on the other end of this pandemic with a capability to deliver every course in our portfolio online, under the right circumstances, Koeltzow said. This gives us options to engage non-traditional learners or people who almost finished their degree but could not do so, due to other circumstances.

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Take-home labs and virtual dissections: How the science courses are adjusting - The Scout

Biochemistry

Walther Cancer Foundation $11 million investment to expand IU-Purdue bioinformatics collaboration – Purdue News Service

October 8, 2020

Nadia Lanman, a research assistant professor in Purdue College of Veterinary Medicine's Department of Comparative Pathobiology and member of the Purdue Center for Cancer Research, plays a key role in the computational bioinformatics program at Purdue University that is supported by the Walther Cancer Foundation. Through computational bioinformatics, Lanman attempts to discover the molecular mechanisms that underlie cancer and that determine the response of patients to chemotherapy. (Photo provided)Download Photo

INDIANAPOLIS AND WEST LAFAYETTE, Ind. - The Walther Cancer Foundation will invest $11 million to advance collaborative cancer research at Indiana University and Purdue University by supporting scientists through bioinformatics an increasingly critical aspect of their work.

Bioinformatics involves managing and analyzing the massive amounts of data generated by scientific research turning data into knowledge that could lead to new cancer treatments.

We hope this gift enables scientists at IU and Purdue to dig more deeply and refine their studies so they can point out new pathways to good patient outcomes in cancer, said Tom Grein, president and CEO of the Walther Cancer Foundation. Sometimes you have so much data, its hard to comprehend where its leading you. I hope the data-driven analysis will uncover nuggets of opportunity that would otherwise never be seen.

Income from the new Walther Cancer Foundation Bioinformatics Fund will continuously support bioinformatics personnel, technology, and other tools shared by the cancer research programs at both universities. In addition, IU and Purdue will make their own investments into the fund.

The Walther Cancer Foundation leadership understands the central importance of data and analytics in developing better treatments and, ultimately, cures for cancer, said IU School of Medicine Dean Jay L. Hess, MD, PhD, MPH.We are tremendously grateful for their support and the confidence they have in our work.

Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research, said the latest gift from the Walther Foundation is a continuation of a longstanding collaboration, commitment and investment that will build on the centers success in cancer drug discovery and development and will help sustain the centers computational genomics and bioinformatics core for years to come. "Once again, we are grateful to the Walther Cancer Foundations vision and generosity, which is so important to our research and success. This continuing partnership, plus our own investments and fundraising, will secure what weve already established and enable us to grow into the future."

Kelvin Lee, M.D., named this week as the new director of the IU Melvin and Bren Simon Comprehensive Cancer Center and the H.H. Gregg Professor of Oncology, said having strong capabilities in bioinformatics is essential to cancer research.

The genetic, biochemical, cellular and immune pathways that can lead to cancer are extraordinarily complex and intertwined. Recent cutting-edge advances in technology means that researchers now have unprecedented amounts of data on these pathways, but this seriously challenges our ability to analyze these huge mounds of information to make sense of what is actually going on, Lee said. We are fortunate that the Walther Cancer Foundation understands that breakthroughs require the expertise and the tools, like artificial intelligence, to help us analyze all this data so we can understand whats really important.

This level of collaboration and sharing of a key resource like a bioinformatics core is unusual among a pair of National Cancer Institute-designated cancer centers. But it also reflects the complementary nature of the two institutions.

Purdues Center for Cancer Research is a basic science cancer research center with more than 110 researchers that is a leader in biomedical engineering and cancer drug development.

The IU Melvin and Bren Simon Comprehensive Cancer Center is a comprehensive cancer center with nearly 250 cancer researchers who conduct basic lab work and drug development but who are also engaged in clinical care and population health research.

Each of them has different capabilities, different levels of expertise, different interests, Grein said. But when you get scientists to collaborate, the outcomes are better.

Since its founding in 1985, the Walther Cancer Foundation has invested more than $165 million in cancer-focused medical research and in research and education aimed at supporting cancer patients and their families.

Walther has previously supported cancer bioinformatics at IU and Purdue on a year-to-year basis. This new gift establishes a fund that will ensure the bioinformatics work continues in perpetuity.

The Walther Foundation endowment provides the opportunity to develop the expertise and the tools that are needed to face current and future challenges in biology and the cancer field, said Majid Kazemian, an assistant professor in Purdues departments of Biochemistry and Computer Science. His research focuses on integrating computational and experimental approaches to study pathogen interaction with host cells and immune system in infectious diseases and cancers caused by pathogens.

"The Purdue University Center for Cancer Research has nearly 100 investigators who are actively engaged in understanding molecular mechanisms of various diseases including lung, liver and prostate cancers, many of which have begun to utilize genomics data in their studies, Kazemian said. "Large genomic public data on many diseases generated over the last decade are a treasure trove of unexplored information. Walther Foundation's funds endowment will enable analysis of big data generated by our centers members and collaborators as well as an exploration of growing public genomics data to contextualize and translate our findings."

Less-costly access to bioinformatics expertise and resources enabled by Walther Foundation will open up

Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research, works in a lab at the center. (Purdue University photo/John Underwood)Download Photo

new avenues for many of the Purdue center's scientists to broaden the impact and clinical translation of their discoveries, Kazemian said. "It will also encourage our scientists to perform large-scale genomics assays and will foster new collaborations.

Harikrishna Nakshatri, Ph.D., the Marian J. Morrison Professor of Breast Cancer Research at IU School of Medicine, said he relies on bioinformaticians to design experiments, analyze data and assist him in publishing research results more quickly. The Walther Foundation gift supports that very expensive process, and the collaboration means researchers have more bioinformaticians available when they are needed. All of it combines, Nakshatri said, to enable scientists to reach conclusions that have real benefits for patients.

If you really believe in your hypothesis, Nakshatri said, now you have a chance to test it because you are not burdened by the financial aspects.

According to Hess, the new resources will allow IUs partnership with Purdue to continue to improve the health of Hoosiers. We have worked closely for decades, Hess said. This new collaboration in data sciences will accelerate our ability to benefit cancer patients across the state and far beyond.

About the Walther Cancer Foundation

The Indianapolis-based Walther Cancer Foundation is a private grant-making foundation that supports and promotes interdisciplinary and inter-institutional cancer research, both bench and clinical. The clinical research it supports encompasses clinical trials as well as behavioral studies, the latter as part of the foundations commitment to Supportive Oncology. The Walther Foundation has two primary goals: to support cancer research with the aim of discovering better treatments, if not cures, and to develop a comprehensive approach for supporting patients with cancer and their families. Since its founding, the foundation has invested over $165 million cancer-focused research.

Dr. Kelvin Lee, director of the IU Melvin and Bren Simon Comprehensive Cancer Center (Photo provided) Download Photo

About the Purdue Center for Cancer Research

Since 1978, the Purdue University Center for Cancer Research has been a National Cancer Institute-designated basic-research cancer center. Only seven institutions in the United States have earned this title. Being a basic-research center means it does not treat cancer patients directly. Its work focuses on investigating cancers where they begin at the cellular level to investigate the cause of, and cure for, one of the most devastating killers of our time. Doctors and scientists throughout the world use the centers discoveries to develop methods, medicines and medical devices to save and enhance patient lives.

About the IU Simon Comprehensive Cancer Center

The Indiana University Melvin and Bren Simon Comprehensive Cancer Center is home to the cure of testicular cancer, the worlds only healthy breast tissue bank and is just one of 51 NCI-designated Comprehensive Cancer Centers in the nation. The prestigious comprehensive designation recognizes the centers excellence in basic, clinical, and population research, outstanding educational activities, and effective community outreach program across the state. Its physician-scientists have made protocol-defining discoveries that have changed the way doctors treat numerous forms of cancer.

Media contacts: Jim Bush, 765-336-1909, jsbush@purdue.edu

Katie Duffey, 317-278-3630, kaduffey@iu.edu

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Walther Cancer Foundation $11 million investment to expand IU-Purdue bioinformatics collaboration - Purdue News Service

Anatomy

Early development of the Neanderthal ribcage reveals a different body shape at birth compared to modern humans – Science Advances

Abstract

Ontogenetic studies provide clues for understanding important paleobiological aspects of extinct species. When compared to that of modern humans, the adult Neanderthal thorax was shorter, deeper, and wider. This is related to the wide Neanderthal body and is consistent with their hypothetical large requirements for energy and oxygen. Whether these differences were already established at birth or appeared later during development is unknown. To delve into this question, we use virtual reconstruction tools and geometric morphometrics to recover the 3D morphology of the ribcages of four Neanderthal individuals from birth to around 3 years old: Mezmaiskaya 1, Le Moustier 2, Dederiyeh 1, and Roc de Marsal. Our results indicate that the comparatively deep and short ribcage of the Neanderthals was already present at birth, as were other skeletal species-specific traits. This morphology possibly represents the plesiomorphic condition shared with Homo erectus, and it is likely linked to large energetic requirements.

Prenatal and early postnatal growth and development are crucial to understanding the adult size and shape of the different anatomical regions because of the large number and high rate of size and shape changes occurring in the human body during those phases (15). Also, from an evolutionary point of view, prenatal and early postnatal ontogeny are decisive because evolution happens via phylogenetic modification of the ontogenetic processes that occur mostly in those phases (3, 6, 7).

Adult morphologies can vary because of interspecific differences in the shape of an anatomical element at the moment of birth that are caused by differences in the prenatal ontogenetic trajectories or because of differences in the shape of an anatomical element that arise after birth that are caused by differences in the postnatal ontogenetic trajectories, either concerning their orientations, lengths, or a combination of both (1). Roughly speaking, if morphological differences are found at birth and the postnatal ontogenetic pattern is equal in the two species, their ontogenetic trajectories will be parallel. Conversely, if they have a similar morphology at birth but show differences in the postnatal ontogenetic pattern, their ontogenetic trajectories will be divergent (13). This distinction is important because parallel postnatal ontogenetic trajectories between two closely related species could point to a consistency of genetic regulation of that anatomical element (1). In addition, the fact that a morphological feature is already present at birth will suggest that it is a relevant taxonomical characteristic not caused by developmental plasticity.

Despite genetic similarities that allowed for admixture (8), there is a well-established consensus that Neanderthals showed significant morphological differences when compared to modern humans (MHs) in the cranium and postcranium (9, 10). Some of these differences are plesiomorphic inherited traits from their Early or Middle Pleistocene ancestors, while others are present exclusively in Neanderthals (autapomorphies) (11, 12). Neanderthals were highly encephalized (4, 13, 14) and heavy-bodied hominins (15, 16) requiring large amounts of energy (1719). It has been proposed that to fulfill these energetic demands, the Neanderthal thorax had a large estimated total lung capacity (19) and a different thoracic shape that included a shorter, slightly deeper, and mediolaterally larger chest with more horizontally oriented ribs and a more invaginated thoracic spine, compared to MH (1926).

The very specific Neanderthal traits found throughout the skeleton (i.e., those different in size and shape from MH) are the result of differences present at birth and/or differences in the postnatal ontogenetic pattern, which may vary in different skeletal regions. However, despite being the best-known extinct human species, there are only a few studies on the Neanderthal postnatal ontogeny due to the paucity of well-preserved subadult fossil remains, especially of the postcranium. Nonetheless, despite the limited record, some patterns have been proposed, providing evolutionary insights. For example, MH and Neanderthal femoral length followed similar growth patterns with no differences at birth (27). Other anatomical traits (e.g., general cranium shape, clavicle length, and femoral and tibial robusticity) seemed to be different at birth between the two species and followed parallel ontogenetic trajectories, resulting in different adult shapes (2, 27, 28). Last, in the case of the mandible (2, 29) and the brain (4, 13, 14), Neanderthals and MH had not only different shapes at birth but also divergent growth patterns. However, there are still many anatomical regions that are relatively well known in the Neanderthal adult record for which there are few ontogenetic studies, which is the case of the thorax (24, 25). Methodological improvements in virtual reconstruction and statistical missing data estimation have improved the knowledge of the adult Neanderthal thorax (26). However, ribs and vertebrae from perinates and infants are smaller and more fragile, which represents a major challenge during the study of the early postnatal ontogeny of the Neanderthal thorax. So far, only basic descriptions and inventories of fossil ribs and vertebrae have been available (30, 31), and artistic license was used when ribcage reconstructions of subadults were made (4).

Apart from this very basic knowledge, the little information we have about this issue comes from (i) descriptive anatomy of the prenatal (32) and early postnatal ontogeny of MH (33, 34) and (ii) late postnatal ontogeny of the Neanderthal first ribs (20). Research on prenatal ontogeny of the MH ribcage has found that all thoracic dimensions (anteroposterior, craniocaudal, and mediolateral) are modified during the fetal period to result in the newborn ribcage (32). All these dimensions develop differently in the different rib levels: For example, all levels have roughly the same anteroposterior relative length in early fetuses, whereas the upper and central ribs of late fetuses are much deeper, relatively, than the lower levels (32). This is consistent with research on later postnatal ontogeny of the human ribcage, which has found that, after birth, the upper and lower thorax have a differential development that gives rise to the adult ribcage of MH, which is relatively expanded in the cranial part and narrow in the caudal part (33, 34). This differential development, controlled by Hox gene expression (35), is crucial because it indicates that slight modifications during development at different rib levels would cause different ribcage morphologies. This could have evolutionary implications for understanding the adult thorax not only in our own species but also in other hominins such as Neanderthals. In addition, the only study that tackled the postnatal ontogeny of the thoracic skeleton in this species was carried out by Bastir et al. (20). They found divergent ontogenetic trajectories in the first ribs of MH and Neanderthals, the latter showing less curved first ribs in the youngest specimen (La Ferrassie 6) and along the entire postnatal ontogeny when compared to MH. However, we do not know to what extent this could be extrapolated to the entire thorax.

In this study, we used virtual and statistical methods to reconstruct the ribcage of four young Neanderthal specimens (Table 1), identifying potential differences with MH in thorax morphology affecting the evolution of body shape and influencing respiration. Specifically, we reconstructed the ribcages of perinatal individuals of Mezmaiskaya 1 [M1; 7 to 14 days (4)] and Le Moustier 2 [LM2; <120 days (36)] and infant individuals from Dederiyeh 1 [D1; 1.41 years (37)] and Roc de Marsal (RdM; 2.54 years (31)]. We also provided the first three-dimensional (3D) morphological assessment of the early postnatal ontogeny of the MH ribcage during the decisive first 3 years of postnatal life to serve as a comparative baseline. Because of the differences in this anatomical region in adults, we tested whether Neanderthal thorax morphology was already different from that of MH at birth.

Final reconstructions of the four Neanderthal ribcages are shown in Fig. 1 and text S1.

Bones that are preserved in the original specimen are shown in red, whereas mirror images are shown in blue and statistical estimations in gray (only for D1 specimen).

The ribcage of MH shows a rapid growth during the first ca. 100 days of life, which changes to a slower growth rate afterward (Fig. 2). For Neanderthals, we measured the centroid size (CS; see Materials and Methods) directly from the thorax reconstruction in D1 and using the costal size and thorax CS correlation (double-checked in the latter 3D reconstruction) in the rest of the individuals (Table 1 and text S1). When plotted with respect to their estimated age (or age ranges), the perinatal M1 individual fits well within MH size variation; the infant D1 is within this variation but above the MH regression line. For the two other Neanderthals, their current age-at-death ranges are wide but consistent with growth patterns observed for M1 and D1. The growth trajectory based on the mean Neanderthal age-at-death estimates roughly overlaps with that of MH during the first ca. 100 days but then diverges, with the Neanderthals growth being slightly faster. This overall pattern, using CS as a proxy for thoracic size, is also present on the tubercle-ventral chord (TVC) of individual ribs (text S2), a classic measurement for evaluating costal size (22, 25).

For the latter, we plotted minimum (triangles), average (squares), and maximum (circles) ages proposed in the literature. The growth trajectories of MH and Neanderthals are displayed in blue and red color, respectively, and Neanderthal trajectories representing minimum and maximum ages are displayed as dotted lines. Note that individuals with very similar CS are overlapped, e.g., the case of Ind27 and Ind29.

When compared to MH of the same CS (as a proxy of volume), the four Neanderthal reconstructions showed metric differences that were consistent in all of them regardless of their age at death (text S3). All the Neanderthals had a craniocaudally shorter thoracic spine and a deeper thorax anterior-posteriorly when compared to MH of equivalent CS. However, the thorax width of the Neanderthals exceeded that of MH only in the oldest individuals (D1 and RdM), but not in the youngest ones (M1 and LM2; Table 2 and text S3).

Thorax width was quantified at the level of rib 7, thorax depth is at the level of T5 from the spinous process to the distal end of rib 5 (average of both sides), and anterior spine length is quantified as the distance between the anterior-superiormost point of T1 body and the anterior-inferiormost point of the T12 body. Standardized values of MHs were calculated on the basis of linear regression of classic measurements on full thorax CS (text S4). Smaller Neanderthal values are labeled with the symbol *, whereas larger values are labeled by the symbol #.

During early postnatal ontogeny, MH changes from a ribcage that is relatively narrow in the cranial part and extremely wide in the caudal part toward a ribcage that is volumetrically expanded in the cranial part and still wide in the caudal part (text S4). Perinatal Neanderthals (M1 and LM2) also have an upper ribcage that is relatively narrower than in older specimens (D1 and RdM), who have a more globular ribcage with similar widths at the upper and lower thorax (Fig. 1). In addition, the exploration of the 3D warps associated with standardized CS in Neanderthals and MH shows consistent interspecific morphological differences throughout the postnatal ontogeny studied here (Fig. 3). The Neanderthal thoracic spine is relatively shorter, and from the third rib onward, the ribcage of the Neanderthals is relatively deeper than in MH. In the most complete individual (D1), it is also possible to observe that its spine is more invaginated within the thorax than in MH (text S5). In this individual, the mid-lower ribs are relatively longer than the uppermost and lowermost ones, when compared to MH of the same CS.

To better visualize the morphological differences between species, we warped a complete MH infant thorax 3D model into the coordinates of the fossil specimens using EVAN Toolbox software. Human standardizations were calculated using a multivariate regression of shape on the size of the 29 individuals from the comparative human sample. Perinatal Neanderthals (M1 and LM2) have an upper ribcage that is relatively narrower than in older specimens (D1 and RdM), who have a more globular ribcage, with similar widths at the upper and lower thorax (Fig. 1). Besides, the Neanderthal thoracic spine is relatively shorter, and from the third rib onward, the ribcage of the Neanderthals is relatively deeper than in MH. In the most complete individual (D1), it is possible to observe that this spine is more invaginated into the thorax than in MH. In this individual, it is also possible to assess that, when compared to MH of the same CS, the mid-lower ribs are relatively larger than the uppermost and lowermost ones. Regarding the orientation of the ribs in the sagittal plane, different declination can be observed at different rib levels, with the upper Neanderthal ribs (from 1st to 6th) more declined than in MH and the lower ribs (from 10th to 12th) more horizontally oriented. Rib torsion also contributes to interspecific differences because Neanderthal central ribs (from 6th to 8th) of early individuals have a stronger torsion (understood as spiraling) than in MH.

Regarding the orientation of the ribs in the sagittal plane, a different declination can be observed at different rib levels, with the upper Neanderthal ribs (from 1st to 6th) being more declined than in MH and the lower ribs (from 10th to 12th) more horizontally oriented. Rib torsion also contributes to interspecific differences because Neanderthal central ribs (from 6th to 8th) of early individuals have a stronger torsion (understood as spiraling along the rib axis) than in MH. Last, other minor differences can also be observed in Fig. 3. For example, both the upper (from 1st to 5th) and very lower (from 10th to 12th) regions of the Neanderthal ribcage are slightly wider than in MH, and their first ribs are less curved than in MH (see details in text S5).

When the morphological ontogenetic variation between species is explored in a Procrustes form space (size + shape; see Materials and Methods) principal components analysis (PCA; Fig. 4), we observe that the PC1 versus PC2 projection (96.57% of the variance of the sample) captures ontogenetic variation along the first PC and interspecific variation along the second PC. During postnatal ontogeny (from the PC1 negative values to the positive ones), the pear-shaped ribcage of newborns changes into a more globular ribcage in infancy. The main changes, which occur in the upper ribcage, are likely related to changes in the rib orientation at the costovertebral joint and the ossification at the distal end of the ribs. The morphological variation between humans and Neanderthals (observed along PC2 and independent of ontogenetic state) shows that the latter present more caudally oriented ribs and spines that are shorter and more invaginated within the thorax than in MH. Last, the relative maximum depth is found in the central-upper thorax in MH, whereas in Neanderthals it is found in the central-lower thorax.

PC1 represents mainly ontogeny, whereas PC2 represents interspecific variation.

This clear ontogenetic and interspecific distribution along PC1 and PC2 allows us to evaluate a hypothetical ontogenetic linear regression for each species, which is almost parallel between humans and Neanderthals during early postnatal ontogeny. The slope of the Neanderthal linear regression (a = 0.008) is clearly within the confidence interval (CI) for their regression slope (a = 0.031; CI, 0.065 to 0.032). This implies that although Neanderthals and MH are different at birth, the morphological trend is similar in both species during early ontogeny, with each species undergoing a volumetric expansion of the ribcage and a lower thorax still relatively wider than the upper one but to a much lesser degree than in adults.

Most authors agree that prenatal ontogeny and the first years of postnatal ontogeny are key to understanding species-specific features of hominin anatomy that we find in adults because of the prominent growth and development during those phases (1, 35, 29). Our results allow us to explore this issue in the Neanderthal ribcage, shed light on their body shape evolution and bioenergetics, and have implications for understanding the evolution of the thorax in MH.

Previous research on Neanderthal adult thorax size found that the upper Neanderthal ribs were similar (25) or even smaller than in MH (20, 24), whereas the central-lower ribs were significantly larger (22, 24, 25). While the Neanderthal costal skeleton as a whole was large, relative to the humeral length (25), the general volume (using CS as a proxy) was similar to MH due to both the shorter thoracic spine and the morphology resulting from the articulation of the costal skeleton with the spine (24, 26).

In general terms, and when compared to MH, our study shows that Neanderthals had similar general thorax sizes around birth but reached slightly larger thorax sizes in infancy (D1 and RdM), suggesting a higher thorax growth rate during the first few years of postnatal life. This would be consistent with the notion of a more rapid life history for Neanderthals based on evidence of dental histology (3840) and also dental development in individual D1, thought to be a 2-year-old because of the development of their incisors (41) despite the estimated histological age at death of ca. 1 year and 5 to 7 months (37). On one hand, we can hypothesize that because the overall adult Neanderthal ribcage was similar to that in MHs, if this rapid growth rate was not limited only to the early postnatal ontogeny and occurred later, the adult size in Neanderthal thoraces would have been reached earlier than in MH. On the other hand, other researchers have proposed that juvenile Neanderthals had a slower fusion of some elements of the thoracic spine compared to MH (27), which could suggest a slowdown of the thoracic growth or a dissociation of the ribcage size increase and the fusion of some spinal elements in Neanderthals. Dissociations of dental development, somatic growth, and life history variables are not infrequent (42), and a more comprehensive approach would include the study of the dental development along with the development of other anatomical elements such as the ribcage or the brain from the same individuals.

In our study, we built a growth trajectory based on the studied individuals (Fig. 2) using an accurate age-at-death estimate for M1 and D1 individuals and a relatively large range for LM2 and RdM. For these individuals, we have used the mean value of the upper and lower limits of the age range. In the case of RdM, the value used (1186 days; i.e., 3.24 years) was similar to the estimated histological age of Engis [3 years (39)], which shows a similar pattern of development to RdM (43). In addition, on the basis of the MH growth trajectory (Fig. 2), we consider it likely that LM2 was less than 75 days old. Other researchers found that for some skeletal values such as humeral length or femoral length, this specimen had slightly lower values than M1 (44), so a slightly younger age for LM2 could be attributed compared to M1.

Once the M1, LM2, D1, and RdM ribcages were reconstructed, the form space PCA assessment still yielded an almost parallel growth trajectory. This is consistent with the parallel growth trajectories from other Neanderthal anatomical traits, such as the general cranium shape, clavicle length, or the femoral and tibial robusticity, features that present interspecific differences already at birth (2, 27, 45).

Our size results based on linear measurements of the ribcage show that shorter and deeper thoraces in Neanderthals are very constant throughout the early postnatal ontogeny, but absolute thorax width changes early in postnatal ontogeny. This is based on the perinatal M1 and LM2 individuals, whose ribcages are absolutely narrower than those of their MH counterparts of the same CS (M1 < MH by 0.5%, LM2 < MH by 0.3%), and on infant D1 and RdM individuals, whose ribcages are absolutely wider than those of their MH counterparts (D1 > MH by 0.5% and RdM > MH by 1.3%). The most complete individual, D1, provides us with two additional features also observed in Neanderthal adults: the relatively longer mid-thoracic ribs compared to the uppermost and lowermost ribs and the presence of a more invaginated spine within the thorax than in MH. The latter feature is also suggested by the more dorsally oriented transverse processes of the lowermost thoracic vertebrae of RdM.

Apart from the traditional measurements, the size based on CS confirms that perinatal Neanderthals already exhibited significant differences in thorax morphology when compared to MH (Figs. 1 to 4). Not only the best-preserved Neanderthal (D1) but also the rest of the individuals that were estimated using an MH reference had several features that are species-specific and distinguish them from MH: the relatively shorter thoracic spine, the deeper thorax, and the (slightly) wider ribcage, features that are also observed in adults (21, 24, 26). The relatively short thoracic spine, which is related to relatively shorter vertebral bodies, was already noticed in the D1 individual (45), and despite the limited adult Neanderthal fossil record, it has been proposed as a specific feature of the adult thoracic vertebrae (21) or the thoracic spine as a whole (26). Our results are also consistent with previous research on body form of LM2, M1 (44), and D1 (45) that hypothesized that perinatal Neanderthals already had a wide body, with a long pubis and robust long bones. Last, this is in concert with the results from the Neanderthal La Ferrassie 6, where the authors hypothesized that the elongation of the Neanderthal pubis was a feature expressed early in ontogeny (46). These features, present at birth and constant in early postnatal ontogeny, would make the trunks of very young Neanderthals volumetrically larger compared to MH, which would underline the presence of different body shapes in Neanderthals throughout their entire ontogeny (1517).

Our results support that, for the very early postnatal ontogeny (0 to 3 years), Neanderthal and MH thoraces followed an almost parallel ontogenetic trajectory, which is in agreement with research on the skull and clavicle (2, 4, 5, 27, 47). However, when looking at other anatomical regions, previous authors suggested divergent trajectories for anatomical traits such as the shape of the brain and mandible (1, 13, 14).

In our specific case, it could be argued that Neanderthals and MH followed parallel or just slightly divergent (not statistically significant) trajectories because we used an MH reference for the Neanderthal growth simulations. The inclusion of older subadult Neanderthal individuals [e.g., El Sidrn J1 (27) and Teshik-Tash 1 (48)] will complement our current understanding of their postnatal thorax growth. For the moment, our ontogenetic interpretations should be restricted to these very early stages. It is possible to find stronger morphological differences in later postnatal ontogeny of the thorax because it is a structure influenced by body composition and energy requirements, which are strongly modified during adolescence, at least in MH (49).

Together, the current evidence indicates that most of the skeletal differences between the Neanderthal and MH thorax are already largely established at birth, the Neanderthal thorax being deeper and shorter than that of MH and showing a strongly invaginated spine at a young age. This is consistent with research on the Neanderthal postcranium of M1 and LM2 that found that, with some exceptions (e.g., radius/humerus proportions), the skeletal differences between Neanderthals and MH were largely established by the time of birth. The fact that the characteristic differences between Neanderthal and MH thoracic morphologies are already present at birth indicates species-specific differences in the prenatal developmental trajectories and their genetic underpinnings. This early determination of shape might fit with paleogenetic studies proposing a selective sweep of RUNX2, a genetic fixation of genes somehow related to ribcage morphology (8).

Note that the thoracic differences between adult Neanderthals and MH were already noted by some 20th century anthropologists, who referred to adult Neanderthals as barrel-chested. However, this is confusing because the ribcages of Homo erectus from Nariokotome and the MH ribcage have also been called barrel-shaped [see references in the work by Franciscus and Churchill (22)]. Thus, while the term barrel-shaped may be useful for differentiating the thoracic bauplan of the late members of the genus Homo from that of great apes [traditionally described as having funnel-shaped ribcages (50)], it is limited when differentiating between taxa such as MH, H. erectus/ergaster, or Neanderthals. We consider the ribcage of the latter two species to be characterized by a short and deep barrel shape, whereas the MH thorax is characterized by a tall and flattened barrel shape (46), consistent with their respective somatotypes (15).

In addition, the fact that morphological differences in the ribcage are already present at birth confirms that these are relevant taxonomical characteristics that are not caused by developmental plasticity. This is consistent with the idea that the Neanderthal body plan is likely plesiomorphic in the genus Homo, inherited at least from their Middle Pleistocene ancestors from Sima de Los Huesos (11, 12, 51) if not already from H. erectus (46). Stocky bodies (high body mass index, combined with nonmodern body proportions) have been proposed for some Early Pleistocene hominins, based on the information from the Gona pelvis (52) and supported by recent estimations of Kenia National Museum-West Turkana (KNM-WT) 15,000 body size (53). Previous researchers also noticed in Neanderthal ribs and vertebrae some plesiomorphic features likely inherited from H. erectus, such as the rounder cross section, the lack of torsion of the lower ribs (22, 54, 55), and the more dorsal orientation of the transverse processes (21, 55). A recent reconstruction of the Nariokotome ribcage shows that thoracic features such as the deep and short thorax of Neanderthals are already found in H. erectus/ergaster (55). This evidence supports the hypothesis that the Neanderthal thorax, linked to a massive body, is (at least partially) inherited from their Early Pleistocene ancestors (text S6). As a consequence, the MH thorax, narrow and shallow with twisted ribs and narrow rib cross sections (12, 22, 54), would be derived within the Homo clade (text S6), suggesting that the Neanderthal ribcage morphology is a phylogenetically informative feature and not caused by developmental plasticity.

Last, the ontogenetic evidence presented here lends further support to the hypothesis that Neanderthals had high metabolic demands: Their distinctive thoracic morphology was already present at birth, and thoracic growth was faster than in MHs (10, 17, 19). Large piriform aperture/nasal bones in the RdM, LM2, D1, and D2 individuals have been observed (14, 31, 41, 56), which would be in concert with a high airflow into the respiratory system through a more projecting face in Neanderthal perinates compared to MH (14) and the hypothetical functional integration between the cranial and postcranial respiratory system (57). In addition, the morphological differences in the Neanderthal thorax found at birth, paralleling their adult state, would show a body shape characterized by shorter, deeper, and (slightly) wider trunks compared to MH of the same size. This would be consistent with previous authors on Neanderthal postcranial anatomy that proposed that perinatal individuals such as M1, LM2, or La Ferrassie 6 would be characterized by a very large ilium relative to femur length, similar to what is observed in adults (4446).

Background information regarding the Neanderthals studied here can be found in the corresponding literature (31, 36, 58, 59). Data acquisition of original thoracic material from the Neanderthals D1 and M1 was performed with helical computed tomography (CT; beam collimation, 1 mm; pitch, 1; slice reconstruction increment, 0.3 to 0.5 mm). The LM2 specimen was scanned at the Muse National de Prhistoire in Les Eyzies-de-Tayac-Sireuil using the portable industrial CT scanner (BIR ACTIS 225/300) of the Max Planck Institute for Evolutionary Anthropology Leipzig (MPI-EVA), with an isotropic voxel resolution of 70 m. The RdM Neanderthal axial skeleton was scanned with an Artec Spider 3D scanner (www.artec3d.com/). The comparative human sample comprises 29 forensic individuals whose ages comprised from birth to 3 years old that were scanned at the Institute of Forensic Medicine of the University of Zurich (text S7). All individuals were scanned in the supine position for postmortem virtual autopsy. Individuals with obvious pathologies affecting skeletal thoracic form were excluded. Because individuals were cadavers, any uncertainty caused by kinematic status while scanning was automatically ruled out. Before analysis, all CT data were anonymized to comply with the Helsinki declaration, and the approval to use these preexisting CT scans for our research was obtained from the Ethical Committee of the Canton of Zurich (BASEC-Nr. Req-2019-00987).

Ribcages were segmented through a semi-automatic protocol for Digital Imaging and Communication On Medicine (DICOM) images using the 3D Slicer software (www.slicer.org/) and subsequently reconstructed as 3D models. These 3D models were imported into Viewbox4 software (www.dhal.com) for (semi-) landmarking using existing protocols (60). Thoracic morphology was quantified through 20 homologous 3D landmarks and semilandmarks on ribs 1 to 10 and 19 3D landmarks and semilandmarks on ribs 11 and 12. Four landmarks were measured on each thoracic vertebra, and two on the sternal manubrium. The thoracic morphology was described by 524 landmarks and sliding semilandmarks (60). Semilandmarks were slid along their corresponding curves concerning the fixed landmarks to minimize bending energy from each individual to the consensus of the sample (61). Missing data in both the MH and the Neanderthals were estimated following a thin-plate spline approach (62). In the reference Neanderthal for the developmental simulations, D1, only 17% of landmarks or semilandmarks were missing, and they were estimated using MH as a reference. Once the whole set of coordinates was obtained, the landmarks were submitted to the Procrustes superimposition and analyzed following standard procedures for size and shape analysis (61). The size was studied through the CS, calculated as the square root of the sum of squared distances of all the landmarks from their centroid (61).

The TVC was used to address differences in linear measurements at different levels of the ribcage. Specifically, we studied the TVC of the 1st, 8th, and 10th ribs of the sample, because those levels were the best represented in the Neanderthal sample. Also, because the 8th and 10th levels are used for full thorax CS estimations of M1, LM2, and RdM, it is important to know whether we are under- or overestimating those sizes using costal size versus full thorax size correlations. These differences were assessed using a biplot of the log-transformed distributions of TVC versus age with the 95% confidence ellipse and the convex hull distribution for MH. In the case of the M1, LM2, and RdM Neanderthals, we plotted their estimated range of maximum and minimum age from the literature (4, 36, 37, 43). Virtual reconstruction of the thoracic elements and ribcage of the D1 subadult ribcage was done in the first place because it was the best-preserved individual of the four Neanderthals studied here. The reconstruction was done through virtual (e.g., mirror image) and statistical methods (text S1), previously validated and published (26, 63). Once the ribcage of this individual was reconstructed, we carried out forward/backward developmental simulations (64) using D1 as a reference for reconstructing the other three ribcages (LM2, M1, and RdM), based on the ontogenetic trajectory of our comparative sample of 29 recent humans from birth to 3 years (text S7).

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Acknowledgments: We acknowledge C. Cretin and P. Jacquement for providing access to the RdM individual and providing technical assistance, respectively. We also acknowledge P. Bayle for providing technical assistance with the CT scans of the LM2 axial skeleton and M. Thali (director of the Institute of Forensic Medicine of the University of Zurich) for approving access to the CT scan data. Last, we acknowledge the contribution of three anonymous reviewers and the editor that improved previous versions of this manuscript. Funding: This work was funded by the IdEx University of Bordeaux Investments for the Future program (ANR-10-IDEX-03-02); projects CGL2012-37279 and CGL2015-63648P (Spanish Ministry of Economy, Industry, and Competitiveness), CGL2015-65387-C3-2-P (MINECO/FEDER), and PGC2018-093925-B-C33 (FEDER/Ministerio de Ciencia e Innovacin-Agencia Estatal de Investigacin); and Research Group IT1044-16 from the Eusko Jaurlaritza-Gobierno Vasco and Group PPG17/05 from the Universidad del Pas Vasco-Euskal Herriko Unibertsitatea. The Juan de la Cierva Formacin program (FJCI-2017-32157), from the Spanish Ministry of Science, Innovation, and Universities, funds D.G.-M. A.G.-O. is funded by a Ramn y Cajal fellowship (RYC-2017-22558). Author contributions: Conception and design of the experiments: D.G.-M., M.B., C.P.E.Z., and M.P.d.L.; acquisition of data: D.G.-M., B.M., L.G., V.D., T.A., O.K., H.I., D.G., C.P.E.Z., and M.P.d.L.; data analysis/interpretation: D.G.-M., M.B., C.P.E.Z., M.P.d.L., A.G.-O., and Y.H.; drafting of the manuscript: D.G.-M. with the help of A.G.-O.; critical revision of the article: D.G.-M., B.M., A.G.-O., L.G., V.D., T.A., O.K., H.I., D.G., C.P.E.Z., M.P.d.L., and Y.H. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Early development of the Neanderthal ribcage reveals a different body shape at birth compared to modern humans - Science Advances

Anatomy

Millie Bobby Brown In Grey’s Anatomy (& 9 Other Child Star Appearances We Forgot About) – Screen Rant

Millie Bobby Brown is known for her work on Stranger Things and Enola Holmes, but like these 9 other child stars, her first work is often forgotten.

Growing up as a child star has its ups and downs. Due to the pressure, being around adults most of the time, and coming into good fortune at a young age, many child stars have issues being in the spotlight by the time they are an adult. Some child actors leave the acting world before growing up, having had their fill and preferring to do other things as an adult. Child stars that were able to make it through therough patches are far and few between, but these 10 stars were able to make it happen.

RELATED:10 Child Stars To Look Out For In The 2020s

These stars are older now and have incredibly successful careers, but they were once coming up in the acting world and had small roles in very popular shows that are often forgotten.

Grey's Anatomyis about to enter its 17th season this November. The show has won countless awards and madeits main cast wealthier than their wildest dreams. With over 360 episodes to its name, it's no surprise that fans have seen famous guest stars over the years.

Millie Bobby Brown is one young actress who made it big with her Netflix hit,Stranger Things, but she had an appearance onGrey's Anatomy. She was in the episode "I Feel the Earth Move," as a young girl named Ruby. Fans can currently see Millie Bobby Brown in the titular role of the hit Netflix film, Enola Holmes.

Imagine That is a comedy starring Eddie Murphy that got lost in the fray. The family-friendly film was released in 2009 and was about an over-worked dad who found the secret to success, thanks to his daughter's imagination.

RELATED:Eddie Murphy's 10 Best Movies (According To IMDb)

Murphy's daughter, Olivia, was played by actress Yara Shahidi when she was not even 10 years old.Black-ishandGrown-ishfans may recognize Olivia because she's now the young Zoey Johnson in both shows. Yara has also been on the big screen, in the movies SaltandAlex Cross.

When people think of Ryan Reynolds, they think of Deadpool, Green Lantern,and Wade Wilson inX-Men Origins: Wolverine.What many don't realize is that Ryan was a young child star, before he made it big.

In the 90s, he had his first role in a TV series calledFifteen,before making an impact on the Canadian soap operaHillside. He continued to make appearances on TV shows before eventually landing the role of Van Wilder inVan Wilder: Party Liaison.

When Regina King was 14 years old, she landed a main role in the show227 as Brenda Jenkins. The show starred big names likeJacke Harry,Helen Martin, andMarla Gibbs, and gave King a foot in Hollywood's door.

RELATED:Regina King's 10 Best Film & TV Roles, Ranked (According To IMDb)

These days, King fans think of her time asMarcee inJerry Maguire,Sam Fuller inMiss Congeniality, and asRiley Freeman inThe Boondocks (among many other roles). King has been in the spotlight for far longer than she's given credit for.

These days, Fergieis a solo artist and known for time with the group Black Eyed Peas, but did you know she used to be a young actress? In the 80s, Fergie (then known as Stacy Ferguson) was the voice of Sally from Peanuts. She was inIt's Flashbeagle, Charlie Brown,Snoopy's Getting Married, Charlie Brown, andThe Charlie Brown and Snoopy Show.

Fergie also did work in front of the camera. From 1984 to 1989, she was Stacy inKids Incorporated.As years went on, Fergie continued to act before realizing music was her true passion.

Lana Condor became an overnight success with her Netflix movies ToAll The Boys I've Loved Before.Fans of the films were wondering where else Lana can be seen, due to her sheer talent on screen. As it turns out, Lana's first professional project was a big one and many fans didn't even notice.

In 2016, Lana landed the role of Jubilee inX-Men: Apocalypse. These days, Lana is continuing with moreTo All The Boys spinoffs, along with other works that are currently in post-production.

Camilla Belle has been a rising star for quite some time. In 1993, she made her first appearance in the TV movieTrouble Shooters: Trapped Beneath the Earth. However, her biggest role as a kid was in The Lost World: Jurassic Park,as a young girl named Cathy.

From there, she snagged the role of young Sandra Bullock inPractical Magic, before getting the main role in Disney'sRip Girls. At 34, Camilla is still acting, with her latest project as Melyssa inDollface.

Michael B. Jordan seems to be everywhere these days andthere's no role he can't ace.But before he made it big withBlack Panther, Creed,andGen: Lock, Michael was in a few episodes ofThe Sopranos,as a kid. He continued in the late 90s when he joinedCosbyand Hardball, before landing a recurring role onThe Wire andAll My Children.

Michael has grown a lot over the years and has proven to be a legendary actor with more to give. According toIMDb, he's currently preparing forCreed IIIandTom Clancy's Without Remorse.

At just 21 years old, Joey King is an actress with over 60 credits to her name, thanks to her childhood acting roles. At the age of seven, Joey had her first role inThe Suite Life of Zack & Cody as Emily.

From there, she lent her voice toHorton Hears a Who!and made appearances onCSI: Crime Scene Investigation,Ghost Whisperer, andCrazy, Stupid, Love,before becoming a young adult and taking on more mature roles. Joey's stardom reached new heights with her roleGypsy Rose Blanchard in Hulu'sThe Act and Netflix'sThe Kissing Booth.

Chlo Grace Moretz is on the move in Hollywood after a long, successful career as a child actress. She joined Ryan Reynolds inAmityville Horror,as his daughter, Chelsea Lutz. She later made appearances inMy Name Is Earl, Desperate Housewives, 500 Days of Summer.

As Chlo got older, she joined forces with the cast of30 RockandNeighbors 2. Most recently, Chlo was inShadow in the Cloud and has four projects in the works for the near future.

NEXT:Chlo Grace Moretz's 10 Best Films, According To IMDb

Next The 15 Best TV Shows Of All Time, According To IMDb

Layne is a nomad who travels the globe on the hunt for her next adventure. A lover of being outside (and finding the best latte in town), Layne loves to write about her favorite topics and shows. When you don't find her playing around outside, you can find her writing away in the closest coffee shop.

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Millie Bobby Brown In Grey's Anatomy (& 9 Other Child Star Appearances We Forgot About) - Screen Rant

Anatomy

Anatomy of play: 49ers TE George Kittles first touchdown pass of the season was the perfect play call – Niners Nation

George Kittle made his return to the starting lineup on Sunday, and the Eagles immediately felt his presence in a big way. The tight end caught 15 passes for 183 yards and one touchdown after missing the last two games due to a knee injury sustained in week one. He was the teams leading receiver and caught more passes than every receiver that had a target for the 49ers that night.

The touchdown pass was on a single high coverage beater in the red zone. Single high in the red zone is already a dangerous game as often times teams cannot adequately cover multiple receivers releasing into vertical routes in such a compressed space where the passes tend to be quicker as well.

Shanahan is a master at exploiting at exploiting single high coverages in the red zone and has done so with regularity over the course of his coaching career.

His best known example of this came in the 2016 divisional round playoffs against the Seahawks when Tevin Coleman caught a touchdown on H scissors out of the back field.

The Seahawks are in a single high coverage, cover-3, and their rules dictate that the corner will travel with the #1 receiver if he goes vertical. The flat route occupies the flat defender, and the safety helps the corner bracket the post route. Easy pickings for Shanahan as Tevin Coleman is left wide open.

On Sunday night, Shanahan called another single high beater for Kittles first touchdown of the season on concept broadly referred to as bench. Bench is a mirrored smash concept with the outside receivers running quick to the flats and the slot receivers running corner routes.

On this particular play, the 49ers are in a condensed 2x2 bunch at the 5-yard line. On the right side of the formation, the route combination is a switch release with a flag route and a drag china route underneath. The formations left side is the more traditional corner by the #2 receiver (Kittle) and the flat route underneath.

The Eagles are in cover-1 single-high coverage. The defenders to the right side of the offensive formation banjo their coverage, meaning the cornerback outside takes the out route by #2 off the switch release, and the inside defender takes the release of #1 inside and up. To the offenses left, linebacker Duke Riley (No. 50) is in man coverage on Kittle.

Riley has essentially no help on the play as Kittle runs by him. Safety Marcus Epps (No. 22) gets caught looking in the backfield instead of moving over to help Riley in coverage when he shouldve been sprinting to help on the backline over the top. The choice route by Jerick McKinnon occupies the defender at the goal line. There was no way Mullens was going to throw the corner route from the far hash.

Mullens drops it in there with the perfect pass over Riley, who doesnt even turn to look for the ball. Kittle makes a nice adjustment to bring it in and get two feet down for the touchdown.

The plays are there for the taking if the offense can execute. Several times this season, both starting quarterbacks have missed opportunities to hit the open guys. Some of that is due to offensive not giving time to throw, some of it is on the quarterbacks for not giving plays a chance to develop or throwing bad passes. But Kyle continues to scheme it up, showing how much he understands his opponents schematic weaknesses.

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Anatomy of play: 49ers TE George Kittles first touchdown pass of the season was the perfect play call - Niners Nation

Anatomy

Kate Burton Movies & TV Shows: Where You Know The Grey’s Anatomy Star – Screen Rant

Kate Burton is an acclaimed screen and theatre actress who is probably best known for Grey's Anatomy, but here's a guide to her other roles.

Here's a guide to the career of Grey's Anatomy actress Kate Burton. It seems a life in the arts was always on the cards for Kate Burton, as she is the daughter of producer Sybil Williams and screen icon Richard Burton. She made her first appearance in the latter's 1969 historical drama Anne Of The Thousand Days, but it wasn't until the early 1980s that she started to move towards an acting career. One of her earliest movie roles came with John Carpenter's martial arts action-adventure Big Trouble In Little China, which bombed on release in 1986 but is considered a classic now.

Much of Kate Burton's early work came with small roles on TV shows and movies, including crime series Spencer: For Hire and short-lived sitcoms like Brooklyn Bridge and Home Fires. She's also had various stints on Law And Order and its offshoots like Criminal Intent. Throughout the 1990s she also appeared in movies projects like 1996's August - starring and directed by Anthony Hopkins - Ang Lee's The Ice Storm and TV movie thriller Mistrialwith Bill Pullman.

Related: Emmet Walsh Movies & TV Shows: Where You Know The Blade Runner Star

Outside of movies and TV, Kate Burton is a prolific stage actress and has won acclaim for her performances in productions of The Elephant Man and The Constant Wife. After appearances in erotic thriller Unfaithfulin 2002 and a lead role in The Diary Of Ellen Rimbauer - a prequel to Stephen King's Rose Red - she landed the key role of Ellis Grey in Grey's Anatomy. This medical drama debuted in 2005 and is still running, and Burton was nominated for her role as the Alzheimer's stricken mother of protagonist Meredith Grey.

While Kate Burton has regularly appeared in movies since Grey's Anatomy such as Max PayneorRemember Me, most of her career has focused on television in the last decade, where she's popped up on shows as varied as Grimmand The Good Wife. She played a major supporting role on Scandal, another Shonda Rhimes created hit. She played Vice President Sally Langston, who got some very juicy plotlines on the series and the performance earned Burton another Emmy nod.

In 2015 Kate Burton played a villain role in Martyrs, a remake of the controversial French original. This English language remake toned down the harsher elements of the original and by all accounts, this made for a weaker movie. Burton is still very active on television, having recently made guest appearances on 13 Reasons Whyand NCIS: New Orleans.

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Kate Burton Movies & TV Shows: Where You Know The Grey's Anatomy Star - Screen Rant