Culture

The way research in bioprinting will be taken forward has been laid out in a roadmap for the field.
Published today in IOP Publishing's Biofabrication, leading researchers define the status, challenges and opportunities in the field, and forecast the required advances in science & technology to overcome the challenges to a range of bioprinting techniques and applications.

In the roadmap:

Professor Binil Starly charts the progress from cell expansion to 3D cell printing

Dr Andrew C. Daly, Professor Jürgen Groll, and Professor Jason A. Burdick examine the developments and challenges in the bioinks used for bioprinting

Gregor Skeldon and Professor Wenmiao Shu look at the bioprinting of stem cells

Dr Jinah Jang and Dr Dong-Woo Cho present a strategy for bioprinting of tissue vascular system and tissue assembly

Dr Minghao Nie and Professor Shoji Takeuchi examine the potential for using 3D-printed biohybrid tissues as in-vitro biological models for studying disease

Dr Serge Ostrovidov and Professor Ali Khademhosseini examine how 3D bioprinting can be used for the development of organs-on-a-chip

Professor Roger D. Kamm covers the biomanufacturing of multi-cellular engineered living systems

Dr Vladimir Mironov and Professor Lorenzo Moroni explore how researchers are pushing boundaries with bioprinting in space

Professor Ibrahim T. Ozbolat examines the developments of bioprinting technologies

Introducing the collection, guest editor Professor Wei Sun, from Drexel University, Philadelphia, USA and Tsinghua University, Beijing, China, said: "Cells are nature's building blocks. Bioprinting uses cells, proteins and biomaterials as building blocks to 3D printed biological models, biological systems and therapeutic products.

"It has rapidly evolved into printing biomaterials for tissue scaffolds and implants, printing cells or organoids for 3D biological models, and printing micro-organ-chips for micro-physiological platforms and engineered living systems, such as cellular machining and biorobots.

"There are a number of challenges to overcome, including: the need for a new generation of novel bioinks with multi-functional properties to better transport, protect and grow cells during and after printing; better printing processes and printers to deliver cells with high survivability and high precision; efficient and effective crosslinking techniques and crosslinkers to maintain the structure integrity and stability after printing; integration with micro-fluidic devices to provide a long term and a simulated physiological environment to culture printed models.

"Due to the rapid advancements in bioprinting techniques and their wide-ranging applications, the direction in which the field should advance is still evolving. The roadmap aims to address this unmet need by providing a comprehensive summary and recommendations, useful to experienced researchers and newcomers to the field alike."

Hospitals, doctors and Medicare Advantage insurance plans that care for some of the most vulnerable patients are not reimbursed fairly by Medicare, according to recent findings in JAMA.

It costs more to care for patients who are frail, have dementia, are depressed or are poor. However providers that treat them and health insurance plans that provide their coverage are not paid fairly to treat these health conditions because Medicare doesn't account for them in its existing risk payment system. That system rates patients based upon how sick they are, which determines Medicare reimbursements.

"While it's an unintended consequence of the current Medicare payment policy, those who are among the most vulnerable are less likely to get the care that they need," said Kenton Johnston, Ph.D., assistant professor of health management and policy at Saint Louis University College for Public Health and Social Justice, and lead author of the paper.

"This disparity has already created an incentive for providers and plans to avoid treating Medicare beneficiaries with those conditions."

Medicare compensates health insurance plans in Medicare Advantage and medical providers under value-based payment models based on how sick their patients are, which is measured by a risk score. Because patients who have higher risk scores cost more to treat than those with lower scores, Medicare pays insurance plans and providers more to treat them.

In this paper, Johnston highlighted a problem with Medicare payments. Medicare does not include frailty, dementia, depression or poverty in its risk scores even though patients with those conditions are sicker and costlier to treat.

Johnston and his co-authors Julie P. W. Bynum, M.D., professor of internal medicine at the University of Michigan Medical School in Ann Arbor, Michigan, and Karen E. Joynt Maddox, M.D., assistant professor of cardiology at Washington University School of Medicine in St. Louis, recommend an easy fix to correct the disparity.

Medicare should include patient frailty, dementia, depression and poverty in its risk scores - conditions for which there are standard diagnosis codes that clinicians can enter at the time they treat patients.

Medicare has resisted the change, Johnston said, arguing clinicians and facilities might over-code those conditions to increase their reimbursement.

"That can be addressed through existing fraud procedures that Medicare already has in place. A clinician who codes a patient for those conditions when the patient does not have the conditions is committing Medicare fraud and can be penalized," Johnston said.

"It is unfair to clinicians, facilities and plans that do treat patients with those conditions to not reimburse them fairly for their services."

The ability to forget our memories - for better or worse - is dependent on microglia and their inclination to weaken and eliminate the synapses connecting engram neurons, according to a new study in mice. The findings - which answer questions about whether microglia, known to be active in brain development, also affect forgetting later in life - present an important mechanism underlying memory erasure and may help aid our understanding of forgetting and amnesia. It's thought that our brains encode and store memories in engrams - neuronal ensembles stitched together by dynamic synaptic circuits. Reactivation of engrams by way of these synaptic connections allows us to recall specific memories; failure to reactivate an engram results in losing the related memory. Synaptic connections in the brain are highly dynamic. Rewiring of synaptic circuits could contribute to the loss of previously formed memories by weakening or severing the networks connecting engram cells. Microglia - the brain's resident macrophage cells - are responsible for trimming excessive synapses during brain development and in regulating the dynamics of synapses throughout life. However, it's unknown if microglial activity also regulates forgetting and memory erasure in the adult brain. Chao Wang and colleagues observed and manipulated microglia and engram cells in the healthy brains of memory-trained mice to reveal their role in regulating forgetting. Depleting microglia or inhibiting their activity prevented forgetting, the authors showed. Intact microglia mediate the dissociation of engram cells, leading to degradation and eventual erasure of the associated memories, the findings suggest. Inhibiting the activity of engram cells also facilitated the elimination of engram cell synapses by microglia, resulting in less active memories to be forgotten.

Clumps of proteins inside cells are a common thread in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease. These clumps, or solid aggregates of proteins, appear to be the result of an abnormality in the process known as liquid-liquid phase separation (LLPS), in which individual proteins come together to form a liquid-like droplet.

To understand how the process goes awry, researchers need a better understanding of the mechanism that drives LLPS in the first place. What is it about any protein that would cause it to condense into a liquid?

Collaborative research between the Pappu Lab, led by Rohit Pappu in the McKelvey School of Engineering at Washington University in St. Louis, and the lab of Tanja Mittag at St. Jude Children's Research Hospital has uncovered the key to translating the patterns written into specific types of protein sequences that contribute to LLPS.

Importantly, they also have uncovered how specific arrangements of amino acids, which stray from the pattern, can negatively impact phase separation and give rise to the formation of solid aggregates instead of liquids.

Their research was published today in Science.

When certain cells are stressed, which happens regularly, cellular response proteins condense into membraneless organelles -- squishy, liquid-like droplets that have defined boundaries but no delimiting membranes.

The droplets form by LLPS, a phenomenon that is conceptually similar to the process by which oil and vinegar separate from one another, forming coexisting liquid droplets.

Although it is called phase separation, LLPS is really a process of coming together, or condensing. Loosely condensed proteins are in a liquid-type phase; the more tightly they are packed, the more solid they become.

Under some circumstances, often due to mutations, an errant process causes some of the material in these protein-rich droplets, also known as biomolecular condensates, to morph into more solid aggregates.

The condensation, in many cases, is driven by the intrinsically disordered regions (IDR) of the protein. These are stretches of the protein with no defined three-dimensional shape, and yet they feature prominently in key functional roles, especially in the brain.

Pappu, the Edwin H. Murty Professor of Engineering, and his coworkers had shown that certain parts of the IDRs were sticky -- they had a tendency to stick to each other on the same protein, or on those nearby. These "stickers," which are actually amino acids on the protein chain, and the material between them, called spacers, are the basis for the sticker-and-spacer model, a framework used to describe LLPS.

The collaboration, which involved Mittag's team at St. Jude team, was driven by experiments performed in the Mittag lab to try to identify the key stickers that are responsible for driving phase separation. To do this, they started by observing interactions essentially down at single amino acid resolution using nuclear magnetic resonance spectroscopy.

The results of their experiments uncovered which amino acids were sticky, but couldn't provide the kind of holistic picture needed to fully understand the relationship between stickers, spacers and LLPS.

That's where Pappu's team came in. Building on experimental data from Mittag's team, Pappu and his colleague Alex Holehouse (who until the end of 2019 was a postdoctoral fellow in the Pappu lab and is now an assistant professor of biochemistry and molecular biophysics in the School of Medicine) developed an open source computational approach known as PIMMS (Polymer Interactions in Multicomponent Mixtures) to arrive at a quantitative and predictive understanding of the interactions among stickers that drive phase separation.

Additional lab experiments at St. Jude were used to test and confirm their predictions.

Together, the models and experiments revealed new aspects of the relationship between these stickers and phase separation.

Although the model showed variations in the number and placement of stickers, "the patterning of the stickers along the chain was very well conserved," Pappu said. "When you see something that is very well conserved in evolution, you decide that it is evolutionarily important."

So, naturally, Holehouse, an assistant professor of biochemistry and molecular biophysics, and Pappu used PIMMS to see what would happen if the important pattern was changed.

The team asked, "What happens if we just bring all of these stickers and put them right next to one another?" The first key finding showed the interactions between the stickers became so strong that proteins began sticking to each other, piling up and growing, eventually growing dense enough to become more solid than liquid.

The second key finding was a better understanding of the importance of the regions between the stickers -- the spacers. Like noncoding or "junk" DNA, the spacers at first showed some interesting traits, but did not seem to have an integral role in protein's functioning.

It turns out, spacers are crucial to understanding LLPS. "The spacers dilute the interaction strength of the stickers, which allows for the formation of a liquid," Mittag said. "Without spacers, the stickers would be too close and proteins would always condense to solids.

Understanding the rules that drive LLPS gives researchers a new way to "read" proteins to determine whether they will condense into a liquid or into the more problematic solid form.

LLPS is relevant to more than neurodegenerative diseases. It also has the potential to transform our understanding of the underlying mechanisms of many biological processes. "This model is relevant to understanding cancers," Mittag said, because of its application to different types of proteins.

The potential held by further collaboration is powerful, Pappu noted.

"We're talking about something that's written into a molecule giving you something that's manifest almost at the cellular scale," Pappu said. "Now you can play engineer and design things. You can think about neurodegenerative disorders and make sense of what might be going wrong.

"The funding provided by St. Jude has been key to catalyzing the collaboration that continues between the Mittag lab and my lab," Pappu said. "The collaboration also benefits from contributions of the Holehouse and Soranno labs in the School of Medicine -- labs that also are an integral part of the Center for Science and Engineering of Living Systems."

WASHINGTON, DC and SAN DIEGO, CA - Feb. 6, 2020 - Empowering Medicare to directly negotiate drug prices, accelerating the adoption of value-based care, using philanthropy as a catalyst for reform and expanding senior-specific models of care are among recommendations for reducing healthcare costs published in a new special report and supplement to the Winter 2019-20 edition of Generations, the journal of the American Society of Aging (ASA).

The report, "Older Adults and America's Healthcare Cost Crisis," sponsored by West Health, a family of nonprofit and nonpartisan organizations committed to lowering healthcare costs to enable seniors to successfully age in place, includes a dozen articles by experts and leaders from healthcare, business, academia and philanthropy.

The authors examine the major drivers of the high cost of healthcare and its impact on patients and then offer solutions that can reduce costs and improve the quality of care for older adults and society at large. Topics include the employer's role in reining in healthcare prices, the high cost of prescription drugs, investing in the social determinants of health, the value of home-based acute care, the need for oral health programs for older adults, value-based payment reform and the geriatric emergency care movement.

"Skyrocketing healthcare costs represent a significant and growing public health crisis that requires more action and less debate," said Shelley Lyford, president and CEO, West Health, one of the authors. "We can all agree Americans are hurting, in some cases dying or going bankrupt, because of a broken system that costs too much and delivers too little. We can no longer delay or defer common sense reforms and better and more cost-effective models of care when the health and financial security of millions hang in the balance."

In the report's lead article, Lyford and Timothy Lash, chief strategy officer of West Health and president of the West Health Policy Center, call for allowing Medicare to directly negotiate drug prices with manufacturers, which is currently prohibited by law. They write it "would be a game-changing lever that could force prescription drug manufacturers to bring down prices and lower costs for older Americans." They also state it's essential to quickly move from unfettered fee-for-service to value-based payment models and that more transparency on price and quality is needed so consumers and other purchasers can make more informed decisions about care.

Other articles offer recommendations including:

Employers demanding greater price accountability from hospitals and health plans and taking the lead in adopting value-based payment models

Value-based payment reform for serious illness

Establishing senior-specific models of care including geriatric emergency departments, which may improve health outcomes and reduce hospital admissions, and senior dental centers, which can address a silent epidemic of oral health problems among older adults

Supporting widespread use of home-based acute care, which increases the value of healthcare and better allows older adults to age in place

In an introduction to the special report, guest editor Robert Blancato, M.P.A., Immediate Past Board Chair of the ASA and a member of the National Board of AARP writes, "As the U.S. population ages, it is increasingly vital to support common sense steps that can reverse the trend of runaway healthcare costs. Unless we advocates take bold actions now to lower healthcare costs, our nation's older adults cannot hope to successfully age in place in the communities they cherish."

As spiraling U.S. healthcare costs dominate policy agendas at the state and federal level, older adults--the largest consumers of healthcare services--have a particularly high stake in solving the crisis. According to a 2019 West Health-Gallup poll, seniors withdrew an estimated $22 billion from long-term savings in the past year to pay for healthcare and an estimated 7.5 million were unable to pay for a prescribed medicine.

Engineers with the University of Cincinnati have created a tiny portable lab that plugs into your phone, connecting it automatically to a doctor's office through a custom app UC developed.

The lab the size of a credit card can diagnose infectious diseases such as coronavirus, malaria, HIV or Lyme disease or countless other health conditions like depression and anxiety.

The patient simply puts a single-use plastic lab chip into his or her mouth then plugs that into a slot in the box to test the saliva.

The device automatically transmits results to the patient's doctor through a custom app UC created for nearly instant results.

UC professor Chong Ahn and his research team used the smartphone device to test for malaria. But the device could be used for smart point of care testing for countless chronic or infectious diseases or to measure hormones related to stress.

"Right now it takes several hours or even days to diagnose in a lab, even when people are showing symptoms. The disease can spread," Ahn said.

The study was published in the Nature journal Microsystems & Nanoengineering.

His research team created a novel lab chip that uses natural capillary action, the tendency for a liquid to adhere to a surface, to draw a sample down two channels called a "microchannel capillary flow assay." One channel mixes the sample with freeze-dried detection antibodies. The other contains a freeze-dried luminescent material to read the results when the split samples combine again on three sensors.

Ahn said the device is accurate, simple to use and inexpensive.

"The performance is comparable to laboratory tests. The cost is cheaper. And it's user-friendly," Ahn said. "We wanted to make it simple so anyone could use it without training or support."

UC doctoral student Sthitodhi Ghosh, the study's lead author, said the biggest advancement in the device is in the novel design of its tiny channels that naturally draw the sample through the sensor arrays using capillary flow. Ahn is Ghosh's Ph.D. advisor.

"The entire test takes place on the chip automatically. You don't have to do anything. This is the future of personal healthcare," Ghosh said.

While the device has applications for diagnosing or monitoring viruses or other diseases, Ahn said he sees potential in the field of mental health, where doctors already utilize smartphones to help track the wellness of patients.

Tinder's meteoric rise in popularity has cemented its position as the go-to dating app for millions of young and not-so-young users. Although it is widely known as a platform to facilitate hookups and casual dating, some of the app's estimated 50 million+ worldwide users are employing it for something altogether different.

From multilevel marketing to political and health campaigning to promoting local gigs, Tinder users are appropriating the platform for their own purposes. And these can often have little to do with sex or dating. This so-called "off-label use" -- a term borrowed from pharmacology describing when people use a product for something other than what the package says -- is explored in a new paper published in the journal The Information Society.

"When people encounter a new technology, whether it's a hammer or a computer, they use it in ways that fit their needs and lifestyle," says author Stefanie Duguay, assistant professor of communication studies in Concordia's Faculty of Arts and Science.

"This is commonly referred to as user appropriation in science and technology studies. However, once you buy a hammer, it doesn't undergo regular updates or develop new features -- apps do. They come with their own marketing, vision for use and sets of features, which they regularly update and often change in response to user activity."

For this reason, Duguay says, the paper engages with Tinder as a way to think through what appropriation looks like in this back-and-forth relationship between users and apps.

What's in a label?

Duguay began her study with a thorough investigation of the Tinder app's design, looking at the mechanics its developers created in order to guide users for its intended purpose. She next looked at dozens of media articles about people using it for purposes other than social, romantic or sexual encounters. Finally, she conducted in-depth interviews with four "off-label" users.

One user's profile was being used to conduct an anti-smoking campaign. Another, an anti-sex trafficking campaign. A third was using the app to market her health products and the last was supporting US Senator Bernie Sanders's Democratic Party presidential nomination run in 2016. She then compared and contrasted these different approaches to off-label use.

"I found that a lot of the time, Tinder's expected use -- dating and hooking up -- informed or complemented their campaigns," she says. "There would be an element of flirtatiousness or they would draw on users' perception of Tinder as a digital context for intimate exchanges."

She adds that many Tinder users who were on the app for its expected uses became upset when they discovered these profiles' actual aims. "That shows that off-label use can be somewhat disruptive on the platform," she says. "Though this depends on how narrowly people see that app's purpose."

A changing ecosystem

Duguay was also curious to gauge Tinder's own reaction to these kinds of user appropriation. Over the course of her research, she got the sense that this activity was only concerning to the company in high volumes.

Spam bots, for instance, became a serious problem soon after the app's launch. Duguay notes that Tinder responded quickly to this wave of off-label use, which often involved bots phishing for credit card numbers, by adding daily swipe limits and block-and-report buttons.

"But those measures also made it difficult to sell products or campaign for something," she says. "They may be very useful in getting rid of massive amounts of spam, but in other ways, this reasserting of on-label use can shut down innovation and creativity."

While profit-making multilevel marketers may be able to overcome swipe limits by affording premium accounts, she writes, non-profit campaigners find these obstacles can ultimately silence them.

Tinder also adopted some of the uses popping up on their platform, wading into the political arena with their "Swipe the Vote" feature, for instance. Non-official campaigns now need Tinder's specific authorization to promote their cause or product.

Not looking down on hooking up

Duguay says conversations involving Tinder tend to not to be taken very seriously because of the app's association with hookup culture. This dismissiveness obscures a larger point, she feels.

"I think sex and dating are very meaningful activities in our society," she says. "But I was also seeing this range of activity on Tinder. Platforms like this are more like an ecosystem, and when users adopt different purposes than the ones they are designed for, the platforms can change their guidelines or features in ways that greatly affect their users."

Giving people the ability to engage in off-label use means that apps like Tinder can feature not only in meaningful social and sexual encounters but also in individuals' political or financial participation and broader endeavours for social good.

New Orleans, LA - Pooja Mehta, M.D., clinical assistant professor of obstetrics & gynecology at LSU Health New Orleans School of Medicine, was a member of a research team that found 13% of deaths occurring during or up to one year after pregnancy among Louisiana women in 2016-17 were homicides. Results are published online in JAMA Pediatrics, available here.

The team conducted a retrospective analysis of vital records data provided by the Louisiana Department of Health of all cases of maternal death that year. Of the 119 maternal deaths, homicide accounted for more deaths than any other single cause. Mortality from homicide was 12.9 per 100,000 compared to mortality from hypertensive disorders at 3.2 or obstetric embolism at 4.8 per 100,000.

"This is distinct from findings that focus on 'pregnancy-related' death - a different definition of 'maternal mortality,' which are deaths confirmed on case review to be directly linked to or worsened by pregnancy," notes Dr. Mehta, who was the Medical Director for the Louisiana Pregnancy-Associated Mortality Review at the time of the study. "The key finding from this study is that pregnant and postpartum women in Louisiana are more likely than others of the same age to experience a homicide."

The authors write that their estimated rate is among the highest reported across a growing number of jurisdictions, possibly due in part to improved case ascertainment through the use of linked and verified data and/or reflecting a truly higher incidence within Louisiana, given the state's consistently high incidence of homicide among women and girls.

"This points to the fact that pregnant people are in fact more vulnerable to violence--those who interact with pregnant and postpartum individuals inside and outside of the health system need to work together to better support these individuals," adds Mehta. "We have to see each death as something that is worth preventing, and within our power to prevent."

Most cells in the tissues of most organisms proliferate through somatic cell division (mitosis). This is a continuous cycle where a single cell doubles its genetic information (chromosomes) and divides equally to create two copies of the original cell. In contrast, germ (egg and sperm) cells are produced through a special type of cell division called meiosis, which takes place in the gonads. This process begins like normal mitosis but switches after some time to create four genetically dissimilar germ cells that have half the original cell's genetic material. The mechanism that causes this switch has been a longstanding research problem and controlling it is an important, yet challenging, global issue in reproductive medicine.

Recently, a group of researchers from Kumamoto University in Japan set out to assess the proteins involved in meiosis to clarify its development. Using mass spectrometry, the group was able to identify a gene that acts as a meiosis on-switch, labeling it "Meiosin" (for meiosis initiator). The Meiosin gene has the extremely rare property of becoming activated only at a specific time--just before the beginning of meiosis in the gonads. In animal experiments, the researchers found that both male and female mice became infertile if the Meiosin gene was artificially inhibited. Further analysis of the mouse male and female gonads clarified that the gene plays an essential role in meiosis activation. The Meiosin gene acts as a control tower that simultaneously switches on hundreds of genes for germ cell formation, and appears to be involved with infertility. The group expects that the discovery will be a big step forward for reproductive medicine.

There are many cases of human infertility where the cause is unknown; this finding potentially reveals a new pathology. Even though these experiments were performed on animal models, the Meiosin gene is present in humans. Abnormal meiosis in the eggs of older women can cause chromosomal abnormalities resulting in miscarriage or Down syndrome. And in societies with increased age of pregnancy, therapies developed from this research could ensure meiosis quality and decrease the instances of these complications.

"Our work shows that the Meiosin gene is the switch that turns on meiosis, the special type of cell division that creates eggs and sperm, and this includes the turning-on of hundreds of other genes in the process. However, the functions of those genes have not yet been fully elucidated," said Associate Professor Kei-Ichiro Ishiguro of the Institute of Molecular Embryology and Genetics at Kumamoto University. "We were quite surprised to find so many genes with undefined functions lying dormant in this study. We have high expectations that the processes involved in germ cell formation will be greatly clarified as the role each of these genes plays is discovered. If it eventually becomes possible to control meiosis, the benefits would be far-reaching for reproductive medicine, agricultural production, and even assisting rare species reproduction."

This research was posted online in Developmental Cell on 6 February 2020.

NEW YORK -- The protein tau has long been implicated in Alzheimer's and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University's Zuckerman Institute and Mayo Clinic in Florida have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person's brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop -- and how quickly that disease will spread throughout the brain.

The study, published today in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain.

"Tau has long been a protein of significant interest due to its prevalence in disease," said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute who led the study. "In today's publication, we lay out compelling evidence that PTMs play an important structural role in tauopathies, the collection of neurodegenerative diseases characterized by toxic buildup of misfolded tau."

No two tauopathies are exactly alike. Each affects different parts of the brain -- even different cell types -- which can lead to different symptoms. Alzheimer's, for example, arises in the hippocampus, and so affects memory. Chronic traumatic encephalopathy, a disorder most often seen in survivors of traumatic brain injury, can lead to problems with movement, memory or emotion, depending on which areas of the brain are affected.

Scientists have used traditional imaging techniques to find clues to how tangles of tau, comprised of individual fibers, or filaments, are implicated in these diseases. But painting a complete picture has proven difficult.

"The brains of patients with neurodegenerative diseases are easy to identify: entire sections have been eaten away, replaced by large clumps and tangles of misfolded proteins like tau," said Tamta Arakhamia, an undergraduate at Columbia's School of General Studies, a research assistant in the Fitzpatrick lab and the paper's co-first author. "However, tau filaments are 10,000 times thinner than the width of a human hair, making them extraordinarily difficult to study in detail."

To address this challenge, Dr. Fitzpatrick recently pioneered the use of cryo-electron microscopy, or cryo-EM, to visualize individual tau filaments from diseased human brain tissue. Cryo-EM is a Nobel Prize-winning technology developed, in part, by researchers at Columbia University. Cryo-EM images samples using a beam of electrons and has proven indispensable for investigations into extremely small biological structures. Using cryo-EM, Dr. Fitzpatrick's team has reconstructed the structures of tau filaments, providing new insights into how they form, grow, and spread throughout the brain.

For all its ability to provide highly detailed snapshots of proteins, cryo-EM has limits. To overcome these limits, Dr. Fitzpatrick and his team to paired it with a second technology: mass spectrometry.

"Cryo-EM does not provide a complete picture because it cannot fully recognize the microscopic PTMs on tau's surface," said Christina Lee, an undergraduate student at Columbia College, a research assistant in the Fitzpatrick lab and the paper's co-first author. "But mass spectrometry can pinpoint the chemical composition of PTMs on the surface of tau."

Working with co-corresponding author Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic in Florida, and Nicholas Seyfried, PhD, professor of biochemistry at Emory University School of Medicine, the researchers used cryo-EM and mass spectrometry to analyze the brain tissue from patients diagnosed with two tauopathies: Alzheimer's disease and corticobasal degeneration, or CBD. CBD is a rare but extremely aggressive tauopathy, affecting only one in every 10,000 people. Unlike Alzheimer's, which is thought to arise due to a number of factors including tau, CBD is primarily associated with misbehaving tau proteins.

"Studying a primary tauopathy like CBD helps us to figure out how tau becomes toxic to brain cells," said Dr. Petrucelli. "We hope to extrapolate that knowledge to secondary tauopathies, such as Alzheimer's disease."

The scientists' analysis of brain tissue samples revealed several key insights. Most notably, the researchers found that cross-talk between PTMs on the surface of tau influences the structure of the tau filaments, contributing to differences in tau filaments observed across the various tauopathies -- and even variations from patient to patient.

"Collectively, these results suggest that PTMs may not only be serving as markers on the proteins' surface, but are actually influencing the behavior of tau," said Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at Columbia's Vagelos College of Physicians and Surgeons.

Moving forward, Dr. Fitzpatrick and his team plan to expand this work to other tauopathies. Today's findings on Alzheimer's and CBD hold immense promise for the field, particularly in the development of new disease models -- such as lab-grown organoids, or mini-brains -- that may serve to accurately recapitulate what is actually happening in the brains of patients.

"Our findings will inspire new approaches for developing diagnostic tools and designing drugs, such as targeting PTM vulnerabilities to slow disease progression," said Dr. Fitzpatrick, who is also a member of Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain. "Neurodegenerative diseases are among the most complex and distressing class of illnesses, but through our work and that of our colleagues and collaborators, we are building a roadmap toward successful diagnostics and therapeutics."

DURHAM, N.C. -- Biomedical engineers at Duke University have developed the most advanced disease model for blood vessels to date and used it to discover a unique role of the endothelium in Hutchinson-Gilford Progeria Syndrome. Called progeria for short, the devastating and extremely rare genetic disease causes symptoms resembling accelerated aging in children.

The model is the first to grow both the smooth muscle and inner lining, or endothelium, layers of blood vessels from stem cells derived from the patients' own skin. Combined with an advanced experimental setup that pushes culture media that models blood through the engineered blood vessels, the model reveals that the endothelium responds differently to flow and shear stress with progeria than it does when healthy.

The study shows that a diseased endothelium alone is enough to produce symptoms of progeria, and also demonstrates a new way of studying blood vessels in dynamic 3D models to better understand and test treatments for serious diseases.

The results appear online on February 6 in the journal Stem Cell Reports.

"The endothelium expresses the toxic protein that causes the symptoms of progeria, but it does so at much lower levels than the outer layer of blood vessels made of smooth muscle," said Nadia Abutaleb, a biomedical engineering PhD student at Duke and co-first author of the paper. "Because of this, the entire field has been focused on smooth muscle, and the few that have looked at the endothelium have mostly looked at it in a static 2D culture. But we've discovered that it's necessary to work dynamically in three dimensions to see the full effects of the disease."

Progeria is a non-hereditary genetic disease caused by a random single-point mutation in the genome. It is so rare and so deadly that there are only about 250 people known to be currently living with the disease worldwide.

Progeria is triggered by a defect in a protein called progerin that leads it to accumulate outside of a cell's nucleus rather than becoming part of the nuclear structural support system. This causes the nucleus to take on an abnormal shape and inhibits its ability to divide. The resulting symptoms look much like accelerated aging, and affected patients usually die of heart disease brought on by weakened blood vessels before the age of 15.

"Progeria isn't considered hereditary, because nobody lives long enough to pass it on," said George Truskey, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering at Duke. "Because the disease is so rare, it's difficult to get enough patients for clinical trials. We're hoping our platform will provide an alternative way to test the numerous compounds under consideration."

Blood vessels are difficult to simulate because their walls have multiple layers of cells, including the endothelium and the media. The endothelium is the innermost lining of all blood vessels that interacts with circulating blood. The media is made mostly of smooth muscle cells that help control the flow and pressure of the blood.

In 2017, the Truskey laboratory engineered the first 3D platform for testing blood vessels grown from skin cells taken from progeria patients. The blood vessels exhibited many of the symptoms seen in people with the disease and responded similarly to pharmaceuticals.

"While the smooth muscle cells in our previous study were created using cells from progeria patients, the endothelial cells were not," said Abutaleb. "We suspected that the endothelial cells might be responsible for some of the lingering symptoms in the original study, so we began working to grow blood vessels with both smooth muscle and endothelial cells derived from the same patient."

By successfully growing endothelial cells derived from progeria patients, the researchers were able to create a more complete model of the disease. They also tested the endothelium's unique contribution to the disease's symptoms by mixing impaired endothelium with healthy smooth muscle.

They found that a diseased endothelium alone was enough to produce many of the symptoms of progeria, but that these results only appeared when the cells were tested under dynamic conditions.

"One of the major findings is that the progeria endothelium responds to flow and shear stresses differently than healthy endothelium," said Abutaleb.

The new model's healthy blood vessels responded to pharmaceuticals more strongly than in past papers, and the diseased blood vessels showed a greater drop in functionality. With this advanced model in hand, the team is now beginning to investigate how new and current drugs for progeria affect a patient's blood vessels.

ANN ARBOR, Michigan -- Women with early stage breast cancer who test positive for an inherited genetic variant are not always receiving cancer treatment that follows current guidelines, a new study finds.

An inherited gene can increase risk of developing a second breast cancer, so strategies such as removing a woman's breasts or ovaries are intended to prevent a future cancer. But women who have already been diagnosed with breast cancer must also consider how best to treat the existing tumor.

"Cancer treatment options are increasingly more complex for patients. Patients must consider a myriad of treatment options for the cancer they have and the implications of genetic test results on cancer prevention strategies for themselves and their family members," says Steven J. Katz, M.D., MPH, senior author of a study led by the University of Michigan Rogel Cancer Center and Stanford University School of Medicine.

More women are receiving genetic testing when they're diagnosed with early stage breast cancer, with increasingly more sophisticated tests that include a panel of at least 30 different genes, each carrying different risks for future cancers.

"We found that breast cancer treatment among women who test positive for an inherited genetic mutation is less in line with practice guidelines, in particular for radiation therapy and chemotherapy," says lead study author Allison W. Kurian, M.D., M.Sc., associate professor of medicine and of health research and policy at Stanford.

"It's challenging to integrate genetic testing into breast cancer care," says Kurian. The significance of the results and future impact on the patient's risk vary widely while meanwhile we must focus on eliminating the cancer the patient faces today."

Researchers collected information from the Georgia and California Cancer Registries from 20,568 women diagnosed with early stage breast cancer and matched it to genetic testing results. All data was linked through an objective third party and deidentified for researchers to analyze. Results are published in JAMA Oncology.

Researchers looked at the characteristics of patients' tumors to assess what the recommended treatment options would be based on standard guidelines. Then they compared actual treatments for women who tested positive for BRCA1 or BRCA2 mutations, which carry the highest risk for additional cancers, those who tested positive for other genes associated with breast cancer, and those whose tests were negative or identified a variant not known to increase breast cancer risk.

They found distinct differences in surgery, radiation and chemotherapy treatments among women who were positive for an inherited genetic mutation.

Surgery: 66% of BRCA-positive patients underwent double mastectomy, compared to 24% of patients with a negative genetic test

Radiation: 51% of BRCA-positive patients who were candidates for radiation received it, compared to 82% of patients with a negative genetic test

Chemotherapy: 38% of BRCA-positive patients who were candidates to forgo chemotherapy got it, compared to 30% of patients with a negative genetic test

The observed relationship of surgical treatment to genetic test results are in line with guidelines supporting double mastectomy as an effective strategy to prevent future cancer risk. But guidelines do not recommend using genetic testing results to determine whether radiation or chemotherapy are needed to treat the diagnosed cancer.

The gaps in radiation were particularly striking as radiation after lumpectomy is considered key to achieving the best outcome with breast conservation. The researchers propose that some patients may have skipped radiation because they intend to have a mastectomy in the future. Another explanation could be concern about whether radiation would increase cancer risk for these patients.

"We need to understand this gap better, because it could have potential implications on patients' outcomes," says Katz, professor of general medicine and of health management and policy at the University of Michigan.

"Our findings should reinforce that physicians who treat cancer need to be increasingly attentive to the clinical implications of genetic testing after diagnosis. Test results must be optimally integrated into the patient's treatment to manage her cancer today and her risk in the future," Kurian says.

In mammalian adult brains, neural stem cells are only present in few specific parts, so called niches. Only these niches are capable of generating new neurons. For the first time, researchers defined the proteome of these niches, the entire set of expressed proteins, and compared it to other regions of the brain. The findings help to identify key regulators for neurogenesis, an important step towards activating neurogenesis after brain injuries.

What distinguishes neural stem cell niches from other parts of the brain? Why do only these niches contain neural stem cells and the rest of the brain does not? So far, we did not know what gives the niches their special function. Also, little was known about factors allowing the integration of new neurons into existing networks in the adult brain. A comparison of the proteome of neural stem cell niches and the region in which new neurons integrate with the remaining part of the brain, aimed to shed light about the unique niche environment allowing neurogenesis in the otherwise non-permissive adult mammalian brain.

Defining the niche characteristics

In a first step, Magdalena Götz and her team characterized the proteome of these specific brain regions. They used the largest neural stem cell niche in the subependymal zone of the brain and the olfactory bulb as this is the region where newly-generated neurons from the subependymal zone migrate, differentiate and integrate. They then compared this proteome to the cerebral cortex, an area where neither neurogenesis nor integration of new neurons occurs as in most parts of the adult mammalian brain. As a result, the team found that the proteome of the neurogenic niche evokes a niche-specific extracellular matrix architecture. One of the most important characteristics was the high solubility of the extracellular matrix. Other characteristic proteins however, such as those of the multifunctional enzyme transglutaminase 2, are hardly soluble meaning strongly cross-linked. Using pharmacological inhibitors as well as genetic experiments, the team was able to show that transglutaminase 2 is crucial for the regulation of neurogenesis. Furthermore, due to its cross-linking properties, the enzyme may contribute to the unique stiffness of the neural stem cell niche in otherwise soft brain tissue.

Turning the injured brain region into a neural stem cell niche

Having established the differences between the proteome of a neurogenic and a non-neurogenic site is a key step. It could help to find ways to convert the one to the other. Equally important for future cell replacement therapies is the generation of a beneficial environment for the integration of new neurons in the cerebral cortex by activating factors from the olfactory bulb, an area where new neurons are constantly being integrated. Next, the researchers want to compare these proteomes to the environment after brain injury. Their aim is to create new neurons after brain injury by turning the injured region into a neurogenic stem cell niche. Injured tissue demonstrates alternative phenotypes, that may create additional barriers for activating neurogenesis: "One of our collaborators at the University of Cambridge showed that scar tissue in the brain is particularly soft - a trait that is hostile to the function of neurogenesis. Overcoming this hurdle and generating a beneficial environment for repair will be the next steps of our research", says Götz.

From plastics to pesticides, it seems like every week delivers fresh news about the dangers of endocrine disruptors--chemicals in the environment that alter the body's hormones and can lead to reproductive, developmental, neurologic and immune problems and cancer.

Industry regulation and individual consumer choice can reduce exposure to such chemicals, but there are few options to counteract damage that has already occurred.

Now new research conducted in worms suggests a path toward changing that.

A naturally occurring antioxidant known as Coenzyme Q10, or CoQ10, reversed most of the reproductive harms caused by exposure to the plasticizer BPA (bisphenol A) in Caenorhabditis elegans worms, according to a study led by the lab of Monica Colaiácovo, professor of genetics in the Blavatnik Institute at Harvard Medical School.

The findings, published Feb. 6 in Genetics, provide the first evidence that at least some BPA-induced fertility damage can be undone.

"Chemicals are so prevalent in our environment that it was critical for us to focus first on identifying which ones are toxic and how they may affect human reproductive health," said Colaiácovo, senior author of the study.

"Now, as we continue to screen for and study how chemicals affect reproductive health, we can also ask the next really important question: Given that we're all exposed, how can we mitigate those effects in order to improve fertility and have healthier births?"

CoQ10 is produced by the body and can be found in many foods, particularly meat and fish. It is also available in over-the-counter dietary supplements, but those are neither regulated nor FDA-approved for any health conditions, and they occasionally cause side effects.

Although CoQ10 is already being recommended in some fertility clinics in the U.S. and Canada, the research team cautions that their findings must be replicated in further animal studies and in human clinical trials before the enzyme is prescribed for BPA-induced fertility damage.

Colaiácovo's lab has documented the reproductive repercussions of many environmental chemicals in worms, including BPA.

When work from her lab and others suggested that BPA hampers reproductive health in part by causing oxidative damage, "it made sense to look at antioxidants" for help, she said.

The team started with CoQ10 because it's readily available in stores, inexpensive and relatively safe, so if it proved effective in animal models, it would be well positioned for testing in people, said Colaiácovo.

The Kaneka Corporation, an international chemical manufacturer, provided the compound for the study. It did not contribute funding. None of the study authors stand to benefit financially from increased sales of CoQ10, Colaiácovo confirmed.

The researchers exposed groups of C. elegans worms to BPA, CoQ10 and a solvent called DMSO, alone and in various combinations. The timing of BPA and CoQ10 exposures were designed to approximate those in humans, and BPA levels detected inside the worms were proportional to the amounts found in the general human population.

The researchers found that CoQ10 improved or reversed multiple types of damage caused by BPA. Worms treated with the antioxidant had lower rates of egg cell death, fewer double-strand DNA breaks and fewer chromosome abnormalities during egg cell division, and lower levels of oxidative stress in egg cells. Early embryos also had fewer instances of abnormal chromosome numbers and other defects.

In humans, these types of abnormalities can lead to infertility, miscarriage and birth defects.

"CoQ10 rescued a lot of the defects we'd reported before," said Colaiácovo. "It's exciting to consider that we could be looking at a simple, low-cost intervention."

C. elegans has proved a useful model organism for studying countless aspects of basic biology. Many of the reproductive abnormalities caused by exposure to environmental toxins observed in worms are also seen in mammals from mice to primates, said Colaiácovo, boosting hope that the CoQ10 findings will similarly translate.

Nevertheless, humans are not big worms, and people should not rush out and start taking CoQ10 as an anti-BPA agent without consulting a doctor, the study authors said.

For one thing, the researchers used "very pure," quality controlled CoQ10, while store-bought supplements vary in CoQ10 content and do not always contain the amounts stated on labels, previous analyses have found.

"Our study underscores the need for tighter regulation and dedicated research on the biological effects of supplements," said Colaiácovo.

For Colaiácovo, the findings offer a glimmer of hope amid a flood of concerning findings.

"When we uncover evidence of toxicity from yet another chemical, often there is a feeling of 'Here we go again,'" she said. "But it's important to see what we can learn from it. I want us to figure out solutions."

Survival may more than double for adults with glioblastoma, the most common and deadly type of brain tumor, if neurosurgeons remove the surrounding tissue as aggressively as they remove the cancerous core of the tumor.

This discovery, reported in a retrospective study headed by researchers at UC San Francisco, is welcome news for those in the glioblastoma community, which celebrated its last breakthrough in 2005 with the introduction of the chemotherapy drug temozolomide.

Removing the "non-contrast-enhancing tumor" -- so called because it does not light up on MRI when a contrast agent is injected into the vein -- represents a paradigm shift for neurosurgeons, according to senior author and neurosurgeon Mitchel Berger, MD, director of the UCSF Brain Tumor Center.

"Traditionally, the goal of neurosurgeons has been to achieve total resection, the complete removal of contrast-enhancing tumor," said Berger, who is also affiliated with the UCSF Weill Institute for Neurosciences. "This study shows that we have to recalibrate the way we have been doing things and, when safe, include non-contrast-enhancing tumor to achieve maximal resection."

Mutant Tumor Type Indicative of Longer Life

Some 22,850 Americans are diagnosed each year with glioblastoma -- one of the most relentless adult cancers and one that may be best known for claiming the lives of senators John McCain and Edward Kennedy, and the son of Vice President Joe Biden. The average survival for the 91 percent of glioblastoma patients whose tumor is characterized by IDH-wild-type mutations is 1.2 years, according to a 2019 study. However, the remaining 9 percent have a type of glioblastoma classified as IDH mutant, with average survival of 3.6 years.

In their study, which publishes in JAMA Oncology on Feb. 6, 2020, the researchers tracked the outcomes of 761 newly diagnosed patients at UCSF who had been treated from 1997 through 2017. The patients, whose average age was 60, were divided into four groups with varying risk based on age, treatment protocols, and extent of resections of both contrast-enhancing and non-contrast-enhancing tumor.

They identified a group of 62 patients whose average survival was 37.3 months (3.1 years). These patients had IDH-mutant tumors, or were under 65 with IDH-wild-type tumors and had undergone both radiation and chemotherapy with temozolomide in virtually all cases. Each had resections with a median of 100 percent of contrast-enhancing tumor and a median of 90 percent of non-contrast-enhancing tumor.

In comparison, their counterparts -- 212 patients under 65 who had received the same therapies, but had more modest resections of the non-enhancing tumor -- survived only 16.5 months (1.4 years) on average, or about half as long. These results were verified with patient cohorts at the Mayo Clinic and the Cleveland Clinic's Ohio Brain Tumor Study.

Resecting Non-Enhancing Tumor Evens Survival Between Tumor Types

Among the group of longer-surviving patients, those with IDH-wild-type tumor did approximately as well as those with the IDH-mutant variant when a portion of the non-contrast enhancing tumor was removed, the authors noted. "The difference was that the patients with IDH-wild-type tumor declined more rapidly after the three-year mark," said first author Annette Molinaro, PhD, from the UCSF Department of Neurological Surgery, and the Department of Epidemiology and Biostatistics.

The researchers caution that maximal resection should only be achieved when it can be safely performed using techniques such as intraoperative brain mapping. This means that areas of the brain responsible for speech, motor, sensory and cognition are tested during surgery to ensure that these functional areas are preserved.

"There is a survival benefit for maximal resection for patients with glioblastoma, but as surgeons we must remove them in a manner that limits injury to the rest of the brain," said co-author and neurosurgeon Shawn Hervey-Jumper, MD, of the UCSF Brain Tumor Center and of the Weill Institute for Neurosciences.

Brain Mapping Is Critical for Aggressive Surgery

"Although these data show a survival benefit associated with maximal resection, it remains critically important that we do our best to remove tumor in a manner that will not harm the patient," Hervey-Jumper said, noting that about 80 percent of medical centers do not offer brain mapping.

While maximal resection of both enhancing and non-enhancing tumor should always be considered, Molinaro said that we are a long way from achieving a cure for glioblastoma.

"It's a complex tumor to treat for a number of reasons," she said. "One challenge is that the blood-brain barrier -- the network of blood vessels that acts as the brain's gatekeeper -- effectively blocks many cancer agents from reaching their target. Another challenge is that these are heterogenous tumors driven by multiple mutations -- if you target one mutation, others will thrive."