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Basic cell health systems wear down in Huntington’s disease, analysis shows

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Using an innovative computational approach to analyze vast brain cell gene expression datasets, researchers at MIT and Sorbonne Université have found that Huntington’s disease may progress to advanced stages more because of a degradation of the cells’ health maintenance systems than because of increased damage from the disease pathology itself.

The analysis yielded a trove of specific gene networks governing molecular pathways that disease researchers may now be able to target to better sustain brain cell health amid the devastating neurodegenerative disorder, says co-senior author Myriam Heiman, associate professor in MIT’s Department of Brain and Cognitive Sciences and an investigator at The Picower Institute for Learning and Memory. Christian Neri of the Sorbonne’s Centre National de la Recherche Scientifique is the co-senior and co-corresponding author of the study published in eLife.

“If we can maintain the expression of these compensatory mechanisms, it may be a more effective therapeutic strategy than just trying to affect one gene at a time,” says Heiman, who is also a member of the Broad Institute of MIT and Harvard.

In the study, the team led by co-corresponding author Lucile Megret created a process called “Geomic” to integrate two large sets of data from Heiman’s lab and one more from University of California at Los Angeles researcher William Yang. Each dataset highlighted different aspects of the disease, such as its effect on gene expression over time, how those effects varied by cell type, and the fate of those cells as gene expression varied.

Geomic created plots of the data that mapped differences pertaining to 4,300 genes along dimensions such as mouse age, the extent of Huntington’s-causing mutation, and cell type (certain neurons and astrocytes in a region of the brain called the striatum are especially vulnerable in Huntington’s). The plots took the form of geometric shapes, like crumpled pieces of paper, whose deformations could be computationally compared to identify genes whose expression changed most consequentially amid the disease. The researchers could then look into how abnormal expression of those genes could affect cellular health and function.

Big breakdowns

The Geomic analysis highlighted a clear pattern. Over time, the cells’ responses to the disease pathology — linked to toxic expansions in a protein called Huntingtin — largely continued intact, but certain highly vulnerable cells lost their ability to sustain gene expression needed for some basic systems that sustain cell health and function. These systems initially leapt into action to compensate for the disease but eventually lost steam.

One of the biggest such breakdowns in an especially vulnerable cell type, Drd-1 expressing neurons, was maintaining the health of energy-producing components called mitochondria. Last year, Heiman’s lab published a study in Neuron showing that in some Huntington’s-afflicted neurons, RNA leaks out of mitochondria provoking a misguided and immune response that leads to cell death. The new findings affirm a key role for mitochondrial integrity and implicate key genes such as Ndufb10, whose diminished expression may undermine the cell’s network of genes supporting the system.

The Geomic approach also highlighted an especially dramatic decline in the Drd-1 neurons and in astrocytes of expression of multiple genes in pathways that govern endosome regulation, an essential process for determining where proteins go and when they are degraded within the cells. Here, too, key genes like Rab8b and Rab7 emerged as culprits within broader gene networks.

The researchers went on to validate some of their top findings by confirming that key alterations of gene expression were also present in post-mortem samples of brain tissue from human Huntington’s patients.

While mitochondrial integrity and endosome regulation are two particularly strong examples, Heiman says, the study lists many others. The Geomic source code and all the data and visualizations it yielded are publicly accessible on a website produced by the authors.

“We’ve created a database of future targets to probe,” Heiman says.

Neri adds: “This database sets a precise basis for studying how to properly reinstate brain cell compensation in Huntington’s disease, and possibly in other neurodegenerative diseases that share common compensatory mechanisms with Huntington’s disease.”

Key among these could be regulators of genetic transcription in these affected pathways, Heiman says.

“One promising future direction is that among the genes that we implicate in these network effects, some of these are transcription factors,” she says. “They may be key targets to bring back the compensatory responses that decline.”

A new way to study disease

While the researchers first applied Geomic’s method of “shape deformation analysis” to Huntington’s disease, it will likely be of equal utility for studying any neurodegenerative disease like Alzheimer’s or Parkinson’s, or even other brain diseases, the authors says.

“This is a new approach to study systems-level changes, rather than just focusing on a particular pathway or a particular gene,” Heiman says. “I think this is a really nice proof of principle and hopefully we can apply this type of methodology to the study of other genomic data from other disease studies.”

In addition to Heiman, Neri, and Megret, the paper’s other authors are Barbara Gris, Satish Nair, Jasmin Cevost, Mary Wertz, Jeff Aaronson, Jim Rosinski, Thomas Vogt, and Hilary Wilkinson.

The Sorbonne Université, the CHDI Foundation, and the National Institutes of Health supported the research. Heiman’s lab is also supported by the JPB Foundation.

Source: https://news.mit.edu/2021/basic-cell-health-systems-wear-down-huntingtons-disease-0224

Biotechnology

An artificial intelligence tool that can help detect melanoma

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Melanoma is a type of malignant tumor responsible for more than 70 percent of all skin cancer-related deaths worldwide. For years, physicians have relied on visual inspection to identify suspicious pigmented lesions (SPLs), which can be an indication of skin cancer. Such early-stage identification of SPLs in primary care settings can improve melanoma prognosis and significantly reduce treatment cost.

The challenge is that quickly finding and prioritizing SPLs is difficult, due to the high volume of pigmented lesions that often need to be evaluated for potential biopsies. Now, researchers from MIT and elsewhere have devised a new artificial intelligence pipeline, using deep convolutional neural networks (DCNNs) and applying them to analyzing SPLs through the use of wide-field photography common in most smartphones and personal cameras.

Animation of a person's unclothed back, showing dozens of spots on the skin. Next, each spot is surrounded by a computer-graphic square of a different color. Finally, a heat map is created from these data.
How it works: A wide-field image, acquired with a smartphone camera, shows large skin sections from a patient in a primary-care setting. An automated system detects, extracts, and analyzes all pigmented skin lesions observable in the wide-field image. A pre-trained deep convolutional neural network (DCNN) determines the suspiciousness of individual pigmented lesions and marks them (yellow = consider further inspection, red = requires further inspection or referral to dermatologist). Extracted features are used to further assess pigmented lesions and to display results in a heatmap format.
Animation courtesy of the researchers.

DCNNs are neural networks that can be used to classify (or “name”) images to then cluster them (such as when performing a photo search). These machine learning algorithms belong to the subset of deep learning.

Using cameras to take wide-field photographs of large areas of patients’ bodies, the program uses DCNNs to quickly and effectively identify and screen for early-stage melanoma, according to Luis R. Soenksen, a postdoc and a medical device expert currently acting as MIT’s first Venture Builder in Artificial Intelligence and Healthcare. Soenksen conducted the research with MIT researchers, including MIT Institute for Medical Engineering and Science (IMES) faculty members Martha J. Gray, W. Kieckhefer Professor of Health Sciences and Technology, professor of electrical engineering and computer science; and James J. Collins, Termeer Professor of Medical Engineering and Science and Biological Engineering.

Soenksen, who is the first author of the recent paper, “Using Deep Learning for Dermatologist-level Detection of Suspicious Pigmented Skin Lesions from Wide-field Images,” published in Science Translational Medicine, explains that “Early detection of SPLs can save lives; however, the current capacity of medical systems to provide comprehensive skin screenings at scale are still lacking.”

The paper describes the development of an SPL analysis system using DCNNs to more quickly and efficiently identify skin lesions that require more investigation, screenings that can be done during routine primary care visits, or even by the patients themselves. The system utilized DCNNs to optimize the identification and classification of SPLs in wide-field images.

Using AI, the researchers trained the system using 20,388 wide-field images from 133 patients at the Hospital Gregorio Marañón in Madrid, as well as publicly available images. The images were taken with a variety of ordinary cameras that are readily available to consumers. Dermatologists working with the researchers visually classified the lesions in the images for comparison. They found that the system achieved more than 90.3 percent sensitivity in distinguishing SPLs from nonsuspicious lesions, skin, and complex backgrounds, by avoiding the need for cumbersome and time-consuming individual lesion imaging. Additionally, the paper presents a new method to extract intra-patient lesion saliency (ugly duckling criteria, or the comparison of the lesions on the skin of one individual that stand out from the rest) on the basis of DCNN features from detected lesions.

“Our research suggests that systems leveraging computer vision and deep neural networks, quantifying such common signs, can achieve comparable accuracy to expert dermatologists,” Soenksen explains. “We hope our research revitalizes the desire to deliver more efficient dermatological screenings in primary care settings to drive adequate referrals.”

Doing so would allow for more rapid and accurate assessments of SPLS and could lead to earlier treatment of melanoma, according to the researchers.

Gray, who is senior author of the paper, explains how this important project developed: “This work originated as a new project developed by fellows (five of the co-authors) in the MIT Catalyst program, a program designed to nucleate projects that solve pressing clinical needs. This work exemplifies the vision of HST/IMES devotee (in which tradition Catalyst was founded) of leveraging science to advance human health.” This work was supported by Abdul Latif Jameel Clinic for Machine Learning in Health and by the Consejería de Educación, Juventud y Deportes de la Comunidad de Madrid through the Madrid-MIT M+Visión Consortium.

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Source: https://news.mit.edu/2021/artificial-intelligence-tool-can-help-detect-melanoma-0402

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Navigating uncertainty through song

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It was his first week on campus, and like most first-year students, Alberto Naveira felt overwhelmed. On top of the usual college fears, he felt trapped between two worlds — his familiar, small, Catholic high school in Puerto Rico versus his new life as an MIT student in Cambridge.

To regain a sense of comfort, Naveira chose to stick with the things he knew well. He spent his time with other Puerto Rican students. He declared a major in biological engineering to continue pursuing his lifelong goal of being a physician. Throughout the transition, Naveira held on to his past to stay grounded. “I was never the type of person to try new things. Suddenly, here I was in a completely different environment, language, and culture. I didn’t know what to do,” he recalls.

As the year went on, Naveira watched as his Puerto Rican classmates grew apart to find new groups of their own. Yet, he struggled to decide where he belonged. By the time he was a sophomore, Naveira knew he was lonely and needed a change. He thought back to high school, during moments when he felt most connected to a community. Most of these memories revolved around singing in his school’s choir. He realized he could revisit his passion by devoting himself to the Chorallaries of MIT, the Institute’s oldest co-ed student a capella group.

After joining, Naveira realized that getting to know members would require him to become more than just a performer. When the president position became available, Naveira realized this was his chance to step up. The demanding role immediately required him to spend countless hours with the group. “I started to feel closer to the others after we spent a good deal of time together coordinating performances. It was through these troubleshooting challenges that we began to actually bond,” he says.

As president, Naveira sought to make important changes to help newcomers like himself feel more welcomed. Along with planned social events, he focused on encouraging more casual get-togethers. “We would often go to the dining halls to catch dinner or brunch together. After performances, I always made sure that we’d acknowledge our accomplishments by having a celebration together,” he says. “They were little things, but I think they allowed us to become closer.”

Naveira also united members by facilitating conversations about the group’s shared traditions and values. When members advocated for new ideas, Naveira found himself championing their causes. “It was brought to my attention that our traditional song had lyrics that were heteronormative and lacked consent. There were also unnecessarily strict rules for the male performance dress code. By talking it through, we were able to make changes that were both fair and true to our customs.”

Throughout the year, Naveira began to see changes in himself as he developed into the role. He found himself speak up without fear, eager to listen and share his ideas. He was finally breaking out of his shell. “It took a while before I was able to confidently go in front of older members and make decisions. But the more time I spent on it, the better I got at projecting myself,” he says.  

While coordinating the group came with challenging moments, Naveira grew to truly appreciate teamwork over singing solo. “There’s something to be said about living music as a social experience,” he says. “Like when you make eye contact with someone during a performance and there’s this shared intense emotion. It’s unlike anything else. You can’t have that on your own.”

Today, Naveira continues to be part of the Chorallaries as a performer, arranger, and audio mixer. Although he now feels at home at MIT, Naveira acknowledges that the process took dedication and self-discovery. He tries to spread this message to other struggling students he tutors through the Talented Scholars Resource Room (TSR^2) in the Office of Minority Education. “As I dug deeper into the communities that shared my interests, I started to feel more at home here,” he shares. “I try to emphasize this to my students whenever I can. If you feel like you haven’t found your place yet, it just takes some time.”

Naveira has also used his time in college to expand his original academic interest in medicine. He says the variety in his courses has shown him new ways of thinking, as well as career alternatives to becoming a physician. His favorite course, 20.309 (Instrumentation and Measurement for Biological Systems), encouraged him to investigate biology by applying principles from other engineering disciplines. “The interdisciplinary nature of the class showed me how medicine expands into other fields. We learned how something like signal processing can be applied to everything from medicine to music,” says Naveiro. “It blew my mind and made me rethink what I know.”

Over the past few months, Naveira has focused less on sticking to a defined path and more on pursuing what he loves. Stepping beyond music performance, he is currently pursuing a second bachelor’s degree in music production at Berklee College of Music. His new skills were used to arrange the Chorallaries’ most recent virtual performance, which won first place in the 2021 ICAA Northeastern Quarterfinal. Naveira plans on continuing to pursue music even after graduation. “Regardless of where I end up, I’m certain that I’ll never be happy unless music is part of my life. It’s something I truly value,” he says.

He also remains open to all types of career paths in medicine. Naveira loves the idea of continuing to apply knowledge from different disciplines to rethink medical problems. “The more I learn, the harder it is to choose a career in a specific field,” Naveira explains. “That’s something I never expected. I always knew that MIT would be a great place for me to grow as a researcher. But I never expected to grow as a musician, a tutor, a friend, and a person in general.”

“This past year has shown me that nothing is guaranteed. Life will always be full of uncertainty and I’ll be forced to try new things. But I feel that, with the right people by my side, I can handle anything.”

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Source: https://news.mit.edu/2021/alberto-naveira-0402

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Signal detection theory can be used to objectively measure cognitive fatigue

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Kessler Foundation research team finds that cognitive fatigue covaries with signal detection theory metrics, providing researchers with new investigative tools

East Hanover, NJ. April 1, 2021. A team of New Jersey researchers has shown that changes in perceptual certainty and response bias, two central metrics of signal detection theory (SDT), correlate with changes in cognitive fatigue. They also show that SDT measures change as a function of changes in brain activation. This finding was reported in Frontiers in Psychology on January 15, 2021, in the open access article “Using Signal Detection Theory to Better Understand Cognitive Fatigue” (doi:10.3389/fpsyg.2020.579188).

The authors are Glenn Wylie, DPhil, Brian Yao, PhD, and John DeLuca, PhD, of Kessler Foundation, and Joshua Sandry, PhD, of Montclair State University.

Cognitive fatigue is a common experience that affects the healthy population as well as individuals with brain injury or neurodegenerative disease. A large body of research shows that subjective feelings of cognitive fatigue do not correlate with performance–that is, a person may experience cognitive fatigue and yet objective measures of their performance, such as their response time or level of accuracy, do not necessarily worsen. As a result, researchers have long lacked an objective behavioral measure that covaries with the subjective experience of fatigue.

While previous research has indicated that one metric of SDT, perceptual certainty, may change as a function of fatigue, it remains unclear whether perceptual certainty covaries with fatigue. Moreover, there has been no research investigating the effect of fatigue on the second key SDT metric, response bias, which is the amount of evidence one requires before releasing a response. Understanding if and how cognitive fatigue covaries with both SDT metrics is essential to the development of effective interventions for people with this condition.

The study was conducted at the Rocco Ortenzio Neuroimaging Center at Kessler Foundation, a specialized facility dedicated solely to rehabilitation research. To investigate cognitive fatigue using SDT, the investigators induced cognitive fatigue in 39 healthy volunteers while acquiring both structural and functional magnetic resonance imaging (fMRI) data. They assessed subjects’ cognitive fatigue using a visual analogue scale of fatigue (VAS-F) at baseline and after each of the eight runs of the tasks. This enabled the team to assess whether perceptual certainty and response bias covary with cognitive fatigue, and whether similar patterns of brain activation underlie cognitive fatigue and SDT measures.

Researchers found that both SDT metrics were correlated with changes in cognitive fatigue. As fatigue increased, subjects became more conservative in their response bias and their perceptual certainty declined. This study is the first to show that changes in cognitive fatigue are correlated with changes in perceptual certainty.

Furthermore, the research team found that activation in the striatum of the basal ganglia–an area of the brain Kessler researchers have previously identified as sensitive to changes in cognitive fatigue–was also related to response bias and perceptual certainty.

“Our results show that cognitive fatigue is related to changes in subjects’ response bias and perceptual certainty,” said lead author Dr. Wylie, director of the Ortenzio Center. “We theorize that as cognitive fatigue increases, subjects make more errors because their perceptual sensitivity declines and they compensate for this by adopting a more conservative response bias,” he emphasized. “Our work demonstrates the relevance of SDT measures in the understanding of fatigue and provides researchers with a new set of tools with which to better understand the nature and consequences of cognitive fatigue.”

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Funding: New Jersey Commission for Brain Injury Research (10.005.BIR1) and the National Multiple Sclerosis Society (RG 4232A1/1)

Learn more about ongoing studies at Kessler Foundation at Join Our Research Studies | Kessler Foundation

About Kessler Foundation

Kessler Foundation, a major nonprofit organization in the field of disability, is a global leader in rehabilitation research that improves cognition, mobility and long-term outcomes, including employment, for people with neurological disabilities caused by diseases and injuries of the brain and spinal cord. Kessler Foundation leads the nation in funding innovative programs that expand opportunities for employment for people with disabilities. Learn more by visiting http://www.KesslerFoundation.org

Contact: Carolann Murphy, PA; [email protected]

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Source: https://bioengineer.org/signal-detection-theory-can-be-used-to-objectively-measure-cognitive-fatigue/

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Bringing gene editing into high schools

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St. Georges Technical High School in southern New Castle County, Delaware is the first high school in the United States to use ChristianaCare Gene Editing Institute’s innovative CRISPR in a Box Educational Toolkit™ in a science class.

CRISPR in a Box brings to life the much-heralded CRISPR gene editing technology – the “genetic scissors” that allow scientists to edit DNA. The toolkit is designed for educational sessions in secondary and post-secondary schools and is suitable for remote learning.

“Gene editing is the future of medicine,” said Eric Kmiec, Ph.D., director of ChristianaCare’s Gene Editing Institute. “Our partnership with the Delaware Department of Education will help cultivate the next generation of genetic scientists and enhance Delaware’s position as a leader in the biosciences.”

“We are thrilled that students at St. Georges Technical High School will be the first In the United States to experience a live demonstration of CRISPR gene editing using our Innovative CRISPR in a Box educational toolkit,” said Siobhan Hawthorne, Education and Community Outreach leader at ChristianaCare’s Gene Editing Institute. “This toolkit will provide STEM students with a visual understanding of how the exciting CRISPR technology can unlock medical treatments to improve lives.”

Delaware Secretary of Education Susan Bunting praised her department’s partnership with ChristianaCare’s Gene Editing Institute to develop the “Seeds of STEM” course that teaches high school students about gene editing.

“Gene editing approaches diseases in new ways and will have significant impact in the health care and agriscience fields,” Bunting said. “This is a great example of an industry and education partnership investing in youth by providing hands-on knowledge and skills around emerging technology.”

“We are so fortunate that ChristianaCare’s Gene Editing Institute reached out to our program to plan a high school ‘first’ opportunity with this new CRISPR experiment,” said Danya Espadas, one of the St. Georges biotech teachers. “Giving students the chance to use a cutting-edge, 21st century tool for medicine in their own high school lab – to have that technology at their fingertips – transcends what they see in a textbook or a video. By being able to do it themselves, it makes it real for them.”

Espadas said the experiment focuses on editing a gene of a non-infectious E.coli bacteria to become resistant to an antibiotic, thereby allowing researchers to create a new class of antibiotics that cannot be overcome by bacteria that are gene resistant.

“We’re talking about eventually saving lives, here,” she said. “What can be more important than that?”

The tools in CRISPR in a Box have been designed based on the pioneering discoveries of the Gene Editing Institute that are currently being used to explore next-generation medical therapies and diagnostics for diseases, including lung cancer and sickle-cell anemia. Component items in the toolkit include the CRISPR/Cas complex, a target DNA molecule, a mammalian cell free extract and a synthetic DNA molecule.

All materials in the kit are safe, synthetic materials. There are no live cultures or viruses involved. The kit is meant to provide a hands-on demonstration of CRISPR’s capabilities, and not allow for manipulations of living organisms.

“The kit is easy and fun to use,” said Kristen Pisarcik, research assistant at the Gene Editing Institute who has taught students at Delaware Technical Community College which first used the toolkit. “In a short period of time students will reliably and successfully complete the laboratory activity and be able to see the results of gene editing,” she said.

Since the foundations of the kit touch upon key themes in biology, it can be readily incorporated into practically any science or biology course with a laboratory component,

“One of the beauties of CRISPR in a Box is that there is no need to purchase specialized equipment. If a teaching lab can support bacterial cultivation, it can perform the in vitro gene editing lab activity,” Pisarcik said.

CRISPR in a Box is the evolution of a partnership between the Gene Editing Institute, Delaware Technical Community College and Rockland Immunochemicals that began in 2017 with a National Science Foundation grant to develop the first-ever gene editing curriculum for community college students.

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About ChristianaCare’s Gene Editing Institute

The Gene Editing Institute, a worldwide leader in CRISPR gene editing technology and the only institute of its kind based within a community health care system, takes a patient-first approach in all its research to improve the lives of people with life-threatening disease. Since 2015, researchers at the Gene Editing Institute have been involved in several ground-breaking firsts in the field, including the development of the first CRISPR gene editing tool to allow DNA repairs outside the human cell which will rapidly speed therapies to patients and a unique version of CRISPR called EXACT that reduces the number of off-target edits to other areas of the genome, which is vital for further research and patient applications. Its researchers are currently developing a patient trial for lung cancer using CRISPR and employing the technology to combat the COVID-19 pandemic.

About the biotech program St. Georges Technical High School

The Biotech career program of study at St. Georges Technical High School is the first such program offered in a Delaware high school. With two teachers and approximately 100 students in grades 10-12, the program presents advanced content in biology and chemistry with opportunities for students to learn basic laboratory techniques and procedures and to maintain and operate common instruments and equipment used in a biotechnology laboratory. St. Georges is a comprehensive career and technical high school with 1,100 students who study in one of 16 different career pathways.

https://news.christianacare.org/wp-content/uploads/2021/04/CC-StGeorges_press_release.html

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Source: https://bioengineer.org/bringing-gene-editing-into-high-schools/

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