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A Biological Fireworks Show 300 Million Years in the Making

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Five years ago, researchers at Northwestern University made international headlines when they discovered that human eggs, when fertilized by sperm, release billions of zinc ions, dubbed “zinc sparks.”

Now, Northwestern has teamed up with the U.S. Department of Energy’s (DOE) Argonne National Laboratory and Michigan State University (MSU) to reveal that these same sparks fly from highly specialized metal-loaded compartments at the egg surface when frog eggs are fertilized. This means that the early chemistry of conception has evolutionary roots going back at least 300 million years, to the last common ancestor between frogs and people.

“This work may help inform our understanding of the interplay of dietary zinc status and human fertility.” — Thomas O’Halloran, professor, Michigan State University

And the research has implications beyond this shared biology and deep-rooted history. It could also help shape future findings about how metals impact the earliest moments in human development.

“This work may help inform our understanding of the interplay of dietary zinc status and human fertility,” said Thomas O’Halloran, the senior author of the research paper published June 21 in the journal Nature Chemistry.

O’Halloran was part of the original zinc spark discovery at Northwestern and, earlier this year, he joined Michigan State as a foundation professor of microbiology and molecular genetics and chemistry. O’Halloran was the founder of Northwestern’s Chemistry of Life Processes Institute, or CLP, and remains a member.

The team also discovered that fertilized frog eggs eject another metal, manganese, in addition to zinc. It appears these ejected manganese ions collide with sperm surrounding the fertilized egg and prevent them from entering.

“These breakthroughs support an emerging picture that transition metals are used by cells to regulate some of the earliest decisions in the life of an organism,” O’Halloran said.

To make these discoveries, the team needed access to some of the most powerful microscopes in the world as well as expertise that spanned chemistry, biology and X-ray physics. That unique combination included collaborators at the Center for Quantitative Element Mapping for the Life Sciences, or QE-Map, an interdisciplinary National Institutes of Health-funded research hub at MSU and Northwestern’s CLP. The research relied heavily on the tools and expertise available at Argonne.

The research team brought sections of frog eggs and embryos to Argonne for analysis. Using both X-ray and electron microscopy, the researchers determined the identity, concentrations and intracellular distributions of metals both before and after fertilization.

X-ray fluorescence microscopy was conducted at beamline 2-ID-D of the Advanced Photon Source (APS), a DOE Office of Science User Facility at Argonne. Barry Lai, group leader at Argonne and an author on the paper, said that the X-ray analysis quantified the amount of zinc, manganese and other metals concentrated in small pockets around the outer layer of the eggs. They found these pockets contained more than 30 times the manganese as the rest of the eggs, and 10 times the zinc.

“We are able to do this analysis because of the elemental sensitivity of the beamline,” Lai said. “In fact, it is so sensitive that substantially lower concentrations can be measured.”

Complementary scans were conducted using transmission electron microscopy at the Center for Nanoscale Materials (CNM), a DOE Office of Science User Facility at Argonne. Further analysis was performed on a separate prototype scanning transmission electron microscope that includes technology developed by Argonne Senior Scientist Nestor Zaluzec, an author on the paper. These scans were performed at smaller scales — down to a few nanometers, about 100,000 times smaller than the width of a human hair — but found the same results: high concentrations of metals in pockets around the outer layer.

Both X-ray and electron microscopy showed that the metals in these pockets were almost completely released after fertilization.

“Argonne has the tools necessary to examine these biological samples at these scales without destroying them with X-rays or electrons,” Zaluzec said. “It’s a combination of the right resources and the right expertise.”

The APS is in the process of undergoing a massive upgrade, one that will increase the brightness of its X-ray beams by up to 500 times. Lai said that an upgraded APS could complete these scans much more quickly or with higher spatial resolution. What took more than an hour for this research could be done in less than one minute after the upgrade, Lai said.

“We often think of genes as key regulating factors, but our work has shown that atoms like zinc and manganese are critical to the first steps in development after fertilization,” said MSU Provost Teresa K. Woodruff, Ph.D., another senior author on the paper.

Woodruff, an MSU foundation professor and former member of CLP, was also a leader of the Northwestern team that discovered zinc sparks five years ago. With the discovery of manganese sparks in African clawed frogs, or Xenopus laevis, the team is excited to explore whether the element is released by human eggs when fertilized.

“These discoveries could only be made by interdisciplinary groups, fearlessly looking into fundamental steps,” she said. “Working across disciplines at the literal edge of technology is one of the most profound ways new discoveries take place.”

“Xenopus is a perfect system for such studies because their eggs are an order of magnitude larger than human or mouse eggs, and are accessible in large numbers ” said Carole LaBonne, another senior author on the study, CLP member, and chair of the Department of Molecular Biosciences at Northwestern. “The discovery of zinc and manganese sparks is exciting, and suggests there may be other fundamental signaling roles for these transition metals.”

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About Argonne’s Center for Nanoscale Materials The Center for Nanoscale Materials is one of the five DOE Nanoscale Science Research Centers, premier national user facilities for interdisciplinary research at the nanoscale supported by the DOE Office of Science. Together the NSRCs comprise a suite of complementary facilities that provide researchers with state-of-the-art capabilities to fabricate, process, characterize and model nanoscale materials, and constitute the largest infrastructure investment of the National Nanotechnology Initiative. The NSRCs are located at DOE’s Argonne, Brookhaven, Lawrence Berkeley, Oak Ridge, Sandia and Los Alamos National Laboratories. For more information about the DOE NSRCs, please visit https://science.osti.gov/User-Facilities/User-Facilities-at-a-Glance.

About the Advanced Photon Source

The U. S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory is one of the world’s most productive X-ray light source facilities. The APS provides high-brightness X-ray beams to a diverse community of researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. These X-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being. Each year, more than 5,000 researchers use the APS to produce over 2,000 publications detailing impactful discoveries, and solve more vital biological protein structures than users of any other X-ray light source research facility. APS scientists and engineers innovate technology that is at the heart of advancing accelerator and light-source operations. This includes the insertion devices that produce extreme-brightness X-rays prized by researchers, lenses that focus the X-rays down to a few nanometers, instrumentation that maximizes the way the X-rays interact with samples being studied, and software that gathers and manages the massive quantity of data resulting from discovery research at the APS.

This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://energy.gov/science.

https://www.anl.gov/article/a-biological-fireworks-show-300-million-years-in-the-making

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Source: bioengineer.org

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African American Breast Cancer Patients Less Likely to Receive Genetic Counseling, Testing

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Researchers at Washington University School of Medicine in St. Louis have surveyed cancer doctors to identify differences in physician attitudes and beliefs that may contribute to a gap in referrals to genetic counseling and testing between Black women and white women with breast cancer.

Researchers at Washington University School of Medicine in St. Louis have surveyed cancer doctors to identify differences in physician attitudes and beliefs that may contribute to a gap in referrals to genetic counseling and testing between Black women and white women with breast cancer.

The breast cancer mortality rate is 41% higher for Black women than white women. Part of the reason for that difference may be that white women are almost five times more likely than Black women to be referred for genetic counseling and testing, suggesting racial disparities in how some doctors refer patients for those services.

Genetic counseling and testing can identify those at high risk for developing breast cancer. It also can be used to personalize cancer prevention for individual patients, and it can guide treatment in those who have hereditary breast cancer caused by gene mutations. Hereditary forms of breast cancer — which account for 5% to 10% of breast cancer cases — affect Black and white women at about the same rates.

The new findings, published Oct. 18 in the Journal of Clinical Oncology, revealed that physicians believe Black women experience more barriers to genetic counseling and testing. The doctors’ self-reported practices with regard to counseling and testing for Black women also indicated that many believed Black women would be less likely to comply with recommendations for genetic counseling and testing.

“For breast cancer patients with genetic mutations, the treatment is different; the surgical options are different; the screening and surveillance going forward is very different — so it’s important to identify those patients through genetic counseling and testing services,” said first author Foluso O. Ademuyiwa, MD, an associate professor of medical oncology. “We wanted to learn why Black women are not being referred for this type of care as frequently. We hope these findings might help change that trajectory. We hope that Black women won’t continue to be less likely to receive information and referrals that may help save their lives and even the lives of some of their family members.”

The researchers surveyed 277 cancer doctors around the country to learn why referrals are made so much less frequently for Black women. Of the doctors surveyed, 67% were white, less than 4% were Black, almost 59% were female and almost 62% practiced at academic medical centers. Although fewer than 2% of doctors surveyed said they were less likely to refer a Black patient than a white patient, other research has found that Black patients are being referred for genetic counseling and testing less than 60% of the time that such testing is recommended by National Comprehensive Cancer Network guidelines. That compares with a referral rate of 93% for white patients.

Ademuyiwa and her colleagues asked doctors whether they believed Black patients were more likely than white patients to refuse genetic counseling and testing. Almost 26% said yes. Another 46% of respondents cited cost as a barrier for Black patients and a potential reason not to refer. Almost 59% said that their Black patients were less likely to trust their doctors’ diagnoses and referrals than white patients were.

“The survey indicated that 14% of physicians felt their patients, in general — regardless of race — probably would not follow through with genetic testing and counseling recommendations,” said Ademuyiwa, who treats patients at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “But more than twice as many, 31%, thought their Black patients would be less likely than white patients to comply with their recommendations for genetic counseling and testing. We feel there is some bias here, and we want to understand how we as physicians can do better in closing this gap.”

Women with mutations in the BRCA1 and BRCA2 genes have a 55% to 85% chance of developing breast cancer during their lifetimes, but several studies have shown that doctors do not refer many of their patients for counseling and testing that could identify those mutations and help guide their treatment.

One issue, Ademuyiwa said, is time. In 30 minutes with a new patient, some doctors may prefer to focus on upcoming surgery or chemotherapy rather than discuss the pros and cons of genetic counseling and testing.

“In a prior study of 250 Black women with breast cancer in the St. Louis region, we found that among women who were eligible for genetic testing based on the National Comprehensive Cancer Network guidelines, only 60% had any testing done,” said Laura Jean Bierut, MD, the Alumni Endowed Professor of Psychiatry and the study’s senior author. “Why were 40% of these women not referred? It’s important to learn why so many patients may not get access to these services.”

Data also suggest Black patients are more comfortable working with providers of the same race, but only about 3% of U.S. oncologists are Black. Based on the results of the new survey, Ademuyiwa and her colleagues are launching a pilot study at Siteman Cancer Center. Facilitators will be matched with patients of the same race and will perform in-person genetic screens of such patients. The facilitators then will share information from the screenings — including family histories and other pertinent details — with treating physicians to see whether this strategy might increase rates of referrals to genetic counseling and testing.

“We want doctors to check themselves, to take stock of what they have been doing and to take a little more time to make sure they are referring patients eligible for genetic counseling and testing,” Ademuyiwa said. “Correctly referring women, regardless of their skin color, is very important and can improve survival for breast cancer patients of all colors in a very real way.”

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Ademuyiwa FO, Salyer P, Tao Y, Luo J, Hensing WL, Afolalu A, Peterson LL, Weilbaecher K, Housten AJ, Baumann AA, Desai M, Jones S, Linnenbringer E, Plichta J, Bierut LJ. Genetic counseling and testing in African American patients with breast cancer. Journal of Clinical Oncology, Oct. 18, 2021.

This work was supported by the American Society of Clinical Oncology’s Research Survey Pool.

Washington University School of Medicine’s 1,700 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, consistently ranking among the top medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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Article: bioengineer.org

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Is Fresh Breast Milk Better for Preemies Than Pumped and Stored?

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Carrie-Ellen Briere studies the cells in human milk, a passion inspired by years of working as a clinical nurse with sick and premature babies in the neonatal intensive care unit (NICU).

Carrie-Ellen Briere studies the cells in human milk, a passion inspired by years of working as a clinical nurse with sick and premature babies in the neonatal intensive care unit (NICU).

The University of Massachusetts Amherst assistant professor of nursing is researching whether fresh breast milk can be shown to provide more benefits to NICU babies than breast milk pumped from the mother that has been refrigerated or frozen. She’s also advancing research that suggests in animal models that breast cells can act like stem cells, turning into functioning cells in such organs as the liver and brain.

To pursue her lab research mentored by a team of veteran UMass Amherst professors, Briere has been awarded a five-year, $730,000 career development grant from the National Institutes of Health’s (NIH) National Institute of Child Health and Human Development.

“A typical newborn breastfeeds directly at the breast, so they’re getting milk right as nature intended,” Briere says. “When babies are in the NICU, moms usually have to pump milk that we refrigerate or freeze because not all the babies who are born early or are sick can eat it right away so we save it for later use. Many preterm infants also have extra nutrients added into milk, so their milk is often prepared in bulk at a set time of day, instead of individually at feedings with fresh milk.

“We know that human milk is protective and beneficial for infants both in the NICU and afterwards, but we’re not quite sure how storing impacts different components of the milk we’re giving to babies and whether it may be taking away some of its beneficial properties.”

Briere is being mentored by an interdisciplinary UMass Amherst team, including breast milk and breast cancer researchers Kathleen Arcaro and D. Joseph Jerry, both professors of veterinary and animal sciences; and nutrition scientist David Sela, associate professor of food science and director of the Fergus M. Clydesdale Center for Foods for Health and Wellness. (Briere is also working with Sela in his NIH-funded investigation into how nitrogen in human milk is used by beneficial microbes in the infant gut.) In addition to the UMass Amherst researchers, Dr. Laura Madore, an assistant professor of pediatrics at UMass Medical School-Baystate and attending neonatologist at Baystate Children’s Hospital, is another member of Briere’s guiding team.

Briere will conduct experiments using fresh, refrigerated and frozen human milk and compare their impacts on lab-based intestinal cells in which an infection has been introduced. “We want to prioritize using fresh milk in the NICU but there are a lot of barriers to that,” she says. “Having actual data showing that having fresh milk is best would help change clinical practice to make sure our sickest little babies are getting the best milk possible, especially early in their life when they’re most vulnerable.”

One way to make that happen, she says, is by coordinating family visit times with feeding times.

In related research, Briere will design new studies in animal models that examine how specific breast milk cells end up moving from the gut and transforming into functional cells in other organs. This could have significant implications for preterm babies whose organs are underdeveloped, she notes.

“Studies have shown that cells in milk, when ingested in animal models, don’t just get swallowed and hang out in the gut,” Briere says. “They actually are finding milk cells in various organs throughout the mouse pups. Somehow the milk cells are traveling through the digestive system and landing in some specific organs as actual functioning cells.”

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Original Source: bioengineer.org

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Scientists Show How AI May Spot Unseen Signs of Heart Failure

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A special artificial intelligence (AI)-based computer algorithm created by Mount Sinai researchers was able to learn how to identify subtle changes in electrocardiograms (also known as ECGs or EKGs) to predict whether a patient was experiencing heart failure.

Credit: Courtesy of Glicksberg and Nadkarni labs, Mount Sinai, N.Y., N.Y.

A special artificial intelligence (AI)-based computer algorithm created by Mount Sinai researchers was able to learn how to identify subtle changes in electrocardiograms (also known as ECGs or EKGs) to predict whether a patient was experiencing heart failure.

“We showed that deep-learning algorithms can recognize blood pumping problems on both sides of the heart from ECG waveform data,” said Benjamin S. Glicksberg, PhD, Assistant Professor of Genetics and Genomic Sciences, a member of the Hasso Plattner Institute for Digital Health at Mount Sinai, and a senior author of the study published in the Journal of the American College of Cardiology: Cardiovascular Imaging. “Ordinarily, diagnosing these type of heart conditions requires expensive and time-consuming procedures. We hope that this algorithm will enable quicker diagnosis of heart failure.”

The study was led by Akhil Vaid, MD, a postdoctoral scholar who works in both the Glicksberg lab and one led by Girish N. Nadkarni, MD, MPH, CPH, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai, Chief of the Division of Data-Driven and Digital Medicine (D3M), and a senior author of the study.

Affecting about 6.2 million Americans, heart failure, or congestive heart failure, occurs when the heart pumps less blood than the body normally needs. For years doctors have relied heavily on an imaging technique called an echocardiogram to assess whether a patient may be experiencing heart failure. While helpful, echocardiograms can be labor-intensive procedures that are only offered at select hospitals.

However, recent breakthroughs in artificial intelligence suggest that electrocardiograms–a widely used electrical recording device–could be a fast and readily available alternative in these cases. For instance, many studies have shown how a “deep-learning” algorithm can detect weakness in the heart’s left ventricle, which pushes freshly oxygenated blood out to the rest of the body. In this study, the researchers described the development of an algorithm that not only assessed the strength of the left ventricle but also the right ventricle, which takes deoxygenated blood streaming in from the body and pumps it to the lungs.

“Although appealing, traditionally it has been challenging for physicians to use ECGs to diagnose heart failure. This is partly because there is no established diagnostic criteria for these assessments and because some changes in ECG readouts are simply too subtle for the human eye to detect,” said Dr. Nadkarni. “This study represents an exciting step forward in finding information hidden within the ECG data which can lead to better screening and treatment paradigms using a relatively simple and widely available test.”

Typically, an electrocardiogram involves a two-step process. Wire leads are taped to different parts of a patient’s chest and within minutes a specially designed, portable machine prints out a series of squiggly lines, or waveforms, representing the heart’s electrical activity. These machines can be found in most hospitals and ambulances throughout the United States and require minimal training to operate.

For this study, the researchers programmed a computer to read patient electrocardiograms along with data extracted from written reports summarizing the results of corresponding echocardiograms taken from the same patients. In this situation, the written reports acted as a standard set of data for the computer to compare with the electrocardiogram data and learn how to spot weaker hearts.

Natural language processing programs helped the computer extract data from the written reports. Meanwhile, special neural networks capable of discovering patterns in images were incorporated to help the algorithm learn to recognize pumping strengths.

“We wanted to push the state of the art by developing AI capable of understanding the entire heart easily and inexpensively,” said Dr. Vaid.

The computer then read more than 700,000 electrocardiograms and echocardiogram reports obtained from 150,000 Mount Sinai Health System patients from 2003 to 2020. Data from four hospitals was used to train the computer, whereas data from a fifth one was used to test how the algorithm would perform in a different experimental setting.

“A potential advantage of this study is that it involved one of the largest collections of ECGs from one of the most diverse patient populations in the world,” said Dr. Nadkarni.

Initial results suggested that the algorithm was effective at predicting which patients would have either healthy or very weak left ventricles. Here strength was defined by left ventricle ejection fraction, an estimate of how much fluid the ventricle pumps out with each beat as observed on echocardiograms. Healthy hearts have an ejection fraction of 50 percent or greater while weak hearts have ones that are equal to or below 40 percent.

The algorithm was 94 percent accurate at predicting which patients had a healthy ejection fraction and 87 percent accurate at predicting those who had an ejection fraction that was below 40 percent.

However the algorithm was not as effective at predicting which patients would have slightly weakened hearts. In this case, the program was 73 percent accurate at predicting the patients who had an ejection fraction that was between 40 and 50 percent.

Further results suggested that the algorithm also learned to detect right valve weaknesses from the electrocardiograms. In this case, weakness was defined by more descriptive terms extracted from the echocardiogram reports. Here the algorithm was 84 percent accurate at predicting which patients had weak right valves.

“Our results suggested that this algorithm may eventually help doctors correctly diagnose failure on either side of the heart,” Dr. Vaid said.

Finally, additional analysis suggested that the algorithm may be effective at detecting heart weakness in all patients, regardless of race and gender.

“Our results suggest that this algorithm could be a useful tool for helping clinical practitioners combat heart failure suffered by a variety of patients,” added Dr. Glicksberg. “We are in the process of carefully designing prospective trials to test out its effectiveness in a more real-world setting.”

This study was supported by the National Institutes of Health (TR001433).

Article

Vaid, A., et al., Using deep learning algorithms to simultaneously identify right and left ventricular dysfunction from the electrocardiogram, Journal of the American College of Cardiology: Cardiovascular Imaging, October 13, 2021, DOI: 10.1016/j.jcmg.2021.08.004.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City’s largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report’s “Honor Roll” of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children’s Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report’s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.

For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.

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Original Article: bioengineer.org

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