NeURoscience Newsletter | Vol 19 | 2023

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NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Vol. 19 - 2023

FROM LAB TO LIFE-CHANGER URMC neuromuscular researchers pave the way for gene therapy revolution PG 4



John J. Foxe, PhD Kilian J. and Caroline F. Schmitt Chair in Neuroscience

Director, Ernest J. Del Monte Institute for Neuroscience

Professor & Chair, Department of Neuroscience

he complexity of the brain dazzles the imagination—and coupled with the drive to find answers and interventions for some of the most complex neuro-related disorders and diseases—it energizes us to pursue great science. I am still feeling inspired by our annual Del Monte Institute for Neuroscience and Intellectual and Developmental Disabilities Research Center Symposium, which exceeded my expectations this year. It was a truly special gathering. I am so grateful for the organizers and scientists who came together for the two-day event titled “Uncovering the Mysteries of Intellectual & Developmental Disabilities: A Scientific Exploration.” Our faculty and students never cease to amaze me, tackling difficult questions in the lab and challenges in our society. The Neuroscience Diversity Commission continues to provide access to research and science to students at all levels from historically marginalized communities. The program NEUROCITY has proven our partnership with City College of New York (CCNY) and support from the Summer Scholars program at the University of Rochester School of Medicine and Dentistry can be life-changing for students and, ultimately, the field of neuroscience. In the pages ahead, read about the alumni who are pursuing graduate degrees they once thought were out of reach.

Del Monte Institute for Neuroscience Executive Committee John Foxe, PhD, Chair, Department of Neuroscience Bradford Berk MD, PhD, Professor of Medicine, Cardiology Robert Dirksen, PhD, Chair, Department of Pharmacology & Physiology Diane Dalecki, PhD, Chair, Department of Biomedical Engineering Jennifer Harvey, MD, Chair, Department of Imaging Sciences Robert Holloway, MD, MPH, Chair, Department of Neurology

We have long been a leader in neuromuscular disease research. Most recently, Medical Center researchers contributed to a monumental advance in a first-of-its-kind treatment for Duchenne Muscular Dystrophy. In the 1990s, our researchers first defined Myotonic dystrophy type 2 (DM2), a rare form of muscular dystrophy. On page 4, learn from some of the researchers in the room that day when the right questions started coming together and where that research is today. In August, we had the great pleasure of hosting the Kilian J. & Caroline F. Schmitt Foundation board. Three recent recipients of Schmitt pilot grant funds shared their novel research with the foundation that has been a loyal supporter of our research for over two decades. We are grateful for their continued interest and support. I am looking forward to seeing many in our Neuroscience community at the Society for Neuroscience Conference in Washington D.C., in November. I hope you can join us for one night as we host a social event to spark collaborations, reunite old friends, and celebrate the success of our alumni and colleagues (see invitation on the back cover). In Science,

John J. Foxe, PhD

Paige Lawrence, PhD, Chair, Department of Environmental Medicine Hochang (Ben) Lee, MD, Chair, Department of Psychiatry Shawn Newlands, MD, PhD, MBA, Chair, Department of Otolaryngology Webster Pilcher, MD, PhD, Chair, Department of Neurosurgery Steven Silverstein, PhD, Professor, Department of Psychiatry Duje Tadin, PhD, Chair, Department of Brain & Cognitive Sciences


NEUROSCIENCE Editor/Writer Kelsie Smith Hayduk Kelsie_Smith-Hayduk@ Contributors Mark Michaud Karin Christensen Feature Photography John Schlia Photography Designer Beth Carr


An unexpected doorway into the ear opens new possibilities for hearing restoration A team of researchers has developed a new method to deliver drugs into the inner ear. The discovery was possible by harnessing the natural flow of fluids in the brain and employing a little-understood backdoor into the cochlea. The passage, called the cochlear aqueduct, is a thin bony channel no larger than a single strand of hair. In the study, led by Maiken Nedergaard, MD, DMSc, and published in the journal Science Translational Medicine, researchers described that the cochlear aqueduct also acts as a conduit between the cerebrospinal fluid found in the inner ear and the rest of the brain. Using this passageway, researchers delivered a gene therapy that repairs inner ear hair cells and restored hearing in deaf mice. This study represents an opportunity to test the drug delivery potential of the glymphatic system and target a previously unreachable part of the auditory system. The glymphatic system is the brain’s unique process of removing waste first described by the Nedergaard lab in 2012.

URMC researcher receives $8.3M to study chronic pain and the brain Understanding the role of chronic pain in the brain could transform treatment and care for a condition that inflicts more than 20 percent of U.S. adults. Paul Geha, MD, associate professor of Psychiatry, has been studying the correlation between brain structure and chronic pain and was recently awarded $8.3 million from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) to continue this work in understanding the link between pain and the brain. The funds will focus on three projects that investigate whether language or facial expressions can be used to diagnose different groups of chronic pain patients and predict whether spinal cord stimulation works in chronic lower-back pain patients, find a structural gray and white matter biomarker in the brain that can help identify who is at risk of low-back pain becoming chronic, and test whether the brain signature of chronic low-back pain can also indicate other chronic musculoskeletal conditions, like knee arthritis pain or nervous systemrelated chronic pain. The research will also consider other chronic conditions—such as major depressive disorder, and whether an individual’s age or sex have an effect on this neural signature.

Online AI-based test for Parkinson’s disease severity shows promising results An artificial intelligence tool developed by researchers at the University of Rochester can help people with Parkinson’s disease remotely assess the severity of their symptoms, within minutes. The research led by Eshan Hoque, PhD, associate professor of Computer Science and Ray Dorsey, MD, the David M. Levy Professor of Neurology, in npj Digital Medicine describes the new tool, which has users tap their fingers 10 times in front of a webcam to assess motor performance on a scale of 0–4. While expert neurologists performed slightly better than the AI model, the AI model outperformed the primary care physicians with UPDRS certification. “These findings could have huge implications for patients who have difficulty gaining access to neurologists, getting appointments, and traveling to the hospital,” Hoque said. “It’s an example of how AI is being gradually introduced into health care to serve people outside of the clinic and improve health equity and access.”




Pathway program proves access can cultivate scientists Chen Li working the Haptics Lab.*


n the summer of 2021, the Del Monte Institute for Neuroscience Diversity Commission and the City College of New York launched the partnership program NEUROCITY. By collaborating with the Summer Scholars Program at the University of Rochester School of Medicine and Dentistry, organizers were able to launch the program that has, to date, put nearly 30 undergraduate students from historically marginalized backgrounds in research labs across the University of Rochester and University of Rochester Medical Center (URMC) campuses. “This has been a really rewarding experience,” said Manuel Gomez-Ramirez, PhD, assistant professor of Brain and Cognitive Sciences at the University of Rochester and chair of the Neuroscience Diversity Commission. “It has been great to see these students, many of whom have minimal research experience, come in and do such a phenomenal job in just 10 weeks. The grit, resolve, and commitment they have displayed has been greatly inspirational.” NEUROCITY has created a pathway to neuroscience research and, for some students, has transformed their future plans. “[NEUROCITY] was a very big reason for helping me figure out what I wanted to pursue after graduation,” said Jose Reynoso, an alumnus of the program who now works in a research lab at URMC. “It is the main reason why I want to go down a research path and pursue graduate school.” Reynoso grew up in the Bronx. Curious about human behavior since childhood, he credits a high school psychology course for giving him his first glimpse into neuroscience. “That is when I started to learn about the mechanisms in the brain that cause some people to behave


differently. That is when I knew I wanted to go into science. I majored in psychology at CCNY, and when I learned about the NEUROCITY program, I saw it as a great opportunity to find out if I wanted to pursue research.” During his time in NEUROCITY, he was in the lab of Duje Tadin, PhD, professor and chair of the Brain and Cognitive Sciences Department at the University of Rochester. Reynoso was part of a team that developed a new task to measure perceptual decision-making. The experiment aims to improve our understanding of how we make small decisions. Like how our brain determines that a sign is a stop sign when driving through the fog, as opposed to a sunny day. Jose Reynoso working with research subject in the Keane Vision & Psychosis Lab.*

“There was a clear point where I realized Jose was well suited for research and would excel at it. At our first research meeting, I asked him if he had any questions. At this point, most students ask 1-2 questions. In contrast, Jose pulled out his notebook and went through a long list of questions


that showed he was well prepared for the meeting and that he had a good understanding of the research we were discussing,” Tadin said. “Being a mentor in NEUROCITY has been an immensely rewarding experience. Broadening access to research is one of the best things we can do to facilitate scientific advancement.” When Reynoso was finishing his senior year, he planned to take a year off before deciding if graduate school was the right path for him until he enrolled in the program. But after ten weeks in Rochester, he took his first step toward graduate school and enrolled in the URMC Post-baccalaureate Research Education Program (PREP). As a result, he is now submitting his first first-author paper that investigates reaching movements guided by vision and proprioception. Today, Reynoso is a lab assistant in the Keane Vision & Psychosis Lab and is applying to graduate schools this fall. “I am very much on board with the philosophy of NEUROCITY—taking bright, motivated students who may have fewer opportunities or more challenging backgrounds and then providing them with experiences, tools, and instruction so that they can successfully pursue a career in neuroscience,” said Assistant Professor of Psychiatry Brian Keane, PhD. “Jose has been fantastic so far. He has jumped right into the varied tasks I have thrown at him. He is highly reliable and a nice person to have in the lab.” Forging her path to Neuroscience “It was amazing. Clearly, since I am still here,” Chen Li said. Li participated in NEUROCITY in the summer of 2022. Today, she is a graduate student in the Brain and Cognitive Sciences Department (BCS) at the University. “Because the University is an R01 research University, I had access to incredible tools. It showed me what a research career would look like.” As a NEUROCITY scholar, Li worked in the Dynamics of Cognition Lab at the URMC. Its principal investigator, Ian Fiebelkorn, PhD, assistant professor of Neuroscience, continues to mentor her alongside Assistant Professor Gomez-Ramirez, principal investigator of the Haptics Lab in BCS. “Before NEUROCITY, I was confused. I did not know if I wanted to pursue my PhD. I had heard horror stories about how difficult it was to be in graduate school,” said Li. “But by the end of the program, I think because of the people I met here, including my mentors, it solidified my decision to come here.” “Chen has grown exponentially as a researcher throughout the ten weeks in my lab as a NEUROCITY student and now as a graduate student,” Fiebelkorn said. “It has been a pleasure watching her confidence and research skills expand.” Li has taken those new skills and confidence and has

Reynoso works with Tadin in his lab in the Brain and Cognitive Sciences Department.*

created a project that utilizes the tools and expertise from the labs of both her mentors. She aims to understand the inner workings of neural modulation that connects the tactile and visual processes—how we touch and see. “I want to understand how the brain modulates between the two different stimuli,” said Li. “For example, if you were in a task and you were given two sets of stimuli, like visual and tactile, how would your brain process the stimuli together and separately.” She utilizes the Haptics Lab to understand the tactile component and the Dynamics of Cognition Lab to study the visual processes. “It has been really fulfilling to see the growth that NEUROCITY scholars, like Chen, experience throughout the program,” said Gomez-Ramirez. “Chen started in my lab in the Spring semester of 2023, and she is currently writing a manuscript for publication for a project she recently completed. This level of progress in such a short period is extraordinary and speaks to her level of commitment and determination. And, quite frankly, many of the students in NEUROCITY exhibit these same qualities.” As a result of the program, NEUROCITY scholars have also been co-authors of peer-reviewed scientific research. Yacinda Hernandez is a co-author of a paper published in PLOS ONE led by Tadin. Jancy Contreras is a co-author on a paper led by Neuroscience Professor Julie Fudge, MD, in Neuroscience.

Chen sits with Ian Fiebelkorn, PhD, at a computer in his lab in the Medical Center.* *Photos by J. Adam Fenster / University of Rochester





yotonic dystrophy type 2 (DM2), a rare form of muscular dystrophy, can trace its origins to a meeting three decades ago in the Garvey Room on the fifth floor of Strong Memorial Hospital. Present at the regular gathering of neuromuscular researchers were Robert (Berch) Griggs, MD, and Richard Moxley, MD, two of the founding fathers of the University of Rochester Medical Center (URMC) Department of Neurology, and Charles Thornton, MD.


URMC neuromuscular researchers pave the way for gene therapy revolution by Mark Michaud


As was a common practice, a patient with a puzzling case joined the group that day. This individual demonstrated the well-established clinical symptoms of myotonic dystrophy but did not possess the genetic flaw associated with the disease. The question put to those in the room was whether this case– one of a growing number identified via a new genetic test–was a completely new disease, a flaw with the test, or something else. “There was a vigorous debate and a wager that involved a six-pack of beer,” Griggs said. “But no one can recall who was on the winning side of the argument and whether beer ever changed hands.” In 1994, Griggs, Moxley, and Thornton published descriptions of three of these cases in the Annals of Neurology, thereby becoming the first to describe DM2. It was proposed at the time that the new disease be named for the trio, but they declined in recognition of other scientific teams around the globe that were arriving at the same conclusions, and the disease eventually came to be known as DM2. A growing wave The discovery of DM2 was the product of neuromuscular clinical and research programs first started in the 1970s by Moxley and Griggs. Later joined by Thornton, Rabi Tawil, MD, a leading authority on facioscapulohumeral dystrophy (FSHD), and David Herrmann, MD, an expert in inherited neuropathies, and others, the URMC neuromuscular team has been instrumental in creating the global research networks, partnerships with the patient community, pipeline of trained clinical researchers, and research tools necessary to study the disease and advance new treatments. One of the centerpieces of these efforts is the National Registry for Myotonic Dystrophy & Facioscapulohumeral Dystrophy, created in 2000 and supported by the NIH-funded


Robert (Berch) Griggs, MD, in the Garvey Room in Strong Memorial Hospital.

From left: Charles Thornton, MD, and Johanna Hamel, MD, at a microscope in their lab in the Medical Center.

Wellstone Muscular Dystrophy Cooperative Research Center program. This detailed database of more than 2,600 people with these conditions has been an invaluable research tool and enabled researchers to better understand the natural history of the disease and recruit participants for clinical trials. This long history and depth of expertise places URMC researchers at the center of efforts to accelerate the study and approval of a growing wave of genetic therapies for neuromuscular disorders that are already revolutionizing care. URMC researchers are playing a leading role in clinical research involving genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy, FSHD, and Charcot Marie Tooth disease. “These treatments are predicated on the ability to target the right tissues. Recent advances have created a diverse set of ways to accomplish this. Parts of the body previously off limits can now be reached with surgical specificity to modify the action of one gene and have no impact on others,” Thornton said.

showed how this defect results in the creation of toxic RNA, which accumulates in the nucleus of cells and interferes with the normal activity of many genes. In a study appearing in the journal Nature in 2012, Thornton and his colleagues showed how a synthetic molecule called an antisense oligonucleotide that mimics a segment of the genetic code restored healthy protein functions in cells. In collaboration with industry partners, the team has recently shifted to employ more effective and targeted drug delivery technologies that employ small interfering RNA, and some of this work is now in early-stage clinical trials. Reaching this point required an understanding of the fundamentals in these diseases, the underlying abnormal gene and why it causes disease, the creation of mouse models, identifying a good target for treatment, and developing something that can impact that target and show how it reverses disease,” Thornton said. “All this has taken more than 20 years to accomplish and all of those steps in myotonic dystrophy occurred here in Rochester.” Johanna Hamel, MD, joined the URMC neuromuscular research group in 2019, after completing fellowships in both neuromuscular medicine and experimental therapeutics. Her research focuses on expanding our understanding of the underlying molecular mechanism in DM1 and DM2, how the diseases progress, and the effectiveness of clinical outcome measures and biomarkers. Critical to these efforts is creating

“Decades of research are helping to build a detailed picture of how these diseases progress over time."

Unraveling the mystery of myotonic dystrophy The underlying genetic cause of myotonic dystrophy type 1 (DM1), a trinucleotide repeat expansion located on chromosome 19, was discovered in 1992. However, it was only a little more than a decade ago that Thornton and others

NEUROSCIENCE | VOL 19 | 2023 5

Chad Heatwole, MD

the infrastructure for more individuals to participate in research remotely. “Many questions about myotonic dystrophy remain unanswered and only a small fraction of people with this disease are involved in research. Remote studies allow us to connect with study participants via video conferences, ship them appropriate devices that measure function, collect genetic information, and improve the sensitivity of biomarkers,” Hamel said. The patients’ voice in research priorities Approximately 80,000 Americans have myotonic dystrophy, making it the most common form of muscular dystrophy. Its name comes from the term myotonia, a prolonged muscle contraction that makes it difficult to relax muscles after use. Eventually, many patients have difficulty walking, swallowing, and breathing. The disease can also affect the eyes, heart, and brain. “Decades of research are helping to build a detailed picture of how these diseases progress over time. In addition, close collaboration with patients and families has enabled us to pinpoint the symptoms that are most important to patients, which is essential given the multisystemic nature of the disease,” said Chad Heatwole, MD, professor of Neurology and director of the Center for Health + Technology, and a


leading expert in DM2. In 2012, Heatwole leveraged these insights to create a patient reported outcome (PRO) measure for DM2. His team has since gone on to develop more than 160 regulatory-grade, disease-specific PROs now being employed by academic, industry, and government researchers around the globe to measure clinically relevant changes in health in response to therapeutic interventions during clinical trials. The PRO tool for DM2 may soon be put to use in a new study involving recombinant human growth hormone and testosterone as a therapy for the disease. Results from Heatwole’s URMC-led open-label study of the same drug combination in FSHD showed that the treatment was safe and study participants experienced improvements in ambulation, strength, muscle mass, and disease burden. Heatwole speculates the treatment regime may also benefit patients with DM2 and other neuromuscular disorders. “Future treatments will likely consist of cocktail therapies. You need to stop the genetic mutation, but you also have to come up with therapies that will improve function to get patients back to a normal state,” said Heatwole. Transforming pediatric neuromuscular care The future is now for children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). URMC


Left: Kel Mitchell, Kim Fields, Pat Sajak, and Penn Jillette on set of Celebrity Wheel of Fortune. Jillette won $133,200 for the Gilbert Gottfried Research Fund at the University of Rochester that support's Heatwole's DM2 research. Gottfried passed away of complications from DM2 in 2021.

Courtesy Celebrity Wheel of Fortune

pediatric neurologist Emma Ciafaloni, MD, was at the center of the clinical trials for newly approved gene therapies for both conditions. SMA is a rare hereditary genetic disease caused by a mutation in motor neurons that disrupts the production of a protein critical to the function of the nerves that control muscles. Symptoms typically appear within six months of birth and include difficulty breathing, swallowing, speaking, and moving, leading to death by age two. In 2019, the FDA approved a new gene therapy that helps re-establish muscle control in children with SMA. Ciafaloni served on a panel overseeing data collection and safety for clinical studies of the

new treatment and was an advisor to the company involved in the initial development of the drug. DMD is a fatal condition found in boys and characterized by progressive muscle weakness, the symptoms of which appear at a young age and progress rapidly leading to significant disability. Eventually spreading to the heart and muscles responsible for breathing, the disease is often fatal by the time the individual reaches their 20s or early 30s. The pediatric neuromuscular team at Golisano Children’s Hospital, which includes Ciafaloni, Sam Mackenzie, MD, PhD, and Bo Lee, MD, are involved in the EMBARK study, an international phase 3 clinical trial for a gene therapy for Kohen Ottenschot, 5, received the gene therapy treatment for DMD at Golisano Children's Hospital. He was one of the first patients in New York State to receive the treatment since the FDA approval. Back from left: Joan Mountain, RN, Sam Mackenzie, MD, PhD, Katy Eichinger, PT, Bo Lee, MD, Amy Luce, NP, Debra Guntrum, NP, Jennifer Sellars, RN. Front from left: Ciera Ottenschot, Kohen Ottenschot, John-Michael Ottenschot, and Heather Romeiser, NP.



From left: Samuel Mackenzie, MD, PhD, and Emma Ciafaloni, MD, walk together in the Golisano Children's Hospital.

Duchenne muscular dystrophy. Ciafaloni also served on the data and safety monitoring board for the early stages of the clinical studies. The muscle weakness associated with DMD is the result of a genetic defect in muscle cells that impairs the production of dystrophin, an important muscle-building protein largely missing in people with the disease. The new treatment consists of a single infusion that, via an associated adenovirus, delivers a functional “micro” version of the dystrophin gene that takes over the production of the protein. “There are boys who have been receiving the drug as part of clinical trials for four to five years. Parents send me videos, and the ability to get off the floor, jump, and run is not something you typically see in a seven, eight, or nine year olds with Duchenne,” Ciafaloni said.

In June, the FDA granted accelerated approval of the drug for four and five year olds. The results from EMBARK study are expected by the end of the year, potentially resulting in expanded eligibility. Ciafaloni is helping lead efforts to have DMD added to the New York State recommended panel of newborn screenings, to catch the disease early when treatments hold the greatest potential. The state added SMA to the screening panel in 2018. While advances in SMA and DMD have already arrived at the clinic and treatments for a number of other neuromuscular disorders are on the horizon, these approaches have opened the door for other even rarer single gene diseases. Mackenzie, who joined URMC in 2021, is among the nation's leading experts in TANGO2 deficiency disorder, a disease that appears in early childhood, and can result in episodes of acute illness called metabolic crisis, heart arrhythmias, breakdown of muscle tissue, seizures, and intellectual impairment. Efforts to study the disease are in the early stages, but Mackenzie is working with a C. elegans model of the disease that he is hopeful can help uncover the cellular function of the TANGO2 protein and accelerate therapeutic development through high-throughput drug screens. He is also working with Hamel in mouse models of DM1 and helping develop a model of congenital myotonic dystrophy. “I have the best job in the world, being able to see patients in clinic, help them through cutting-edge clinical trials, and spend the rest of the day watching things light up under a microscope," Mackenzie said. “It is impressive what this group has accomplished in neuromuscular medicine, and I feel very fortunate to be a small part of the Rochester tradition.”


The Del Monte Institute for Neuroscience and Department of Neuroscience were delighted to host the board of the Kilian J. & Caroline F. Schmitt Foundation in August 2023. The foundation’s support has generated almost $100 million since 2000.


The annual Del Monte Institute for Neuroscience and UR-IDDRC Symposium was held at the Memorial Art Gallery in September 2023. The title for this year's meeting was Mysteries of Intellectual and Developmental Disabilities: A Scientific Exploration.



Erin Bojanek, PhD Erin Bojanek, PhD, BS (’14), is an instructor in the Frederick J. and Marion A. Schindler Cognitive Neurophysiology Lab (CNL). She was an undergraduate in the Brain and Cognitive Sciences Department at the University of Rochester and received her doctorate in Clinical Child Psychology at the University of Kansas. Her research focuses on understanding the underlying mechanisms of sensory processing differences in autism spectrum disorder (ASD). “In my current study, I am looking at how kids with autism process and complete visual information. And this ties into the idea of local-global processing,” said Bojanek. “How do individuals with autism complete pictures when they are given incomplete information? Are people with autism focused more on the individual segments? For example, do they see the trees but not the forest? If that is the case, how can they put that information together to identify a complete picture and what does their brain look like while they are completing this task? Then we can figure out how this differs from visual perception in neurotypical kids.” Bojanek chose Rochester, in part, because of her positive experience during undergrad, but mostly because she can work at an academic medical center that is also an Intellectual

Erin Bojanek, PhD

and Developmental Disabilities Research Center (IDDRC). “It is important to be somewhere where my clinical work and research can integrate. My research in the CNL lab allows me to learn new techniques and ask different questions. I had no experience with EEG before working in this lab with John Foxe, PhD, and Edward Freedman, PhD. And clinically, I am pursuing my clinical psychology license and gaining expertise in autism diagnostic assessments.” Laura Silverman, PhD, and Heather Adams, PhD, are Bojanek’s clinical supervisors and are integral to her learning how her clinical skills inform her research. Bojanek has always been interested in working with kids; her mom was a special education teacher. But it would be the mentorship of Tris Smith, PhD, a pioneer in autism research, during her undergraduate training at the University that solidified her pursuit to study autism. “His [Smith] work was so impactful. He was an awesome mentor to me and so many people.” Bojanek plans to continue a mostly research-focused career while maintaining a clinical component.

Bojenak and Tris Smith, PhD, at her graduation from University of Rochester in 2014.



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