Alcohol‐associated liver disease, which is caused by chronic alcohol use, can lead to inflammation and scarring of the liver. In severe cases it can lead to liver failure, with some patients requiring a liver transplant. The condition accounts for nearly half of the liver-disease-related deaths in the U.S., according to the National Institutes of Health.

“We do not have effective therapies for alcohol‐associated liver disease,” said Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology. “Abstaining from alcohol can arrest this condition but this is often difficult to achieve. To save lives, we need to target drivers of alcohol-associated liver disease that promote inflammation and scarring. ”

Lu is co-corresponding author of a study, published in Hepatology, which connected a protein called FOXM1 with scarring and inflammation in alcohol‐associated liver disease. Another recent Cedars-Sinai study, published in Science Advances, showed that alcohol caused an enzyme known as SRC to alter the liver’s immune responses.

In Lu’s study, investigators examined alcohol-exposed human liver tissue samples and cells, and those of laboratory mice. They found that the FOXM1 protein controlled a network of genes and proteins that worked together to cause liver scarring and inflammation. FOXM1 is known to be involved in multiple liver diseases, including cancer. When the investigators suppressed the action of FOXM1, liver scarring was reversed.

“We found that FOXM1 is a key regulator of alcohol-associated liver disease progression and represents a promising target for therapeutic intervention,” Lu said.

The Science Advances study demonstrated how alcohol exposure—through the action of the enzyme SRC and the protein called UBC9—triggered inflammation and immune changes in the liver. When investigators used gene editing or enzymes to block SRC activity,  inflammation was reduced.

“The strong effect of enzymes suggests the possibility of therapeutic targets against alcohol‐associated liver disease,” said Maria Lauda Tomasi, PhD, associate professor of Medicine and Biomedical Sciences at Cedars-Sinai and the study’s co-corresponding author.

The findings also highlight UBC9 as a key regulator of the immune response, which could have implications beyond the liver for cancer and other inflammatory diseases, Tomasi said.

“These rigorous studies contribute greatly to our understanding of alcohol‐associated liver disease,” said David E. Cohen, MD, PhD, chair of the Department of Medicine. “The findings could open new pathways for the development of urgently needed treatments.”

Other Cedars-Sinai authors of the Hepatology study include Bing Yang, Liqing Lu, Jiaohong Wang, Lucía Barbier-Torres, Jing Zhang, Jyoti Chhimwal, Sonal Sinha, Brent Beadel, Guo Zhang, Takashi Tsuchiya, Maria Lauda Tomasi and Heping Yang. The other author was Ting Liu.

Funding: This work was supported by NIH grant R01AA026759 (Shelly C. Lu, Heping Yang, and Maria Lauda Tomasi).

Other Cedars-Sinai authors of the Science Advances study include Swati Chandla, Youngyi Lim, Andrea Floris, Michael Mazarei, Xi Yang, Takashi Tsuchiya, Manisha Dagar, Alfonso Darmawan, Monica Justo, Ramachandran Murali, Alexandra Gangi, Nirmala Mavila and Komal Ramani. The other author was Ivan Tomasi.

Funding: This work was supported by the National Institutes of Health, grant 

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“Astrocytes are critical responders to disease and disorders of the central nervous system—the brain and spinal cord,” said neuroscientist Joshua Burda, PhD, assistant professor of Biomedical Sciences and Neurology at Cedars-Sinai and senior author of the study. “We discovered that astrocytes far from the site of an injury actually help drive spinal cord repair. Our research also uncovered a mechanism used by these unique astrocytes to signal the immune system to clean up debris resulting from the injury, which is a critical step in the tissue-healing process.”

The investigators dubbed these astrocytes “lesion-remote astrocytes,” or LRAs, and identified several distinct LRA subtypes. Their study describes for the first time how one LRA subtype remotely senses and responds to tissue injury.

The spinal cord is a bundle of nerve tissue that runs from the brain down the back. At its center is gray matter, which contains the bodies of nerve cells and support cells called astrocytes. Surrounding it is white matter, made up of astrocytes and long nerve fibers that stretch up and down the cord to send signals between the brain and the rest of the body. Astrocytes help keep the nervous system healthy and ensure that these signals flow smoothly.

Spinal cord injuries damage nerve fibers, paralyzing parts of the body and disrupting sensory input such as touch and temperature. The severed fibers die off and become debris. In most other types of tissue in the body, inflammation takes place only at the site of injury. But because of the length of nerve fibers in the spinal cord, damage and inflammation extend far beyond the injury site.  

Investigators looked at laboratory mice with spinal cord injury and found that LRAs play an important role in supporting nervous system repair. They saw strong evidence of the same mechanism in tissue samples from human patients with spinal cord injury.

The Burda Lab identified one LRA subtype that sends out a protein called CCN1 to signal to immune cells called microglia.

“One function of microglia is to serve as chief garbage collectors in the central nervous system,” Burda said. “After tissue damage, they eat up pieces of nerve fiber debris—which are very fatty and can cause them to get a kind of indigestion. Our experiments showed that astrocyte CCN1 signals the microglia to change their metabolism so they can better digest all that fat.”

Burda said this efficient debris clearing might have a role in the spontaneous recovery found in many patients with spinal cord injury. In the absence of the astrocyte-derived CCN1 protein, the investigators found that recovery is drastically impaired.

“If we remove astrocyte CCN1, the microglia eat, but they don't digest. They call in more microglia, which also eat but don't digest,” Burda said. “Big clusters of debris-filled microglia form, heightening inflammation up and down the spinal cord. And when that happens, the tissue doesn’t repair as well.”

When investigators looked at spinal cord tissue from human patients with multiple sclerosis, they found the same mechanism at work, Burda said. He added that these fundamental principles of tissue repair likely apply to any sort of injury of the brain or spinal cord.

“The role of astrocytes in central nervous system healing is remarkably understudied,” said David Underhill, PhD, chair of the Department of Biomedical Sciences. “This work strongly suggests that lesion-remote astrocytes offer a viable path for limiting chronic inflammation, enhancing functionally meaningful regeneration, and promoting neurological recovery after brain and spinal cord injury and in disease.”

Burda is now leading efforts to harness this CCN1 mechanism in spinal cord healing and to further investigate the role of astrocyte CCN1 in inflammatory neurodegenerative disease and in aging.  

Additional Cedars-Sinai authors include Sarah McCallum, Keshav B. Suresh, Timothy S. Islam, Manish K. Tripathi, Ann W. Saustad, Oksana Shelest, Aditya Patil, David Lee, Brandon Kwon, Katherine Leitholf, Inga Yenokian, Sophia E. Shaka, Jasmine Plummer, Vinicius F. Calsavara, and Simon R.V. Knott.

Other authors include Connor H. Beveridge, Palak Manchandra, Caitlin E. Randolph, Gordon P. Meares, Ranjan Dutta, Riki Kawaguchi, and Gaurav Chopra.

Funding: This work was supported by: the US National Institutes of Health (NIH) 5R01NS128094, R00NS105915, K99NS105915 (to J.E.B.), F31NS129372 (to K.S.), K99AG084864 (S.M.) R35 NS097303 and R01 NS123532 (RD), R01MH128866, U18TR004146, P30 CA023168 and ASPIRE Challenge and Reduction-to-Practice award (to G.C.); the Paralyzed Veterans Research Foundation of America (to J.E.B.); Wings for Life (to J.E.B.); Cedars-Sinai Center for Neuroscience and Medicine Postdoctoral Fellowship (to S.M.); American Academy of Neurology Neuroscience Research Fellowship (to S.M.); California Institute for Regenerative Medicine Postdoctoral Scholarship (to S.M.); The United States Department of Defense USAMRAA award W81XWH2010665 through the Peer Reviewed Alzheimer’s Research Program (to G.C.); The Arnold O. Beckman Postdoctoral Fellowship (to C.E.R.); The Purdue University Center for Cancer Research funded by NIH grant P30 CA023168 is also acknowledged.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

(HSU). They are the first to enroll in the new Chuck Lorre Allied Health School, Health Artificial Intelligence PhD program in the Graduate School of Biomedical Sciences and the Master of Science in Regenerative Medicine program.

“Regardless of their chosen discipline, students in the Health Sciences University will be immersed in the healthcare environment and our clinical care continuums,” said Jeffrey Golden, MD, executive vice dean of Research and Education, director of the Burns and Allen Research Institute, and the Linda and Jim Lippman Distinguished Chair in Academic Medicine at Cedars-Sinai. “Students will train side by side with experts to advance basic, translational and clinical sciences, then witness how their efforts help shape the care Cedars-Sinai delivers.”

The students’ experience will include hands-on training from prominent experts and access to advanced technologies and innovative clinical trials.

The Cedars-Sinai Chuck Lorre Allied Health School was established in 2022 with a $30 million gift from The Chuck Lorre Family Foundation. The vocational school offers training in allied healthcare roles, starting with clinical laboratory scientists, pharmacy technicians, respiratory therapy and radiation therapy technicians.

“When the opportunity presented itself to provide training and certificates for underserved individuals in our community, which in some instances would double their salaries, I was all in,” Lorre said. “Partnering with Cedars-Sinai to create the school of allied health will allow us to see long-term impacts in our communities.”

Students in the allied health programs will receive hands-on training in a clinical setting through rotations at Cedars-Sinai and its affiliates Huntington Health and Torrance Memorial Health. The programs lead to associate degrees, bachelor’s degrees or certificates. Graduates are eligible to obtain licensure and take certification exams in their chosen fields.

“The transformational gift made by The Chuck Lorre Family Foundation meets a tremendous need for allied health specialists, both at Cedars-Sinai and in the broader Los Angeles community,” Golden said.

Alexia Furbert, a 21-year-old Los Angeles resident, is one of the first students to enroll in the pharmacy technician program in the Cedars-Sinai Chuck Lorre Allied Health School.

“When I learned about the program, I was finishing my last semester at West Los Angeles College to complete my associate degree,” Furbert said. “Feeling uncertain about my career goals, I questioned whether transferring to a four-year university was the right decision for me. This program offered an opportunity to explore potential career paths and contribute to chronically understaffed areas of healthcare.”

Also new to the Cedars-Sinai Health Sciences University is the PhD in Health Artificial Intelligence (AI), which offers rigorous training in AI algorithms and methods, with a focus on analyzing clinical data to enhance patient care.

“We are elated to welcome our incoming students, who will experience a hands‑on, active approach to teaching that reinforces AI concepts through clinical rotations and scholarly collaboration with physicians and medical staff,” said Graciela Gonzalez-Hernandez, PhD, director of the Graduate Program in Artificial Intelligence. “Graduates will be positioned to directly improve healthcare and patient outcomes through the rigorous development and deployment of AI algorithms and software.”

Another new offering is the Master of Science in Regenerative Medicine, a 20-month program where students focus on stem cell research that can be used to both model and treat human diseases. The curriculum will focus on three professional paths: cell biomanufacturing, academic research into stem cell biology and learning about how stem cells can be used with different clinical specialties.

“We designed the master’s program to teach students about regenerative medicine and how stem cells hold an interesting promise for medicine,” said Wafa Tawackoli, PhD, director of Education and Training at the Board of Governors Regenerative Medicine Institute. “We are focused on giving these students an advantage as they move forward in their chosen career paths through a carefully designed curriculum. Everything we do is tailored to the future.”

The university offers other graduate degrees, including a PhD in Biomedical Sciences, that merges scientific and translational medicine curricula with mentoring by researchers and clinicians, a Master of Science in Health Systems and a Master of Science in Magnetic Resonance in Medicine.

The university also is home to several professional training programs, including nondegree educational certifications, formal trainings, internships and other ongoing opportunities to benefit students and professionals at all levels of their careers.

“We are eager to welcome our new and returning students,” Golden said, “and for them to begin their journey of understanding human diseases, how to diagnose them and how to determine the best treatments for individual patients.”

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“We discovered that abnormal tau proteins accumulate in retinal ganglion cells, which are key nerve cells in the eye that send information to the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “We also identified a correlation between early accumulation of abnormal tau and the damage and death of retinal ganglion cells in people showing symptoms of mild cognitive impairment and Alzheimer’s disease.”

People with mild cognitive impairment and Alzheimer’s disease had 46%–57% fewer retinal ganglion cells than people with normal cognition, and their retinal ganglion cells were misshapen and prone to die. Harmful tau proteins were two to three times more common in the retinal ganglion cells of these people, and the amount of tau-related damage in the retina was linked to Alzheimer’s-related damage to the brain and a decline in cognitive function, Koronyo-Hamaoui said.

Additional Cedars-Sinai Authors: Miyah R. Davis, Edward Robinson, Yosef Koronyo, Altan Rentsendorj, Bhakta P. Gaire, Nazanin Mirzaei, Alexander V. Ljubimov, Keith L. Black, Dieu-Trang Fuchs

Additional Authors: Elena Salobrar-Garcia, Rakez Kayed, Alfredo A. Sadun, Lon S. Schneider, Debra Hawes

Funding: This work was supported by the National Institutes of Health (NIH)/the National Institute on Aging (NIA) through the following grants: R01 AG055865 and R01 AG056478 (M.K.H.), The Hertz Innovation Fund (M.K.H.), and the Gordon, Wilstein, and Saban Private Foundations (M.K.H.). Y.K., A.R., B.P.G., D.-T.F., M.K.H. are also supported, in part, by the NIH/NIA R01AG075998 grant. M.R.D. and E.R. are supported by The Ray Charles Foundation. E.S.G. is supported by José Castillejo grants for mobility stays abroad for young doctors 2023 (CAS22/00049, Ministerio de Ciencia, Investigación y Universidades) and Complutense del Amo Grants 2023, Complutense University of Madrid.

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“The incidence of pancreatic cancer among the Black population is at least 50% higher than the incidence of other racial groups. Furthermore, research has shown that Black patients have the lowest survival rate,” said Debiao Li, PhD, director of the Biomedical Imaging Research Institute and professor of Biomedical Sciences and Imaging at Cedars-Sinai, and co-principal investigator of the study. “We know that there are genetic, socioeconomic and lifestyle differences between ethnic and racial populations, and we suspect some of these differences might affect pancreatic tissue and pancreatic cancer risk.”

Li and co-investigators received a grant from the National Cancer Institute in 2022 and developed a tool that uses CT scans and AI to detect minute changes in the pancreas, which is part of the digestive system. These changes can indicate a patient is likely to develop pancreatic cancer years before they develop the disease, thus enabling an earlier diagnosis when treatments are most effective. This investigative team has received a new grant to conduct a pilot study that will allow them to determine whether those characteristics differ in Black patients.

The team will collaborate with Cemal Yazici, MD, associate professor of Medicine at the University of Illinois Chicago, which, like Cedars-Sinai, serves a large population of Black patients.

Predictive models for pancreatic cancer based on symptoms, genetics and weight haven’t been shown to be accurate on their own, said Stephen Pandol, MD, director of Basic and Translational Pancreas Research at Cedars-Sinai and co-principal investigator of the study. Meanwhile, blood and urine tests for pancreas cancer are still in development.

“Packaging these tests with our imaging tool could eventually prove effective in predicting who will develop pancreatic cancer,” Pandol said. “Our goal is to perfect our tool, then apply it to a population to see if we can diagnose individuals earlier.”

Pancreatic cancer is one of the deadliest cancers, with only around 10% of patients surviving five years after diagnosis. Early detection and surgical intervention can increase five-year survival rates to more than 50%, but this is rare because early pancreatic cancer causes few symptoms.

“Drilling down to understand cancer risk at precision levels is key to the Cedars-Sinai Cancer mission to bring personalized cancer care to every patient,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. "This work in early detection nicely complements recent work showing that a new AI-based precision medicine approach called the Molecular Twin Precision Oncology Platform can predict outcomes of pancreatic cancer."

With the help of improved predictive tools, patients at the highest risk can be monitored via annual imaging so any cancer that develops is detected at the earliest stage.

“If we can diagnose a patient’s pancreatic cancer two or three years earlier, that could make a life-and-death difference,” Li said.

Read more on the Cedars-Sinai Blog: Pancreatic Cancer Clinic Saves Time and Lives

is creating a resource laboratory to help advance stem cell-based technologies throughout Cedars-Sinai and across California. The institute will serve as a hub for the development of organ-on-a-chip and organoid models that bring precision to patient care and research.  

“We’ve developed extensive expertise in creating induced pluripotent stem cells from patients, then turning those into models of the liver, kidney, heart, lung, brain, spine, pituitary gland, pancreas and other organs,” said Clive Svendsen, PhD, executive director of the Board of Governors Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine at Cedars-Sinai. “We’re now going to provide a core resource so that investigators across Cedars-Sinai and beyond can learn to use these technologies.”

The Cedars-Sinai Shared Resources Laboratory for Advanced Stem Cell Modeling is funded through a $4 million infrastructure grant from the California Institute for Regenerative Medicine (CIRM). The lab will be available to scientists throughout California.

“The Cedars-Sinai Shared Resources Laboratory will be part of a collaborative network of 11 such laboratories across California,” said Uta Grieshammer, CIRM SRL Program lead. “We are looking forward to supporting this network of labs as they share their expertise and provide access to cutting edge technologies, with the goal of accelerating discoveries in regenerative medicine and growing and diversifying the cohort of stem cell researchers in the state.”

Induced pluripotent stem cells, or iPSCs, are cells that can be turned into many different cell types. These cells, in turn, can be grown on specialized chips that allow them to function the way they would in organs in the body. The cells also can be developed into organoids, which are miniaturized, simplified cell groups that mimic some of the key functions of organs.

In recent years, Cedars-Sinai investigators have used organoids and organ-chip technology to study gastrointestinal disease, neurological disorders, Crohn’s disease, musculoskeletal disorders, pituitary tumors, liver diseases, ovarian and breast cancer, lung fibrosis, the cardiotoxicity of cancer therapies, and how cancer develops.

“IPSC-derived organoids hold tremendous promise as a way to further our understanding of cancer development and progression,” said Joshua Breunig, PhD, director of the Cell, Organoid, and Cancer Engineering Special Resource in the Board of Governors Regenerative Medicine Institute. “We can collect a patient’s normal cells, engineer them to become iPSCs and pair the resulting organoids with genetically engineered self-renewing tumors, allowing us to discover and test therapeutics in a more natural tissue-like context.”

In this way, the organoids can truly “personalize” disease models, Breunig said.

“This new resource will give researchers throughout California access to this exciting and powerful new technology,” said Arun Sharma, PhD, research scientist in the Board of Governors Regenerative Medicine Institute and the Smidt Heart Institute at Cedars-Sinai and project director of the new laboratory. “Several of our faculty are highly experienced in this area of research and we will provide outstanding training to others through our educational programs. This includes trainees from underrepresented groups who otherwise might not have access to these systems.”

Cedars-Sinai has received several previous grants from CIRM, including grants for training of graduate and postdoctoral students, grants to develop stem cell-based disease treatments, and grants for biomanufacturing of induced pluripotent stem cells.

“We have developed nearly 1,200 iPSC lines—from healthy patients as well as those with ALS [amyotrophic lateral sclerosis], Parkinson’s disease, Alzheimer’s disease, inflammatory bowel disease, pancreatic cancer and other conditions,” said Dhruv Sareen, PhD, founding executive director of the Cedars-Sinai Biomanufacturing Center and the iPSC Core. “We are putting these into organ-chip models to help us understand disease characteristics and discover new treatments. This new lab will help us—and scientists throughout California—make progress to benefit patients everywhere.”

Read more from Discoveries: Gut Check

The body’s immune system includes white blood cells called phagocytes that function like the video game character Pac-Man, circulating through the body to detect and ingest intruders like bacteria and fungi.

Once the invading microbe is engulfed, a process called phagocytosis, the phagocyte kills it. The microbe is killed by fusing with an intracellular organelle called a phagosome, which contains proteins, that destroy the invader.

David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, notes that once the microbe is inside, a phagosome generates signals that guide local inflammatory responses, and many of these signals are microbe specific.

“With this knowledge, we developed a novel technique, termed PhagoPL, to identify all of the proteins involved in attacking different kinds of microbes,” said Underhill, senior and corresponding author of the study. “We then used this technique to study three types of phagosomes: one containing yeast, and two containing different types of bacteria.”

Underhill said his team of investigators also found that many proteins found in phagosomes are common to the different types of phagosomes.

“While we found that many phagosome proteins are common with different pathogens, we found that each microbe also recruits unique proteins that are specific to that microbe, suggesting that these proteins help drive inflammatory responses that are targeted for specific microbes,” Underhill said.

Even more unexpected, the Cedars-Sinai investigators found that a cell surface protein called PD-L1 is recruited specifically to yeast-containing phagosomes and turns out to be a fungal-binding receptor. PD-L1 has been previously known to regulate activation of T cells, which help the immune system fight off infections, and researchers say PD-L1 is an exciting protein being targeted by cancer immunotherapy strategies.

“We would never have guessed that PD-L1 would have such a specific role in sensing fungi,” said Kai Li, PhD, a project scientist and lead author of the study. “In fact, we focused our study on PD-L1 because it stood out to us as a protein that we felt really shouldn’t be found associated with these microbes.”

Underhill said the discovery of a novel function for PD-L1 is proof-in-principle of the power of PhagoPL, the new methodology created with broad applicability for the discovery of phagosome proteins and mechanisms of immunity.

Jeffrey A. Golden, MD, executive vice dean of Research and Education and director of the Burns and Allen Research Institute at Cedars-Sinai, said this study is likely to impact future research.

“These findings have provided new insight into how phagocytes function and has the potential to fundamentally change our current view of PD-L1. This information can potentially be leveraged to develop novel, or improve current, anti-tumor immunotherapies,” said Golden, who was not involved in the study.

Because of the versatility of the PhagoPL technique, Underhill and team are eager to apply their findings to study many more phagosomes containing different fungi, bacteria, or other nonmicrobial materials.

“We aim to uncover more mechanisms related to how we defend ourselves against infection and uncover how autoimmunity and anti-tumor immunity are regulated,” Underhill said. “We are also keen to collaborate with and provide technical support to those interested in using the PhagoPL technique to address scientific questions.”

Other Cedars-Sinai investigators involved in the study include Avradip Chatterjee, Chen Qian, Katherine Lagree, Yang Wang, Courtney A. Becker, Michael R. Freeman, Ramachandran Murali, and Wei Yang.

This work was supported by National Institutes of Health grant R01AI071116 (DMU).

Read more on the Cedars-Sinai Blog: Meet David Underhill, PhD

Neuroprosthetics, a technology that allows the brain to control external devices such as robotic limbs, is beginning to emerge as a viable option for patients disabled by amputation or neurological conditions such as stroke. Cedars-Sinai investigators, in a study published in the peer-reviewed journal

“Neuroprosthetics have largely tapped the brain’s outermost cerebral cortex. The cerebellum has a well-known role in movement but has been ignored in neuroprosthetic research,” said Tanuj Gulati, PhD, assistant professor of Biomedical Sciences and Neurology and researcher in the Center for Neural Science and Medicine at Cedars-Sinai, and senior author of the study. “We are the first to record what is happening in the cerebellum as the brain learns to manipulate these devices, and we found that its involvement is essential for device use.”

Patients who use neuroprosthetic devices have electrodes permanently implanted in the portion of the brain—usually the cerebral cortex—that controls movement for the function the device is replacing. This technique can be used to help patients control a robotic limb, a motorized wheelchair or a computer keyboard, among other devices.

To learn how the cerebellum helps in learning neuroprosthetic control, Gulati and his team trained laboratory rats to use only their motor cortex activity to move a neuroprosthetic tube that delivered them water. The rats had electrodes implanted in the motor cortex and the cerebellum, and investigators listened in on the activity of neurons in both brain regions during the experiments.

“We found that activity of the neurons in the cerebellum was coordinated with the motor cortex, and that activity in the cerebellum was critical for neuroprosthetic task performance,” said Aamir Abbasi, PhD, a postdoctoral scientist in the Gulati Lab and the first author of the study.

Investigators next used an advanced technology called optogenetics to selectively silence different neuron populations in the laboratory rats’ brains during experiments. Optogenetics delivers light-sensitive proteins into brain cells, allowing light exposure to control these cells’ activity.

When they silenced neurons in the outer layer of the cerebellum, where the cerebellum receives input from other brain regions, they found that the laboratory rats had a difficult time learning to control movement of the pipe. When they silenced neurons deep in the cerebellum, which are responsible for outward communication from the cerebellum to the motor cortex, the rats had difficulty maintaining accurate control of the pipe.

“These results could help make neuroprosthetics an option for patients with damage to the motor cortex due to brain injury, stroke or diseases such as Parkinson’s or multiple sclerosis,” said Nancy L. Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “It’s possible that, eventually, implants in the cerebellar region could be used to help these patients manipulate external devices.”

It’s an exciting era for neuroprosthetics, said David Underhill, PhD, chair of the Department of Biomedical Sciences at Cedars-Sinai.

“There is a lot of buzz about neuroprosthetic technology, but there are still many unsolved problems,” Underhill said. “This study suggests that some of those could be resolved by involving the cerebellum as well as the motor cortex to help patients gain use of neuroprosthetic devices more quickly and improve their ability to control them accurately.”

Other authors involved in the study include Rohit Rangwani, Daniel W. Bowen, Andrew W. Fealy, and Nathan P. Danielsen.

This work was supported by American Heart Association postdoctoral fellowship 897265, American Heart Association predoctoral fellowship 1018175, American Heart Association career development award 847486, National Institutes of Health grants R00NS097620 and R01NS128469, National Science Foundation grant 2048231, and a Cedars-Sinai Medical Center’s Center for Neural Science and Medicine postdoctoral fellowship.

No conflicts of interest to disclose.

Read more on the Cedars-Sinai Blog: Bolster Your Brain by Stimulating the Vagus Nerve

The Rutishauser Lab collaborates with several leading universities and medical centers, including the California Institute of Technology, Johns Hopkins University, the University of Toronto, Boston Children’s Hospital and the University of Colorado at Denver. A key aspect of this collaboration is open data-sharing. Cedars-Sinai is part of the National Institutes of Health BRAIN Initiative Research Opportunities in Humans Consortium, representatives of which recently penned an article for the peer-reviewed journal Neuron on the benefits of data-sharing.

“Dr. Rutishauser’s work advances our understanding of the workings of the human brain and also connects Cedars-Sinai with top medical institutions across the country and beyond,” said Jeffrey Golden, MD, vice dean of Research and Research Education at Cedars-Sinai. “Work of this caliber simply isn’t possible if institutions guard their discoveries and data, encumbering collaboration.”

Rutishauser, who holds the Board of Governors Chair in Neurosciences, sat down with the Cedars-Sinai Newsroom to discuss the role of data-sharing and scientific collaboration in his work and the broader scientific community.

What type of data does your lab’s research generate, and how has it advanced our understanding of the human brain?

Our data is acquired from patients with epilepsy who are undergoing depth-electrode monitoring, which means they have tiny electrodes surgically inserted into the brain to monitor seizure activity.

We use these recordings of the electrical pulses sent between individual neurons within the brain to study how the brain records and recalls memories, how we make decisions, and how these processes go wrong under certain conditions. For example, we have discovered how we monitor our own behavior for errors using this approach.

The same data, which is rare and difficult to acquire, can also be used to study many other aspects of the human brain, but this is only possible if the data is made accessible to other investigators inside and outside of Cedars-Sinai.

What is the current state of data-sharing in human neuroscience?

Funding agencies and journals require that research teams make their data available to others. However, they require sharing of only the exact data needed to reproduce a given study, often only on request.

This requirement is often viewed as a burden by investigators. But in our recent editorial, we point out the many benefits of investigators sharing all of their data freely and in a standardized format, so it is easily accessible. We found that when we, as the data producer, released data in this way, we discovered new collaborators who used our data to explore questions we had never thought about. Within our own lab, using a standardized data format also facilitated reuse of that data. And schools and universities have even used the data for teaching purposes.

Why is cross-institutional collaboration so important to the future of science?

Collaborating and sharing data is a way for us to broaden our impact. One of the inherent difficulties of the work I do is that the experiments are challenging to perform and the number of patients available is limited. To increase the amount of data available, we collaborate with research groups at other institutions. This allows us to perform large, well-powered studies and increases confidence in our findings by replicating findings at other institutions.

What challenges need to be overcome to increase data-sharing in neuroscience?

There are three challenges. First, the field has to agree on a standard data format. While there are formats that could fill this requirement, there’s no universal agreement on which should be the standard format. The use of a single standard data format in the field of neuroimaging, for example, shows the immense benefits of the practice. Second, we need data archives where very large files can be uploaded, stored and made available. Third, and perhaps most challenging, investigators must be willing to openly share their data.

What is your advice for investigators who want to share their data?

I strongly advise using a standardized data format. We chose to use the Neural Data Without Borders (NWB) format. Develop an expectation in your lab that when a project is finished, your team will export the data in that format, document it and publicly release it upon publication.

Their findings, published today in the peer-reviewed journal Cell Reports, could aid future studies looking at the effects of diet and the microbiome, especially the process of fiber metabolism by gut microbes.

The team of investigators—led by Ivan Vujkovic-Cvijin, PhD, assistant professor in the department of Biomedical Sciences and department of Gastroenterology at Cedars-Sinai—are among the first to find that looking for fiber metabolites—molecules that strengthen gut barrier integrity and immune function—in blood samples, versus traditional stool samples, provides a more accurate representation of production of these metabolites by the gut microbiome.  

With this knowledge, investigators also discovered that gut microbial production of these fiber metabolites is related to the prevention of heart disease and death in people with HIV, the virus that causes acquired immunodeficiency syndrome (AIDS).

“This is an important step in the human microbiome field because the high-fiber diet has been shown to protect from a remarkable number of diseases, but the field has struggled to quantify the immediate effects of such diets,” said Vujkovic-Cvijin, corresponding and senior author of the study. “We anticipate our discovery will allow better quantification of microbial fiber metabolism and will lead to a greater understanding of the precise pathways that link fiber metabolites to protection from diseases and early death in people with HIV.”

People with HIV have long been known to experience higher rates of many diseases and premature death, despite being treated with optimal antiretroviral therapy. The medical field also knows, based on past studies from Vujkovic-Cvijin and team, that the gut microbiota of people with HIV is different from that of those who are HIV-negative.

This latest research sheds light on the “why.”

Investigators found that an abundance of microbial enzymes involved in fiber deprivation correlates more strongly with fiber metabolite levels in blood than in stool.

Through this research, the team also found that significantly higher levels of these microbial enzymes were found in people who did not later succumb to heart disease or death, suggesting the importance of this pathway in the health of people with HIV.

“Thanks to this important research, we now understand that a lack of ability of the gut microbiome to digest fiber precedes medical conditions like heart disease, suggesting this function of the microbiome may also contribute to their development,” said David Underhill, PhD, chair of the Department of Biomedical Sciences, who was not involved in the research study.

Underhill said future studies may also gain more information by examining blood levels of fiber metabolites, instead of examining stool samples.

“Blood samples appear to paint a clearer picture of who might best benefit from fiber, and which types,” said Underhill.

Looking ahead, Vujkovic-Cvijin also plans to focus future research efforts on the precise pathways that may link fiber metabolites to protection from disease and early death in people with HIV.

“There are several likely candidates, and we hope to uncover which of these pathways might have the greatest impact on health,” said Vujkovic-Cvijin.

Additional Cedars-Sinai authors include Alice Lo and Jacob Gifford. Other authors include Irini Sereti, Myrthe L. Verburgh, Anders Boyd, Eveline Verheij, Aswin Verhoeven, Ferdinand W.N.M. Wit, Maarten F. Schim van der Loeff, Martin Giera, Neeltje A. Kootstra, and Peter Reiss.  

DOI: 10.1016/j.celrep.2023.113336

Funding: Vujkovic-Cvijin was funded by the Crohn’s & Colitis Foundation Career Development Award. This work was supported in part by The Netherlands Organization for Health Research and Development and AIDS Fonds and by the intramural research program of NIAID/NIH.

Read more from the Cedars-Sinai Blog: Cedars-Sinai Investigators Exploring the Connection Between the Microbiome and Diabetes

The research, led by the study’s senior author, Christie Jeon, ScD, associate professor of Biomedical Sciences, along with Dhiraj Yadav, MD, professor of Medicine at University of Pittsburgh, emphasizes the need for early intervention strategies to prevent pancreatitis in people who drink heavily.

According to the study, acute pancreatitis is a leading cause of gastrointestinal disease-related hospitalizations in the United States, with a 1%-2% mortality rate. The study's findings emphasize the significant role of sustained alcohol consumption in patients who were diagnosed with the condition.

"Our research suggests that alcohol, in combination with other factors, makes the pancreas more vulnerable to inflammation," Jeon said.

The study assessed the drinking patterns of patients who had been using alcohol regularly for an average of around 20 years, and who were hospitalized with acute pancreatitis or recurrent acute pancreatitis. Investigators found that the levels of drinking and the extent of alcohol consumption were considerably high in those patients who consumed, on average, 7-10 drinks per drinking day.

"Our major finding was that there was a significant amount of drinking, both in duration and intensity, in patients diagnosed with acute pancreatitis,” Jeon said.

The study also found that 28% of acute pancreatitis patients and 49% of recurring acute pancreatitis patients had recurrence within less than 12 months. The study suggests that recurring acute pancreatitis patients, due to their alcohol consumption, may be progressing toward chronic pancreatitis, which can result from repeated acute pancreatitis episodes.

"What we're seeing is that these patients have had long and intense exposure to alcohol," said Jeon. “In particular, patients with recurring acute pancreatitis show a similar intensity and sustained level of drinking as those patients who have chronic pancreatitis.”

Jeon said the research underscores the need for early intervention in patients who regularly use alcohol, to prevent the progression to chronic pancreatitis.

The study also delves into the complex relationship between alcohol consumption, mental health conditions and negative life events. Many patients with acute pancreatitis or recurring acute pancreatitis reported concurrent mental health disorders, such as depression and anxiety, or negative life circumstances, such as family problems, death or financial strain.

“These findings highlight the need for a comprehensive approach to intervention that addresses both alcohol cessation and underlying mental health issues,” said David Underhill, PhD, chair of the Department of Biomedical Sciences.

Jeon said that a multidisciplinary intervention, which combines counseling, substance addiction medication and holistic care, may help stop disease progression in these types of patients.

"It has to go beyond pancreatitis, beyond alcohol, to really look at the patient as a whole," she said.

Jeon said that the development of substance-use-focused prevention and management guidelines for acute pancreatitis, which currently do not exist, would be a step in the right direction.

“Our findings highlight the urgency of targeted intervention,” Jeon said. “By addressing alcohol consumption and its interplay with mental health and social factors, clinicians can mitigate the risk of disease progression and better care for patients.”

Further research from Jeon’s team is focused on developing treatments to relieve symptoms and improve quality of life for patients with persistent forms of pancreatitis.

Funding: This study was funded by the Department of Defense award W81XWH-19-1-0888 (PI: Pandol). The sponsor has not taken any part in the conduct of the study and reporting of the findings.

Read more on the Cedars-Sinai Blog: New Research Explores Link Among Diabetes, Pancreatitis and Pancreatic Cancer

Specifically, the investigators have improved understanding of the steps that lead to the production of IL-1 beta, a potent inflammatory protein signal released during many inflammatory responses.

“We now have a clearer understanding of the stepwise process that leads to the production of IL-1 beta,” said Andrea Wolf, PhD, assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai, and a senior and corresponding author on the new study. “By understanding the process, we hope to one day find a treatment for diseases associated with this inflammatory response.”

When the innate immune system—the defense system we were born with—identifies a potentially harmful bacterium, virus, or other external invader, it unleashes white blood cells to surround and attack the foreign agent. This can cause swelling, redness, heat and pain in the body’s tissues that—in a healthy body—eventually go away.

Some people, however, get stuck in the inflammation phase. This causes what is known as chronic inflammation. Chronic inflammation can damage healthy cells in the body and is thought to lead to serious conditions like Type 2 diabetes, heart disease and depression.

“Inflammation, in many instances, is vital to a thriving immune system and healthy body,” said David Underhill, PhD, chair of the Department of Biomedical Sciences and the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease, who is also a senior and corresponding author on the study. “However, prolonged inflammation can wreak havoc on the body. This underscores the importance of understanding the cellular process of how inflammation is activated so we can work toward finding new treatments to curb chronic inflammation.”

The study published today is a follow-up to Cedars-Sinai research published in 2016 that explains how cells act to detect an infection. In that study, investigators discovered that an enzyme called hexokinase, typically used by cells to convert glucose into energy, has a second, inflammatory function. They discovered that hexokinase binds to a sugar from the cell wall of bacteria and activates the inflammasomes, leading to the production of IL-1 beta. Inflammasomes are receptors of the innate immune system that recognize microbes and tissue damage.

The current work presents a more complete picture of this process.  

The investigators discovered that hexokinase leaves the mitochondria, the part of a cell that generates energy. This jump-starts an immune response: The release of hexokinase destabilizes the mitochondria and alerts the cell that something is wrong. This leads to clustering of a channel called VDAC in the membrane of the mitochondria, which interacts with another protein called NLRP3 to initiate inflammasome assembly. The inflammasomes then produce IL-1 beta, a driver of inflammation.

The investigators studied cells that were derived from laboratory mice to understand the steps involved in the IL-1 beta pathway. The team used substances called inhibitors that block cellular functions as well as gene-editing technology to turn off certain genes and the proteins they express. This allowed them to understand which proteins are vital to triggering inflammation.

Cedars-Sinai postdoctoral scientist Sung Hoon Baik, PhD, used the super-resolution microscope that is part of the Cedars-Sinai Biobank and Research Pathology Resource to visualize and measure the steps of this inflammatory process within individual cells.

“Being able to target specific steps in this pathway is vital, because in addition to being important for inflammation, the components of this pathway also play a vital role in maintaining energy within the cell,” Wolf said. “We want to home in on its inflammatory role, not just turn it all off, because that would be bad for the cell.”

The investigators are continuing to study the cellular steps leading up to, and resulting from, hexokinase’s role in the activation of inflammasomes. They are also using the results from this study to begin to target this inflammatory pathway in different diseases.

Other Cedars-Sinai investigators who worked on the study include Courtney Becker, manager of the Underhill Laboratory at Cedars-Sinai; Sarah Fett, research associate at Cedars-Sinai; and V. Krishnan Ramanujan, PhD, research associate professor in the Department of Medicine at Cedars-Sinai and director of the Cedars-Sinai Biobank.

Funding: The study was funded by the National Institutes of Health (award numbers R01AI148465, R01GM085796, R01AI071116).

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Read more on the Cedars-Sinai Blog:  Autoimmune Diseases: When Your Body Turns On You