Tag: University of California San Diego

Ring in the New Year with Changemaker Week

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Newswise — From volunteering in a beach cleanup to learning new ways to promote equity, the start of a new year is the perfect time to take steps to help spark positive change. UC San Diego’s Changemaker Kickoff Week showcases various ways to foster this changemaking spirit, where campus community members can jump into opportunities to continue building the knowledge and skills needed to make the world a better place.

Led by the Changemaker Institute at UC San Diego, Changemaker Kickoff Week features a lineup of engaging and meaningful programs hosted by units across the university. The weeklong celebration spans from Jan. 14–20, plus includes a special kick-off event on Jan. 11 for new and returning students to meet like-minded Tritons, connect to changemaker opportunities through student organizations and build community.

“Changemaker Kickoff Week is an important way UC San Diego continues to demonstrate our long tradition of fostering innovation that contributes to the greater good,” said Chancellor Pradeep K. Khosla. “We are pleased that this annual week of service enables our campus community to gather, share knowledge and drive positive change in our regional community and beyond. From cutting-edge research to public service that addresses our most pressing societal issues, our students, faculty and staff have a deep understanding that real change cannot be achieved alone.”

Changemaker Kickoff Week is held in conjunction with Martin Luther King, Jr. Day, a holiday dedicated to honoring the civil rights leader’s life and legacy. On Jan. 14, the Center for Student Involvement (CSI), in partnership with the Changemaker Institute, presents an opportunity to give back to the local community with the 22nd Annual Martin Luther King, Jr. Day of Service. The following day, CSI invites students, staff, faculty and alumni to participate in another beloved tradition: marching in the city’s 41st annual Martin Luther King, Jr. Parade.

“We see this week as a celebratory start to all the wonderful changemaking achievements and initiatives that will happen in 2023,” said Audra Buck-Coleman, associate director for the Changemaker Institute. “We hope participants come away inspired by the stories they have heard about the UC San Diego community’s changemaker achievements and gain a better understanding of the many ways to engage in changemaking, which is intentional activity that leads to a more just, inclusive and sustainable world.”

2023 will also welcome in the university’s first cohort of Changemaker Student Ambassadors. Hired by the Changemaker Institute and CSI, the group of six students will work to plan changemaker programming that is authentic and meaningful to UC San Diego’s student population. The ambassadors will foster collaborations and partnerships, facilitate workshops, gather event feedback and more.

“These six new Changemaker Student Ambassadors will serve as a sounding board for the Institute as we establish programs and priorities,” said Buck-Coleman. “Our ambassadors are stepping into their roles as the inaugural team, and we are excited for changemaker ideas and opportunities they will help shape.”

While Changemaker Kickoff Week is designed to jump start the new year through public and community service, social entrepreneurship and more, UC San Diego offers plenty of ongoing opportunities throughout the year to drive positive change. There are more than 70 service and changemaking organizations registered with the Center for Student Involvement, such as Engineering World Health, Houselessness Service Club at UC San Diego and San Diego Tutoring Tree. UC San Diego’s colleges have changemaker opportunities as well, including the Muir Environmental Corps, Roosevelt’s Mxntorship at Raza and Warren Grow! Community Garden Organization.

All Changemaker Kickoff Week 2023 events are free to register and participate. To view the full lineup, please visit the online calendar. Here is a sampling of this year’s events:

Jan. 11

Changemaker Hot Cocoa Happy Hour

The Changemaker Hot Cocoa Happy Hour invites new and returning students to meet like-minded Tritons, build community and find changemaker opportunities that fit their passions. Kicking off at 4 p.m. at Price Center’s East Ballroom, the free event will showcase the greater UC San Diego community to various student organizations and on-campus resources. Students will enjoy a hot chocolate bar, desserts, giveaway prizes, music and more. There will also be a raffle to win one of 30 free 30 Squishmallows.

Jan. 14

21st Annual Martin Luther King, Jr. Day of Service

This annual tradition was established in 2002 as a way for the UC San Diego community to give back. This year, join as fellow Tritons return to Mission Bay High School for a day of community building and connection to honor the life and legacy of Dr. Martin Luther King, Jr. To participate, sign up at the online registration form.

Jan. 14

MRSEC Beach Clean-Up

Meet near Ellen Browning Scripps Memorial Pier at 9 a.m. for this beach clean-up with the UC San Diego Materials Research Science and Engineering Center (MRSEC), where attendees can learn about the problem with existing plastics and their impact on our environment. The morning activity is coordinated with “I Love A Clean San Diego” and gloves, buckets and trash pickers will be provided to all participants. Sign up to participate at the online registration form.

Jan. 15

41st Annual Martin Luther King, Jr. Parade: A Campus Tradition

Join UC San Diego’s students, staff, and faculty and alumni as they march in San Diego’s Martin Luther King, Jr. Parade from 2-4 p.m. The UC San Diego contingent will be led by a large “UC San Diego” banner, followed by the UC San Diego Pep Band, the seven Colleges and members of the campus community.

Jan. 15

UC San Diego Campus Clean-Up

Love to teach, serve the community and enjoy working with kids? Sign up online to join in a short hike and campus cleanup while learning about San Diego Tutor Tree, an organization that provides free tutoring for K-12 students in need of assistance. Participants will meet at the Price Center and then head to the hiking trails near the Challenge Course.

Jan. 17

Changemaker 101

In this virtual workshop beginning at noon, all students are invited to learn about the Changemaker 101 curriculum while understanding new ways to make a positive social, environmental and restorative impact in their community. Hosted by the Changemaker Institute, this session will also allow students to discover where they stand on the changemaker continuum and learn how to get involved in community efforts on campus. Students can register to attend the Zoom webinar online.

Jan. 17

Changemaking with College Corps

This year, more than 100 Tritons have undertaken a year of service as part of the inaugural #CaliforniansForAll College Corps program. These undergraduates are gaining valuable skills and meaningful experiences, in addition to $10,000 in financial compensation. Their work focuses on K-12 education, food insecurity and climate change. Beginning at 2 p.m., the Changemaker Institute will host a panel discussion with current fellows who will talk about their experiences in the Dolores Huerta—Philip Vera Cruz Room in the original Student Union. Attendees will hear stories about being a College Corps fellow and learn how to apply for next year’s cohort.

Jan. 18

Pathways to Leadership: Social Change Model: From Me to We

Building leadership skills is not just about boosting a résumé, but can serve as a means to impact the world around us. During this 1 p.m. virtual session hosted by Muir College, attendees can broaden their perspective of leadership and move towards being a driving force for positive change. An online registration form is now available to sign up.

Jan. 19

Global Seminars Changemaker Panel

In this virtual event at noon, a panel of Global Seminars faculty leaders will share the way that their summer programs abroad inspire participants to make change. Most of these professors are Changemaker Faculty Fellows, and their programs focus on topics such as community engagement, global health, social justice and sustainable development. Registration is now open to attend the session.

Jan. 19

Restorative Practices in Education: Learn About EducationCorps

Led by UC San Diego EducationCorps student representatives, this virtual workshop will explore the inequities in educational systems and share how to navigate these structural cycles using a restorative lens. Beginning at 6 p.m., attendees will have the opportunity to reflect on how structural inequalities impact our education system and learn new ways to support equity and anti-racism in K-12 schools. Sign up on the online registration form to attend.

Jan. 20

New Year’s Resolutions

Do you feel pressure to completely transform your life starting Jan. 1? Come visit the Women’s Center to discuss how diet culture, beauty standards, and more affect the popularity of New Year’s Resolutions. Attendees can also set some positive intentions for your year. The workshop begins at noon; snacks and beverages will be provided.

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January 10, 2023
New Computer Program ‘Learns’ to Identify Mosaic Mutations That Cause Disease

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Newswise — Genetic mutations cause hundreds of unsolved and untreatable disorders. Among them, DNA mutations in a small percentage of cells, called mosaic mutations, are extremely difficult to detect because they exist in a tiny percentage of the cells.

Current DNA mutation software detectors, while scanning the 3 billion bases of the human genome, are not well suited to discern mosaic mutations hiding among normal DNA sequences. Often medical geneticists must review DNA sequences by eye to try to identify or confirm mosaic mutations — a time-consuming endeavor fraught with the possibility of error.

Writing in the January 2, 2023 issue of Nature Biotechnology, researchers from the University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine describe a method for teaching a computer how to spot mosaic mutations using an artificial intelligence approach termed “deep learning.”

Deep learning, sometimes referred to as artificial neural networks, is a machine learning technique that teaches computers to do what comes naturally to humans: learn by example, especially from large amounts of information. Compared with traditional statistical models, deep learning models use artificial neural networks to process visually represented data. The models function in ways similar to human visual processing, with much greater accuracy and attention to detail, leading to major advances in computational abilities, including mutation detection.

“One example of an unsolved disorder is focal epilepsy,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine.

“Epilepsy affects 4% of the population, and about one-quarter of focal seizures fail to respond to common medication. These patients often require surgical excision of the short-circuited focal part of the brain to stop seizures. Among these patients, mosaic mutations within the brain can cause epileptic focus.

“We have had many epilepsy patients where we were not able to spot the cause, but once we applied our method, called ‘DeepMosaic,’ to the genomic data, the mutation became obvious. This has allowed us to improve the sensitivity of DNA sequencing in certain forms of epilepsy, and had led to discoveries that point to new ways to treat brain disease.”

Gleeson said accurate detection of mosaic mutations is the first step in medical research toward developing treatments for many diseases.

Co-first and co-corresponding author Xiaoxu Yang, Ph.D., a postdoctoral scholar in Gleeson’s lab, said DeepMosaic was trained on almost 200,000 simulated and biological variants across the genome until, “finally, we were satisfied with its ability to detect variants from data it had never encountered before.”

To train the computer, the authors fed examples of trustworthy mosaic mutations as well as many normal DNA sequences and taught the computer to tell the difference. By repeatedly training and retraining with ever-more complex datasets and selection between a dozen of models, the computer was eventually able to identify mosaic mutations much better than human eyes and prior methods. DeepMosaic was also tested on several independent large-scale sequencing datasets that it had never seen, outperforming prior approaches.

“DeepMosaic surpassed traditional tools in detecting mosaicism from genomic and exonic sequences,” said co-first author Xin Xu, a former undergraduate research assistant at UC San Diego School of Medicine and now a research data scientist at Novartis. “The prominent visual features picked up by the deep learning models are very similar to what experts are focusing on when manually examining variants.”

DeepMosaic is freely available to scientists. It is not a single computer program, but rather an open-source platform that can enable other researchers to train their own neural networks to achieve a more targeted detection of mutations using a similar image-based setup, the researchers said.

Co-authors include: Martin W. Breuss, Danny Antaki, Laurel L. Ball, Changuk Chung, Jiawei Shen, Chen Li and Renee D. George, UC San Diego and Rady Children’s Institute for Genomic Medicine; Yifan Wang, Taejeong Bae and Alexei Abyzov, Mayo Clinic; Yuhe Cheng, Ludmil B. Alexandrov and Jonathan L. Sebat, UC San Diego; Liping Wei, Peking University; and NIMH Brain Somatic Mosaicism Network.

Funding for this research came, in part, from the National Institutes of Health (grants U01MH108898 and R01MH124890), the San Diego Supercomputer Center and UC San Diego Institute of Genomic Medicine.

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January 2, 2023
Rewriting the Textbook on Gene Regulation: It’s the Big Picture That Counts

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Newswise — A fundamental principle of molecular biology governs how proteins are made within the cell, which happens in two stages called transcription and translation. During transcription, information stored in DNA is copied into messenger RNA (mRNA). Then during translation, the ribosomes assemble proteins one amino acid at a time based on the instruction specified on the mRNA.

The understanding of this process is so fundamental that the mere direction of the information flow from DNA to mRNA to protein is called the “central dogma” of molecular biology, a term coined by Nobel laureate Francis Crick. Since the advent of systems biology 20 years ago, researchers have been trying to establish how cells regulate transcription and translation processes based on gene expression data — which mRNAs and proteins are made under what conditions.

Deciphering how cells regulate these activities would provide insight into how they process environmental information to modulate their behavior. It would also allow scientists to formulate strategies for the precise manipulation of protein levels — a critical step in synthetic biology, which seeks to solve problems in medicine, manufacturing and agriculture through the redesign and re-engineering of genes and their interactions.

For the first time, researchers at the University of California San Diego have shown that changes in gene expression for the model bacterium E. coli happen almost entirely during the transcription stage while the cells are growing. The researchers have provided a simple quantitative formula linking regulatory control to mRNA and protein levels. The results and formula were published in a recent issue of Science.

“Ultimately what we provide is a quantitative relationship that scientists can use to interpret how pathogenic bacteria evade antibiotic treatment and host immunity,” stated Terry Hwa, UC San Diego Distinguished Professor of Physics and Biological Sciences, and principal investigator for the project. “In the synthetic biology context, it will allow bacteria to be redesigned and rewired for uses such as detecting and cleaning up toxic waste, or being sent into the body to kill cancer cells.”

The central dogma of molecular biology is linear, moving from DNA to mRNA to protein. It’s straightforward on an individual-gene level: turn on a gene, make mRNA, create proteins from the mRNA. Often, biologists think of gene regulation in such a linear fashion because they design experiments that change only a single gene or the few genes specific to their studies without drastically affecting the entire cell system.

According to this line of thinking, making twice as many mRNAs would yield twice as many proteins; however, when considered at a systems level, with all the genes together, this is not true, and the linear way of thinking about the central dogma doesn’t hold.

This is because cells must deal with certain global constraints. For example, the total protein concentration in a cell is approximately constant. When the environment changes and cells adapt by regulating the expression of certain genes, these global constraints force additional changes in the expression of not only these genes, but also others that are not directly regulated.

While systems biologists have not considered these global constraints when writing equations to model gene expression, Hwa’s group looked at the problem from the opposite end. They started with the constraints and then made quantitative statements with absolute measurements, beyond the relative measurements that are commonly used.

“We invested a lot of time and effort in quantifying these changes so we could filter out the small-magnitude changes that are really just distractions on a global level,” stated Hwa. “Absolute quantitative measurements will allow researchers to quantitatively relate mRNA levels to protein levels and vice versa. One cannot make these kinds of statements based on relative measurements.”

Hwa believes this research will reframe how gene expression and regulation is taught in biology textbooks and classrooms around the world, saying it already runs contrary to things he currently teaches in his own classroom.

Controlling gene expression is a complex process. A good design rule is essential so the same genetic circuit can work in multiple conditions. Currently scientists often see circuits they spent much effort developing in one environment fail in another.

“We were using the wrong framework,” stated Hwa. “Now this work has provided a simple recipe that can be used to decipher gene-gene interactions in bacterial responses and can be used to design genetic circuits more effectively in synthetic biology, helping to solve some of the world’s pressing issues in biotech and health sciences.”

Co-first authors on this paper were Rohan Balakrishnan and Matteo Mori (both UC San Diego). Other contributors include Igor Segota and Zhongge Zhang (both UC San Diego), Ruedi Aebersold (University of Zurich), and Christina Ludwig (Technical University of Munich).

This work was supported by NIH grant R01GM109069 and NSF grant MCB1818384.

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December 22, 2022
CRISPR Technology Improves Huntington’s Disease Symptoms in Models

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Newswise — Huntington’s disease (HD) is a neurological disorder that causes progressive loss of movement, coordination and cognitive function. It is caused by a mutation in a single gene called huntingtin or HTT. More than 200,000 people worldwide live with the genetic condition, approximately 30,000 in the United States. More than a quarter of a million Americans are at risk of inheriting HD from an affected parent. There is no cure.

But in a new study, published December 12, 2022 in Nature Neuroscience, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, describe using RNA-targeting CRISPR/Cas13d technology to develop a new therapeutic strategy that specifically eliminates toxic RNA that causes HD.

CRISPR is known as a genome-editing tool that allows scientists to add, remove or alter genetic material at specific locations in the genome. It is based on a naturally occurring immune-defense system used by bacteria. However, current strategies run the risk of off-target edits at unintended sites that may cause permanent and inheritable chromosomal insertions or genome alterations. Because of this, significant efforts have focused on identifying CRISPR systems that target RNA directly without altering the genome.

In the case of HD, the condition is caused by repetitive and damaging sequences in the HTT gene.

Our cells have a hard time copying repetitive DNA, and these copying errors can cause repetitive sequences to grow longer with each generation,” said senior study author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.

“In the Huntingtin gene, these repeats can sometimes grow to many times their normal length, with the resulting repeat-expanded protein tending to aggregate and form toxic clumps in a part of the brain called the striatum that is important for regulating movement. The loss of functional neurons in the striatum ultimately leads to HD symptoms.”

With colleagues at UC Irvine and Johns Hopkins University, Yeo and his team investigated whether recently described RNA-targeting CRISPR technology could be used to affect RNA (a chemical intermediate between DNA instructions and protein production) accumulation associated with HD.

They used viral vehicles to deliver the therapy to neuronal cultures, which were developed from stem cells derived from patients with HD, and found that the approach not only targeted and destroyed mutant RNA molecules, but also cleared out toxic protein buildup. They also demonstrated that expression of other human genes was generally not disrupted by the therapy.

“Our goal was to engineer a type of therapy that would only target the toxic RNA that causes HD and could keep the rest of the human genome and transcriptome intact,” said co-first author Kathryn Morelli, PhD, a research fellow in Yeo’s lab. “We specifically screened our top therapeutic constructs in HD patient cell lines to make sure of it.”

Development of effective therapies for HD has proven challenging. In 2021, for example, two clinical trials for promising gene therapies were halted following disappointing results performance. Both potential drugs had been touted as game-changers for HD. Currently, no treatments can alter the course of the disease, though medications can lessen some symptoms.

“The Huntington’s community was devastated when the clinical trials failed, primarily due to target specificity and toxic effects,” said Yeo. “But their termination has only re-energized the scientific community to find alternative strategies.”

Yeo’s lab collaborated with Wenzhen Duan, MD, PhD, professor of psychiatry and behavioral sciences, at Johns Hopkins Medicine to conduct preclinical testing in mice. Duan, with co-first author Qian Wu, PhD, found that the therapy improved motor coordination, attenuated striatal degradation and reduced toxic protein levels in a mouse model of HD. The improvements lasted for at least 8 months without adverse effects and minimal off-target effects on other RNA molecules.

Co-authors include: Maya L. Gosztyla, Ryan J. Marina, Kari Lee, Krysten L. Jones, Megan Huang and Allison Li, all at UC San Diego; Hongshuai Liu, Minmin Yao and Chuangchuang Zhang, Johns Hopkins University; Jiaxu Chen, Beijing University of Chinese Medicine; and Charlene Smith-Geater and Leslie M. Thompson, UC Irvine.

Funding for this research came, in part, from the National Institutes of Health (grants EY029166, NS103172,MH107367, AI132122, HG004659, HG009889, NS099397, NS124084, T32GM008666 ) the Bev Hartig Huntington’s Disease Foundation, an NIH NS112654-03 postdoctoral fellowship, a University of California President’s Postdoctoral Fellowship, the Paul G. Allen Foundation, the China Scholarship Council and the National Natural Science Foundation of China (82174278 and 81973748), the Hereditary Disease Foundation, an NIH predoctoral fellowship (NS111859), a National Science Foundation Graduate Research Fellowship (DGE-2038238),a Myotonic Dystrophy Foundation Doctoral Research Fellowship, an Association for Women in Science Scholarship and a Triton Research and an Experiential Learning Scholarship from Eureka! Research Scholarship.

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Disclosures: Gene Yeo is a scientific advisory board member of Jumpcode Genomics and a co-founder, member of the Board of Directors, scientific advisory board member, equity holder and paid consultant for Locanabio and Eclipse BioInnovations. He is also a Distinguished Visiting Professor at the National University of Singapore.

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December 12, 2022
UC San Diego Awarded $8M to Expand Stem Cell Therapy Clinical Trials

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Newswise — Stem cells show particular promise in treating diseases for which few other effective treatments exist. In these therapies, stem cells are introduced into the body where they develop into specialized cells that repair, restore, replace or regenerate cells that have been damaged by the disease.

As part of a state-wide effort to advance stem cell therapies, the California Institute for Regenerative Medicine (CIRM) has awarded $8 million to the UC San Diego Alpha Stem Cell Clinic. The funding will support the clinic’s mission of bringing new stem cell-based therapies to patients with difficult-to-treat diseases.

The Alpha Clinics — named for being the first of their kind — are a network of clinics spanning the state of California, designed to bridge the gap between stem cell research and clinical application. The system brings together clinical, research, regulatory and administrative teams in order to expedite clinical trials and streamline the patient experience.

“We’re trying to change the way we do medicine,” said Catriona Jamieson, MD, PhD, director of the UC San Diego Alpha Stem Cell Clinic and chief of the Division of Regenerative Medicine at UC San Diego School of Medicine. “The Alpha Clinic helps academic and industry experts join forces to bring world-class technologies directly to the patients.”

The grant is part of a series of recent CIRM awards totaling $72 million to expand the Alpha Clinics network. UC San Diego was one of three founding institutions when the project launched in 2015. The new funding will expand the program to nine sites across the state.

In the seven years since its inception, the UC San Diego Alpha Stem Cell Clinic has launched 59 clinical trials and treated 277 patients with new therapies for neurodegeneration, diabetes and various forms of cancer. The trials largely test cell, gene and immunotherapies developed through growing partnerships between UC San Diego and local biotechnology and pharmaceutical companies.

Recent milestones include the completion of a Phase I trial using neural stem cells to treat spinal cord injury, in which patients showed improved motor function after the treatment, as well as approval from the U.S. Food and Drug Administration (FDA) for a Phase III registration trial of a blood cancer stem cell-targeting monoclonal antibody.

The latest funding will help expand clinical trials at both La Jolla and Hillcrest Medical Centers and create a Clinical Fellowship Program to educate additional physicians in advanced regenerative medicine therapies.

Another major goal of the clinic is to improve accessibility and awareness of stem cell science. A portion of the funding will go towards new patient education programs and efforts to make treatments more accessible to historically underserved communities in San Diego and Imperial Counties.

“Patients come to us when nothing else has worked, so we are thrilled to be able to provide new treatments to our community that are not available in other parts of the country,” said Jamieson. “The Alpha Clinics’ highly collaborative infrastructure will help us develop and validate high-quality stem cell therapies at an unprecedented speed, and the effects will be seen across California and beyond.”

Funding for the UC San Diego Alpha Stem Cell Clinic comes from the California Institute for Regenerative Medicine (grant INFR4-13597).

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November 21, 2022
Artificial Neural Networks Learn Better When They Spend Time Not Learning at All

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Newswise — Depending on age, humans need 7 to 13 hours of sleep per 24 hours. During this time, a lot happens: Heart rate, breathing and metabolism ebb and flow; hormone levels adjust; the body relaxes. Not so much in the brain.

“The brain is very busy when we sleep, repeating what we have learned during the day,” said Maxim Bazhenov, PhD, professor of medicine and a sleep researcher at University of California San Diego School of Medicine. “Sleep helps reorganize memories and presents them in the most efficient way.”

In previous published work, Bazhenov and colleagues have reported how sleep builds rational memory, the ability to remember arbitrary or indirect associations between objects, people or events, and protects against forgetting old memories.

Artificial neural networks leverage the architecture of the human brain to improve numerous technologies and systems, from basic science and medicine to finance and social media. In some ways, they have achieved superhuman performance, such as computational speed, but they fail in one key aspect: When artificial neural networks learn sequentially, new information overwrites previous information, a phenomenon called catastrophic forgetting.

“In contrast, the human brain learns continuously and incorporates new data into existing knowledge,” said Bazhenov, “and it typically learns best when new training is interleaved with periods of sleep for memory consolidation.”

Writing in the November 18, 2022 issue of PLOS Computational Biology, senior author Bazhenov and colleagues discuss how biological models may help mitigate the threat of catastrophic forgetting in artificial neural networks, boosting their utility across a spectrum of research interests.

The scientists used spiking neural networks that artificially mimic natural neural systems: Instead of information being communicated continuously, it is transmitted as discrete events (spikes) at certain time points.

They found that when the spiking networks were trained on a new task, but with occasional off-line periods that mimicked sleep, catastrophic forgetting was mitigated. Like the human brain, said the study authors, “sleep” for the networks allowed them to replay old memories without explicitly using old training data.

Memories are represented in the human brain by patterns of synaptic weight — the strength or amplitude of a connection between two neurons.

“When we learn new information,” said Bazhenov, “neurons fire in specific order and this increases synapses between them. During sleep, the spiking patterns learned during our awake state are repeated spontaneously. It’s called reactivation or replay.

“Synaptic plasticity, the capacity to be altered or molded, is still in place during sleep and it can further enhance synaptic weight patterns that represent the memory, helping to prevent forgetting or to enable transfer of knowledge from old to new tasks.”

When Bazhenov and colleagues applied this approach to artificial neural networks, they found that it helped the networks avoid catastrophic forgetting.

“It meant that these networks could learn continuously, like humans or animals. Understanding how human brain processes information during sleep can help to augment memory in human subjects. Augmenting sleep rhythms can lead to better memory.

“In other projects, we use computer models to develop optimal strategies to apply stimulation during sleep, such as auditory tones, that enhance sleep rhythms and improve learning. This may be particularly important when memory is non-optimal, such as when memory declines in aging or in some conditions like Alzheimer’s disease.”

Co-authors include: Ryan Golden and Jean Erik Delanois, both at UC San Diego; and Pavel Sanda, Institute of Computer Science of the Czech Academy of Sciences.

Funding for this research came, in part, the Office of naval Research (grant N00014-16-1-2829), DARPA Lifelong Learning Machines program (HR0011-18-2-0021), National Science Foundation (IIS-1724405) and National Institutes of Health (1RF1MH117155, 1R01MH125557, 1R01NS109553).

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November 18, 2022
Phage Trial to Treat CF Patients With Multi-Drug Resistant Bacterial Infections

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Newswise — Cystic fibrosis (CF) is an inherited disorder that causes severe damage to the lungs and other organs in the body. Nearly 40,000 children and adults in the United States live with CF, an often difficult existence exacerbated by an opportunistic bacterium called Pseudomonas aeruginosa, which is a major cause of chronic, life-threatening lung infections.

P. aeruginosa infections are not easily treated. The pathogen can be resistant to most current antibiotics. However, an early-stage clinical trial led by scientists at University of California San Diego School of Medicine, with collaborators across the country, has launched to assess the safety and efficacy of treating P. aeruginosa lung infections in CF patients with a different biological weapon: bacteriophages.

Bacteriophages are viruses that have evolved to target and destroy specific bacterial species or strains. Phages are more abundant than all other life forms on Earth combined and are found wherever bacteria exist. Discovered in the early 20th century, they have long been investigated for their therapeutic potential, but increasingly so with the rise and spread of antibiotic-resistant bacteria.

In 2016, scientists and physicians at UC San Diego School of Medicine and UC San Diego Health used an experimental intravenous phage therapy to successfully treat and cure colleague Tom Patterson, PhD, who was near death from a multidrug-resistant bacterial infection. Patterson’s was the first documented case in the U.S. to employ intravenous phages to eradicate a systemic bacterial infection. Subsequent successful cases helped lead to creation of the Center for Innovative Phage Applications and Therapeutics (IPATH) at UC San Diego, the first such center in North America.

In 2020, IPATH researchers published data from 10 cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections, all at UC San Diego. In 7 of 10 cases, there was a successful outcome.

The new phase 1b/2 clinical trial advances this work. The trial is co-led by Robert Schooley, MD, professor of medicine and an infectious disease expert at UC San Diego School of Medicine who is co-director of IPATH and helped lead the clinical team that treated and cured Patterson in 2016.

It will consist of three elements, all intended to assess the safety and microbiological activity of a single dose of intravenous phage therapy in males and non-pregnant females 18 years and older, all residing in the United States.

The dose is a cocktail of four phages that target P. aeruginosa, a bacterial species commonly found in the environment (soil and water) that can cause infections in the blood, lungs and other parts of the body after surgery.

For persons with CF, P. aeruginosa is a familiar and sometimes fatal foe. The Cystic Fibrosis Foundation estimates that roughly half of all people with CF are infected by Pseudomonas. Previous studies have indicated that chronic P. aeruginosa lung infections negatively impact life expectancy of CF patients, who currently live, on average, to approximately 44 years.

In the first stage of the trial, two “sentinel subjects” will receive one of three dosing strengths of the IV bacteriophage therapy. If, after 96 hours and no adverse effects, the second stage (2a) will enroll 32 participants into one of four arms: the three doses and a placebo.

After multiple follow-up visits over 30 days and an analysis of which dosing strength exhibited the most favorable safety and microbiologic activity, i.e. most effective at reducing P. aeruginosa, stage 2b will recruit up to 72 participants to either receive that IV dose or a placebo.

Enrollment will occur at 16 cystic fibrosis clinical research sites in the United States, including UC San Diego. It is randomized, double-blind and placebo-controlled. The trial is being conducted through the Antibacterial Resistance Leadership Group and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, with additional support for the UC San Diego trial site from the Mallory Smith Legacy Fund.

Mallory Smith was born with cystic fibrosis and died in 2017 at the age of 25 from a multidrug-resistant bacterial infection following a double lung transplant.

“Mallory’s death was a preventable tragedy,” said her mother, Diane Shader Smith. “We are supporting the IPATH trial through Mallory’s Legacy Fund because Mark and I deeply believe in the promise of phage therapy to save lives by combatting multidrug-resistant bacteria.”

In an article published in 2020 in Nature Microbiology, Schooley and Steffanie Strathdee, PhD, associate dean of global health sciences and Harold Simon Professor in the Department of Medicine and IPATH co-director, describe phages as “living antibiotics.”

As such, said Schooley, researchers need to learn how to best use them to benefit patients through the same systematic clinical trials employed to evaluate traditional antibiotics.

The primary objectives of the new trial are first to determine the safety of a single IV phage dose in clinically stable patients with CF who are also infected with P. aeruginosa, said Schooley.

“Second, it’s to describe the microbiological activity of a single IV dose and third, to assess the benefit-to-risk profile for CF patients with P. aeruginosa infections. This is one study, with a distinct patient cohort and carefully prescribed goals. It’s a step, but an important one that can, if ultimately proven successful, help address the growing, global problem of antimicrobial resistance and measurably improve patients’ lives.”

Estimated study completion date is early 2025.

For more information on the clinical trial and participant eligibility criteria, visit clinicaltrials.gov or visit IPATH and click on the Contact Us button.

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October 11, 2022
Survival Is a Mixed Matter for Deadliest of Pancreatic Cancers

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Newswise — Pancreatic ductal adenocarcinoma (PDAC) is the most common and most lethal form of pancreatic cancer. The overall 5-year survival for patients with PDAC is just 7.1 percent.

All cancers are different. A unique feature of PDAC is extensive tumor desmoplasia or fibrous connective tissue within the tumor, which is caused by infiltration of the tumor mass by fibroblasts and the extracellular matrix they secrete. The main component of the matrix is type I collagen or Col 1, a protein broadly used in the body to form the basic structure of bone, skin, blood vessels and connective tissues.

The effect of Col 1 on PDAC development and its response to therapy has been a matter of intense debate among researchers, with some arguing that Col 1 promotes tumor growth and spread and others contending that it restricts tumor growth and protects the cancer cells from immune attack.

In a new study, published October 5, 2022, in Nature, co-first authors Hua Su, PhD, a postdoctoral fellow in the lab of senior author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at University of California San Diego School of Medicine, and Fei Yang, PhD, a scientist working with Beicheng Sun, MD, PhD, at Nanjing University School of Medicine, settle the debate by showing that it is not the amount of Col 1 present in the tumor that matters, but its quality and nature.

Specifically, they report that Col 1 that has been cleaved by matrix metalloproteases (enzymes that break down matrix proteins, such as collagen) stimulates tumor growth while intact and non-cleaved Col 1 inhibits tumor growth.

“Moreover,” said Su, “cleaved Col 1 activates a signaling pathway that stimulates energy production in pancreatic cancer cells by binding to a receptor protein called DDR1. Non-cleaved Col 1 inhibits this pathway by inducing the degradation of DDR1.”

The research was conducted using mice models and a novel culture system in which PDAC cells were plated on extracellular matrix that contained either cleaved or non-cleaved Col 1.

The authors said the findings have important clinical implications.

The relative amounts of cleaved versus non-cleaved Col 1 in the human PDAC stroma or connective tissue strongly affect patient survival after surgical resection. Patients whose tumors were enriched in cleaved Col 1 and whose cancerous cells expressed high levels of DDR1 fared poorly, with most succumbing to their disease within two years of surgery.

This patient group represented 75 percent of the 106 patients analyzed as part of the study, using cancer specimens provided by Beicheng Sun, MD, PhD, and colleagues at the Affiliated Drum Tower Hospital of Nanjing University Medical School in China.

In contrast, the 25 percent of patients whose tumors mainly contained non-cleaved Col 1 with low levels of DDR1 expression experienced much better survival prospects.

“This work is important because it provides a simple way for patient stratification and suggests that patients with high levels of cleaved Col 1 and DDR1 expression need more aggressive post-surgery treatments,” said Karin.

“It also provides evidence that the most effective therapy for this group of patients should include inhibitors of DDR1 or key components of its signaling pathway whose activation results in increased number of mitochondria, the cellular power plants, in PDAC cells.”

In addition to DDR1 inhibitors not yet in clinical practice, the authors suggested another treatment option, shown to be effective in PDAC-bearing mice, is the U.S. Food and Drug Administration approved antibiotic tigecycline, which can inhibit mitochondrial protein synthesis and decrease the number of energy-producing PDAC mitochondria.

Co-authors include: Rao Fu, Nanjing University Medical School; Brittney Trinh, Nina Sun, Junlai Liu, Jacopo Baglieri, Nachanok Sinchai, Jeremy Siruno, Stephen Dozier, Ajay Nair, Aveline Filliol, Sara Brin Rosenthal, Jennifer Santini, Anthony Molina, Robert F. Schwabe, Andrew M. Lowy and David Brenner, all at UC San Diego; and Avi Kumar and Christian M. Metallo, Salk Institute.

Funding for this research came, in part, from the National Institutes of Health (grants R01CA211794, R37AI043477, P01DK098108, U01AA027681, U01CA274295), the Padres Pedal the Cause/C3, the Cancer Center Support Grant and UC San Diego School of Medicine Microscopy Core.

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University of California San Diego

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October 5, 2022