Biomedical Research

Researchers strive to help models learn from ‘noisy’ data

Anonymous — Mon, 23 Oct 2023 22:13:43 +0000

Researchers strive to help models learn from ‘noisy’ data Anonymous (not verified) Mon, 10/23/2023 - 16:13

�� Boulder’s Bortz group, in applied math, wins $1.88 million National Institutes of Health grant to study methods for learning models directly from data

David Bortz, a University of Colorado Boulder professor of applied mathematics, has received a $1.88 million National Institutes of Health (NIH) Maximizing Investigators’ Research Award to support research on computational methods for data-driven modeling in the biomedical sciences.

Data-driven discovery methods are a recently developed class of machine learning algorithms that can reveal “governing model equations” directly from data. They leverage more than 70 years of advances in computational mathematics and mathematical modeling to bypass many of the current challenges modelers face.

Unfortunately, the first generation of these methods has not dealt well with the types of intrinsic noise and measurement errors commonly found in biomedical data.

�� Boulder researcher David Bortz recently received a $1.88 million National Institutes of Health (NIH) Maximizing Investigators’ Research Award.

With this grant, Bortz and his group will develop robust methods and use them to study important questions in two biomedical applications. The first area involves a collaboration with Xuedong Liu, a �� Boulder professor of biochemisty, to help understand what biochemical and biomechanical communication between cells drives collective motion during wound healing.

The second area builds on Bortz's work on the Colorado COVID-19 modeling team. The collaboration with Beth Carlton, a �� Anschutz associate professor of environmental and occupational health, will develop a framework for rapid analysis of infectious disease data to infer time varying infection rates as well as forecast likely hospitalization needs in different regions of the state.

The analysis methods are all built on the Weak form Sparse Identification of Nonlinear Dynamics (WSINDy) algorithm created by Bortz and Dan Messenger, a former PhD student and now postdoctoral researcher in the group. WSINDy learns a noise-filtered version of the equations that is both robust to large, biomedically relevant levels of noise and scientifically interpretable.

"The proposed research and methods supported by this grant completely bypasses the traditional mathematical model development/simulation/validation/refinement loop, focusing directly on the process of model creation itself," says Bortz.

He notes that WSINDy has already found success in a wide range of applications. For example, Messenger and Bortz, in collaboration with Liu, recently published a paper showing how it can be used to learn the biomechanical models that cells use during collective migration. There is also forthcoming work by April Tran, a PhD student in the group, that applies WSINDy to discover noise robust and fast surrogate models for use when a full model is computationally prohibitive.

"We are excited and grateful to the Division of Biophysics, Biomedical Technology and Computational Biosciences for funding this work and look forward to advancing methods for data-driven modeling, discovering novel therapeutic targets for enhanced wound healing and providing public health officials with the most accurate disease prevalence forecasts," says Bortz.

According to the National Institute of General Medical Sciences (NIGMS), "The goal of MIRA is to increase the efficiency of NIGMS funding by providing investigators with greater stability and flexibility, thereby enhancing scientific productivity and the chances for important breakthroughs."

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�� Boulder’s Bortz group, in applied math, wins $1.88 million National Institutes of Health grant to study methods for learning models directly from noisy data.

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Not just the powerhouse of a cell

Anonymous — Thu, 19 Oct 2023 18:23:48 +0000

Not just the powerhouse of a cell Anonymous (not verified) Thu, 10/19/2023 - 12:23

Rachel Sauer

Newly published �� Boulder research reveals previously unknown qualities of a gene vital to a cell’s mitochondrial structure and function

A key takeaway from first-year biology is that mitochondria are the powerhouses of cells—it’s the thing most people know about them.

However, mitochondria perform a large array of functions for cells beyond generating the chemical energy that powers a cell’s biochemical reactions. They play a role calcium signaling and storage, signaling between cells and cell death. And through these various and vital mitochondrial functions, a master regulator is the OPA1 gene.

For a long time, researchers have known that OPA1 plays a crucial role in mitochondria. For example, OPA1 helps maintain the architecture of the mitochondria’s inner membrane. Without that maintenance, a protein, cytochrome c, can leak into the cell and trigger cell death at the wrong time.

While researchers have long known that OPA1 is vital to mitochondria and mitochondrial membranes in human cells, not much has been known about how OPA1 does its work. But research recently published in the journal Nature sheds new light on how OPA1 helps reshape mitochondrial membranes and how that translates to cellular health.

Halil Aydin, a �� Boulder assistant professor of biochemistry, led research that discovered surprising plasticity in the vital OPA1 gene.

“We’ve known for a long time that this gene exists, we know that it’s important in a variety of diseases, including cardiovascular disease, cancer, neurodegenerative disease,” says principal investigator Halil Aydin, a University of Colorado Boulder assistant professor of biochemistry. “What we didn’t know is how it functions. Our goal is to understand how it works and then in the future use that as a blueprint for developing therapeutic strategies or drugs.”

Unexpected plasticity

Aydin and his research group first separated OPA1 from cells and studied it in vitro to understand its atomic structure, which was no easy feat. When OPA1 is remodeling mitochondrial membranes in the cell, that process happens extremely fast, “we’re talking at the microsecond level,” Aydin says. “This was always confusing to me as a biologist, how it can happen so fast.”

One of the research group's biggest discoveries in studying OPA1 outside the cell was its plasticity and flexibility. Aydin says he had not been expecting to see that degree of plasticity, and while it went a long way toward explaining how OPA1 is so dynamic, it makes getting a clear photo very difficult.

The researchers used an electron microscope to study OPA1, “but imagine taking a picture with your phone,” Aydin says. “You move it even a little, something in the background moves even a tiny bit, and the picture is blurry. So, it was tough for us to find the conditions where we could just lock in on OPA1 and see it clearly. We were shocked by how dynamic and flexible it is.”

With a better understanding of OPA1’s atomic structure, Aydin and his research colleagues were better able to study it at work in mitochondrial membranes. They saw that through a particular lipid-binding process in mitochondrial membranes, OPA1 can help shape and reshape the mitochondria.

“Mitochondria are shaped like a tubule,” Aydin says. “If you think about them like a balloon animal, OPA1 changes the chape of the balloon depending on cellular needs or energy demands. OPA1 is like the person making the balloon animals.”

Aydin and his research group are currently collaborating with researchers at Vanderbilt University to directly study OPA1 activity in stem cell-derived neurons. Via molecular manipulation, they are studying how changes in OPA1’s activity affect essential cellular functions.

A clearer path

A broader aim of the newly published and ongoing research is to understand how molecular observations in the lab translate to cellular health, Aydin says. There are more than 400 disease variants that affect the OPA1 protein, and by determining its molecular architecture “we can better map all these disease mutations and understand how they affect protein functions,” Aydin says. “In the case of the neurons, that can lead to a decrease in neuronal health and cause optic neuropathies and other neurodegenerative disorders.”

For example, autosomal dominant optic atrophy, a hereditary disorder that can lead to progressive loss of vision or childhood blindness, is caused by mutations in the OPA1 gene. A goal of gene therapies in the future will be targeting and correcting this mutation, Aydin says.

“In science, we call this the bottom-up approach,” he says. “We start by looking at a single molecule, then the organelle, then the cell, then tissue, then systems. The power of this is that once we understand something at the atomic level, that translation gets clearer at each step that follows. So, as we learn more about how OPA1 functions, the path to better drugs and therapeutics becomes clearer.”

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Newly published �� Boulder research reveals previously unknown qualities of a gene vital to a cell’s mitochondrial structure and function.

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Three �� Boulder profs win Boettcher Foundation awards

Anonymous — Mon, 12 Jun 2023 23:12:26 +0000

Three �� Boulder profs win Boettcher Foundation awards Anonymous (not verified) Mon, 06/12/2023 - 17:12

The awards are part of $1.88 million in 2023 biomedical research grant funding for Colorado researchers

Three University of Colorado Boulder assistant professors have been named 2023 Boettcher Investigators, each earning $235,000 in grant funding to support up to three years of biomedical research. The 13-year-old program invests in leading Colorado researchers during the early stages of their careers, providing support to fund their independent scientific research.

Nuris Figueroa Morales studies the complex interactions between microorganisms and their environment.

The three �� Boulder award winners and their fields of study are:

Nuris Figueroa, assistant professor, physics; studying the mechanics of mucus organization and transport;
Halil Aydin, assistant professor, biochemistry; investigating cellular and molecular mechanisms of mitochondrial form and function in human health and disease; and
Nick Bottenus, assistant professor, biomedical, mechanics of materials, and robotics and systems design in the College of Engineering and Applied Science; studying binding kinetics of targeted microbubble agents.

Funding for the awards is made possible in part by the Webb-Waring Biomedical Research Awards program, which is administered by the Boettcher Foundation.

“It’s an honor to be acknowledged by a distinguished organization,” Aydin said of the Boettcher Foundation. “The Boettcher Foundation Webb-Waring Biomedical Research Award will grant our laboratory the opportunity to develop novel approaches and push the boundaries of high-resolution imaging and structural cell biology to advance our understanding of how cellular machines function normally, and how they are corrupted by disease. An integrative understanding of how protein machines function has implications for targeting cardiovascular diseases, metabolic disorders, cancers, aging and a wide range of neurodegenerative diseases.”

Halil Aydin is an expert in membrane biology, cell signaling, proteins and enzymology, molecular biophysics, structural biology, and electron cryo-microscopy (cryoEM).

Figueroa also expressed thanks to the Boettcher Webb-Waring Biomedical Research Program and for what the funding will mean for her research team’s work.

“With this research grant, my team and I will have the means to investigate mechanical properties of lung mucus, how it flows, and how bacteria navigate in it,” she said. “Our research will look at the biophysics of lung-obstructive diseases using new quantitative and interdisciplinary tools, to further understand causes and consequences of failed mucus clearance and hopefully device solutions.”

Bottenus said, “Being named a Boettcher Investigator is an amazing career milestone. I’m grateful to become a part of a rich community of biomedical researchers throughout Colorado. This award will allow my group to grow in new directions, applying our acoustics and signal processing techniques to more fundamental biological investigations. I hope that our work will translate to improved diagnostic imaging, personalized medicine, and accessible health care technologies as we pursue new approaches to molecular imaging.”

Assistant Professor Nick Bottenus' research is focused on developing system-level solutions to problems in diagnostic ultrasound imaging.

The awards given to the three �� Boulder assistant professors are part of a larger pot of $1.88 million grant funding awarded to eight individuals from four of Colorado’s research institutions: �� Boulder, University of Colorado Anschutz Medical Campus,Colorado State University and National Jewish Health.

“We are thrilled to support our 2023 Boettcher Investigators, and as proud investors in their work, we are confident that these exceptional researchers will continue to push the boundaries of discovery and medical breakthrough,” said Katie Kramer, president and CEO of the Boettcher Foundation. “Their innovative research holds the promise of transformational impact that will drive progress in health care and make a meaningful difference in the lives of Coloradans.”

Since its inception in 2010, the Webb-Waring Biomedical Research Awards program has advanced the work of 98 Boettcher Investigators with more than $20 million in grant funds. The researchers have attracted more than $150 million in additional independent research funding from federal, state and private sources.

“Colorado BioScience Association applauds Boettcher Foundation’s support of Colorado’s most dynamic and promising researchers,” said Elyse Blazevich, president and CEO of the Colorado BioScience Association.

“The Webb-Waring Biomedical Awards program invests in Colorado researchers at a pivotal time in their careers and encourages them to deepen their roots in Colorado as they contribute to the leading-edge health innovations coming from our state.”

The awards are part of $1.88 million in 2023 biomedical research grant funding for Colorado researchers.

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