Xuesong “Simon” Zhou says there are several variables that make up his vision for an ideal transportation system of the future.
First is creating a carbon neutral environment by 2050. The second involves improving access to transportation for disabled, low-income and other minority groups to create equity with the driving population. Xuesong Zhou, an associate professor of civil and environmental engineering in the Ira A. Fulton Schools of Engineering, has spent a majority of his career working to create a universal mapping system for transportation researchers to use to look at the multiple levels of interaction that happen between cars, bikes and pedestrians in complex networks. Image courtesy Xuesong Zhou/ASU Download Full Image
These are not easy feats on their own and for these changes to be effective, they must happen at the same time. This presents even more of a challenge for transportation researchers like Zhou.
Before about 1940, walking, bicycling and public transit were recognized as important travel modes, but for most of the last century, transport planning has been automobile oriented. As a result, most communities now have well-developed road systems that allow motorists to drive to most destinations safely and with relative convenience; at worst they may be delayed by peak period congestion or pay tolls and parking fees at some destinations. However, such planning ignored the needs of people who use non-automobile travel modes.
Zhou, an associate professor focusing on multimodal transportation research in the School of Sustainable Engineering and the Built Environment, one of the seven Ira A. Fulton Schools of Engineering at Arizona State University, says that is where his work comes into play.
“We need to have a seamless connection between design planning and execution,” Zhou says. “The two steps are reliant on one another, so if we plan for an effective implementation, we plan for a better design and vice versa.”Cars, buses, bikes and pedestrians
Zhou’s multimodal transportation research investigates how various transportation options play an integral role in meeting the mobility needs of the populations that rely on them, how each transit option impacts the usage of other modes of transportation as well as the infrastructure needed to support the multiple transportation options.
Urban intersections in the United States have many of the same components, such as a number of lanes utilized by vehicles or buses, other lanes for bikes and sidewalks for pedestrians. Each element represents a critical component of a multimodal network that needs to be considered when creating models and planning out cities.
In recent years, Zhou has worked with numerous transportation researchers and practitioners to find ways to streamline research in the field of multimodal transportation modeling. In most instances, researchers create their own data sets and unique maps for the regions where they conducted their research. As a result, when researchers from other areas want to replicate the study design in their region, they need to start from scratch.
“There was no universal system for building models and the networks upon which they are built,” Zhou says. “We created a way to convert General Transit Feed Specification, or GTFS, and OpenStreetMaps, which are industry standards, into the General Modeling Network Specification, or GMNS, a common human and machine readable format that can be shared between transportation researchers.” Zhou’s universal mapping system allows researchers to model transportation systems at multiple scales. Graphic courtesy Xuesong Zhou
Zhou’s universal mapping system allows researchers to model transportation systems at multiple scales. Graphic courtesy Xuesong Zhou
The project is called osm2gmns, and is available to professionals around the world at no cost. It is a joint effort with Jiawei “Jay” Lu, a civil, environmental and sustainable engineering doctoral student at ASU, and many others.
In addition to creating a standard map for network analysis, Zhou’s work allows researchers to model at a more in-depth level than before with multi-level resolution. Using ASU research computing facilities, Zhou’s team also created an entire U.S. driving network from OpenStreetMap with 20 million nodes, and the related Python package has been installed more than 40,000 times.
“Traditionally, in city planning, you would look at an intersection as one point of interaction, but when you add in a pedestrian crosswalk, you now have to factor in left and right turn lanes creating more points of interaction,” Zhou says. “The same goes for adding in bike lanes; you now have to go lane by lane and determine the points of interaction among transportation system users.”
Zhou says that having an integrated transportation model at different scales including macro-, meso- and micro-levels, allows for a better cost-benefit analysis of adding various elements such as major intersections, bike lanes and even stop lights where they can be used most effectively.
“Dr. Zhou is one of the most methodologically gifted transportation scholars in the profession,” says Ram Pendyala, a fellow transportation researcher and director of the School of Sustainable Engineering and the Built Environment. “What sets him apart is that he works tirelessly to translate research into practice through the development of sophisticated software tools and systems that can be readily adopted and used in real-world planning applications.”Supply and demand
The city of Tempe, Arizona, is characterized by multi-lane streets, bike lanes, light rail tracks and a newly added streetcar line. Due to commuting patterns, those modes of transportation can become congested as individuals start and end their work day. Determining ways to overcome this congestion and make transportation networks operate in the most time- and cost-efficient ways is a key area of Zhou’s research.
For decades, researchers have used a more traditional supply and demand curve to model the usage of transportation options. This methodology focused on one point in time and couldn’t account as accurately for multiple modes of transportation operating simultaneously in the same time.
Zhou’s most recent study, “A meso-to-macro cross-resolution performance approach for connecting polynomial arrival queue model to volume-delay function with inflow demand-to-capacity ratio,” has introduced new mathematical equations that rectify this oversight. Associate Professor Xuesong Zhou.
“We are finally able to go from the macroscale to the microscale much more easily without using simulation,” Zhou says. “Why is this so important? Because it will save us time from doing heavy duty computational work and still provide us a precise evaluation of alternatives.
“We are still using simulations to mimic vehicle-by-vehicle congestion, but we can use this analytical tool to calculate delay time dependencies hour by hour.”
Zhou’s work in transportation modeling has sparked the interest of researchers across the world, and many are looking to Zhou for insight into their own work and the sphere of transportation research as a whole.
Zhou was recently elected to the national executive board of the Zephyr Foundation for Advancing Travel Analysis. The nonprofit organization has sought to create open-source tools, similar to those that Zhou has developed, and formulate industry standards so that transportation modeling research can be replicated easily across contexts.
“His work in modeling and optimizing dynamics of transportation networks, traffic flow and emerging mobility services is groundbreaking, and being adopted by cities and transportation planning agencies around the world,” Pendyala says.
“In the School of Sustainable Engineering and the Built Environment, we are constantly striving to advance use-inspired research that will render our future infrastructure systems more sustainable, efficient, resilient and equitable. Dr. Zhou’s work in the transportation systems analysis space contributes immensely to advancing our mission, and he is educating and training a next-generation transportation workforce fully equipped to harness the power of technology and leverage the capabilities of artificial intelligence, deep learning and operations research to achieve these goals.”
Communications Specialist, Ira A. Fulton Schools of Engineering
602-543-5075 Monica.S.Williams@asu.edu
Cardiovascular diseases remain a leading cause of death around the world. A primary contributor to these afflictions is high blood pressure, or hypertension.While treatments exist for the condition, which affects tens of millions of Americans, these remedies are not without side effects, and some variants of the disorder are treatment-resistant. The need for more effective therapies to address hyp...
Cardiovascular diseases remain a leading cause of death around the world. A primary contributor to these afflictions is high blood pressure, or hypertension.
While treatments exist for the condition, which affects tens of millions of Americans, these remedies are not without side effects, and some variants of the disorder are treatment-resistant. The need for more effective therapies to address hypertension-related disease is therefore acute. The illustration shows a portion of the receptor pGC-A, known as the extracellular domain, which protrudes from cell surfaces in the cardiovascular system. Small molecules bind with the receptor and exert subtle control over blood pressure. The new research offers the first sneak peek at the full-length receptor, a vital step in the development of new drugs to treat hypertension and other afflictions. Graphic by Jason Drees Download Full Image
To accomplish this however, biologists need more detailed maps of the mechanisms underlying cardiovascular regulation. One such regulator is a protein receptor that sits atop cardiovascular cells, acting as a conduit for messages that are transmitted when specific hormone molecules bind with them.
Known as pGC-A, this membrane receptor acts a bit like a thermostat, sensitively adjusting the body’s blood pressure to maintain a homeostatic balance essential for health. The receptor acts not only as a vital cellular component for vascular and cardiac homeostasis, but also plays an important role in lipid metabolism and is implicated in cancer development.
In a new study, published in the current issue of the journal Scientific Reports, researchers from Arizona State University's Biodesign Center for Applied Structural Discovery and their colleagues, in collaboration with Mayo Clinic, Rochester, make critical progress toward unveiling the structure of pGC-A.
The study provides the first purification, characterization and preliminary structural analysis of the full-length protein receptor. The research advances include crystallizing the protein and showing that these crystals diffract X-rays — two critical steps essential to solving the structure.
A clearer understanding of this complex receptor and its signaling mechanisms paves the way for a new suite of anti-hypertensive drugs, which could help stave off heart attacks and strokes and improve recovery from these incidents. Debbie Hansen
"This accomplishment is the first described X-ray diffraction for a new class of membrane protein receptors, and represents an extraordinary effort by our graduate student, Shangji Zhang,” says co-author and Biodesign researcher Debbie Hansen. “Structures of unique classes of membrane proteins often require years of effort and are built on similar critical advances."
Co-author John C. Burnett Jr., from the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, has been working to develop candidate molecules for new anti-hypertensive drugs, based on the structure of the pGC-A receptor.Heart-stopping threat
According to the World Health Organization, over a third of all deaths worldwide may be attributed to cardiovascular disease. Hypertension is among the leading factors contributing to the progression of cardiovascular disease.
The burden of hypertension has been steadily growing, resulting in a recent recommendation by the Report of the National Heart, Lung and Blood Institute Working Group on Hypertension to “develop new drugs and treatments to target diverse hypertensive patient populations, such as patients with resistant hypertension.”
Treatment-resistant forms of hypertension, which are more likely to occur in patients with obesity, diabetes or renal dysfunction, account for 12–15% of hypertensive patients. Such individuals show limited or poor response to existing therapeutics. The condition can develop when the blood vessels become calcified and inelastic, losing their ability to fully contract and relax. Clinical studies show that treating high blood pressure reduces the risk of stroke by 35–40%, and the risk of heart failure by 50%.
Cardiovascular diseases include rheumatic and congenital heart disease; coronary, cerebral and peripheral arterial disease; deep vein thrombosis; and pulmonary embolism. Coronary artery disease, a leading killer, occurs when blood flow to heart muscle cells is reduced or obstructed, which can lead to heart failure. In the United States alone, the condition is projected to increase to $70 billion by the year 2030.New insights begin to crystalize
The pGC-A membrane receptor exists in three primary forms. This class of receptors are so important, they comprise the majority of pharmaceutical drug targets. For most organisms, whether prokaryotes like bacteria or eukaryotes like mammals, a full 20–30% of the genome is devoted to the expression of membrane proteins. Such receptors protrude from the outer cell membrane and penetrate deep into the cell’s interior, often acting as conduits for external signals that modify the cell’s behavior.
Designing drugs to target membrane proteins however, requires a highly detailed blueprint of the receptor structure, usually with atomic-scale resolution. Using this information, drug designers can engineer a drug that will bind in a selective and precise manner with the cell receptor, to produce a given outcome.
In the case of pGC-A, the binding molecules are peptide hormones produced by cells of the cardiovascular system. Known as natriuretic peptide hormones, they occur in natural variations and can also be synthetically designed, using genetic mutation. Part of the receptor’s activity involves the conversion of GTP to cGMP, a molecule essential for the normal function of vital organs.
“The heart is not only a pump but an endocrine gland which produces a highly beneficial hormone called atrial natriuretic peptide (ANP),” Burnett says. “This hormone plays an important role in blood pressure, kidney and over all metabolic balance.” Digging deeper
To date, only the extracellular component of the pGC-A receptor has been characterized. The current work is a major step toward characterizing the full-length structure, particularly the transmembrane domain and functional intracellular domain regions, about which little is currently known.
To achieve this, the researchers use a method known as baculovirus protein expression. The process involves turning insect cells into tiny protein production factories. Insect cells resemble human cells in terms of their protein-processing machinery yet are easier and cheaper to grow than mammalian cells. Baculoviral vectors allow researchers to turn an insect virus into a vehicle for delivering the genetic recipe for a protein.
The process involves inserting a gene for making the receptor into a special type of DNA vector or carrier known as a bacmid. The recombinant bacmid carrying the receptor gene is then used to infect insect cells, which begin manufacturing recombinant baculoviruses.
The pGC-A receptor protein can then be extracted, purified and subjected to X-ray crystallography, to determine its structure. The process is tricky, labor-intensive and prone to failure for a variety of reasons. Only a small number of the many existing membrane proteins have been fully characterized, making the preliminary characterization of pGC-A an impressive achievement.
The insect cell expression system offers several advantages for protein expression, particularly in the case of membrane proteins like pGC-A. The technique makes it easier for researchers to extract properly folded membrane proteins directly from the cell membrane, compared with the bacterial expression of misfolded and non-functional proteins common with traditional expression in Escherichia coli (E. coli) bacteria.Horizon line Shangji Zhang
First author Zhang, who graduated with a doctorate in biochemistry from ASU in 2021 and is a scientist at 21st Century Bio in Davis, California, carried out the purification of the full-length protein.
“This was a massive accomplishment," Hansen says. "Membrane proteins are not trivial to purify, and she was also able to get crystallization of the protein and X-ray diffraction.”
Further purification and better diffraction data will ultimately enable atomic-level structural characterization.
The research opens the door to the detailed characterization of other membrane proteins, which may ultimately find their way into effective drugs to control hypertension and a broad range of other medical conditions.
“A major goal is to develop breakthrough drugs based on ANP and its target receptor in humans to treat high blood pressure, heart failure as well as obesity,” Burnett says. “The work done by the ASU and Mayo teams and reported in Scientific Reports helps unlock the secret of the receptor target and will accelerate the development of new drugs and truly help patients worldwide.” Petra Fromme
Petra Fromme, director of the Center for Applied Structural Discovery, who is the senior author of this study and served as the PhD supervisor of Zhang, is excited about the high impact of this work.
“Metabolic diseases are one of the most important health threats of the 21st century, with diabetes, high blood pressure and heart diseases taking the lives of millions each year — and the numbers are rising. The work on the pGC-A receptor has the potential to develop an effective drug that reduces the symptoms without serious side effects,” she said.
This project was supported by an award to J.C.B. and P.F. from the Mayo/ASU Structural Biology Alliance and by the Biodesign Center for Applied Structural Discovery at Arizona State University. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
The research was carried out with the generous assistance of the Biodesign Center for Innovations in Medicine and the Center for Personalized Diagnostics.
Science writer, Biodesign Institute at ASU
480-727-0378 richard.harth@asu.edu