Category Archives: Biochemistry

Biochemistry

U of T’s Medicine by Design invests $1 million to advance new ideas in regenerative medicine – News@UofT

Patients with cystic fibrosis experience recurrent lung infections that eventually destroy their airways, shortening their average life expectancy to 50 years in Canada. Current drug treatments, which target a malfunctioning pathway in cells that causes the infections, are costly and have varying effectiveness.

Now, with funding from Medicine by Design, a researcher at the Hospital for Sick Children (SickKids) is combining stem cells, gene editing and computational modelling to try to hijack an alternative cell pathway in the hopes of restoring lung function in these patients.

If successful, our study will be the first to provide proof-of-concept that this alternative approach to treating cystic fibrosis is effective, saysAmy Wong, a scientist working in developmental and stem cell biology at SickKids who is also an assistant professor in the department of laboratory medicine and pathobiology in the University of Torontos Temerty Faculty of Medicine.

Wongs project is one of seven across U of T and its affiliated hospitals that have been awarded 2020New Ideas AwardsandSeed Fundawards from Medicine by Design. Through a $1 million investment, Medicine by Design is supporting research aimed at advancing new concepts expected to be important to regenerative medicine in the coming years. The funded projects will have potential impacts in diseases and conditions such as vision loss, amyotrophic lateral sclerosis (ALS), intestinal disease in premature babies and more.

Supporting novel strategies and approaches is crucial to moving regenerative medicine into the future, saysMichael Sefton, executive director of Medicine by Designand a University Professor at U of Ts Institute of Biomedical Engineeringand thedepartment of chemical engineering & applied chemistry in the Faculty of Applied Science & Engineering.

Our 2020 New Ideas project portfolio integrates mathematical modelling, physics and computational biology with stem cell biology and biomedical engineering, and strengthens engagement with clinicians who are key to translating our research into patient impact. We are particularly delighted this year to support so many outstanding early-career researchers, who will ensure Toronto remains a global leader in regenerative medicine for years to come.

Wong is one of three investigators to receive a 2020 New Ideas Award, which is valued at $100,000 per year for up to two years. Four additional projects were selected for Seed Fund Awards of $100,000 each for one year to further develop their potential.

Medicine by Design selected the funded projects from among 36 short-listed proposals, which were evaluated and ranked through an external peer review process. Applications were submitted by clinicians and researchers at U of T and its affiliated hospitals from a wide range of disciplines including biochemistry, biomedical engineering, developmental and stem cell biology, immunology, neuroscience and surgery.

Medicine by Design builds on decades of made-in-Canada excellence in regenerative medicine dating back to the discovery of stem cells in the early 1960s by Toronto researchers James Till and Ernest McCulloch. Regenerative medicine uses stem cells to replace diseased tissues and organs, creating therapies in which cells are the biological product. It can also mean triggering stem cells that are already present in the human body to repair damaged tissues or to modulate immune responses. Increasingly, regenerative medicine researchers are using a stem cell lens to identify critical interactions or defects that prepare the ground for disease, paving the way for new approaches to preventing disease before it starts. Medicine by Design is made possible thanks in part to a $114-million grant from theCanada First Research Excellence Fund.

Current cystic fibrosis drug treatments target a genetic mutation that causes epithelial cells, which line the airway and act as a barrier against viruses, to function improperly. The mutation affects the function of an important ion channel in cells, called CFTR, which helps to maintain the right balance of fluid in the airways. Poor function causes mucosal obstructions in the airways and prevents clearance of foreign pathogens, which leads to chronic infections and ultimately destroys airway tissue.

In her project, Wong will explore an alternative ion channel in the epithelial cells to determine if it can be hijacked and used to compensate for the lack of function caused by the mutant CFTR. The research will be conducted using a combination of stem cell-derived lung models, gene editing and computational modelling.

Wongs project builds on decades of cystic fibrosis research at SickKids, where the cystic fibrosis gene was first identified 30 years ago.

To date, more than 2,000 mutations in the cystic fibrosis gene have been identified, says Wong. SickKids scientists and U of T researchers have become the epicentre of incredible cystic fibrosis research to understand how this disease works at the genetic and molecular level.

Wong says that, while the idea of targeting an alternative pathway is not necessarily ground-breaking on its own, its the array of tools now available that makes the idea a potential game changer.

We have access to an incredible resource of primary cells and stem cells from more than 100 individuals with cystic fibrosis harbouring various mutations. Wong says.Our lab has developed human lung models from stem cells that can be used to model lung disease such as cystic fibrosis. And with new advanced tools in single-cell genomics and gene-editing, coupled with key collaborations for computational modelling, we are poised to find new therapeutic targets for cystic fibrosis.

Leo Chou, an assistant professor at the Institute of Biomedical Engineering, andHyun Kate Lee, an assistant professor in the department of biochemistry in the Temerty Faculty of Medicineboth Medicine by Design New Investigators are also leading 2020 New Ideas projects.

Chou, along with co-investigatorsJulie Lefebvre, a scientist at SickKids and U of T assistant professor of molecular genetics, andValerie Wallace, a senior scientist at the Krembil Research Institute, University Health Network and a U of T professor of laboratory medicine and pathobiology and ophthalmology, will focus on cell transplantation in the retina, a process that has demonstrated encouraging pre-clinical results such as partial vision restoration in several animal disease models.

Recent research had demonstrated that this restoration is a result of the transfer of proteins complex molecules required for the structure, function and regulation of the bodys tissues between host tissue and donor cells. But the scope of that transfer process is not well understood. Chous project will develop an imaging approach to detect the transfer of mRNA molecules between host and donor cells. The outcomes from this project will inform the future design of cell transplantation therapies and lead to novel methods to deliver therapeutics. This project could improve therapies for retinal diseases and visual impairments, and inform strategies for other degenerative disorders.

Lee and co-investigatorPenney Gilbert,an associate professor at the Institute of Biomedical Engineering, will look at a common but not well-understood structure called the neuromuscular junction (NMJ), which mediates communication between neurons and muscles throughout the body. Defects in NMJ integrity and function underlie fatal diseases such as ALS. NMJ diseases, which affect more than 500,000 people globally, lack effective treatments. This project will use stem cells derived from reprogrammed skin cells of healthy people to develop NMJs in culture. Through high-resolution imaging, the healthy human NMJs will be studied both on their own and along with NMJs built from ALS patient cells. Through this work, the research team aims to identify genes to target to improve the health of NMJs, which could eventually help prevent or delay NMJ degeneration and even promote regeneration.

Michael Garton, an assistant professor at the Institute of Biomedical Engineering, has received a Seed Fund award to tackle the challenge of translating the genetic tools of synthetic biology an area of research that aims to create or redesign biological components using engineering methods into effective medical therapies against a number of diseases.

But they are difficult to translate into human therapies, Garton says, because the bodys T-cells immune cells that detect and destroy cells containing foreign material will identify these tools as foreign and destroy them.

Instead of switching off the T-cells, Gartons goal is to use computational modelling and high-throughput screening to selectively turn off the bodys foreign antigen display system so the immune system will still respond to foreign invaders when necessary, but allow cells containing synthetic tools to survive. If successful, this approach could enable a new generation of synthetic biology-enhanced cell therapies for a range of diseases.

Medicine by Design funding will help to facilitate the integration of synthetic biology and regenerative medicine and aid the development of cell-based therapies that perform better than nature, says Garton.

Other Seed Fund projects will encompass research in repairing the heart after paediatric cardiac surgery, treating an intestinal emergency in premature babies and creating a database for cell lineage paths.

John Parkinson, a senior scientist at SickKids and a U of T professor of biochemistry and molecular genetics, along with co-investigatorsJason Maynes, Wasser Chair in Anesthesia and Pain Medicine at SickKids and a U of Tassociate professor of anesthesiology and biochemistry, andWilliam Navarre, an associate professor in the department of molecular genetics, will investigate manipulating the microbiome, or community of microorganisms in the gut, to improve cardiac repair in post-operative treatment of a congenital heart disorder. Through a process that will identify prebiotics in breast milk that help enhance the production of molecules that research has shown can aid cardiac repair, the team will organize both observational (how disease alters the microbiome) and interventional (how the microbiome alters the disease) multi-site trials, which will provide the opportunity to immediately translate findings into changes in patient care regimens and improve outcomes.

CliniciansAgostino Pierro, a surgeon at the Division of General and Thoracic Surgery at SickKids and a U of T professor of surgery and physiology, and Philip Sherman, a senior scientist and gastroenterologist at the Division of Gastroenterology, Hepatology and Nutrition at SickKids and U of T professor of dentistry, pediatrics and laboratory medicine and pathobiology, have proposed a novel way of enhancing gut repair for a common intestinal emergency in premature babies, called necrotizing enterocolitis (NEC). A leading cause of death for these infants, NEC causes complications such as blindness, intellectual disability, repeat hospitalizations and gut damage even in those that survive. This project will look at whether intestinal organoids organ-like structures grown in the laboratory from stem cells that mimic some of the functions of native intestines can potentially stimulate repair of the gut and recovery from NEC. The project will define how to best transplant organoids, identify how the organoids protect the intestine from injury and assess if organoid transplantation is a valid new treatment for NEC.

Lincoln Stein, who is head of adaptive oncology at the Ontario Institute for Cancer Research and a professor in the department of molecular genetics at U of T, has received seed funding to build a database called Cytomics Reactome, which will be freely available to Canadian and international researchers. The database will build on recent technologies that open the door to the possibility of deciphering cell lineage paths the series of steps that lead a young, undifferentiated cell into a specialized one at single-cell resolution. To accelerate the path from basic research to clinical application, the database will systematically organize pre-existing knowledge of cell lineage paths into a comprehensive, interactive and easily accessible map that can serve as a framework for interpretation and integration of the latest experimental findings.

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U of T's Medicine by Design invests $1 million to advance new ideas in regenerative medicine - News@UofT

Biochemistry

Faculty and Staff Receive Nearly $9 Million in Grants, Contracts in Q1 – CSUF News

Cal State Fullerton faculty and staff received close to $9 million in funding during the first quarter of the university's 2020-21 fiscal year. Supported projects ranged from developing a robotic aid system for blinded veterans and documenting the experiences of underrepresented women in California agriculture, to funding CSUF's GEAR UP and Upward Bound programs.

Dawn Macy, director of the Center for Internships and Community Engagement: $1,780,840 in total funding

Joshua Bilbrew,director of CSUFs GEAR UP program: $1,116,440 from the U.S. Department of Education in support of Gaining Early Awareness and Readiness for Undergraduate Programs (GEAR UP).

Diana Vasquez, director of CSUF Upward Bound: $728,821 in total from the U.S. Department of Education

David Chenot, professor of social work: $658,279 continuing award from the Health Resources and Service Administration for the Health Careers Opportunity Program.Related: Program Helps Students See the Opportunities inAllied Health Care

Sadeeka Al-Majid, professor of nursing: $650,000 in first-year funding for a $3.25 million grant from the Health Resources and Services Administration for the project "Scholarships for Disadvantaged Students/Enriching Nursing Representation to Impact Community Health."Related: $3.25 Million Grant to Increase Pipeline of Nurses in Underserved Communities

Alyssa Hernandez, director of Educational Talent Search: continuation awards totaling $605,788 from the U.S. Department of Education

Brady Heiner, associate professor of philosophy: $540,218 in total. He received $50,000 from the North Orange County Public Safety Task Force for the "Project Rebound House Initiative, CSUF Year 4" project, and $490,218 from the State of California

Related: Boundless Opportunity: Project Rebound Opens Doors for the Formerly Incarcerated

Stephanie Vaughn, professor of nursing emeritus: $494,061 continuing grant from the Health Resources and Services Administration for the project titled "EMBRACE: Enrichment Markers of Better Relationship, Academics and Cultural Enhancement."Related: EMBRACE Promotes Cultural Sensitivity, Workforce Diversity in Nursing

Nicholas Brubaker, assistant professor of mathematics, and Wylie Ahmed, assistant professor of physics: $364,582 from the National Science Foundation for the project titled "RUI: Active Noise in the Dynamics of Self-Propelled Particles Stochastic Modeling and Experiments."

Gina Passante, associate professor of physics: $347,901 from the National Science Foundation for the project titled "Collaborative Research: Connecting Spins-First Quantum Mechanics Instruction to Quantum Information Science."

Kelvin Billingsley, associate professor of chemistry and biochemistry: $319,500 in continuing funding from the National Institutes of Health for the project titled "Hyperpolarized 13C Probes for Imaging Warburg Metabolism in Cancer."

Joshua Smith, professor of physics: $254,559 in total from the National Science Foundation

Kiran George, professor of computer engineering: $199,211 from the U.S. Department of Veterans Affairs for "Design and Development of a Teach-by-Showing Paradigm-Based Robotic Aid System for Blinded Veterans."

Sara Johnson, professor of anthropology: $150,000 from the U.S. Department of Agriculture for the "U-ACRE Project: Broadening Opportunities for High Impact Service-Learning Experiences in Agroecological Research" project.Related: Lessons From the Lowly Sweet Potato: U-ACRE Researchers Unearth Knowledge and Cultivate Sustainability

Adam Roberts, assistant professor of psychology: $110,985 from the National Institute of Health for the "Mapping Neural Connectivity in Zebrafish Larvae Using a Photoconvertible Protein" project.

Yinfei Kong, associate professor of information systems and decision sciences: $98,632 continuing award as part of a four-year National Institutes of Health grant for the project "Gender Disparities in Access and Engagement In Medication-Assisted Treatment for Opioid Use Disorder" in collaboration with the University of Chicago.Related: Titan Data Scientist to Study Gender Differences inOpioid Treatment

Geoffrey Lovelace, associate professor of physics: $84,668 continuing award from the National Science Foundation for the CAREER project titled "Computational Gravitational-Wave Science and Education."

Zair Ibragimov, professor of mathematics: two awards from University Enterprises, Inc., totaling $82,500 for "CSU-LSAMP 2018-2023." The Louis Stokes Alliance for Minority Participation is a program to increase disadvantaged students' preparedness, persistence and retention in STEM programs.

Adriana Badillo, program director of the Center for Educational Partnerships: $76,621 continuation award from the City of Anaheim for the College Internship Program.

Jocelyn Read, assistant professor of physics: $67,213 from the National Science Foundation for "RUI: Dense Matter and Gravitational Waves: The Coalescence of Neutron Star Binaries."

Michael Boytim, assistant director of the nurse anesthesia program: $44,630 from the Health Resources and Services Administration for the Nurse Anesthetist Traineeships project.Related: Titans Test Use of Anesthesia Machinesas Ventilators for COVID-19 Patients

Danielle Zacherl, professor of biological sciences: $33,304 from Orange County Coastkeepers for the project titled "Newport Bay Living Shorelines Project."

Marcelo Tolmasky, professor of biological science: $24,659 from the San Diego State University Research Foundation for the San Diego-MHRT project.

Natalie Fousekis, professor of history: $24,580 from the U.S. Department of Interior, National Park Service for "Documenting the Experiences of Mexican, Filipina and Chicana Women in California Agriculture."

Jessica Jaynes, assistant professor of mathematics and Valerie Poynor, assistant professor of mathematics: $19,812 from Los Angeles City College for the "STEM Pathways Program Summer Research 2020" project.

Robert Lockie, associate professor of kinesiology: $19,071 from the National Strength and Conditioning Association Foundation for the project titled "The Effects of Structured Strength and Conditioning Programs on Motor Skills, Movement Competency and Physical Fitness of High School Athletes."

Jennifer Burnaford, professor of biological science: $16,238 continuing award from UC Santa Cruz for "Assessment of Rocky Intertidal habitats for the California Marine Protected Area Monitoring Program."

Michael Groves, assistant professor of chemistry and biochemistry: $16,005 in first-year funding of a three-year award from the American Chemical Society for the project titled "Calculating Reaction Barriers for Benzene Hydroxylation to Phenol Using Graphene Based Catalysts."

Dorothy Woolum, professor emeritus of physics: $10,000 from the California Institute of Technology for the project titled "Genesis Samples."

Do Kyeong Lee, assistant professor of kinesiology: $8,820 continuation award from New York University for the "Play and Learning Across a Year" project.

Bo Y. Park, assistant professor of public health: $8,000 from the University of Southern California for "Planning and Engaging in Advance Care for Health (PEACH)."

Contact: Karen Lindell, klindell@fullerton.edu

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Faculty and Staff Receive Nearly $9 Million in Grants, Contracts in Q1 - CSUF News

Biochemistry

UCI researcher receives NIH Transformative Research Award – UCI News

Irvine, Calif., Oct. 6, 2020 University of California, Irvine biomedical engineer Chang Liu is the recipient of one of nine Directors Transformative Research Awards this year from the National Institutes of Health under its High-Risk, High-Reward Research Program, the agency announced today.

Lius five-year, $8.4 million grant will support a project to develop a system for making antibody generation a routine and widely accessible process.

It is hard to overstate the importance of monoclonal antibodies in the life sciences, said Liu, UCI associate professor of biomedical engineering who also holds appointments in the Department of Chemistry and Department of Molecular Biology & Biochemistry. Antibodies are critical tools in biomedical research and diagnostics, and they are a growing class of therapeutics to combat cancer and pathogens up to and including the virus responsible for COVID-19.

Liu said current methods for making custom antibodies are slow, costly, inaccessible to most researchers and often unsuccessful. His NIH proposal centers on simplifying the process through continuous and rapid evolution of high-quality antibodies requiring only the simple culturing of yeast cells.

He said his autonomously evolving yeast-displayed antibodies technology could have a transformative impact across the biomedicine field by turning monoclonal antibody generation into a rapid, scalable and accessible process where any lab with standard molecular biology capabilities can generate custom antibodies on demand.

We believe this can be achieved by combining our new technology for continuous protein evolution, a yeast antigen-presenting cell that we will engineer, and cutting-edge generative machine learning algorithms for antibody library design, he said.

Liu said that in addition to the continuous directed-evolution techniques that he has invented in his UCI laboratory, the project will rely on antibody design and artificial intelligence expertise provided by his collaborators and co-PIs of the project, Andrew Kruse and Debora Marks at Harvard Medical School.

The project could potentially result in an explosion of crowdsourced antibody sequence data that will train our machine-learning algorithms to design better antibody libraries for our autonomous evolution system, starting a virtuous cycle, he said.

In addition to contributing to cancer and anti-viral therapies, Liu said he and his fellow researchers will attempt to generate nanobodies against biogenic receptors that respond to acetylcholine, adrenaline, dopamine and other neurotransmitters. The goal of this work will be to develop a better understanding of psychopharmaceuticals in neurobiology and addiction.

In the past, the Transformative Research Award has allowed some of the most ambitious and impactful ideas in biomedicine to blossom, and several previous winners are scientific heroes of mine, said Liu. We have big shoes to fill, but we are up to the challenge.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 222 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

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UCI researcher receives NIH Transformative Research Award - UCI News

Biochemistry

Growth of Electrolyte and Biochemistry Analyzers in Global IndustryOverview, Size and Share 2020-2025 – PRnews Leader

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Growth of Electrolyte and Biochemistry Analyzers in Global IndustryOverview, Size and Share 2020-2025 - PRnews Leader

Biochemistry

CCM Professor’s Research to Assist with Finding Drugs to Combat Coronavirus Providing Maps of Virus Proteins for the World’s Scientific Community -…

RANDOLPH, NJ Professor Brian Olson, of the Department of Biology and Chemistry at County College of Morris (CCM), recently had his research on coronavirus targets published in the peer-reviewed Journal of Computer-Aided Molecular Design to assist with the development of drugs to combat the virus.

Olson, the lead author on the paper, worked with Dr. Tom Kurtzman of Lehman College to put together a team of researchers this past March when he realized how extensive the COVID-19 pandemic would become. In the paper,An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets, the researchers provide maps of water moleculeson the virus proteins that also are known as solvation maps. Olson explains that knowing which water molecules need to be displaced, and which do not, provides essential information to guide the development of drugs to treat COVID-19. The first step toward determining that is mapping where the water molecules are located on the proteins.

In March, Olson, who had been tracking the coronavirus on several databases, was certain COVID-19 would turn into a pandemic.

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We were seeing clusters on multiple continents and were unable to trace the sources of infection. It was clear this was going to be an immediate and international public health issue, he says. That compelled me to do something.

Utilizing the computational tool, GIST, developed by Kurtzman, the researchers worked from their homes during the pandemic. Prior to being published in the Journal of Computer-Aided Molecular Design, the research was posted by the team on Chemrxiv so it could be accessed early while the peer-review process was taking place.

Now that solvation maps of the COVID-19 virus are available, Olson and his team plan to use that information to search for new drugs. Making the information public and free also will aid others in their search for new and effective pharmaceuticals to defeat the coronavirus. According to Altmetrics Attention Score, which measures the online attention and activity of research papers, the work conducted by the Olson team ranks in the top 25 percent. Given that ranking, based on more than 2,200 views and over 300 downloads of the paper, Olson is encouraged about the development of drugs to fight the coronavirus.

I have never seen the international scientific community come together the way it has now to find some answers, says Olson. There is international collaboration and the sharing of information that previously would not have been shared.

Olson, who teaches forensic science at CCM, joined the colleges faculty in 2018. At CCM, he and several other professors, developed the colleges first virtual reality class to teach students forensic science skills by analyzing murder scenes. Along with his work on the coronavirus, he is researching the development of pain killers to replace opiates.

Olson earned his associate degree in science from the Borough of Manhattan Community College, his bachelors in biochemistry from Hunter College, his masters in biochemistry from the City University of New York (CUNY) Graduate Center, and is working on his doctorate in biochemistry from CUNY Graduate Center.

He is a strong advocate for community colleges, and CCM in particular. Community colleges place a high value on quality teaching, he says. I am so fortunate. I have fun researching tiny molecules and on top of that I get paid to talk to students about narcotics, murders and other fascinating topics. I cant imagine having a better job.

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CCM Professor's Research to Assist with Finding Drugs to Combat Coronavirus Providing Maps of Virus Proteins for the World's Scientific Community -...

Biochemistry

Scientists zoom in on HIV inside a test tube, find critical steps in infection – Live Science

Scientists have finally recreated the initial steps of HIV infection in a test tube, offering an incredibly zoomed-in view of the virus in action.

The amazing images show a cone-shaped shell of geometric tiles, called the capsid, that sits at the virus's center and contains its genetic material, known as RNA. Before infiltrating a cell, the capsid is surrounded by an envelope of fatty molecules; this envelope fuses to the host cell to let the capsid inside, where it then carries the RNA to the cell's nucleus. On the way, the RNA replicates, and once inside the nucleus, it invades the host's DNA.

By granting a closer look at this replication process, the new study highlights that the capsid itself plays a critical role in infection and that specific criteria must be met for the virus to interweave its genome with the host cell's.

Knowing how to recreate the initial steps of HIV infection "means we have many more tools for dissecting the process of replication," said study author Wesley Sundquist, a distinguished professor of biochemistry at University of Utah Health. In particular, the study, published Oct. 8 in the journal Science, describes a cell-free system that can be used to study how HIV invades the host genome such a system could "revolutionize HIV experiments in many labs," Leo James, a group leader at the MRC Laboratory of Molecular Biology, who was not involved in the study, told Live Science in an email.

"To have accomplished all this is a real tour de force," James said. Beyond basic research, the system could also help explain how experimental drugs that target the capsid work to limit HIV replication, Sundquist said in a statement.

Related: 12 amazing images in medicine

Although the test tube experiments capture aspects of HIV infection in superb detail, they cannot recreate every step in the process, Sundquist noted. Infection typically starts when the outer membrane of the virus fuses with the membrane of a host cell, allowing the capsid and its innards to sneak inside. But with a cell-free system, the authors had to bypass this initial step.

They instead used a compound found in bee venom, called melittin, to "permeabilize" the viral membrane and release the capsid held within.

The HIV capsid has tiny pores in it, and normally, as a virus particle floats through a human cell's cytoplasm, it picks up the cellular building blocks of DNA, called deoxynucleotide triphosphates, that are already there, according to a 2017 report in the journal Nature. As it travels to the nucleus, the virus particle uses those building blocks to make copies of full strands of DNA, thanks to a special enzyme housed inside the capsid. This is how the virus copies its genetic material to later insert into the host genome. How the virus "knows" when to start this so-called reverse transcription is still somewhat mysterious, but studies hint that biochemical properties of the host cell act as cues for the reaction to begin.

But a test tube doesn't automatically have DNA building blocks in solution, so to jumpstart reverse transcription, the authors added them. "This method has been around for a while, but it's tricky to get the reaction to go until completion," James noted. But the study authors managed to get reverse transcription running smoothly; to do so, they learned that the capsid must stay mostly intact throughout the process.

Related: Going viral: 6 new findings about viruses

"The capsid has to be largely intact, and it has to be of the proper stability or flexibility, to support reverse transcription," meaning the capsid must be bound tightly enough to not fall apart during reverse transcription, but able to open up when the capsid enters the nucleus, in order to unleash its copied DNA, Sundquist said. Fortunately, scientists recently discovered a way to keep the capsid just stable enough.

Study author Owen Pornillos, an associate professor of molecular physiology and biological physics at the University of Virginia, and his colleagues found that a compound called IP6 binds to the capsid's tiled surface, they reported in 2018 in the journal Nature. IP6 carries a negative charge, while each tile carries a positive charge on the side that points in toward the center of the capsid; since opposites attract, when IP6 binds to the capsid, it helps pull the tiles into a tighter, more stable arrangement.

"Before the discovery of IP6, someone would remove the [viral] envelope in vitro and everything would fall apart and they could not see anything," said Joo Mamede, an assistant professor in the Department of Microbial Pathogens and Immunity at Rush University, who was not involved in the study.

IP6 is "quite abundant" in cells, so in their test tube experiments, the authors added similar concentrations of the compound as would be found in cells, Sundquist said. "That was really the trick," he added. "Until we knew it, we were working with capsids that were far too unstable."

Using computer models of molecules and an electron microscope, the authors could literally see that the 240 tiles making up the capsid held their lattice-like structure stable throughout reverse transcription. As the DNA strands grew larger, their ends sometimes poked through tiny gaps in the lattice weave, the authors noted, and sometimes singular tiles could be seen dislodging while the rest of the capsid stayed intact.

The capsid may need to stay stable to keep the RNA and transcribing enzyme close to each other, said Christopher Aiken, a professor of pathology, microbiology and immunology at Vanderbilt University, who was not involved in the study. The enzyme tends to fall off the RNA during transcription, so "by keeping the enzyme contained, it can rebind the template and continue DNA synthesis," Aiken told Live Science in an email.

With reverse transcription complete, the authors then moved on to the next step in infection: integration, where the viral DNA infiltrates the host genome. They introduced DNA strands known as plasmids into their test tubes, to serve as proxies for the DNA in a human nucleus, but integration would not begin without an additional ingredient. Only "whole cell extracts," a mix of proteins and molecules drawn from cells, would allow the viral DNA to pervade the plasmids.

In the future, the team hopes to pinpoint precisely which ingredients in the cell extracts trigger integration, Sundquist said. "It's likely to be more than one thing," he noted. One challenge is that, in test tube experiments, "it's always difficult to know if you're missing something," he said.

Related: The 12 deadliest viruses on Earth

One limitation of the study is that it can't perfectly recreate cellular conditions, James said.

"Any in vitro system, however powerful, can only be used to test the components we know about and can add into the reaction," James said. For instance, in actual cells, the capsid must travel to the cell nucleus, where the DNA is held, and then slip through portals known as the nuclear pores. There may be unknown factors that alter the capsid during this journey, Sundquist noted.

That said, the new cell-free system could help reveal the identity of those unknown factors, Mamede added. Scientists can now make observations in a cell-free environment and then check to see if the same behavior appears in actual cells, he said.

In addition, the system could be useful in drug development. "You can test [new drugs] more readily with one of these simplified systems than with a cell," Mamede told Live Science. "This way, you can see mechanistically what it's really doing to the virus."

The pharmaceutical company Gilead Sciences currently has a new drug in human trials that targets the HIV capsid specifically, according to ClinicalTrials.gov. Based on early data, the drug appears to alter the capsid at various points of infection, including during reverse transcription. Sundquist said that the cell-free study underscores that the capsid is a "critical component" of HIV infection, and that corrupting the capsid can limit the virus's ability to multiply.

Originally published on Live Science.

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Scientists zoom in on HIV inside a test tube, find critical steps in infection - Live Science

Biochemistry

Scientists recreate initial steps of HIV infection in a test tube – News-Medical.Net

Reviewed by Emily Henderson, B.Sc.Oct 9 2020

Accomplishing a feat that had been a pipe dream for decades, scientists have recreated in a test tube the first steps of infection by HIV (human immunodeficiency virus), the virus that causes AIDS (acquired immunodeficiency syndrome).

Doing so has provided up-close access to the virus-;which is otherwise obstructed from view deep within the cell-;and enabled identification of essential components that HIV needs to replicate within its human host.

Specifically, the scientists were able to monitor the virus as it replicated its genome and inserted it into target DNA, mirroring steps that ordinarily take place within the host. Published in Science on October 9, these advances yield a new understanding of how HIV works, the authors say, allowing for explorations of early stages of the virus life cycle in unprecedented detail.

Such knowledge could lead to improved treatments for AIDS, a lifelong disease that can only be kept under control with a continuous medication regimen.

"This is teaching us how HIV infects," says Wesley I. Sundquist, Ph.D., distinguished professor of biochemistry at University of Utah Health. He is co-senior author of the study with his former trainee, Owen Pornillos, Ph.D., now an associate professor at the University of Virginia.

The co-first authors are Devin Christensen, Ph.D., and Barbie Ganser-Pornillos, Ph.D. "We are learning new things about one of the most significant pathogens that humans have ever encountered, and that is important."

For all its danger, HIV is deceptively simple in appearance. The virus resembles a rounded ice cream cone, where an outer shell encapsulates the virus' genetic material inside. Previously, it had been thought that the main role of the shell, called the capsid, was to protect its precious cargo. But the investigations by Sundquist and Pornillos' team show that the capsid also plays an active role in infection.

Carrying out initial steps of infection in a test tube allowed the research team to precisely manipulate HIV in ways that had not been possible before.

They found that when they used genetic and biochemical methods to destabilize the capsid, HIV could not effectively replicate its genetic material. It was the first direct demonstration that, rather than serving merely as packaging, the capsid is an essential component of the HIV infection process itself.

If seeing is believing, then watching the HIV molecule in action gave credence to the experimental finding. Recent advances in cryo-electron microscopy and molecular modeling have made it possible to see the virus-;which, at 130nm, is about 60 times smaller than a red blood cell-;in exquisite detail.

Using these techniques, the team visualized each of the 240 tiny protein "tiles" that fit together to make the cone-shaped outer shell. With the up-close view, the scientists could literally see that the capsid remained largely intact throughout the replication process, called reverse transcription.

This is different than in the textbooks. Our data indicate that the viral capsid plays an active and indispensable role in supporting efficient reverse transcription."

Wesley I. Sundquist, Ph.D., Distinguished Professor Department of Biochemistry, University of Utah Health

Sundquist says that the discovery may help explain why an investigative HIV drug developed by Gilead, the first to target the capsid, is a potent inhibitor of the virus. Previous work by Sundquist, Pornillos, and others elucidating the structure and function of the HIV capsid informed the design of the drug, which has performed well in phase 1 clinical trials. Additional insights gained through the test tube system could improve drug design even further.

Advances in microscope technology, coupled with dogged persistence, led to the new view of HIV, which was first discovered as the cause of AIDS more than 35 years ago.

It took years of trial and error to determine the minimum components required for recapitulating the process in a test tube, outside the cell. Now that the simplified system is up and running, Pornillos says, it opens doors to learning more fundamental truths about a familiar foe.

"For me, there is both the fundamental knowledge aspect of it, but also the translational aspect that could help us come up with better ways to stop HIV," Pornillos says. "That's why it's great research."

Source:

Journal reference:

Christensen, D. E., et al. (2020) Reconstitution and visualization of HIV-1 capsiddependent replication and integration in vitro. Science. doi.org/10.1126/science.abc8420

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Scientists recreate initial steps of HIV infection in a test tube - News-Medical.Net

Biochemistry

Take-home labs and virtual dissections: How the science courses are adjusting – The Scout

Labs have gone hybrid as classes are in person or remote. Photo by Morgan Patrick.

One of the biggest shifts as college and the COVID-19 pandemic collided may have been in the sciences, where a hands-on curriculum plays a big role in student academics.

This past summer, a team of about 40 professors from all departments across campus had meetings to discuss virtual learning and to determine how much face-to-face interaction would be necessary.

In biology, all the labs were kept in-person except for the anatomy labs and major level genetics labs. These labs involve dissections, which could prove difficult to continue if the university decided to shut down all in-person classes. Hence, professors deemed it best to keep these labs virtual instead of shifting back and forth, given the uncertain possibilities.

We discovered very quickly that the virtual dissections that are now available are of high quality and were not even available five years ago, said Kelly McConnaughay, biology professor and acting dean of the College of Liberal Arts and Sciences.

Students have responded positively to these online labs.

My lab professor gives us an informative walk through the experiment outlines as we identify the three-dimensional structures of proteins, genetic mutations, etc., said Dainaly Campuzeno, a senior biomedical science and psychology major. Its been a pretty good experience so far, but it definitely does not beat hands-on experience.

Some other labs, like the Science 101 series, provided remote learners with kits to work on experiments from the comfort of their own homes while being challenged to come up with hypotheses and discover ways to either accept or reject them.

In our department, we have never given students cookbook labs, like Mix this with this and pour this, then write this number down, said Sherri Morris, chair and professor of biology and co-director of Bradleys Center of STEM Education. We encourage them to make observations and challenge themselves to have a certain level of engagement.

In the biochemistry department, all senior-level students are taking their labs in-person due to smaller class numbers and lack of remote learners.

The associate professor and chair of the chemistry and biochemistry department, Michelle Fry, said that students who had to quarantine could even make up missed labs after the quarantine period.

The psychology department is offering the behavioral neuroscience lab this semester, both virtually and in-person. The lab includes the dissection of sheep brains. Students learn about the biological basis of behaviors in animals by locating important structures in the brain that are responsible for daily functions. The lab is offered in-person and virtually.Even though our intent this summer was to be face-to-face during the fall, I dont think we fully grasped the challenges that came with it, like wearing masks and classroom sizes, said Timothy Koeltzow, associate professor and chair of the psychology department.

For virtual learners, a document camera is used to show the dissections while students in the classroom do the brain dissecting themselves in the labs.

There are other internship opportunities through community partnerships offered this semester in the psychology department, which were impacted by the pandemic. Most of the training for those partnerships had to be moved online to reduce contact, as much as possible.

Something good about all of this is that we will be on the other end of this pandemic with a capability to deliver every course in our portfolio online, under the right circumstances, Koeltzow said. This gives us options to engage non-traditional learners or people who almost finished their degree but could not do so, due to other circumstances.

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Take-home labs and virtual dissections: How the science courses are adjusting - The Scout

Biochemistry

Walther Cancer Foundation $11 million investment to expand IU-Purdue bioinformatics collaboration – Purdue News Service

October 8, 2020

Nadia Lanman, a research assistant professor in Purdue College of Veterinary Medicine's Department of Comparative Pathobiology and member of the Purdue Center for Cancer Research, plays a key role in the computational bioinformatics program at Purdue University that is supported by the Walther Cancer Foundation. Through computational bioinformatics, Lanman attempts to discover the molecular mechanisms that underlie cancer and that determine the response of patients to chemotherapy. (Photo provided)Download Photo

INDIANAPOLIS AND WEST LAFAYETTE, Ind. - The Walther Cancer Foundation will invest $11 million to advance collaborative cancer research at Indiana University and Purdue University by supporting scientists through bioinformatics an increasingly critical aspect of their work.

Bioinformatics involves managing and analyzing the massive amounts of data generated by scientific research turning data into knowledge that could lead to new cancer treatments.

We hope this gift enables scientists at IU and Purdue to dig more deeply and refine their studies so they can point out new pathways to good patient outcomes in cancer, said Tom Grein, president and CEO of the Walther Cancer Foundation. Sometimes you have so much data, its hard to comprehend where its leading you. I hope the data-driven analysis will uncover nuggets of opportunity that would otherwise never be seen.

Income from the new Walther Cancer Foundation Bioinformatics Fund will continuously support bioinformatics personnel, technology, and other tools shared by the cancer research programs at both universities. In addition, IU and Purdue will make their own investments into the fund.

The Walther Cancer Foundation leadership understands the central importance of data and analytics in developing better treatments and, ultimately, cures for cancer, said IU School of Medicine Dean Jay L. Hess, MD, PhD, MPH.We are tremendously grateful for their support and the confidence they have in our work.

Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research, said the latest gift from the Walther Foundation is a continuation of a longstanding collaboration, commitment and investment that will build on the centers success in cancer drug discovery and development and will help sustain the centers computational genomics and bioinformatics core for years to come. "Once again, we are grateful to the Walther Cancer Foundations vision and generosity, which is so important to our research and success. This continuing partnership, plus our own investments and fundraising, will secure what weve already established and enable us to grow into the future."

Kelvin Lee, M.D., named this week as the new director of the IU Melvin and Bren Simon Comprehensive Cancer Center and the H.H. Gregg Professor of Oncology, said having strong capabilities in bioinformatics is essential to cancer research.

The genetic, biochemical, cellular and immune pathways that can lead to cancer are extraordinarily complex and intertwined. Recent cutting-edge advances in technology means that researchers now have unprecedented amounts of data on these pathways, but this seriously challenges our ability to analyze these huge mounds of information to make sense of what is actually going on, Lee said. We are fortunate that the Walther Cancer Foundation understands that breakthroughs require the expertise and the tools, like artificial intelligence, to help us analyze all this data so we can understand whats really important.

This level of collaboration and sharing of a key resource like a bioinformatics core is unusual among a pair of National Cancer Institute-designated cancer centers. But it also reflects the complementary nature of the two institutions.

Purdues Center for Cancer Research is a basic science cancer research center with more than 110 researchers that is a leader in biomedical engineering and cancer drug development.

The IU Melvin and Bren Simon Comprehensive Cancer Center is a comprehensive cancer center with nearly 250 cancer researchers who conduct basic lab work and drug development but who are also engaged in clinical care and population health research.

Each of them has different capabilities, different levels of expertise, different interests, Grein said. But when you get scientists to collaborate, the outcomes are better.

Since its founding in 1985, the Walther Cancer Foundation has invested more than $165 million in cancer-focused medical research and in research and education aimed at supporting cancer patients and their families.

Walther has previously supported cancer bioinformatics at IU and Purdue on a year-to-year basis. This new gift establishes a fund that will ensure the bioinformatics work continues in perpetuity.

The Walther Foundation endowment provides the opportunity to develop the expertise and the tools that are needed to face current and future challenges in biology and the cancer field, said Majid Kazemian, an assistant professor in Purdues departments of Biochemistry and Computer Science. His research focuses on integrating computational and experimental approaches to study pathogen interaction with host cells and immune system in infectious diseases and cancers caused by pathogens.

"The Purdue University Center for Cancer Research has nearly 100 investigators who are actively engaged in understanding molecular mechanisms of various diseases including lung, liver and prostate cancers, many of which have begun to utilize genomics data in their studies, Kazemian said. "Large genomic public data on many diseases generated over the last decade are a treasure trove of unexplored information. Walther Foundation's funds endowment will enable analysis of big data generated by our centers members and collaborators as well as an exploration of growing public genomics data to contextualize and translate our findings."

Less-costly access to bioinformatics expertise and resources enabled by Walther Foundation will open up

Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for Cancer Research, works in a lab at the center. (Purdue University photo/John Underwood)Download Photo

new avenues for many of the Purdue center's scientists to broaden the impact and clinical translation of their discoveries, Kazemian said. "It will also encourage our scientists to perform large-scale genomics assays and will foster new collaborations.

Harikrishna Nakshatri, Ph.D., the Marian J. Morrison Professor of Breast Cancer Research at IU School of Medicine, said he relies on bioinformaticians to design experiments, analyze data and assist him in publishing research results more quickly. The Walther Foundation gift supports that very expensive process, and the collaboration means researchers have more bioinformaticians available when they are needed. All of it combines, Nakshatri said, to enable scientists to reach conclusions that have real benefits for patients.

If you really believe in your hypothesis, Nakshatri said, now you have a chance to test it because you are not burdened by the financial aspects.

According to Hess, the new resources will allow IUs partnership with Purdue to continue to improve the health of Hoosiers. We have worked closely for decades, Hess said. This new collaboration in data sciences will accelerate our ability to benefit cancer patients across the state and far beyond.

About the Walther Cancer Foundation

The Indianapolis-based Walther Cancer Foundation is a private grant-making foundation that supports and promotes interdisciplinary and inter-institutional cancer research, both bench and clinical. The clinical research it supports encompasses clinical trials as well as behavioral studies, the latter as part of the foundations commitment to Supportive Oncology. The Walther Foundation has two primary goals: to support cancer research with the aim of discovering better treatments, if not cures, and to develop a comprehensive approach for supporting patients with cancer and their families. Since its founding, the foundation has invested over $165 million cancer-focused research.

Dr. Kelvin Lee, director of the IU Melvin and Bren Simon Comprehensive Cancer Center (Photo provided) Download Photo

About the Purdue Center for Cancer Research

Since 1978, the Purdue University Center for Cancer Research has been a National Cancer Institute-designated basic-research cancer center. Only seven institutions in the United States have earned this title. Being a basic-research center means it does not treat cancer patients directly. Its work focuses on investigating cancers where they begin at the cellular level to investigate the cause of, and cure for, one of the most devastating killers of our time. Doctors and scientists throughout the world use the centers discoveries to develop methods, medicines and medical devices to save and enhance patient lives.

About the IU Simon Comprehensive Cancer Center

The Indiana University Melvin and Bren Simon Comprehensive Cancer Center is home to the cure of testicular cancer, the worlds only healthy breast tissue bank and is just one of 51 NCI-designated Comprehensive Cancer Centers in the nation. The prestigious comprehensive designation recognizes the centers excellence in basic, clinical, and population research, outstanding educational activities, and effective community outreach program across the state. Its physician-scientists have made protocol-defining discoveries that have changed the way doctors treat numerous forms of cancer.

Media contacts: Jim Bush, 765-336-1909, jsbush@purdue.edu

Katie Duffey, 317-278-3630, kaduffey@iu.edu

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Biochemistry

Nitrous oxide, more harmful to the climate than CO2, increasing in atmosphere, study finds – CBC.ca

A new study published in the journal Nature suggests that nitrous oxide a gas that is 300 times more harmful to the climate than carbon dioxide is steadily increasing in the atmosphere.

While nitrous oxide is produced in different ways, the study found the largest contributor is agriculture,where it is produced as a by-product of nitrogen, largely used in agriculture as a fertilizer.

The atmosphere's nitrous oxide had 270 parts per billion in 1750, according to the study, and had risen to 331 parts per billion in 2018. The fastest rise was in the last five decades.

The international team of authors say that, on the current trajectory, the additional nitrous oxide could push the global temperature to 3 C above the pre-industrial average by 2100, which is far past the target of 1.5 C or 2 C laid out by the Intergovernmental Panel on Climate Change (IPCC).

"Currently, the emissions are on the path to cause a global temperature increase above three degrees by the end of this century," said Hanqin Tian, co-lead author of the study and director of the International Center for Climate and Global Change Research at Auburn University's School of Forestry and Wildlife Sciences in Alabama.

"It highlights the urgency and it's critically important to think about this."

When it comes to climate change, three main greenhousegases are of particular concern: carbon dioxide (CO2), methane and nitrous oxide (N2O).

While most of the focus has been on CO2, there's beenrising concern about methane and N2O.

But nitrous oxide has largely been underestimated, according toanother of the study's authors.

"I don't think many people know about nitrous oxide, I would say, in terms of the magnitude of the emissions," said Parvadha Suntharalingamof the University of East Anglia's School of Environmental Sciences.

"On a sort of per molecule basis, oxide is more than 300 times as strong as a molecule of CO2 in terms of its global warming potential. So even though the magnitude of the emissions is less, the potency of the gas is much stronger. A little of it goes a long way."

"What's also been surprising is that we found that the emissions of nitrous oxide have been rising pretty sharply and much more sharply than [what was] predicted really in some of these emission scenarios developed for the IPCC."

The study found that agriculture was responsible for almost 70 per cent of the global human-causedN2O between 2007-16 with most coming from East Asia, Europe, South Asia and North America. But the highest growth rates were found in emerging economies like Brazil, India and China.

The authors suggest that with better farming practices, however, decreases could be significant, thus curbing the climb in N2O emissions.

What On Earth27:00Is regenerative farming hope for a hotter planet?

For example, they note Europe has seen a decline in N2O emissions due to the introduction of emissions trading and because of many countries moving to a more efficient use of fertilizer. The chemical industry also helped by reducing emissions.

Illimar Altosaar, a professor in the department of biochemistry, microbiology and immunology at the University of Ottawa who was not involved in the study, says it's a good study, but more needs to be investigated as to the role oceans play in emissions of N2O.

"The ocean is the key," he said. "We don't know the biochemistry [of the oceans]and it's the phytoplanktonand the blue green algae that are doing a lot of this gas exchange."

Suntharalingamsays another consideration that is still not well-known is how climate feedback affects N2O emissions such as increased precipitation caused by climate change affects moisture content in the soil, whichcan affect how much N2Ois generated.

The authors stress the importance of agriculture and believe that it just needs to change in some countries.

"You need fertilizer. You need the food industry, and you can't get away from the application of fertilizer," Suntharalingam said. "I think a takeaway is that managed fertilizer application can be very successful in reducing emissions and that Europe managed to reduce emissions but not depress food production.

"You just need to make sure that how much you apply when you apply it and how you apply it is carefully managed, and you can maintain crop yields, but you can definitely reduce the emissions from the soils. Managed fertilizer application is a very important mitigation strategy."

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