Study reveals how thiamine affects the gut microbe, B. thetaiotaomicron
The study identified the diverse strategies employed by Bacteroidetes, a widespread and important group of microbes that also inhabit the human gut, to acquire thiamine. All microbes require thiamine, and Bacteroidetes can make their own, take it in from the environment or both. Experiments by Zachary Costliow, a graduate student in the laboratory of microbiology professor Patrick Degnan, revealed that both thiamine biosynthesis and transport are crucial for the surivial of B. thetaiotaomicron in a competitive environment.
Humans require thiamine as well. “Thiamine, or Vitamin B1, is found in whole grains, meat, and fish, and is essential for metabolizing carbohydrates and maintaining the health of the central nervous system,” Costliow said. “Thiamine deficiencies can lead to serious problems with vision, stability, and memory, among other effects.”
In addition to dietary sources, there is evidence that thiamine availability is modulated by or acquired from the dense and diverse microbial communities present in the gastrointestinal tract. As such, the new study contributes to understanding how microbial mechanisms influence the availability of this essential vitamin, the researchers said.
Degnan, the principal investigator on the research, said that diseases such as diabetes, Alzheimer’s, obesity, and even cancer are associated with radical changes in the composition of the gut’s microbes.
“Thiamine influences how the gut’s microbial community is structured, and that means thiamine may be an excellent target for developing treatments for these diseases,” he said.
The Degnan lab’s research is funded by an investigator award from the Roy J. Carver Charitable Trust to PHD (#15-4501), and School of MCB at the University of Illinois at Urbana-Champaign.
Dr. Thomas Kehl-Fie Named 2017 Vallee Scholar
The Vallee Scholars Program recognizes outstanding early career scientists at a critical juncture in their careers. It provides $250,000 in discretionary funds for basic biomedical research. Candidates are competitively selected based on their originality, innovation, and quality of the proposal, in addition to their record of accomplishment.
Using an interdisciplinary approach, which combines microbiological and biochemical approaches with advanced elemental analysis, the Kehl-Fie group is working to understand how pathogens maximize their ability to compete with the host for essential nutrients and elucidate the adaptations that enable bacteria to grow even when nutritional immunity prevents them from satiating their appetite.
Due to the continued emergence and spread of antibiotic resistance, more than 10 million people per year are expected to die worldwide from infectious diseases exceeding the number of people who die from cancer by 2050. Elucidating how bacteria overcome the host’s defenses has the potential to identify new opportunities for therapeutic intervention and blunt the growing threat of infection.
Dr. Kehl-Fie is an assistant professor of microbiology in the School of Molecular and Cellular Biology. He is also an affiliate member of the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign.
The Vallee Foundation was established by Bert L and N Kuggie Vallee as their legacy to the advancement of medical science and medical education. The Foundation stimulates development of interdisciplinary sciences related to human health by promoting interaction between productive scientists worldwide.
Posted September 13, 2017
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Glial cell line-derived neurotrophic factor signaling inhibits development of the prostate gland
Molecular and Integrative Physiology Assistant Professor Eric Bolton. Immunohistochemistry for KRT5, a basal epithelial antigen, and KRT8, a luminal epithelial antigen, shows that luminal epithelial cells are absent from prostate epithelial (PrE) buds of Ret WT urogenital sinuses co-treated with androgen and GDNF compared to those treated with androgen alone. In contrast, luminal epithelial cells are present at PrE buds in DHT-induced Ret KO urogenital sinuses regardless of GDNF exposure. Adapted from Park and Bolton (Development 2017).
The prostate gland is formed from the embryonic urogenital sinus, where the urethra joins the bladder. The androgen receptor (AR) is required for prostate development, and AR signaling acts in concert with other signaling pathways to orchestrate the proliferation and differentiation of mesenchymal and epithelial cells of the developing prostate. Importantly, the disruption of AR-mediated prostate development predisposes humans and rodents to prostate neoplasia by altering the gland’s phenotype early in life.
The study by Park and Bolton demonstrates that RET-mediated GDNF signaling in the mouse urogenital sinus increases proliferation of mesenchymal cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, thereby inhibiting prostate development. The study also establishes novel reciprocal regulatory crosstalk between AR and GDNF signaling in the cellular and molecular mechanism of androgen-induced prostate development. The researchers propose that the reciprocal regulatory crosstalk may serve to balance GDNF-induced proliferation of mesenchymal cells with androgen-induced proliferation and differentiation of prostate epithelial cells, which are mediated by AR signaling in mesenchymal cells. Thus, if the GDNF signaling pathway is not downregulated early in prostate development, elevated levels of GDNF signaling may lead to disruption of AR-mediated prostate development and increased risk for prostate neoplasia.
The National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health and the Campus Research Board at the University of Illinois funded this research.
Professor Satish Nair, postdoctoral researcher, Shi-Hui Dong, and colleagues find that slowing dangerous bacteria may be more effective than killing them
Researchers at the University of Illinois have discovered a mechanism that allows bacteria of the same species to communicate when their survival is threatened. The study suggests that it may be possible to slow dangerous infections by manipulating the messages these microbes send to each other, allowing the body to defeat an infection without causing the bacteria to develop resistance to the treatment.
The study, reported in the Proceedings of the National Academy of Sciences, builds on work conducted by other researchers at Illinois, including biochemist John Woodland Hastings, who died in 2014, and John Cronan, a professor and the head of the department of microbiology.
“Bacteria are intelligent little organisms. They can survive almost anywhere and quickly adapt to new conditions,” said U. of I. biochemistry professor Satish Nair, a co-author of the study with postdoctoral researcher Shi-Hui Dong and other colleagues.
When bacteria compete with other microbes for scarce resources, the more successful group will produce a unique molecule – an antibiotic – to kill off the other species. When population growth of one group of bacteria outpaces availability of the nutrients it needs to survive, the group produces another unique molecule that tells it to go into a dormant, but more virulent, state and slow growth until more food is available, Nair said.
“Ever since Alexander Fleming discovered penicillin in 1928, we have been using antibiotic molecules developed by one microorganism to kill another microorganism,” Nair said. “Unfortunately, the bacteria have quickly adapted to resist antibiotics, and in a short time, antibiotics will be ineffective.
“On average, nearly every species of bacteria is resistant to at least one antibiotic. Two years ago, researchers in Europe and Asia discovered a so-called superbug that is resistant to all known antibiotics,” Nair said. “Bacteria can share adaptations very easily, and there are so many bacteria with different adaptations to share, which is why they can develop resistance so quickly.”
“Broad-spectrum antibiotics and the overuse of antibiotics are problematic because antibiotics kill off many types of bacteria, even good ones, and the survivors figure out ways to adapt, sharing their strategies with other bacteria,” Dong said.
“No pharmaceutical company is going to invest in 10 years’ worth of research and development if a new antibiotic has a shelf-life of only two years,” Nair said. “It’s not enough time to recover the costs of production.”
Nair and Dong’s new study targets the language, or group signal, that bacteria use to slow down growth rather than the antibiotic signal to kill. The researchers say understanding how bacteria produce the dormancy-signal molecule paves the way for developing molecules that can disrupt the communication of specific bacteria, with little chance for drug resistance to develop.
“We don’t need to kill bacteria to treat disease and infection; we can just slow them down and make them less potent,” Nair said. “That way, there is little chance for any resistance to develop.”
Nair is an affiliate of the Carl R. Woese Institute for Genomic Biology at Illinois. Research in the Nair lab is funded by the National Institutes of Health.
Auinash Kalsotra Awarded MDA Grant for Studying Myotonic Dystrophy
Assistant professor of biochemistry, Auinash Kalsotra, has been awarded a nationally competitive research award from Muscular Dystrophy Association (MDA). Created in 1950, the MDA is the country’s largest private funder of research pursuing cures and treatments for over 40 neuromuscular diseases, including muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and Friedreich’s ataxia (FA). The grant to Prof. Kalsotra provides $300,000 over a three-year period to study the molecular basis for cardiac arrhythmias in Myotonic Dystrophy, a multi-systemic disease that affects about 1 in 8000 people with no cure.
“Myotonic dystrophy type I (DM1) is caused by an unusual mutation in which a small DNA segment of the mutated gene is repeated hundreds of times”, said Kalsotra. “The mutated gene, when copied into RNA, becomes toxic and particularly harmful because instead of its normal exit to the cytoplasm, the RNA with repeats gets trapped within the nucleus, which alters the normal function of many genes, not just the gene with the mutation,” he explained.
While the mutation affects multiple tissues, cardiac defects – particularly arrhythmias – are the second leading cause of death amongst DM1 individuals; however, the underlying mechanism(s) responsible remain poorly understood. The Kalsotra laboratory is investigating the disrupted function of a previously unknown RNA binding protein in DM1 cardiac pathogenesis. The team will be using novel CRISPR based mouse models, in vitro cell culture systems, and next-generation sequencing approaches to decipher the exact role of this RNA binding protein in promoting cardiac arrhythmias in DM1.
The mission of the MDA is to build the field of neuromuscular disease research, while simultaneously nurturing clinical care to significantly improve both quality and length of lives for those affected by neuromuscular diseases. MDA annually invests over $40 million on research projects. All grant applications go through a rigorous peer-review process by MDA’s Medical and Scientific Advisory Committees, composed of world-renowned experts in neuromuscular diseases. Each year, about 500 researchers apply to MDA for funding; only the top 10-15% of proposals typically receive support. This puts Prof. Kalsotra in an elite club of neuromuscular disease researchers around the globe who, for more than 60 years, have brought hope to countless individuals.
“The value of MDA research funding cannot be underestimated in making this line of investigation possible in my laboratory. The support of MDA allows us to generate exciting new tools for research and study previously unrecognized pathogenic mechanisms for this debilitating disease, ” said Kalsotra. Prof. Kalsotra holds appointments in the School of Molecular and Cellular Biology and Carl. R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign.
Posted August 03, 2017
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Study: Omega-3 Fatty Acids Fight Inflammation via Cannabinoids
Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its euphoric effects, but it also has anti-inflammatory benefits. A new study in animal tissue reveals the cascade of chemical reactions that convert omega-3 fatty acids into cannabinoids that have anti-inflammatory benefits – but without the psychotropic high.
The findings are published in the Proceedings of the National Academy of Sciences.
Foods such as meat, eggs, fish and nuts contain omega-3 and omega-6 fatty acids, which the body converts into endocannabinoids – cannabinoids that the body produces naturally, said Aditi Das, a University of Illinois professor of comparative biosciences and biochemistry, who led the study. Cannabinoids in marijuana and endocannabinoids produced in the body can support the body’s immune system and therefore are attractive targets for the development of anti-inflammatory therapeutics, she said.
In 1964, the Israeli chemist Raphael Mechoulam was the first to discover and isolate THC from marijuana. To test whether he had found the compound that produces euphoria, he dosed cake slices with 10 milligrams of pure THC and gave them to willing friends at a party. Their reactions, from nonstop laughter, to lethargy, to talkativeness, confirmed that THC was a psychotropic cannabinoid.
It wasn’t until 1992 that researchers discovered endocannabinoids produced naturally in the body. Since then, several other endocannabinoids have been identified, but not all have known functions.
Cannabinoids bind to two types of cannabinoid receptors in the body – one that is found predominantly in the nervous system and one in the immune system, Das said.
“Some cannabinoids, such as THC in marijuana or endocannabinoids can bind to these receptors and elicit anti-inflammatory and anti-pain action,” she said.
“Our team discovered an enzymatic pathway that converts omega-3-derived endocannabinoids into more potent anti-inflammatory molecules that predominantly bind to the receptors found in the immune system,” Das said. “This finding demonstrates how omega-3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect.”
The study was an interdisciplinary effort led by recent comparative biosciences alumnus Daniel McDougle and supported by current biochemistry graduate student Josephine Watson. The team included U. of I. animal sciences professor Rodney Johnson; U. of I. bioengineering professor Kristopher Kilian; Michael Holinstat, of the University of Michigan; and Lucas Li, the director of the Metabolomics Center at the Roy J. Carver Biotechnology Center at Illinois.
Das also is an affiliate of the Department of Biochemistry and the Beckman Institute for Advanced Science and Technology at Illinois.
The National Institutes of Health and the American Heart Association supported this research.
Study identifies key player in heart enlargement
The heart is a dynamic muscle that grows and shrinks in response to stressors such as exercise and disease. The secret to its malleability lies in individual cells, which get bigger or smaller depending on the heart’s needs. A new study of mouse hearts reveals a previously unknown mechanism by which heart cells control their size by ramping up or stopping the production of a key factor called PABPC1.
The findings, reported in the journal eLife, could assist in the development of therapeutics that promote healthy heart growth and prevent disease.
During exercise, the heart beats harder to pump oxygen to the muscles, and heart cells adapt over time by boosting production of specific proteins to increase in size, said University of Illinois biochemistry professor Auinash Kalsotra, who led the new study with postdoctoral researcher Sandip Chorghade and graduate student Joseph Seimetz. After a prolonged period without exercise, the heart cells return to a normal size, Kalsotra said.
“Heart cells also grow during cardiovascular disease – again requiring greater amounts of new protein synthesis to support the growth,” he said. “However, even though this is initially a protective response, this prolonged growth leads to further complications that can eventually lead to heart failure.”
In the new study, the researchers focused on PABPC1, a protein that binds to RNA and aids in the process of translating the RNA into proteins. Scientists had long assumed all cells needed PABPC1 to survive and make new proteins. The new study challenges this assumption.
Even though PABPC1 RNA is present in all human and mouse cells, the protein itself is absent in the adult heart, Kalsotra and his colleagues discovered.
“Our study revealed that the protein disappears in adult heart cells, reappearing only when the cells need to grow during exercise and disease,” Kalsotra said.
“The finding explains why heart cells produce much lower levels of new proteins than other tissues in the body, a fact that was known but not understood until now,” Seimetz said.
“Maintaining a heartbeat takes an enormous amount of energy. Because of this, heart cells need to be more efficient at making proteins,” Seimetz said. “However, during growth, when cells need to make extra proteins, they turn on the PABPC1 switch to give protein production a boost.”
“The finding that PABPC1 is usually not present in adult heart cells until needed for growth suggests that if you could control the function of this protein, then you could promote healthy growth and prevent disease,” said Kalsotra, who also is affiliated with the Carl R. Woese Institute for Genomic Biology at Illinois.
The National Institutes of Health supported this research.
Rachel Whitaker Receives Allen Distinguished Investigator Award from The Paul G. Allen Frontiers Group
The Paul G. Allen Frontiers Group today announced five new Allen Distinguished Investigator (ADI) awards to researchers conducting pioneering research in epigenetics, aging, and evolution, including Rachel Whitaker, Associate Professor of Microbiology and leader of the Infection Genomics for One Health research theme at the IGB. Each ADI is funded at $1.5 million over three years, totaling $7.5 million in funding.
“Viruses and other mobile genetics elements do not follow the rules of classical Darwinian evolution. Individual organisms share mobile DNA, forming a dynamic network of genetic connections. Measuring and modeling the dynamics of mobile DNA will revolutionize our understanding of the evolutionary process itself,” said Whitaker. “This Allen Distinguished Investigator award will enable interdisciplinary collaboration among colleagues at University of Illinois, University of Chicago, and Geisel School of Medicine at Dartmouth. Stepping outside our traditional silos, we will integrate our expertise toward the common objective of developing this promising new evolutionary paradigm.”
Whitaker’s award in the area of microbial evolution focuses on recent research which has unearthed regions of the genome that are capable of moving rapidly between cells, creating a sea of dramatic and unpredictable genetic changes. These mobile genetic elements (MGEs) are particularly exploited by infectious bacteria, which evade antibiotics through rapid evolution. While the scientific response to infectious disease has focused on identifying new ways to target and kill bacteria, antimicrobial resistance, virulence, and many other properties of pathogens are evolutionary problems driven by mobile elements. An evidence-based predictive understanding of the evolutionary forces that drive the emergence and spread of these traits is needed in order to stop them. Whitaker’s project will create models of MGEs and their evolutionary roles within a human system, and compare and refine those models against longitudinal data in order to capture and better understand this crucial evolutionary process.
“Each of these awards is given to researchers with the bold ideas and new perspectives we need to make the next big leap in bioscience,” said Tom Skalak, Ph.D., Executive Director of The Paul G. Allen Frontiers Group. “Epigenetics, aging, and evolution are all fields with great impact on human health and wellbeing, but that currently face significant gaps in knowledge. With these awards, we hope to make strides toward the kind of breakthrough insights that can change the direction of an entire area of research.”
While evolution is typically modeled as a series of small mutations, new knowledge suggests that large, highly mobile sections of the genome can flow rapidly among organisms: a strategy employed by infectious bacteria to evade antibiotics. Preventing the next pandemic will require understanding and modeling these mobile genetic elements in bacteria and humans.
The Allen Distinguished Investigator program supports early-stage research with the potential to reinvent entire fields. Allen Distinguished Investigators are passionate thought leaders, explorers and innovators who seek world-changing breakthroughs. The Frontiers Group provides these scientists with support to produce new directions in their respective fields.
The other ADI program award recipients were Dr. Fei Chen, Broad Institute, and Dr. Jason Buenrostro, Broad Institute and Harvard University; Dr. Jan Ellenberg, European Molecular Biology Laboratory, and Dr. Ralf Jungmann, Max Planck Institute of Biochemistry & LMU Munich; Dr. Charles A. Gersbach, Duke University; and Dr. Steve Horvath, University of California, Los Angeles.
About The Paul G. Allen Frontiers Group
The Paul G. Allen Frontiers Group is dedicated to exploring the landscape of science to identify and fund pioneers with ideas that will advance knowledge and make the world better. Through continuous dialogue with scientists across the world, The Paul G. Allen Frontiers Group seeks opportunities to expand the boundaries of knowledge and solve important problems. Programs include the Allen Discovery Centers at partner institutions for leadership-driven, compass-guided research, and the Allen Distinguished Investigators for frontier explorations with exceptional creativity and potential impact. The Paul G. Allen Frontiers Group was founded in 2016 by philanthropist and visionary Paul G. Allen, and is a division of the Allen Institute, an independent 501(c)(3) medical research organization. For more information, visit allenfrontiersgroup.org.
Posted June 20, 2017
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Milan Bagchi appointed new director of the School of Molecular and Cellular Biology.
"I welcome the opportunity to work with the College of Liberal Arts and Sciences and the campus leadership to continue to promote the tradition of excellence in the School of MCB, which is a leading academic and research enterprise with broad impact on knowledge, creativity and discovery," said Bagchi.
"With focus on innovative and emerging research areas, astute selection of new faculty, and new partnerships, the School has the opportunity to maximize the productivity of its four departments and synergistically interact with other disciplines, such as bioengineering, computational biology, and medicine to enhance the education and training of our students and advance understanding of health and disease for the betterment of society," he said.
"Please join me in thanking Steve Sligar for his service as MCB Director," said Feng Sheng Hu, Dean of the College of Liberal Arts and Sciences. "Steve has been a tireless advocate for MCB, and we are grateful for his dedication and all that he has accomplished for the school."
Posted June 02, 2017
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Professor John Gerlt named the 2017 Gordon Hammes Lectureship winner
The lectureship is sponsored by the Division of Biological Chemistry of the American Chemical Society and the American Chemical Society’s “Biochemistry” journal.
The objective is to recognize and honor a single individual whose scientific contributions have had a major impact on research at the interface of chemistry and biology.
“Dr. Gerlt’s track record in defining the field of enzymology, and more recently, leading break-through technologies and biological applications to define functions for proteins of unknown function, has been a game-changer in biomedical sciences around the world,” says Susan Martinis, Head of the Department of Biochemistry and Stephen G. Sligar endowed professor.
“[Gerlt] is a visionary scientist whose impact on our understanding of protein function cannot be overstated,” says Alanna Schepartz, Editor-in-Chief of Biochemistry.
The Gordon Hammes Lectureship Award is named in honor of the father of University of Illinois Chemistry Professor Sharon Hammes-Schiffer.
Gerlt will present the Gordon Hammes lecture at a session in his honor at the 254th ACS National Meeting & Exposition in Washington, D.C., in August 2017.
Posted May 22, 2017
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Researchers uncover a nutrient-sensing epigenetic pathway that controls autophagy
Autophagy or “self-eating” is a highly conserved catabolic process that digests and recycles cytoplasmic components and damaged organelles in cells and is essential for cellular survival under nutrient-deprived conditions. After a meal, autophagy is suppressed to maintain homeostasis and normal cellular functioning. Defective autophagy is associated with many diseases and promotes cellular aging, but excess autophagy is also harmful because it may lead to cell death and provide nutrients for tumor growth. Autophagy must, therefore, be tightly regulated to maintain homeostasis and for normal cellular functioning.
Molecular and Integrative Physiology Professor, Jongsook Kim Kemper, the leading author of the study, Sangwon Byun, Young Kim and colleagues identified a novel postprandial FGF19-SHP-LSD1 pathway that epigenetically represses hepatic autophagy gene networks in response to feeding, published in the EMBO Journal. Their findings could have important implications for the treatment of human diseases associated with autophagy dysfunction, including metabolic disorder, neuro-degenerative disease, and cancer.
Autophagy is known to occur under extremely stressful starvation conditions, but recent studies from the Kemper’s group and others showed that it also occurs during fasting/feeding cycles under normal physiological conditions. Autophagy was also thought to be mainly regulated acutely by nutrient-sensing cytoplasmic kinases, such as mTOR and AMPK, that phosphorylate autophagy-related proteins, but recent studies from the Kemper lab demonstrated that nuclear transcriptional events are also important for sustained autophagy regulation. This new study shows that in response to feeding or treatment with a late fed-state hormone, FGF19, SHP recruits the epigenetic regulator LSD1 histone demethylase to a subset of autophagy genes. LSD1 mediates the demethylation of histones at the autophagic genes, which results in epigenetic repression of these genes and decreased autophagic flux and macroautophagy, including lipophagy. An earlier study from the Kemper lab (Nature, 2014) had shown that another feeding-sensing bile acid nuclear receptor, FXR, also directly inhibited autophagy genes early after a meal. FXR also induces expression of both FGF19 and SHP, which act later in the late-fed state, which effectively sustains postprandial repression of autophagy.
This study was supported by grants from National Institutes of Health and American Diabetes Association to Prof. Kemper and a post-doctoral fellowship to Dr. Byun, and a scientist development award to Dr. Kim, both from the American Heart Association.
John Cronan elected Member of the National Academy of Sciences
The National Academy of Sciences (NAS) is a private, non-profit society of distinguished scholars. Established by an Act of Congress, signed by President Abraham Lincoln in 1863, the NAS is charged with providing independent, objective advice to the nation on matters related to science and technology. Scientists are elected by their peers to membership in the NAS for outstanding contributions to research. The NAS is committed to furthering science in America, and its members are active contributors to the international scientific community. Nearly 500 members of the NAS have won Nobel Prizes, and the Proceedings of the National Academy of Sciences, founded in 1914, is today one of the premier international journals publishing the results of original research.
Because membership is achieved by election, there is no membership application process. Although many names are suggested informally, only Academy members may submit formal nominations. Consideration of a candidate begins with his or her nomination, followed by an extensive and careful vetting process that results in a final ballot at the Academy's annual meeting in April each year. Currently, a maximum of 84 members may be elected annually. Members must be U.S. citizens; non-citizens are elected as foreign associates, with a maximum of 21 elected annually.
Cronan has over 40 years of expertise discovery of bacterial metabolic pathways and their regulation. He is best known as a pioneer in bacterial fatty acid biosynthesis. His laboratory is responsible for developing the methods to isolate and study mutants in fatty acid biosynthesis using E. coli. This work formed the paradigm for our current understanding of fatty acid synthetic proteins and sequences in bacteria, plants and mammals and the regulation of fatty acid biosynthesis during growth. He has made additional contributions including: 1) unraveling the mechanism that couples the synthesis of fatty acids to cell growth and phospholipid synthesis which has been exploited by the biofuels industry; 2) discovering the first fatty acid responsive transcriptional regulator and its novel mode of action; 3) pioneering demonstrations that synthesis of the covalently-bound enzyme cofactor, lipoic acid, proceeds by assembly on its cognate enzymes; 4) that the early steps of biotin synthesis proceed by a modified fatty acid pathway that uses temporally disguised substrates; and 5) demonstration that bacterial biotin synthesis is regulated by supply of proteins requiring biotinylation. Cronan also discovered a new anaerobic pathway for fatty acid degradation and determined the mechanisms of synthesis of several bacterial quorum-sensing molecules. These contributions have many practical applications and form the intellectual basis for the fermentative production of fatty acid based biofuels. Enzymes originally characterized in his work now represent targets for new antimicrobials. His work on in vivo protein biotinylation led to many new technologies, enabling the synthesis of the tetrameric major histocompatibility complex (MHC)/peptide complexes and proximity-dependent biotinylation in cell biology.
Professor Cronan was elected along with Jeffrey Moore, Murchison-Mallory Professor of Chemistry and Professor of Materials Science and Engineering; Donald Ort, Robert Emerson Professor of Plant Biology, USDA/ARS Photosynthesis Research Unit and Adjunct Professor of Crop Sciences; and Gary Parker, W.H. Johnson Professor of Geology and a professor of civil and environmental engineering.
Posted May 12, 2017
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Chris Seward's image "Clear Mind" takes 2nd place in Image of Research contest
Novel imaging techniques are necessary for examining whole brain protein expression patterns. Animal brains are large, complex structures that are difficult to image comprehensively. Neurons can be several inches long, while only a few nanometers in width and can branch in many directions connecting different regions of the brain.
Laser light has trouble penetrating the dense, opaque tissue, which usually means brains can only be imaged in extremely thin slices that fail to image complete cell processes. To solve these problems, we have modified a technique called CLARITY that allows us to make a whole mouse brain completely transparent, while keeping fluorescent labels intact. This process allows us to visualize the connections of an intact brain at extremely high resolution in three dimensions.
The goal of our study is to identify the proteins activated after a social stimulus, such as an intruder in an animal’s home. This image shows inhibitory neurons in green and neuron bundles expressing a protein that is triggered by a social experience in red. The blue background stain reveals important brain structures. These images allow us to connect the expression of a gene in one area of the brain, and follow it’s signal to other areas.
Posted May 11, 2017
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Dr. Supriya Prasanth, associate professor of cell and developmental biology, awarded the Lynn M. Martin Award for Distinguished Women Teachers
Dr. Prasanth’s primary teaching responsibility has been the creation and delivery of MCB 400 Cancer Cell Biology, one of the most popular undergraduate elective courses. She is consistently ranked as excellent by her students each semester.
In addition to her classroom teaching, Dr. Prasanth has been an outstanding mentor to students engaged in undergraduate research. Training undergraduate research students in the lab involves significant commitments of time, effort, and resources, and the 15 students she has trained demonstrate her commitment to creating opportunities for undergraduates. Currently, her lab has three undergraduate students performing research under her guidance.
Many of her former students are on their way to successful careers- three have gone on to graduate school, four to medical school, two to research positions, and one is a director of private healthcare company in India. Several of her research students have won awards and recognition for their work.
Dr. Prasanth’s lectures are known for their clarity and her ability to explain complex topics. Her lectures noted for being lively, enthusiastic, and engaging, even during a 1.5 hour session.
The Department of Cell and Developmental Biology recognizes her dedication, talent, and effectiveness in teaching.
Named for the founder of the award, the Lynn M. Martin Award for Distinguished Women Teachers is designated to promote exceptional achievement in undergraduate teaching by women. Two awards (one for Teaching Assistants and one for Faculty members) are awarded by the College of Liberal Arts and Sciences.
Posted May 09, 2017
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Emad Tajkhorshid named the J. Woodland Hastings Endowed Chair in Biochemistry
One of the highest honors that a faculty member can receive, this endowed chair is named for the late John Woodland “Woody” Hastings (1927-2014), and set up by donors George and Tamara Mitchell. Hastings was a decorated scholar who served as a faculty member at Illinois from 1957-66 and was best known for his innovation in the field of bioluminescence. He was also a founder in the field of circadian biology, focusing on the biological cycles of plants, animals, fungi, and other living things. Tajkhorshid is a professor of biochemistry, biophysics, and computational biology. He is also professor and head of pharmacology, and interim head of the medical biochemistry. He joined the Department of Biochemistry and pharmacology in 2007, and has since developed an extensive research portfolio. He was chosen for the award by a committee of his senior colleagues who hold endowed positions. He is a member of the Beckman Institute for Advanced Science and Technology. George W. Mitchell III (1942-2016) earned his master’s degree in chemistry from U of I in 1966 while working under the mentorship of Professor Hastings. He moved with Hastings to Harvard University, where he continued his research to receive a doctoral degree in 1969. University of Illinois faculty influenced Mitchell greatly throughout his career and entrepreneurial efforts, which revolutionized biomedical research and patient care. Mitchell co-founded SLM Instruments along with David Laker and Dick Spencer (MS, ’67 PhD, ’70; chemistry; MBA, ’92) who also were affiliated with the College of Liberal Arts and Sciences (Laker was a machinist for the department). SLM Instruments designed and built the first commercial instrument to measure biological fluorescence – a groundbreaking advance in medicine and biological research. Tamara T. Mitchell was employed by Carle Clinic and Carle Foundation Hospital as well as serving as a clinical associate professor with the Regional College of Medicine at U of I from 1970-2001. Her medical and research interests focused on family practice, rural health, and farm safety. At the time of her retirement in 2001, she was serving as a medical director at Carle Clinic. Tamara Mitchell was chosen by her peers as among the Best Doctors in the Midwest in 1996. Tamara Mitchell spoke at the ceremony, held at the Beckman Institute, and described Hastings as a scientist of passion and generosity who “was never in it for the money, rather for his own curiosity and love of science.” Tajkhorshid has authored over 180 research articles with over 17,500 citations in high-profile journals such as Nature, Science, eLife, and PNAS. He has delivered nearly 150 invited lectures at international meetings, universities, and research institutes. He serves on the editorial boards of multiple journals, including Biophysical Journal, Journal of Biological Chemistry, and PLoS Computational Biology. He started his career with pharmacy and doctoral degrees in medicinal chemistry at Tehran University. He then earned a second doctoral degree in molecular biophysics from the University of Heidelberg before he moved to the U of I at Urbana-Champaign, where he completed postdoctoral studies in computational biophysics at the Beckman Institute. Tajkhorshid joined the faculty as a professor of biochemistry and pharmacology in 2007, was promoted to associate professor in 2010, and then again to the rank of professor in 2013. In 2015, Tajkhorshid was named a University of Illinois Scholar, after being nominated by both the Urbana-Champaign and Chicago campuses, and was then awarded the Faculty Excellence Award from the School of Molecular and Cellular Biology in 2016. Speakers at the ceremony included U of I Provost John Wilkin, Feng Sheng Hu, the Harry E. Preble Dean of the College of LAS, Steve Sligar, director of the School of Molecular and Cellular Biology, and Susan Martinis, head of the Department of Biochemistry. Martinis said Tajkhorshid’s potential was obvious from early in his career. “We often talk about the powerful legacy of the Department of Biochemistry and the University of Illinois. All aspects of Emad’s career in academia honor that and continue that legacy,” she said. Martinis added: “Many people in this room know how wonderful a collaborator Emad is, because they work closely with him—that collaborative spirit for Emad extends worldwide.” Tajkhorshid thanked George and Tamara Mitchell for their “generosity, vision and commitment.” He added that their “contribution is invaluable to research throughout the university and [he is] very glad to be one of the groups that is benefitting from [their] contribution.” “Most importantly, I would like to acknowledge my students, post-docs and colleagues,” Tajkhorshid said. “They are the reason I’m standing here, presenting what they have been doing for many, many years; I really appreciate and enjoy working with them.” By Logan Weeter, College of Liberal Arts and Sciences communications
Posted May 01, 2017
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Study offers new insight into powerful inflammatory regulator
A new study in mice reveals how a protein called Brd4 boosts the inflammatory response – for better and for worse, depending on the ailment. The study is the first to show that this protein, while problematic in some circumstances, also can protect the body from infection. The findings are reported in the Proceedings of the National Academy of Sciences.
The heat, swelling, redness and pain associated with inflammation are evidence that the immune system is working to protect the body. Once its job is complete, the acute inflammation normally recedes and disappears.
Sometimes inflammation fails to stop, and instead turns against the body, attacking healthy tissues and leading to chronic inflammatory diseases such as asthma, arthritis, diabetes and cancer.
One very powerful protein complex, called NF-kappaB, influences the expression of numerous genes and governs both beneficial and harmful inflammatory responses. When NF-kappaB regulates discriminately, the body heals and survives. When NF-kappaB overreacts, inflammation can become dangerous.
The NF-kappaB protein is a primary target for research looking for a way to stop inflammatory diseases.
The new study, led by University of Illinois biochemistry professor Lin-Feng Chen, reveals how Brd4 influences NF-kappaB and contributes to inflammation.
“Brd4 acts like a turboboost for the NF-kappaB protein that regulates inflammation. For NF-kappaB to be 100 percent productive, it needs the help from Brd4,” Chen said.
Earlier work in Chen’s lab revealed that Brd4 attaches to the NF-kappaB protein by recognizing a chemical tag. If Brd4 or the tag is not present, the potential of NF-kappaB protein to act as inflammation regulator is compromised.
The new study in mice confirmed that Brd4 plays a major role in acute inflammatory responses. The researchers deleted the mouse Brd4 gene in certain types of immune cells, including macrophages, and monitored the immune response of these mice. Many of the NF-kappaB-dependent, inflammation-related genes involved in fighting infection were down-regulated in Brd4-deficient macrophages.
“We found that in the absence of Brd4, the immune system of mice was compromised. They were more resistant to a massive immune response, but more susceptible to bacterial infection,” Chen said.
“Cancers and some inflammatory diseases use Brd4 to boost the expression of genes that lead to the growth or persistence of the disease, but Brd4 has the same effect on inflammation that is needed to kill bacteria and viruses,” he said.
The researchers also discovered a new mechanism for the reduced inflammatory gene expression in cells lacking Brd4. They found that deletion of Brd4 enhanced the protein synthesis of a NF-kappaB inhibitor, preventing the NF-kappaB from stimulating inflammatory gene expression.
“The next step is to test whether the absence of the gene for Brd4 would weaken the strength of the NF-kappaB protein – and inhibit chronic inflammatory diseases – without compromising the body’s ability to fight off bacteria and viruses,” Chen said.
“Pharmaceutical companies are currently investing enormous resources – to the tune of hundreds of millions of dollars – seeking molecules that will inhibit the Brd4,” Chen said. “Our findings urge caution and further foundational research before treatments involving the inhibition of Brd4 are used on patients.”
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Posted April 07, 2017
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Assistant Professor Nien-Pei Tsai’s lab has published a study in PLOS Genetics on how a novel epilepsy-associated gene controls neuronal excitability
Human genetic studies have identified many epilepsy-associated genes, but the mechanisms by which those genes are linked to brain circuit excitability and seizures are largely unknown.
A recent study published in PLOS Genetics by Assistant Professor Nien-Pei Tsai’s lab at the Department of Molecular and Integrative Physiology uncovered how the disruption of a novel epilepsy-associated gene, named ‘neural precursor cell expressed developmentally down-regulated gene 4-like’, or Nedd4-2, leads to neuronal hyperexcitability and seizures.
Nedd4-2 encodes a ubiquitin ligase that is responsible for degrading specific substrate proteins. Dr. Tsai’s lab has previously identified a neurotransmitter receptor, named ‘AMPA receptor’, as a novel substrate of Nedd4-2.
In this current study, using a mouse model in which one of the major forms of Nedd4-2 in the brain is selectively deficient, they found that the spontaneous neuronal activity in cortical neurons is basally elevated and very sensitive to the blockage of AMPA receptor when compared with wild-type neurons.
Most importantly, the elevated seizure susceptibility in this mouse model can be normalized when the AMPA receptors are genetically reduced. When studying the Nedd4-2 that carries one of the three epilepsy-associated mutations, they found that all mutations reduce the affinity of Nedd4-2 to modulate the degradation of AMPA receptors. These findings suggest that impaired AMPA receptor degradation contributes to Nedd4-2-dependent neuronal hyperexcitability and seizures. The pharmacologically targeting of AMPA receptors has already been applied clinically for treating patients with epilepsies. This study suggests a promising therapeutic target and introduces a currently available therapy for alleviating epilepsy symptoms in patients who carry mutations of Nedd4-2.
Kehl-Fie and team discover how bacteria exploit a chink in the body’s armor
Researchers at the University of Illinois at Urbana-Champaign and Newcastle University in the UK are investigating how infectious microbes can survive attacks by the body’s immune system. By better understanding the bacteria’s defenses, new strategies can be developed to cure infections that are currently resistant to treatments.
The study, reported in PLoS Pathogens, focused on the bacterium Staphylococcus aureus (which, in its most pathogenic form, is renowned as the so-called ‘superbug’ methicillin-resistant S. aureus, or MRSA). S. aureus is found on approximately half of the population. While it usually safely coexists with healthy individuals, it has the ability to infect nearly the entire body.
The human body uses a diverse array of weapons to fight off bacteria. “Our immune system is very effective and prevents the majority of microbes we encounter from causing infections,” said U. of I. microbiology professor Thomas Kehl-Fie, who led the study with Kevin Waldron, of Newcastle University. “But pathogens such as S. aureus have developed ways to subvert the immune response.”
S. aureus can overcome one of the body’s key defenses known as “nutritional immunity.” Other, less pathogenic relatives are stopped by this defense, which prevents bacteria from obtaining critical nutrients. It starves S. aureus of manganese, a metal needed by the bacterial enzyme superoxide dismutase, or SOD. This enzyme functions as a shield, minimizing the damage from another weapon in the body’s arsenal, the oxidative burst. Together, the two host weapons usually function as a one-two punch, with nutritional immunity weakening the bacteria’s shields, enabling the oxidative burst to kill the bacterium.
S. aureus is particularly adept at causing devastating infections. Differing from other closely related species, S. aureus possesses two superoxide dismutases. The team discovered that the second superoxide dismutase enhances the ability of S. aureus to resist nutritional immunity and cause disease.
“This realization was both exciting and perplexing, as both SODs were thought to utilize manganese and therefore should be inactivated by manganese starvation,” said Dr. Kehl-Fie.
The most prevalent family of SODs, to which both of the S. aureus SOD enzymes belong, has long been thought to come in two flavors: those that are dependent on manganese for function and those that use iron.
In light of their findings, the team tested whether the second staphylococcal SOD was dependent on iron. To their surprise, they discovered that the second SOD was capable of using either metal. While the existence of these “cambialistic” SODs, capable of using both iron and manganese, was proposed decades ago, the existence of this type of enzyme was largely dismissed as a quirk of chemistry, unimportant in real biological systems. The team’s findings dispel this notion, demonstrating that cambialistic SODs critically contribute to infection.
The team found that, when starved of manganese by the body, S. aureus activated the cambialitic SOD with iron instead of manganese, ensuring its critical bacterial defensive barrier was maintained.
“The cambialistic SOD plays a key role in this bacterium’s ability to evade the immune defense,” said Dr. Kevin Waldron of Newcastle University. “Importantly, we suspect similar enzymes may be present in other pathogenic bacteria. Therefore it could be possible to target this system with drugs for future antibacterial therapies.”
The emergence and spread of antibiotic resistant bacteria, such as MRSA, make such infections increasingly difficult, if not impossible, to treat.
This has led leading health organizations, such as the Centers for Disease Control and Prevention and the World Health Organization, to issue an urgent call for new approaches to combat the threat of antibiotic resistance.