Contact:

Mentors: Kenneth Saag, MD, MSc, PD/PI and Monika Safford, MD, Co-Directors.  For questions regarding eligibility, program requirements and the application process, please contact Ryan Outman routman@uab.edu.


The Health Services/Comparative Effectiveness Research Training Program (HSR/CERTP) at UAB  is a combined fellowship mentored research training program in health services & outcomes research and comparative effectiveness research (Kenneth Saag, MD, MSc, PD/PI; Monika Safford, MD, Co-Director). The training program prepares independent investigators to pursue careers in health services & outcomes research focused on translating research evidence into practice and on comparative effectiveness research methods for evaluating the benefits and harms of different treatment strategies and interventions health conditions on patient outcomes in real world settings. Skills development will include exposure to relevant epidemiological, statistical, experimental, and quasi-experimental methodologies, analysis of large data sets, health outcomes assessment, and economic evaluation, all with an emphasis on the practical application of outcomes research methodology. Our research and training base includes a partnership of UAB interdisciplinary research centers and programs and is primarily drawn from across 7 UAB Schools (Medicine, Public Health, Health Professions, Nursing, Dentistry, Business, and College of Arts and Science), offering a pool of almost 25 experienced HSR/CER Mentors.

CONTACT: For questions regarding eligibility, program requirements and the application process, please contact Ryan Outman at routman@uab.edu. To request an application packet, please contact Joan Hargrove at jhargrove@dopm.uab.edu.

 

 

Postdocs in UAB News

  • A novel toxin – and the first ever found – for a deadly pathogen, M. tuberculosis
    Until now, no toxin had been found in 132 years of study for the deadly pathogen Mycobacterium tuberculosis, which infects 9 million people a year and kills more than 1 million. The novel toxin induces necrotic cell death of macrophages to help the tuberculosis pathogen escape and spread to other cells.

    Despite 132 years of study, no toxin had ever been found for the deadly pathogen Mycobacterium tuberculosis, which infects 9 million people a year and kills more than 1 million.

    Now, Michael Niederweis, Ph.D., professor of microbiology at the University of Alabama at Birmingham, and colleagues have described the first known toxin of this pathogenic bacterium. This toxin — Tuberculosis Necrotizing Toxin, or TNT — is the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. Before the Niederweis discovery, those toxins were identified only as the “Domain of Unknown Function 4237.”

    Bacteria with those newly recognized toxins include Yersinia pestis, the pathogen that caused the bubonic plague known as the Black Death in Medieval Europe, and Listeria monocytogenes, one of the most virulent and deadly food-borne infections and the cause of Blue Bell Creameries recalls this year.

    The lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death.

    M. tuberculosis is notable for its survival inside macrophages, the immune cells that ingest and destroy infectious bacteria. The newly identified TNT, Niederweis says, plays a key role to induce necrotic death of the infected macrophage. Thus, TNT enables the M. tuberculosis bacteria to escape from the macrophage and disseminate to other host cells in a person infected with tuberculosis, thus contributing to the survival of M. tuberculosis and spreading the disease.

    “The battle between M. tuberculosis and the human immune system to control the fate of infected macrophages is critical in determining the outcome of the infection,” Niederweis wrote in the TNT paper. “The control of host cell death is of utmost importance for the survival, escape and dissemination of M. tuberculosis.”

    The paper, “The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD,” was published online Aug. 3 in Nature Structural & Molecular Biology.

    How did this toxin evade discovery for more than a century? First, it is produced in vitro only in very small quantities — the Niederweis lab could detect it only in a cell culture filtrate that was concentrated 1,000-fold, equivalent to concentrating a gallon of milk to about one-third of a teaspoon. Second, the toxin is deadly only when it is inside the host-cell cytosol; if the toxin is in the bloodstream or is added to the culture medium of in vitro host cells, it has no effect. Third, the toxin has no similarities to any other known toxin.

    Niederweis discovered TNT while searching for something completely different. He was hunting for outer-membrane proteins that can act as a door to let nutrients outside the bacteria pass through the extremely impermeable, outer-membrane barrier of M. tuberculosis. The Niederweis group thought they had found such a porin protein; but it had an unusual property — the end portion of the protein broke off after the pore formed in the outer membrane, and that end portion was extremely toxic, both in simple prokaryotic cells like bacteria and in the more complex eukaryotic cells of yeast, mammals and fish. In a paper published in Proceedings of the National Academy of Sciences in 2014, Niederweis said this discovery “challenges the paradigm that M. tuberculosis is one of few bacterial pathogens that does not produce toxins.”

    In this illustration, the Tuberculosis Necrotizing Toxin — symbolized by the explosives — causes necrotic cell death and enables release of the tuberculosis bacteria from the destroyed macrophage. Credit: Mathew Schwartz (Advanced Institutes of Convergence Technology, SNU)The current paper fully establishes this new paradigm by identifying the mechanism of TNT-induced necrotic cell death at the functional and structural levels. Like an optical illusion where at first one sees a vase, and it then appears to be two faces peering at each other, Niederweis initially he believed he had found an outer-membrane porin that lets nutrients in and carried an artefact. Now he sees the pore part of that protein as a bacterial autotransporter (similar to those seen in other bacteria) that exports its TNT protein cargo to the outside of the outer membrane. After that export is done, the transporter pore remains in the outer membrane.

    The similarity of the tnt gene to DNA sequences in more than 600 other bacterial and fungal species will enable research on how this novel class of toxins may function in other pathogens, especially in microorganisms that depend on induction of necrosis to survive or spread.

    Here are some details of TNT:

    1. In a laborious search for the molecular function of TNT, Jim Sun, Ph.D., a postdoc in the Niederweis lab, found that TNT hydrolyzes the essential co-enzyme nicotinamide adenine dinucleotide (NAD+). This explains why it kills every type of cell it is cloned into, because NAD+ is necessary for the cell’s normal metabolism. Researchers were able to clone the TNT gene only by placing it next to an inducible promoter that tightly represses transcription until induced. The TNT enzyme hydrolyzes NAD+ inside of cells and in vitro. It is blocked by antibodies against TNT, and specific TNT point mutations that eliminate all enzymatic activity.
    2. That noncatalytic TNT mutant is not able to kill macrophages, showing that the hydrolase activity is required for TNT-induced cell death.
    3. If TNT were produced inside M. tuberculosis, it would kill the cell. Niederweis and colleagues found that M. tuberculosis, similar to the bacterial pathogen Streptococcus pyogenes, produces an antitoxin to its toxin. The TNT antitoxin binds to the toxin and blocks its hydrolase activity, thus making it harmless inside the bacteria. The researchers have named the antitoxin immunity factor for TNT (IFT).
    4. Cloning the genes for both TNT and IFT into E. coli, where IFT protects the bacteria from death, allowed the researchers to produce milligram quantities of TNT and IFT. In a collaborative effort, Gino Cingolani, Ph.D., a professor from the Thomas Jefferson University, produced crystals of the purified protein complex and determined its molecular structure to an astonishing resolution of 1.1 Å in a matter of weeks. The TNT molecule is shaped like a grasping hand, with fingers on one side and an extended thumb on the other. The IFT fits into the TNT like a ball held in a hand.
    5. When pathogenic M. tuberculosis grows inside a macrophage phagosome, the TNT rapidly gains access to the cytosol of the infected macrophage and hydrolyzes NAD+, depleting that essential co-factor. This initiates necrotic cell death through downstream signals that are not yet characterized.

    Curiously, a literature search revealed that an uncharacterized, heat-stable NAD+-glycohydrolase activity in M. tuberculosis cell extracts had been described half a century ago, as well as an uncharacterized heat-labile inhibitor of that hydrolase activity. Several biochemical characteristics of TNT and IFT found by the Niederweis lab match those of the uncharacterized proteins described in the reports from the 1960s.

    However, the lack of the modern equipment and antibodies of today, and the very low levels of TNT present in M. tuberculosis, prevented those researchers from finding the toxin.

    Co-authors of the paper are Jim Sun, Ph.D., Axel Siroy, Ph.D., Alexander Speer, Ph.D., and Kathryn Doornbos, all in the Department of Microbiology, UAB School of Medicine; and Ravi Lokareddy, Ph.D., and Gino Cingolani, Ph.D., Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia. Siroy is now at the University of Maastricht, the Netherlands.

  • Floyd named president-elect of National Neurotrauma Society

    UAB’s Candace Floyd is set to take a top leadership post with the National Neurotrauma Society.

    Candace Floyd, Ph.D., associate professor in the University of Alabama at BirminghamDepartment of Physical Medicine and Rehabilitation, is the president-elect of the National Neurotrauma Society. The president-elect will assume the duties of president in June 2016 for a one-year term. Floyd previously served terms as vice president and secretary/treasurer.

    The National Neurotrauma Society seeks to accelerate research that will provide answers for clinicians and ultimately improve the treatments available to patients. It is open to scientists interested in neurotrauma research and promotes excellence in the field by providing opportunities for scientists, establishing standards in both basic and clinical research, encouraging and supporting research, and promoting liaisons with other organizations that influence the care and cure of neurotrauma victims.

    Floyd is the holder of the Women’s Committee of Spain Rehabilitation Center Endowed Chair in Rehabilitation Neuroscience Research and the director of Research for the Department of Physical Medicine and Rehabilitation. The central focus of her research is to develop new treatments for spinal cord injury and traumatic brain injury.

    She earned her doctorate from the Medical College of Virginia/Virginia Commonwealth University and did postdoctoral training in traumatic central nervous system injury research at the University of California, Davis. She joined UAB in 2006.

    She serves as grant reviewer for the National Institutes of Health, the Department of Defense and the Department of Veterans Affairs. Her research is currently supported by the Department of Defense, the National Institutes of Health and private organizations including the National Football League.

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UAB Research News

  • The last hope: UAB’s Undiagnosed Diseases Program
    UAB’s Undiagnosed Diseases Program is the court of last resort for those with baffling diseases that have never been diagnosed.

    Bruce Korf, M.D., Ph.D., Wayne H. and Sara Crews Finley Chair in Medical Genetics, Professor and Chair, Department of GeneticsFor a medical mystery that defies explanation or diagnosis, the Undiagnosed Diseases Program at the University of Alabama at Birmingham is the court of last resort. Launched in October 2013, the program aims to unravel the most perplexing medical cases in which a diagnosis has not previously been made.

    “Undiagnosed diseases present a critical unmet need, with patients often cycling through the medical system with no satisfactory treatment plan,” said Bruce R. Korf, M.D., Ph.D., professor and chair of the UAB Department of Genetics and director of the UDP. “Some of these conditions may be so rare that only a handful of people in the world have them. Others may be more common, but have symptoms that present in an unusual way, making diagnosis difficult.”

    The National Institutes of Health Office of Rare Diseases Research says there are about 500 diseases common enough to be in any physician’s repertoire for diagnosis, while another 6,500 are known but are extremely rare.

    For patients and their families slogging through the medical system with no answers and no plan, the UDP can be a ray of hope.

    During its short lifetime, the UAB program has already diagnosed one patient whose condition had been described in the international medical literature only once before. In other cases, the UDP has produced a diagnosis for conditions that have stymied referring physicians and their patients for years.

    Primary team members are Korf, Maria Descartes, M.D., professor in the Department of Genetics, and Martin Rodriguez, M.D., associate professor of medicine in the Division of Infectious Diseases. The core team also includes two nurse practitioners, Carol Dahl, CRNP, and Tammi Skelton, CRNP, who serve as clinical coordinators for adult and pediatric patients, respectively. Meagan Cochran, M.S., is the certified genetic counselor. The program can also draw on a variety of UAB specialists according to the needs of each patient.

    Diagnoses are made through a combination of cutting-edge technology allied with more traditional medical strategies such as comprehensive review of records andhistory and time spent listening to the patient or family. Sometimes the team simply engages in contemplation and consultation.

    “Each specialist, looking through his or her unique lens, is able to offer differing perspectives,” Korf said. “We have resources and expertise that are unavailable elsewhere in the UAB system, and we often find the best method is an integration of cutting-edge and traditional medicine, leading to a blended, individualized approach. Even then, we sometimes come up empty-handed.”

    The program did not come up empty-handed for the Smith siblings, Mandalynn, Aiden and Gage. All three suffered from conditions including severe inflammation of their joints and delayed intellectual development. After countless physician visits spanning more than 20 years in South Carolina, Florida and Washington, the most frequent stab at a diagnosis was “unknown bone disease.”

    “We have resources and expertise that are unavailable elsewhere in the UAB system, and we often find the best method is an integration of cutting-edge and traditional medicine, leading to a blended, individualized approach. Even then, we sometimes come up empty-handed.”

    “We were told that we’d probably never know for sure what had affected three of our children but not the other two,” said the children’s mother, Stephanie Smith. “As a mother, that was not good enough.”

    After moving to Alabama, the family began seeing physicians at UAB and were referred to the Undiagnosed Diseases Program.

    The team employed a cutting-edge technique known as whole exome sequencing, which identifies the genes responsible for encoding the sequence of proteins. Results revealed that all three siblings had two variants in a gene associated with mucolipidosis III, an inherited disorder classified as a lysosomal storage disease. One variant came from the father and the other variant from the mother.

    “With a diagnosis confirmed, we were able to set up a monitoring program to look for issues known to be associated with mucolipidosis III, and to recommend infusions of a bisphosphonate medication, which have shown promise in treating the musculoskeletal symptoms related to this condition,” Korf said.

    The Smiths say they are aware of only about 650 cases of mucolipidosis III worldwide, and while there is not a cure for the condition, the family now has answers they did not have before, treatment options they did not know existed and knowledge that will help them plan going forward.

    Exome sequencing was employed in another case of a newborn with profound developmental issues at birth. Pope Terry, of Camden, Alabama, is blind and deaf and suffers from multiple seizures. He has never smiled or sat up, and he exists in what can only be described as a vegetative state. Now 3, he lives with his parents, Wesley Ann and Steve, and his healthy older brother, Haas.

    “I wanted to know the name of the monster that took Pope’s ability to see, hear, talk, walk, eat, look me in the eye, to chase his big brother around the yard, and to say, ‘I love you, Mommy,’” said Wesley Ann Terry. “I wanted to blame something. I wanted to scream and cry and hate a diagnosis.”

    But no diagnosis was forthcoming until Pope and his parents came to the UDP and underwent whole exome sequencing. The results revealed that he had two gene mutations, one associated with seizures and the other involved with impaired cognitive development.

    “It would be extremely unlikely that this sort of condition would be recognized in a setting outside a program such as ours — it had been described only once before in the medical literature,” Korf said.

    The mutations were categorized as de novo, or new mutations, meaning they spontaneously occurred in Pope. The positive news for the family is that the parents have a very small risk that such mutations would occur again should they have another child. In addition, the risk to older brother Haas for fathering a child with these mutations and their associated conditions is the same as in the general population.  

    “We were happy to receive a diagnosis even if it doesn’t change Pope’s future,” said Terry. “I understand Pope’s life is not going to improve by labeling his genetic syndrome, but it may offer hope and potential for future children and families. It also helped us determine if expanding our family was even an option.”

    The diagnosis also answered a burning question that troubled Terry.

    “For all of Pope’s life, the question consumed me,” she said. “Did one of my genes do this to my child? Am I the one to blame?”

    “We all carry genetic variants which can have different effects — or no effect at all — depending on the gene’s location and whether it changes the function of essential proteins,” Korf said. “Genetic variants are commonplace and unpredictable. We try to impress on parents, patients and families that these are naturally occurring variations.”

    The UAB program is modeled on a similar program at NIH and is funded by UAB Medicine and patient revenues. It is one of the first undiagnosed diseases programs at an academic medical center.

    Patients must be referred to the UAB UDP by their primary care physician or a physician providing ongoing care for the condition under evaluation. The condition should have been present for at least six months.

    The program expects to see no more than 40-50 cases per year, and not every patient is guaranteed to receive a diagnosis or treatment plan; in those circumstances, patients will be referred to appropriate UAB specialists for symptom management.

    Smith says getting a diagnosis for her three children was comforting, although still a bit overwhelming.

    “For us, taking things day by day is too much; we go moment to moment,” she said. “My message to other parents is to be your child’s advocate. Keep searching, and never accept ‘no’ as an answer. Fight for them.”

    For the Terrys, the diagnosis brought a bit of closure.

    “We had prayed for ‘diagnosis day’ ever since Pope was born,” said Terry. “I wanted to know. I deserved to know. And finally we have a name, which has given us some peace.”

  • UAB students use performance, interactivity and alternative materials to create art for one-night-only exhibition Aug. 5
    Sculptural objects, masks, puppets, performances and art installations created by Department of Art and Art History students will be shown in a one-night-only exhibition.

    Sculptural objects, masks, puppets, performances and art installations will be shown in a one-night-only exhibition Wednesday, August 5, presented by the University of Alabama at BirminghamCollege of Arts and SciencesDepartment of Art and Art History.

    Two one-night-only exhibitions will be presented from 6-8 p.m. Students in Assistant Professor of Sculpture Stacey Holloway’s summer interdisciplinary Interlude: Space & Body course engaged in projects that consider the role of performance and interactivity within contemporary art making. Works by each student can be seen in the exhibition in the Department of Art and Art History Project Space, on the first floor of the Humanities Building, 900 13th St. South.  

    “In this course, students focused on three main projects: relationships between audience and sculptural objects; creating narratives through objects and performance; and puppetry and set design,” Holloway said. After researching contemporary artists who use their own bodies in interactive and performance art practice, such as Janine Antoni, Joseph Beuys, Felix Gonzalez-Torres, Basil Twist and Tomás Saraceno, the students experimented with 3-D sketches, audience interaction and performance while working with nontraditional materials. 

    “Through the investigation of mixed media, including but not limited to drawing, sculpture, photography, video and installation, students explored the possibilities that occur when the body, space and the art object merge,” Holloway said. 

    The students are Tori Absher, Corey Bright, Hannah Hensley, Keila Kirkwood, Bryce Martinez, Jenifer Moore, Lisa Nguyen, Jennifer Rice, Caelum Soverow, Adam Sterrett, Annie Strong and Kylee Williams.

    Also presented Aug. 6 from 6-8 p.m., students from Adjunct Professor Lane Cooper’s summer figure drawing course will open “The Eccentric Nine” in the UAB Painting Studio, located on the third floor of the Humanities Building. Students who will have works featured are Amanda Halbrooks, Marlena Roberts, Augusta McKewen, Ashlee Boren, Ellory Nichols, Jack Vest, Ricardo Munoz, Corey Bright, and Chris Golson.

    The Department of Art and Art History’s Project Space is an adaptive space that cultivates and supports meaningful creative investigation, interdisciplinary collaboration, innovation and entrepreneurship by providing an alternative platform for students, faculty and community to engage teaching, research, public service and visual art practices.

    “Throughout the summer, students were introduced to formal figurative drawing and challenged to consider the figure in contemporary art practice,” says Cooper, “while the second half of the semester involved working with ideas, themes, texts and practical concerns of figurative themes.”

    The Department of Art and Art History’s Project Space is an adaptive space that cultivates and supports meaningful creative investigation, interdisciplinary collaboration, innovation and entrepreneurship by providing an alternative platform for UAB Department of Art and Art History students, faculty and community to engage teaching, research, public service and visual art practices.

    For more information, contact Assistant Professor of Sculpture Stacey Holloway at shollow@uab.edu.

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