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VICB Weekly Seminar Schedule - Fall 2014

Paul Baker — AB SCIEX
Wednesday, September 3, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"New Strategies in Lipid Profiling: Resolving the Complexity of the Lipidome Using Differential Mobility Separation"  

Key Lecture Points:
·   Unambiguous lipid profiling is challenging due to extensive isobaric overlap of different lipid molecular species within the lipidome
·   Two general methods for lipid profiling by mass spectrometry are used: the ‘shotgun’ approach and the liquid chromatography approach—both have their benefits and limitations
·   A new technique to resolve lipid classes from a complex mixture, Differential Mobility Separation (DMS), has been developed that resolves issues related to isobaric interference
·   DMS can be used with LC or infusion techniques and cleanly resolves different lipid categories and classes; a novel approach to lipid profiling will be presented
·   The use of DMS has been extended to rapidly resolve eicosanoid enantiomers, triglyceride positional isomers and hexosyl ceramide isomers without the need for complex chromatography

Qi Zhang — UNC Chapel Hill
Wednesday, September 10, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Chemical Tools to Monitor and Regulate Lipid Signaling Pathways"

Key Lecture Points:
·  The roles of phosphatidylinositides in development and diseases are not well understood
·  We have developed new chemical approaches to probe signaling pathways regulated by PIs
·  The application of these chemical tools to probe the role of PIs and ARF in the canonical Wnt/β
  catenin pathway will also be discussed

Matt Holden — Universit of Massachusetts, Amherst
Wednesday, September 17, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Caught in the Act: Direct Measurement of Protein Translocation Across Membranes" 

Key Lecture Points:
·  Directed macromolecular transport across membranes key in 21st century medicine
·  We employ a model membrane to quantitate transport as a function of lipids and forces
·  Membrane asymmetry can be a driving force for carrier-mediated transport
·  We also measure protein transport through toxins
·  On route to mechanistic studies of proton-powered Brownian Ratchet
· Model membrane also used for screening ion channel/drug interactions
· Developed a teaching kit based on model membrane system

Dong Wang — UCSD, Skaggs School of Pharmacy & Pharmaceutical Sciences
Wednesday, September 24, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Transcriptional Fidelity Control and Lesion Recognition" 

Key Lecture Points:
·   Structural basis of Pol II elongation complex
·  Three key checkingpoint steps for transcriptional fidelity
·  Structural features of nucleic acids recognized by Pol II
·  DNA modification recognition by Pol II
·  Lesion recognition by Pol II

David Rotella — Montclair State University
Wednesday, October 1, 2014 — 9:00 A.M. to 10:00 A.M. — 214 Light Hall
"1) A Natural Product Template for Medicinal Chemistry 2) Toward the Synthesis of Conformationally Restricted Diamine Scaffolds" 

Co-Sponsored by the Department of Pharmacology

Key Lecture Points:
·   Semi synthetic and synthetic analogs of the natural product (-)-epigallocatechin gallate were evaluated for activity as Hsp90 inhibitors, HCV entry inhibitors and for neuroprotective activity.
·  Structure activity trends were established for the first time for Hsp90 activity; HCV and neuroprotective structure activity studies are ongoing.
·  More "drug-like" analogs of epigallocatechin gallate were identified that are being used for discovery of second generation compounds.
·  Novel, conformationally restricted diamines were and are being synthesized as templates for structure-activity studies with selected GPCRs and enzyme.

Daniel Rabinovich — University of North Carolina, Charlotte
Wednesday, October 8, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"The World of X-Rays on Postage Stamps: From Radiology to Protein Crystallography" 

Key Lecture Points:
·  A philatelic tribute to the International Year of Crystallography (2014)
·  An overview of the key scientists involved in the discovery of X-rays and the development of X-ray crystallography
·  Postage stamps used to describe molecular structures and the impact of X-ray diffraction in chemistry, biochemistry, mineralogy, medicine, physics, and related fields 

Alexander Tropsha — University of North Carolina, Chapel Hill
Wednesday, October 15, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Integration of Cheminformatics with Additional Data Streams Offers Improved Strategies for Identifying Novel Bioactive and Safe Compounds" 

Key Lecture Points:
This lecture will address...
·  Common challenges facing cheminformatics investigations including data quality (chemical and biological data curation), dataset “modelability," model acceptance criteria, statistical predictive power vs. transparency and interpretability of models.
·  Examples of application of QSAR models to virtual screening resulting in the discovery of novel experimentally confirmed hit compounds.
·   Novel integrative strategies for predicting in vivo effects of chemicals by concordant exploitation of both computed descriptors of chemical structures and additional data streams such as short term biological assay data or side effect profiles.
·   M odel interpretation and will end the talk by summarizing current and developing trends in the field of chemical data modeling.

Gary Sulikowski — Vanderbilt Universityl
Wednesday, October 29, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Synthesis and Study of Natural Products of Relevance to Human Health" 

Key Lecture Points:
·  Apoptolidin and ammocidin microbial derived natural products are reported to be cell selective cytotoxic agents.
·  Structure-activity relationship studies of apopotlidins and ammocidins are enabled using a combination of chemical synthesis, microbial fermentation and biosynthetic manipulation.
·  Chemical synthesis of novel arachidonic acid metabolites.

George Wang — Georgia State University
Wednesday, November 12, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Chemical Biology of Carbohydrates: Design a Synthetic Probe to Investigate a New Drug Mechanism, and Making Glycoconjugate Libraries"

Key Lecture Points:
·  Design, synthesize and biological investigation of the cellular target and mechanism of a antitumor drug for cancer stem cells
·  Chemo-enzymatic synthesis of several sugar libraries for biological evaluation

Robert Eoff — University of Arkansas
Wednesday, November 19, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Translesion DNA Polymerase Kappa Activity is Regulated by the Aryl Hydrocarbon Receptor and Promotes Genomic Instability in Glioma Cells" 

Key Lecture Points:
· Translesion DNA synthesis is involved in the replication stress response
· Mis-regulation of translesion polymerases (pols), such as human pol kappa, occurs in many cancers
· The aryl hydrocarbon receptor stimulates pol kappa expression in glioma cells, which promotes genomic instability
· Indole-derived compounds can act as inhibitors of DNA synthesis
· Small-molecule inhibitors of translesion pols may sensitize tumor cells to genotoxic anti-cancer drugs

Randall Peterson — Harvard
Wednesday, December 3, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"In Vivo Chemical Biology" 

Key Lecture Points:
· Rationale for in vivo small molecule discovery
· Discovery of a novel cardioprotective compound
· Elucidation of the mechanism of cardioprotection from chemotherapy
· Discovery and characterization of novel behavior-modifying compounds

Taekjip Ha — University of Illinois
Wednesday, December 17, 2014 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Surprising Physics of DNA and Nucleosomes and Potential Roles in Gene Regulation" 

Co-hosted by the Department of Pharmacology

Key Lecture Points:
· Rationale for in vivo small molecule discovery
· Single molecule fluorescence-force spectroscopy reveals asymmetry in nucleosome stability
     under tension
· Sequence-dependent DNA flexibility governs nucleosome stability
· Genome-wide mapping of DNA flexibility
· Association between double stranded DNA molecules depends on AT-content and CpG




VICB Weekly Seminar SchedulE - WINTER / SPRING 2015

Thomas O'Halloran — Northwestern University
Wednesday, January 7, 2015 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Transition Metal-Receptor Interactions in Control of Cellular Decisions: Gene Regulation via DNA Distortion and Cooperativity-Based Mechanisms"

Key Lecture Points:
•  Tight-binding metalloenzymes account for many of the transition metal binding sites within a cell. The number of metals bound in regulatory, trafficking and compartmentalized homeostasis sites is significant as well.
• Metal ion movement in and out of these sites is not random and appears to regulate key cellular decisions involving cell cycle control and differentiation.
• The developmental progression of the mammalian egg and the first step of embryo formation require a stepwise series of massive zinc fluctuations.
• These new regulatory mechanisms in the egg, embryo and other cells involve key metal-specific receptors as well as wholesale fluctuations in zinc content and activity in subcellular locations. In this sense zinc joins calcium and phosphorous as conductors of information in biological signaling networks.
• The intracellular movement of transition metals is managed in part by metal-specific transport, metallochaperone and metalloregulatory proteins, which conduct a metal to appropriate intracellular targets or sense changes in metal availability and turn on or off specific genes.
• Recent structural and mechanistic studies of several metalloregulatory proteins reveal novel biophysical mechanisms for transduction of the signal as well as the molecular basis for the remarkable thermodynamic sensitivity of these metal-sensing molecular switches.

Olga Boudker — Cornell University
Wednesday, January 14, 2015 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"Transition Metal-Receptor Interactions in Control of Cellular Decisions: Gene Regulation via DNA Distortion and Cooperativity-Based Mechanisms"

Key Lecture Points:
•  Glutamate transporters are responsible for the clearance of the neurotransmitter glutamate from the synaptic cleft. They maintain a million fold concentration gradient of the transmitter across the membrane by utilizing the energy of electrochemical ionic, principally sodium and potassium, gradients.
• Much of our mechanistic knowledge on these transporters stems from studies on GltPh, a homologue form hyperthermophilic archaeon. Crystallographic studies on GltPh revealed that these transporters function by “elevator” mechanism, whereby a distinct so-called transport domain, which binds substrate and ions, translocates across the membrane within a scaffold provided by a central trimerization domain.
• During transport cycle, the energy of the sodium gradients is harvested primarily during binding, such that sodium ions and substrate bind cooperatively to the transporter. Structural studies reveal the origin of this cooperativity and also demonstrate why the transport domain bound only to sodium is unable to traverse the membrane.
• Contrary to earlier work, our recent studies indicate that GltPh might be similar to the mammalian glutamate transporters in their coupling to potassium. Structural studies suggest the mechanism of how substrate uptake is coupled to the counter-transport of potassium.
• Studies of transporter dynamics using single molecule FRET (smFRET) imaging methods suggest that the transporter constantly samples the states, in which transport domain is positioned on the extracellular and intracellular sides of the membrane, both when it is loaded with substrates and ions and when it is empty. Moreover, the rate of these transitions is limiting to the overall substrate uptake rate.
• Further smFRET, crystallographic and computational studies suggest that the event that determines the rate of transport domain translocation is the structural “unlocking” of the transport domain from the scaffold, which precedes translocation. This process might be facilitated by lipids.

Jay Horton — UT Southwestern
Wednesday, January 28, 2015 — 12:15 P.M. to 1:15 P.M. — 1220 MRB III
"PCSK9: From Gene to Therapeutic Target for Hypercholesterolemia"

Research Overview:
• In clinical digestive diseases, Dr. Horton has an interest in conditions that lead to steatosis
and obesity. Currently the laboratory is investigating molecular mediators of steatosis using
various mouse models. Investigations from the laboratory have revealed how the primary
transcriptional regulators of cholesterol metabolism (sterol regulatory element-binding proteins)
are also key regulators of fatty acid synthesis in liver.
• A major focus of the laboratory is to determine how these transcriptional regulators contribute
to the development of steatosis in various disease processes such as diabetes, obesity,
and beta-oxidation defects.
• A second area of investigation centers on determining the function of PCSK9, a protein that
is involved in determining plasma LDL cholesterol levels through its ability to post-transcriptionally
regulate the expression of the LDL receptor in liver.








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