Sunday, April 6, 2008

April 18 2008 -- Molly Maleckar

Location: Clark 110 Homewood Campus

Title: Searching High and Low: Incorporating various levels of structure and function to more realistically model cardiac arrhythmias

Abstract: Myocytes and fibroblasts are the two major cell types in healthy mammalian myocardium. Although myocytes are primarily responsible for the mechanical function and occupy most of the tissue volume, fibroblasts outnumber myocytes by a ratio of approximately 3:2. In canine left ventricle, fibroblasts have been identified in the immediate vicinity of each myocyte. Gap junctional proteins, connexins 43 (Cx43) and 45 (Cx45), are expressed by cardiac fibroblasts, and dye coupling from fibroblasts to atrial and ventricular myocytes has been demonstrated, suggesting that myocytes and fibroblasts are functionally coupled by gap junctions and may interact via two-way electrotonic signaling. Studies involving electrophysiological coupling have shown that when variable numbers of myofibroblasts were cultured over sheets of neonatal myocytes, recordings from myocytes showed that the rate of action potential depolarization and conduction velocity decreased with increasing density of myofibroblasts. Previous work had shown that mechanosensitive atrial or sinoatrial fibroblasts were also coupled electrotonically to adjacent myocytes Thus, electrotonic coupling can occur in vivo as well as in vitro settings. In addition to having potentially significant effects upon the electrophysiological responses of the myocyte and the local conduction environment, the role of fibroblast membrane kinetics and fibroblast-myocyte coupling in the pathophysiological setting of myocardial fibrosis remains poorly understood. This presentation will offer an overview of a pair of studies whose goal is to elucidate the effects of fibroblast-myocyte interactions on conduction and excitation at the tissue and cellular levels, respectively.

Laboratory: Computational Cardiac Electrophysiology Lab -- Dr. Trayanova

Tuesday, April 1, 2008

Friday Student Seminar and Happy Hour (FSSHH)

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April 4 2008 -- John Issa

Location: Talbot Library Med Campus

Title: Calcium-dependent facilitation of P/Q-type calcium channels

Abstract: Due to its importance in many cellular processes, intracellular calcium is under tight control, thus allowing cells to be sensitive to small changes in calcium levels. One example of this control is the P/Q-type calcium channel, commonly found in neural synapses. Specifically, while a rise in global calcium causes a decrease in currents through these channels, a rise in local calcium on a short timescale causes an increase in currents, a process known as calcium-dependent facilitation (CDF). In this study, we analyzed the nature of this mechanism by recording currents through single P/Q-type channels and comparing the ability of candidate kinetic models to explain the data. Our findings suggest that CDF occurs by an increase in a channel's open probability and not just by increased kinetics or a reduction of inhibition.

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February 29 2008 -- Marcus Jeschke

Location: Clark 110 Homewood Campus

Title: Gamma oscillations during an auditory target-discrimination task reflect matches with short-term memory –
A parallel study in humans and rodents

Abstract: Gamma-band oscillations have been implicated in a variety of cognitive functions as well as more basic stimulus-related aspects of neuronal activity. In an effort to combine a large body of these findings it has recently been proposed that gamma-band oscillations reflect the interaction of incoming sensory information with information about past stimuli stored in memory. Here we investigated the prediction of this ’match-and-utilization’ model that the strength of gamma oscillations depends on the similarity of present stimuli with stored memory templates. We employed an auditory target-discrimination task in which the subjects had to respond to one out of four frequency-modulated tones that varied with respect to two stimulus dimensions, viz. "spectral content" and "modulation direction". We conducted the study in rodents and in humans to exploit the complementary advantages of both paradigms, viz. easy intracerebral recording from primary sensory cortex and monitoring of learning-effects in the rodent experiment, and whole scalp accessibility of EEG signals and straightforward instruction of subjects in the human experiment. In both species, we found that the early, evoked gamma-band activity did not show task- or learning-related modulations, indicating that it reflects aspects of the physical nature of the stimuli. In contrast, the late, induced gamma-band activity was significantly influenced by the task. In both paradigms the target always elicited the strongest gamma-band response, while partial matches with the target resulted in intermediate response strengths. Assigning the role of the target to different stimuli led to the same result in the human subjects. In the
animal subjects, the dependence of the gamma-band response strength on the similarity with the target developed with learning and was not found in naïve animals. In combination, our results add further support for the general validity of the match-and-utilization model of gamma-band oscillations.

Laboratory: Laboratory of Auditory Neurophysiology -- Dr. Wang -- http://www.jhu.edu/xwang/



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February 15 2008 -- Laura Doyle

Location: Clark 110 Homewood Campus

Title: A virtual environment simulator for cataract surgery

Abstract: Phacoemulsification cataract surgery is one of the most commonly performed surgical procedures in the western world. Conventional training for this procedure involves didactic lectures and practice on pig and human cadaver eyes, none of which allow trainees to form an accurate predictive model of human tissue behavior during surgery. A virtual environment simulator for capsulorrhexis, one of the first steps in cataract surgery, has been developed. The simulator invokes a deformable mass-spring-damper mesh model of the tissue that can be grasped and torn via shearing. The trainee controls tool motion using a 3-degree-of-freedom haptic device, and haptic feedback is provided from the virtual tissue.

Laboratory: Haptics Laboratory -- Dr. Okamura -- http://haptics.lcsr.jhu.edu/Main_Page


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November 30 2007 -- Mike Tadross

Location: Talbot Library Med Campus

Title: Mechanism of Spatial Ca2+ Selectivity within Nanometers of a Ca 2+ Source

Abstract: A prototype for Ca2+ sensors positioned within nanometers of a Ca 2+ source is calmodulin (CaM) in complex with Ca2+ channels. The C-lobe of CaM senses local, large Ca2+ oscillations due to Ca 2+ influx from its home channel, and its N-lobe senses global, albeit diminutive Ca2+ changes arising from distant sources. Though biologically essential, the mechanism of global Ca2+ sensing has defied explanation. Here, we advance a theory of how global selectivity arises, and validate this proposal with new experimental tools enabling millisecond control of Ca 2+ oscillations within nanometers of intact channels. We find that global selectivity arises from rapid Ca2+ release from CaM combined with greater affinity of the channel for Ca2+‑free versus Ca2+-bound CaM. The emergence of complex decoding properties from the combination of common elements, and the techniques developed herein, promise generalization to numerous molecules residing near Ca 2+ sources.

Laboratory: Calcium Signals Laboratory -- Dr. Yue -- http://webhost5.nts.jhu.edu/csl/

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November 16 2007-- Ivy Dick

Location: Talbot Library Med Campus

Title: Modular transformation of spatial Ca2+ selectivity in the calmodulin regulation of Ca2+ channels

Abstract: Ca2+/calmodulin-dependent regulation of voltage-gated CaV1-2 Ca2+ channels exhibits extraordinary modes of spatial Ca2+ decoding and channel modulation1-6, which are vital for many biological functions6-9 . A single calmodulin (CaM) constitutively associates with the channel carboxy tail3,10-13, and Ca2+ binding to the C- and N-terminal lobes of CaM can each initiate distinct channel regulatory processes2,14. As expected from close channel proximity, the C-lobe responds rapidly to the ~100 mM pulses driven by the associated channel15,16, a behavior defined as ‘local Ca2+ selectivity.’ Conversely, all prior observations indicate that the N-lobe somehow senses the far weaker signals from distant Ca2+ sources 2,3,17,18. This ‘global Ca2+ selectivity’ satisfies a general signaling requirement, enabling a resident molecule to remotely sense cellular Ca2+ activity, which would otherwise be overshadowed by Ca2+ entry through the host channel5,6. Here, we report that the spatial Ca2+ selectivity of N-lobe CaM regulation is not invariably global, but can be switched by a novel Ca2+/CaM binding site within the amino terminus of channels (NSCaTE, N-terminal Spatial Ca2+ Transforming Element). Native CaV2.2 channels lack this element, and display N-lobe regulation with a global selectivity. Upon introducing NSCaTE into these channels, spatial Ca2+ selectivity transforms from a global to local profile. Given this effect, we examine CaV1.2/CaV1.3 channels, which naturally contain NSCaTE, and find that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus differences in spatial selectivity between advanced CaV1 and CaV 2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel amino terminus indicates that CaM can bridge the amino and carboxy termini of channels. Finally, the modularity of NSC
aTE offers practical means to understand the basis of global Ca2+ selectivity19.

Laboratory: Calcium Signals Laboratory -- Dr. Yue -- http://webhost5.nts.jhu.edu/csl/

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October 12 2007 -- Hermenegild Arevalo

Location: Clark 110 Homewood Campus

Title: Role of intrinsic heterogeneities in organization of ventricular fibrillation

Abstract: Although ventricular fibrillation (VF) is the prevalent cause of sudden cardiac death, the mechanisms that underlie VF remain elusive. Two hypothesis have been presented concerning the organization of electrical activity during VF. One posits that VF is driven by dynamic break-up of wavefronts due to functional heterogeneities, while the other predicts that intrinsic heterogeneity can lead to the formation of a single rotor that drives the fibrillatory activity in the entire heart. To provide insight into this mechanism, we incorporate action potential duration (APD) heterogeneity between the left and right ventricles in a computational model of the rabbit heart. Our simulations show that APD heterogeneity contributes to the initiation and maintenance of VF by providing regions of different refractoriness which serves as sites of wave break and rotor formation. The 3D computer simulations suggest that APD spatial heterogeneity alone can not lead to the formation of a stable
rotor. Although the results of this study support the multiple wavelet hypothesis, I will present new results suggesting that the incorporation of other types of intrinsic heterogeneity can lead to the formation of mother rotor activity.

Laboratory: Computational Cardiac Electrophysiology Lab -- Dr. Trayanova --
http://www.jhu.edu/trayanova/research/lab/lab.html



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September 21 2007 -- Elias Issa

Location: Talbot Library Med Campus

Title: Why you do not hear as well while you sleep

Abstract: Whereas the eyelids block most incoming light, the ears are open to sounds even when you sleep. Somewhere in the brain, activity may be switched off. Surprisingly, though, researchers have found sound-evoked activity as far as primary auditory cortex during sleep. We hypothesized that the switch may lie in the next stage, secondary auditory cortex. Instead, we found that activity is not attenuated even in this higher brain area. An alternative hypothesis is that the switch may not be a simple on/off. Supporting this notion, we find that responses to quiet sounds but not loud sounds are depressed, and inhibitory, not excitatory, processes are selectively turned off. Both phenomena limit the dynamic range available for processing sounds without necessarily switching off responses. The emerging view is that general monitoring of sounds can still occur during sleep but that active, fine-grained listening may only be possible while awake.

Laboratory: Laboratory of Auditory Neurophysiology -- Dr. Wang -- http://www.jhu.edu/xwang/





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September 7 2007 -- Manos Karagiannis

Location: Talbot Library Med Campus

Title: Deciphering the antiangiogenic code: Genome-wide identification of novel endogenous angiogenesis inhibitors

Abstract: Angiogenesis, or neovascularization, is tightly orchestrated by endogenous regulators that promote or inhibit the process. The fine-tuning of these pro- and antiangiogenic elements (the angiogenic balance) helps establishing the homeostasis in tissues, and aberrations lead to pathologic conditions. To date, the quest for the experimental identification of novel angiogenesis inhibitors has been an empirical time-consuming process. In this presentation, we will describe a computational bioinformatics methodology followed by in vitro, ex vivo and in vivo experimental screening to identify and classify 110 novel endogenous putative antiangiogenic peptides. By integrating computational and experimental approaches we introduce a novel systematic methodology to identify endogenous bioactive peptides. The identification of such novel peptides enhances our knowledge of the control of the angiogenic balance and can lead to development of diverse antiangiogenic therapies.

Laboratory: Systems Biology Laboratory -- Dr. Popel -- http://www.jhu.edu/apopel/





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August 24 2007 -- Yasmin Hashambhoy

Location: Clark 110 Homewood Campus

Title: Why CaMKII is important to YOU

Abstract: I will briefly talk about the Winslow lab's cardiac ventricular myocyte models and how such mathematical representations can be used to further drive experiments. For the most part, the presentation will focus on calmodulin kinase II (CaMKII), a protein kinase that is suspected to play a significant role in the generation of arrhythmias. I will describe the approach I am taking to build a mechanistic model of the kinase with its substrates, and the fluorescence reporter I will use to test predictions generated from my model.

Laboratory: Center for Cardiovascular Bioinformatics and Modeling -- Dr. Winslow -- http://www.ccbm.jhu.edu/index.php

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August 3 2007 -- Charles Fisher

Location: Talbot Library Med Campus

Title: Surface-induced organization of Filamentous Actin

Abstract: Crucial for cell motility, actin polymerization generates forces against a surface. However, direct physical characterization has been sparse. Using indirect methods, we first showed anomalous mechanical motions of particles in actin gels correlate with surface binding. Although depletion of actin filaments has been suggested as an explanation, electron microscopy has been inconclusive. Using confocal microscopy, we directly characterize the concentration profile of fluorescently modified actin near a flat surface. Marked with a different fluorescent label, the glass surface is the fiducial reference. As expected, surfaces that bind actin show an enrichment near the surface. Interestingly, a non-actin binding surface shows a monotonic depletion of F-actin concentration, often starting more than three micrometers from the surface. In contrast, monomeric actin has a uniform concentration throughout the depth of the slide. Starting with monomeric actin, depletion proceeds concomitantly with polymerization. With higher actin concentrations, depletion kinetics are faster but the extent is reduced. Because F-actin is semiflexible, we hypothesize depletion is dependent on both persistence length and average length. Consistent with this notion, phalloidin increases while capping protein reduces the depletion zone. This work provides the first direct evidence of mechanically induced rearrangement of F-actin proximal to a surface. The unexpected size of the depletion zone suggests a new role for actin regulatory processes to properly localize F-actin within cells.

Laboratory: Advanced Optics Laboratory -- Dr. Kuo -- http://www.jhu.edu/cmml/index.html




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July 20 2007 -- Eric Tuday

Location: Talbot Library Med Campus

Title: Microgravity Induced Changes in Aortic Stiffness and Their Role in Orthostatic Intolerance

Abstract:

Microgravity (µG) induced orthostatic intolerance (OI) in astronauts, a common consequence of manned spaceflight, is characterized by a marked decrease in cardiac output (CO) in response to an orthostatic stress. Since CO is highly dependent on venous return, alterations in the resistance to venous return (RVR) may be important in contributing to OI. The RVR is directly dependent on arterial compliance (CA), where aortic compliance (Ca) contributes up to 60% of CA. We tested the hypothesis that µG induced changes in Ca may represent a protective mechanism against OI. A retrospective analysis on hemodynamic data collected from astronauts after 5-18 day spaceflight missions revealed that orthostatically tolerant (OT) astronauts showed a significant decrease in Ca after spaceflight (1.996±0.09741 ml/mmHg to 1.707±0.08313 ml/mmHg; p=0.0011; N =40) while OI astronauts showed a slight increase in Ca. A ground based animal model simulating µG, hindlimb unweighted rats, was used to explore this phenomenon. Two independent assessments of Ca, in vivo pulse wave velocity (PWV) and in vitro pressure-diameter squared relationships were determined, both showed significant increases in aortic stiffness compared to control (PWV: 7.227±0.1375 m/s vs. 4.074±0.1879 m/s, p<0.0001). id="jccu">a. The difference in Ca in OT and OI astronaut suggests that the µG induced decrease in Ca is a protective adaptation to spaceflight that reduces the RVR and allows for the maintenance of adequate CO in response to an orthostatic stress.



Laboratory: Cardiovascular Systems Laboratory -- Dr. Shoukas -- http://webhost5.nts.jhu.edu/shoukas/



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June 22 2007 -- Tricia Arauz

Location: Talbot Library Med Campus

Title: Characterization of Fibroblast-Derived Extracellular Matrices for Tissue Engineering

Abstract: Cellular functions, such as proliferation and differentiation, are affected by their microenvironment. Cells cultured on typical two dimensional plastic culture dishes do not mimic the natural three dimensional extracellular matrix (ECM) environment found in vivo and thus, the cells respond differently in the two different environments. Synthetic materials have been developed to mimic the regulatory characteristics of natural ECM. However, these simplified models lack the essential spatial and temporal complexity found in vivo. We have developed a technique in which fibroblast-produced ECM can be used as a scaffold to study three dimensional culture of endothelial cells. We have characterized the biochemical, structural, and mechanical properties of the ECM. Finally, we have seeded endothelial cells onto the ECMs to study the cell interaction with the matrices and their potential use as a tissue engineering scaffold.

Laboratory: Cellular and Molecular Medicine -- Dr. Romer -- http://cmm.jhmi.edu/index.php?title=Home

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June 8 2007 -- Brock Tice

Location: Clark 110 Homewood Campus

Title: Using PubMed, HubMed, RSS, and Cite-U-Like to collect and manage references

Abstract: Over the past few years, a number of new reference tools, as well as new methods for accessing older reference tools, have emerged. The tools to be covered in this talk are PubMed, which you are probably familiar with, HubMed, which is a cleaner interface to PubMed with some nice features, how to get RSS feeds that deliver the papers you want on a regular basis automatically, and Cite-U-Like (an online reference manager) to wrangle your findings from the others. I will present a brief overview of how to search PubMed and HubMed, perhaps in ways you're not familiar with, the nature of RSS in case you're not familiar with it, and how to get and use RSS feeds from both. I'll demonstrate the key features of Cite-U-Like, how to post articles to it, how to add your personal PDF copies of articles, and how to set up a Cite-U-Like group for your lab. Finally, I'll demonstrate typical workflows for pulling references from a journal article and posting them to Cite-U-Like, and for processing incoming RSS feeds and adding important items from them to Cite-U-Like.

I'll work hard to keep it concise and useful, and leave plenty of time for questions.

Laboratory: Computational Cardiac Electrophysiology Lab -- Dr. Trayanova --
http://www.jhu.edu/trayanova/research/lab/lab.html

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May 11 2007 -- Chris Long

Location: Talbot Library Med Campus

Title: Molecular Imaging in Tumor Immunology

Abstract: Cancer vaccines have been used in the clinic for two decades obtaining only low objective response rates. The field is in need of adjuvants to aide in vaccine responses. However, to date, most studies have focused on clinical responses without monitoring relevant immune responses. A combination will help us improve the use of adjuvants and extend our ability to monitor the benefits of cancer vaccines. I will describe one such scenario where we monitor dendritic cell trafficking using magnetic resonance imaging in an attempt to develop a better adjuvant-vaccine combination.

Laboratory: Institute for Cellular Engineering, Vascular Biology -- Dr. Bulte --
http://www.hopkins-ice.org/vascular/int/bulte.html


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April 27 2007 -- Brock Tice

Location: Clark 110 Homewood Campus

Title: Development and Study of Models of Endocardial Microstructure

Abstract: Optical Coherence Tomography (OCT) can be used to acquire high-resolution images from relatively thin preparations. In collaboration with the lab of Igor Efimov, we have used OCT data from the rabbit right-ventricular endocardium to develop three small wedge models of the endocardial surface. Experimentally, it has been shown that small to medium structures on the endocardial surface of the atria can precipitate the breakup of electrical conduction at high pacing rate. We are using these small models of the right-ventricular endocardium to find out whether, and under what conditions, this can occur in the endocardial microstructure of the ventricles. Experimental techniques that image activity in the endocardium typically use optical mapping of voltage-sensitive dyes, which results in "blurred" data due to light scattering. Using these small, high-resolution computational models, we are able to determine which structures affect propagation and breakup when rapid stimuli are applied.

Laboratory: Computational Cardiac Electrophysiology Lab -- Dr. Trayanova --
http://www.jhu.edu/trayanova/research/lab/lab.html

http://virtuallyshocking.com/about/

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April 13 2007 -- Dan Bendor

Location:
Talbot Library Med Campus

Title: How do monkeys hear sounds?

Abstract: We recognize a musical tune, by identifying the pattern of changing pitches (melody) and temporal rates (rhythm). By studying the brain areas of the marmoset monkey involved in hearing, I have identified neurons that recognize the pitch and temporal rate of sounds. This talk will discuss how we record single neuron activity in awake monkeys, and briefly summarize my findings.

Laboratory: Laboratory of Auditory Neurophysiology -- Dr. Wang -- http://www.jhu.edu/xwang/

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