Faculty Bibliography

There are two promising herpes viral-based anticancer strategies: one involves replication-defective viruses to transfer therapeutic transgenes, and the other involves replication-conditional oncolytic viruses, which selectively infect and destroy cancer cells directly. This study examines a novel dual herpesvirus preparation, which combines the immunostimulatory effects of amplicon-mediated IL2 expression with direct viral-induced oncolysis. The oncolytic virus G207 was used as the helper virus to package a herpes simplex virus (HSV)-amplicon vector carrying the gene IL2 (HSV-IL2), yielding a single preparation with two complementary modes of action. In vivo comparison was carried out in a syngeneic squamous cell carcinoma flank tumor model. We directly injected established tumors with HSV-IL2, G207, G207 mixed with HSV-IL2, or G207-packaged HSV-amplicon carrying the IL2 transgene (G207[IL2]). Significant inhibition of tumor growth was seen at 2 weeks in the G207[IL2]-treated tumors relative to controls (0.57+/-0.44 cm(3) versus 39.45+/-5.13 cm(3), P<0.00001), HSV-IL2 (20.97+/-4.60 cm(3)), and the G207 group (7.71+/-2.10 cm(3)). This unique use of a replication-conditional, oncolytic virus to package a replication-incompetent amplicon vector demonstrates impressive efficacy in vitro and in vivo, and avoids the theoretical concerns of recombination with reversion to wild type

Organelle transport by myosin-V is down-regulated during mitosis, presumably by myosin-V phosphorylation. We used mass spectrometry phosphopeptide mapping to show that the tail of myosin-V was phosphorylated in mitotic Xenopus egg extract on a single serine residue localized in the carboxyl-terminal organelle-binding domain. Phosphorylation resulted in the release of the motor from the organelle. The phosphorylation site matched the consensus sequence of calcium/calmodulin-dependent protein kinase II (CaMKII), and inhibitors of CaMKII prevented myosin-V release. The modulation of cargo binding by phosphorylation is likely to represent a general mechanism regulating organelle transport by myosin-V

The flow of activity in the cortical microcircuitry is poorly understood. We use calcium imaging to reconstruct, with millisecond and single-cell resolution, the spontaneous activity of populations of neurons in unstimulated slices from mouse visual cortex. We find spontaneous activity correlated among networks of layer 5 pyramidal cells. Synchronous ensembles occupy overlapping territories, often share neurons, and are repeatedly activated. Sets of neurons are also sequentially activated numerous times. Network synchronization and sequential correlations are blocked by glutamatergic antagonists, even though spontaneous firing persists in many 'autonomously active' neurons. This autonomous activity is periodic and depends on hyperpolarization-activated cationic (H) and persistent sodium (Na(p)) currents. We conclude that the isolated neocortical microcircuit generates spontaneous activity, mediated by a combination of intrinsic and circuit mechanisms, and that this activity can be temporally precise

Two of the primary cues used to localize the sources of sounds are interaural level differences (ILDs) and interaural time differences (ITDs). We conducted two experiments to explore how practice affects the human discrimination of values of ILDs and ongoing ITDs presented over headphones. We measured discrimination thresholds of 13 to 32 naive listeners in a variety of conditions during a pretest and again, 2 weeks later, during a posttest. Between those two tests, we trained a subset of listeners 1 h per day for 9 days on a single ILD or ITD condition. Listeners improved on both ILD and ITD discrimination. Improvement was initially rapid for both cue types and appeared to generalize broadly across conditions, indicating conceptual or procedural learning. A subsequent slower-improvement stage, which occurred solely for the ILD cue, only affected conditions with the trained stimulus frequency, suggesting that stimulus processing had fundamentally changed. These different learning patterns indicate that practice affects the attention to, or low-level encoding of, ILDs and ITDs at sites at which the two cue types are processed separately. Thus, these data reveal differences in the effect of practice on ILD and ITD discrimination, and provide insight into the encoding of these two cues to sound-source location in humans

In many areas of the nervous system, excitatory and inhibitory synapses are reconfigured during early development. We have previously described the anatomical refinement of an inhibitory projection from the medial nucleus of the trapezoid body to the lateral superior olive in the developing gerbil auditory brain stem. Furthermore, these inhibitory synapses display an age-dependent form of long-lasting depression when activated at a low rate, suggesting that this process could support inhibitory synaptic refinement. Since the inhibitory synapses release both glycine and GABA during maturation, we tested whether GABA(B) receptor signaling could initiate the decrease in synaptic strength. When whole cell recordings were made from lateral superior olive neurons in a brain slice preparation, the long-lasting depression of medial nucleus of the trapezoid body-evoked inhibitory potentials was eliminated by the GABA(B) receptor antagonist, SCH-50911. In addition, inhibitory potentials could be depressed by repeated exposure to the GABA(B) receptor agonist, baclofen. Since GABA(B) receptor signaling may not account entirely for inhibitory synaptic depression, we examined the influence of neurotrophin signaling pathways located in the developing superior olive. Bath application of brain-derived neurotrophic factor or neurotrophin-3 depressed evoked inhibitory potentials, and use-dependent depression was blocked by the tyrosine kinase antagonist, K-252a. We suggest that early expression of GABAergic and neurotrophin signaling mediates inhibitory synaptic plasticity, and this mechanism may support the anatomical refinement of inhibitory connections

OBJECTIVES/HYPOTHESIS: Unilateral vocal fold paralysis resulting in glottal incompetence can cause significant morbidity attributable to impaired speech, swallowing, and ability to protect the airway. Type I thyroplasty in combination with arytenoid adduction is a proven technique for medialization of the paralyzed vocal fold but must be evaluated in light of potential complications following laryngeal framework surgery. STUDY DESIGN AND METHODS: The charts of 237 patients who underwent unilateral vocal fold medialization surgery between July 1, 1991, and August 30, 1999, at a tertiary care cancer referral center were retrospectively reviewed. RESULTS: There were 98 cases of type I thyroplasty alone and 96 cases of type I thyroplasty with arytenoid adduction. The two groups had similar patient characteristics. Mean time of surgery (45 vs. 73 min, P <.0001) and length of hospital stay (1.1 vs. 1.8 d, P <.0001) were increased when arytenoid adduction was performed. Overall improvement of symptoms was similar in both groups (93%-94%), but posterior glottic closure appeared subjectively improved when arytenoid adduction was used (P =.0054). Overall complication rates were slightly higher in the arytenoid adduction group (14% vs. 19%), primarily because of transient vocal fold edema and wound complications (9 vs. 19 cases), but the increase was not statistically significant (P =.1401). Complications warranting medical or surgical intervention occurred in 8% of cases. Two patients who underwent type I thyroplasty with arytenoid adduction required tracheotomy as a consequence of postoperative complications. The three patients who had extrusion of the implant underwent type I thyroplasty alone. CONCLUSION: Using the appropriate technique, the potential benefits of improved glottic function following type I thyroplasty with arytenoid adduction outweigh the small risk of significant complications observed

This paper considers the information transmitted in absolute judgments as encoded in a stimulus-response matrix (e.g., see Garner and Hake, 1951). When transmitted information is plotted against the number of stimulus categories in the matrix, one obtains a curve that increases monotonically toward a plateau, which is the maximum information transmittable per stimulus for the particular range of stimuli employed. We demonstrate that although the maximum information transmitted is an attribute of the stimulus continuum itself, the shape of the curve is an empirical property of the stimulus-response matrix, which is determined, in part, by maintaining a constant stimulus category width. Therefore, in principle, each curve of information transmitted vs number of stimulus categories can be determined by a single point: the rightmost point on the graph.