bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of Apoptosis by G3139 in Melanoma Cells
Authors: BENIMETSKAYA LUBA , LAI JOHNATHAN C. , KHVOROVA ANASTASIA , WU SIJIAN , MILLER PAUL , STEIN C A
Published: January 2006

G3139 is an 18mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl‐2 mRNA. Because of the ability of this antisense construct to downregulate the expression of Bcl‐2 mRNA and protein, it has entered phase III clinical trials in a number of human cancers, including advanced melanoma. However, the actual mechanism of this agent is far from certain. In this work, we demonstrate that G3139 induces the relatively rapid release of cytochrome c into the cytoplasm of treated 518A2 melanoma cells. This release activates the intrinsic pathway of apoptosis, eventually leading to a mitochondrial permeability transition and cell death. By employing an siRNA strategy, we also show that this entire process appears to be Bcl‐2 independent, as downregulation of Bcl‐2 protein expression does not alter the induction of apoptosis by G3139. Furthermore, forced overexpression of Bcl‐2 protein contributes relatively little to chemoresistance in this cell line. While these results may or may not be reflective of the in vivo situation, the value of Bcl‐2 as a target in advanced melanoma must at least be questioned.
Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal Function
Authors: Mita Alain C. , Sweeney Christopher J. , Baker Sharyn D. , Goetz Andrew , Hammond Lisa A. , Patnaik Amita , Tolcher Anthony W. , Villalona-Calero Miguel , Sandler Alan , Chaudhuri Tuhin , Molpus Kathleen , Latz Jane E. , Simms Lorinda , Chaudhary Ajai K. , Johnson Robert D. , Rowinsky Eric K. , Takimoto Chris H.
Published: January 2006

Purpose

This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.

Patients and Methods

Patients received a 10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from ≥ 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12.

Results

Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and nonsupplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR ≥ 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2.

Conclusion

Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR ≥ 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Palifermin Reduces Patient-Reported Mouth and Throat Soreness and Improves Patient Functioning in the Hematopoietic Stem-Cell Transplantation Setting
Authors: Stiff Patrick J. , Emmanouilides Christos , Bensinger William I. , Gentile Teresa , Blazar Bruce , Shea Thomas C. , Lu John , Isitt John , Cesano Alessandra , Spielberger Ricardo
Published: January 2006

Purpose

To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians' assessments of oral mucositis using objective scales.

Patients and Methods

Patients (n = 212) received palifermin (60 μg/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients' self-assessment data were compared with clinicians' assessments of oral mucositis using the objective scales.

Results

Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians' assessments. Patients receiving palifermin reported statistically significant improvements (P < .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P < .001); improvement in the patient's overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire.

Conclusion

These results support the clinical benefit of palifermin in the HSCT setting, providing evidence that a patient's self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.
The RhoA/ROCK-I/MLC pathway is involved in the ethanol-induced apoptosis by anoikis in astrocytes
Authors: Miñambres Rebeca , Guasch Rosa M. , Perez-Aragó Amparo , Guerri Consuelo
Published: January 2006

Anoikis is a programmed cell death induced by loss of anchorage that is involved in tissue homeostasis and disease. Ethanol is an important teratogen that induces marked central nervous system (CNS) dysfunctions. Here we show that astrocytes exposed to ethanol undergo morphological changes associated with anoikis, including the peripheral reorganization of both focal adhesions and actin-myosin system, cell contraction, membrane blebbing and chromatin condensation. We found that either the small GTPase RhoA or its effector ROCK-I (Rho kinase), promotes membrane blebbing in astrocytes. Ethanol induces a ROCK-I activation that is mediated by RhoA, rather than by caspase-3 cleavage. Accordingly, the RhoA inhibitor C3, completely abolishes the ethanol-induced ROCK-I activation. Furthermore, inhibition of both RhoA and ROCK prevents the membrane blebbing induced by ethanol. Ethanol also promotes myosin light chain (MLC) phosphorylation, which might be involved in the actin-myosin contraction. All of these findings strongly support that ethanol-exposed astrocytes undergo apoptosis by anoikis and also that the RhoA/ROCK-I/MLC pathway participates in this process.
Uncoupling proteasome peptidase and ATPase activities results in cytosolic release of an ER polytopic protein
Authors: Oberdorf Jon , Carlson Eric J. , Skach William R.
Published: January 2006

The 26S proteasome is the primary protease responsible for degrading misfolded membrane proteins in the endoplasmic reticulum. Here we examine the specific role of β subunit function on polypeptide cleavage and membrane release of CFTR, a prototypical ER-associated degradation substrate with 12 transmembrane segments. In the presence of ATP, cytosol and fully active proteasomes, CFTR was rapidly degraded and released into the cytosol solely in the form of trichloroacetic acid (TCA)-soluble peptide fragments. Inhibition of proteasome β subunits markedly decreased CFTR degradation but surprisingly, had relatively minor effects on membrane extraction and release. As a result, large TCA-insoluble degradation intermediates derived from multiple CFTR domains accumulated in the cytosol where they remained stably bound to inhibited proteasomes. Production of TCA-insoluble fragments varied for different proteasome inhibitors and correlated inversely with the cumulative proteolytic activities of β1, β2 and β5 subunits. By contrast, ATPase inhibition decreased CFTR release but had no effect on the TCA solubility of the released fragments. Our results indicate that the physiologic balance between membrane extraction and peptide cleavage is maintained by excess proteolytic capacity of the 20S subunit. Active site inhibitors reduce this capacity, uncouple ATPase and peptidase activities, and generate cytosolic degradation intermediates by allowing the rate of unfolding to exceed the rate of polypeptide cleavage.
Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking
Authors: Zeng Xuehuo , Overmeyer Jean H. , Maltese William A.
Published: January 2006

Beclin 1 was originally identified as a novel Bcl-2-interacting protein, but co-immunoprecipitation studies suggest that the major physiological partner for Beclin 1 is the mammalian class III phosphatidylinositol 3-kinase (PI 3-kinase) Vps34. Beclin 1 has been proposed to function as a tumor suppressor by promoting cellular macroautophagy, a process that is known to depend on Vps34. However, an alternative role for Beclin 1 in modulating normal Vps34-dependent protein trafficking pathways has not been ruled out. This possibility was examined in U-251 glioblastoma cells. Immunoprecipitates of endogenous Beclin 1 contained human Vps34 (hVps34), but not Bcl-2. Suppression of Beclin 1 expression by short interfering (si)RNA-mediated gene silencing blunted the autophagic response of the cells to nutrient deprivation or C2-ceramide. However, other PI 3-kinase-dependent trafficking pathways, such as the post-endocytic sorting of the epidermal growth factor receptor (EGFR) or the proteolytic processing of procathepsin D en route from the trans-Golgi network (TGN) to lysosomes, were not affected. Depletion of Beclin 1 did not reduce endocytic internalization of a fluid phase marker (horseradish peroxidase, HRP) or cause swelling of late endosomal compartments typically seen in cells where the function of hVps34 is impaired. These findings argue against a role for Beclin 1 as an essential chaperone or adaptor for hVps34 in normal vesicular trafficking, and they support the hypothesis that Beclin 1 functions mainly to engage hVps34 in the autophagic pathway.
Mdy2, a ubiquitin-like (UBL)-domain protein, is required for efficient mating in Saccharomyces cerevisiae
Authors: Hu Zheng , Potthoff Bernd , Hollenberg Cornelis P. , Ramezani-Rad Massoud
Published: January 2006

MDY2, a gene required for efficient mating of the yeast Saccharomyces cerevisiae, was characterized in this study. The gene encodes a protein of 212 amino acids, which contains a ubiquitin-like (UBL) domain (residues 74-149). Deletion of MDY2 is associated with a five- to sevenfold reduction in mating efficiency, mainly due to defects in nuclear migration and karyogamy at the prezygotic stage. However, prior to mating pair fusion, shmoo formation is reduced by 30%, with a concomitant failure to form mating pairs. Strikingly, migration of the nucleus into the shmoo tip is also delayed or fails to occur. In addition, we show that in mdy2 mutants, microtubule bundles, as well as the microtubule end-binding protein Kar9, fail to localize properly to the shmoo tip, suggesting that the nuclear migration defect could be due to aberrant localization of Kar9. Pheromone signal transduction (as measured by FUS1 induction by α-factor) is not affected in mdy2Δ mutants and mitosis is also normal in these cells. MDY2 is not induced by mating pheromone. In vegetatively growing cells, GFP-Mdy2 is localized in the nucleus, and remains nuclear after exposure of cells to α-factor. His-tagged Mdy2 shows no evidence of the C-terminal processing typical of ubiquitin, and also localizes to the nucleus. Thus MDY2 is a novel gene, whose product plays a role in shmoo formation and in nuclear migration in the pre-zygote, possibly by interacting with other UBL-type proteins that possess ubiquitin association (UBA) domains.
Oxidative stress during stressful heat exposure and recovery in the North Sea eelpoutZoarces viviparusL.
Authors: Heise Katja , Puntarulo Susana , Nikinmaa Mikko , Abele Doris , Pörtner Hans-O.
Published: January 2006

The interplay between antioxidants, heat shock proteins and hypoxic signaling is supposed to be important for passive survival of critical temperature stress, e.g. during unfavorable conditions in hot summers. We investigated the effect of mild (18°C), critical (22°C) and severe(26°C) experimental heat stress, assumed to induce different degrees of functional hypoxia, as well as the effect of recovery following heat stress on these parameters in liver samples of the common eelpout Zoarces viviparus.

Upon heat exposure to critical and higher temperatures we found an increase in oxidative damage markers such as TBARS (thiobarbituric reactive substances)and a more oxidized cellular redox potential, combined with reduced activities of the antioxidant enzyme superoxide dismutase at 26°C. Together, these point to higher oxidative stress levels during hyperthermia. In a recovery-time series, heat-induced hypoxia and subsequent reoxygenation upon return of the fishes to 12°C led to increased protein oxidation and chemiluminescence rates within the first 12 h of recovery, therein resembling ischemia/reperfusion injury in mammals.

HSP70 levels were found to be only slightly elevated after recovery from sub-lethal heat stress, indicating minor importance of the heat shock response in this species. The DNA binding activity of the hypoxia-inducible transcription factor (HIF-1) was elevated only during mild heat exposure(18°C), but appeared impaired at more severe heat stress. We suppose that the more oxidized redox state during extreme heat may interfere with the hypoxic signaling response.
Dynamics of geckos running vertically
Authors: Autumn K. , Hsieh S. T. , Dudek D. M. , Chen J. , Chitaphan C. , Full R. J.
Published: January 2006

Geckos with adhesive toe pads rapidly climb even smooth vertical surfaces. We challenged geckos (Hemidactylus garnotii) to climb up a smooth vertical track that contained a force platform. Geckos climbed vertically at up to 77 cm s-1 with a stride frequency of 15 Hz using a trotting gait. During each step, whole body fore–aft, lateral and normal forces all decreased to zero when the animal attached or detached its toe pads. Peak fore–aft force was twice body weight at mid-step. Geckos climbed at a constant average velocity without generating decelerating forces on their center of mass in the direction of motion. Although mass-specific mechanical power to climb was ten times the value expected for level running, the total mechanical energy of climbing was only 5–11% greater than the potential energy change. Fore- and hindlegs both pulled toward the midline, possibly loading the attachment mechanisms. Attachment and detachment of feet occupied 13% and 37% of stance time, respectively. As climbing speed increased, the absolute time required to attach and detach did not decrease, suggesting that the period of fore–aft force production might be constrained. During ascent, the forelegs pulled toward, while hindlegs pushed away from the vertical surface, generating a net pitching moment toward the surface to counterbalance pitch-back away from the surface. Differential leg function appears essential for effective vertical as well as horizontal locomotion.
Neural responses of goldfish lateral line afferents to vortex motions
Authors: Chagnaud Boris Phillippe , Bleckmann Horst , Engelmann Jacob
Published: January 2006

The lateral line system of fish is sensitive to weak water motions. We recorded from posterior lateral line nerve afferents while stimulating goldfish, Carassius auratus, with unidirectional water flow and with a vortex ring. Posterior lateral line afferents of goldfish were either flow sensitive or flow insensitive. Both types of afferents responded to a vortex ring that passed the fish laterally with one to three reproducible patterns of neural activity, followed by activity patterns that were less reproducible. Using particle image velocimetry, we visualized and quantified the water motions in the vertical plane next to the surface of the fish while recording from lateral line afferents. Early response components correlated with the direction of water motions that occurred at the position of the neuromast recorded from. By contrast, neural activity that occurred after the vortex had passed the fish barely predicted the direction of water motions. These results are in agreement with the known directional sensitivity of hair cells and indicate that fish might be able to extract sensory information from complex stimuli like vortices by comparing the activity of a whole array of neuromasts. The stimulus used in this study is novel to lateral line research and resembles some of the hydrodynamic stimuli that fish might encounter in their natural environments. We expect that by combining naturalistic hydrodynamic stimuli and central nervous recordings, we will learn if and how hydrodynamic feature detection is accomplished by the lateral line system.
Parvalbumin correlates with relaxation rate in the swimming muscle of sheepshead and kingfish
Authors: Wilwert Jennifer L. , Madhoun Nisreen M. , Coughlin David J.
Published: January 2006

Parvalbumin is a muscle protein that aids in relaxation from contraction. Parvalbumin binds myoplasmic Ca2+ during contractions, reducing calcium concentration and enhancing relaxation. Different isoforms of parvalbumin have varying affinities for calcium, and relaxation rates in skeletal muscle may be affected by variations in the isoforms of parvalbumin expressed. This study examines the effect of expression levels of parvalbumin isoforms on relaxation rate in the sheepshead, Archosargus probatocephalus (Pisces, F. Sparidae). We measured relaxation rate of each of the three fiber types, white (fast-twitch), red (slow-twitch) and pink(intermediate), from three longitudinal body positions. Sheepshead show a significant longitudinal shift in relaxation rate in red muscle, with anterior muscle displaying faster rates of relaxation than posterior, but this pattern was not significant in the pink and white muscle. We hypothesized that patterns of parvalbumin expression determine relaxation rate along the length of the fish. The prediction is that total parvalbumin content and the relative expression of parvalbumin isoforms will differ between the anterior and posterior red muscle, but little longitudinal variation will be observed in parvalbumin expression in white and pink muscle. We successfully employed protein electrophoresis (SDS–PAGE) with western blots to identify two parvalbumin isoforms in each muscle fiber type. SDS–PAGE and densitometry were used to determine the relative expression levels of the two parvalbumin isoforms and total parvalbumin expression. Red muscle displays a significant shift, from anterior to posterior, in the relative expression of the two isoforms, both in their relative contribution and in total parvalbumin content, but white and pink muscle did not. The red muscle of southern kingfish, Menticirrhus americanus (Pisces, F. Scianidae) showed a pattern similar to the red muscle of sheepshead.
Vasotab, a vasoactive peptide from horse flyHybomitra bimaculata(Diptera, Tabanidae) salivary glands
Authors: Takáč Peter , Nunn Miles A. , Mészáros János , Pecháňová Olga , Vrbjar Norbert , Vlasáková Petra , Kozánek Milan , Kazimírová Mária , Hart George , Nuttall Patricia A. , Labuda Milan
Published: January 2006

Horse flies feed from superficial haematomas and probably rely heavily on the pharmacological properties of their saliva to find blood. Here we describe the first evidence of vasodilators in horse fly Hybomitra bimaculata(Diptera, Tabanidae) salivary gland extract and clone and express one of the active peptides (termed vasotab). Physiological tests using crude salivary gland extracts and reverse-phase HPLC fractions demonstrated positive inotropism in isolated rat hearts, vasodilatation of coronary and peripheral vessels, and Na, K-ATPase inhibition. One of the vasoactive fractions was analysed by N-terminal Edman degradation and a 47-amino-acid sequence obtained. A full-length cDNA encoding the peptide was cloned from a phage library using degenerate primer PCR and the peptide expressed in insect cells. A 20-amino-acid signal sequence precedes the mature 56-amino-acid vasotab peptide, which is a member of the Kazal-type protease inhibitor family. The peptide has a unique 7-amino-acid insertion between the third and fourth cysteine residues. The recombinant peptide prolonged the action potential and caused positive inotropism of isolated rat heart myocytes, and may be an ion channel modulator.
In situhybridisation of a large repertoire of muscle-specific transcripts in fish larvae: the new superficial slow-twitch fibres exhibit characteristics of fast-twitch differentiation
Authors: Chauvigné F. , Ralliere C. , Cauty C. , Rescan P. Y.
Published: January 2006

Much of the present information on muscle differentiation in fish concerns the early embryonic stages. To learn more about the maturation and the diversification of the fish myotomal fibres in later stages of ontogeny, we investigated, by means of in situ hybridisation, the developmental expression of a large repertoire of muscle-specific genes in trout larvae from hatching to yolk resorption. At hatching, transcripts for fast and slow muscle protein isoforms, namely myosins, tropomyosins, troponins and myosin binding protein C were present in the deep fast and the superficial slow areas of the myotome, respectively. During myotome expansion that follows hatching, the expression of fast isoforms became progressively confined to the borders of the fast muscle mass, whereas, in contrast, slow muscle isoform transcripts were uniformly expressed in all the slow fibres. Transcripts for several enzymes involved in oxidative metabolism such as citrate synthase, cytochrome oxidase component IV and succinate dehydrogenase, were present throughout the whole myotome of hatching embryos but in later stages became concentrated in slow fibre as well as in lateral fast fibres. Surprisingly, the slow fibres that are added externally to the single superficial layer of the embryonic(original) slow muscle fibres expressed not only slow twitch muscle isoforms but also, transiently, a subset of fast twitch muscle isoforms including MyLC1, MyLC3, MyHC and myosin binding protein C. Taken together these observations show that the growth of the myotome of the fish larvae is associated with complex patterns of muscular gene expression and demonstrate the unexpected presence of fast muscle isoform-expressing fibres in the most superficial part of the slow muscle.
Methylene Blue for Management of Ifosfamide-Induced Encephalopathy
Authors: Patel Priti N
Published: January 2006

Objective:

To evaluate the use of methylene blue for the treatment of ifosfamide-induced encephalopathy.

Data Sources:

MEDLINE (1966–August 2005) and International Pharmaceutical Abstracts (1971–August 2005) were searched, using the terms methylene blue, ifosfamide, encephalopathy, and neurotoxicity.

Data Synthesis:

Several case reports and one retrospective chart review described the use of methylene blue for ifosfamide-induced encephalopathy, but no controlled clinical trials were found. Methylene blue appeared to aid in the resolution of encephalopathic symptoms as rapidly as within 10 minutes of administration in some patients, but it had modest efficacy in most patients. Symptoms in patients who did not receive methylene blue resolved in the same time frame; this indicates that ifosfamide-induced encephalopathy may resolve without treatment.

Conclusions:

Available data from case reports indicate that methylene blue is an option in the treatment of ifosfamide-induced encephalopathy, especially in patients with severe symptoms of toxicity. However, the lack of controlled clinical trials and the possibility of spontaneous resolution of encephalopathy make the usefulness of methylene blue unclear.
Auditory Midbrain and Nerve Responses to Sinusoidal Variations in Interaural Correlation
Authors: Joris Philip X. , van de Sande Bram , Recio-Spinoso Alberto , van der Heijden Marcel
Published: January 2006

The human sensitivity to interaural temporal differences in the acoustic waveforms to the two ears shows remarkable acuity but is also very sluggish. Fast changes in binaural parameters are not detectable, and this inability contrasts sharply with the excellent temporal resolution of the monaural auditory system. We studied the response of binaural neurons in the inferior colliculus of the cat to sinusoidal changes in the interaural correlation of broadband noise. Responses to the same waveforms were also obtained from auditory nerve fibers and further analyzed with a coincidence analysis. Overall, the auditory nerve and inferior colliculus showed a similar ability to code changes in interaural correlation. This ability extended to modulation frequencies an order of magnitude higher than the highest frequencies detected binaurally in humans. We conclude that binaural sluggishness is not caused by a lack of temporal encoding of fast binaural changes at the level of the midbrain. We hypothesize that there is no neural substrate at the level of the midbrain or higher to read out this temporal code and that this constitutes a low-pass “sluggishness” filter.
Decorrelation Sensitivity of Auditory Nerve and Anteroventral Cochlear Nucleus Fibers to Broadband and Narrowband Noise
Authors: Louage Dries H. G. , Joris Philip X. , van der Heijden Marcel
Published: January 2006

Binaural neurons show remarkable sensitivity to temporal differences in the waveforms at the two ears. This ability obviously requires temporal coding of sound waveforms in the monaural afferents that converge on such binaural neurons. We introduce a new analysis to investigate how well responses of single monaural neurons support discrimination of decorrelations in waveforms. Spike trains from auditory nerve (AN) and anteroventral cochlear nucleus (AVCN) neurons of cats to many repetitions of a set of broadband and narrowband noise tokens were obtained. The normalized correlation between the noise tokens ranged from 0.99 to –1. A coincidence and signal detection analysis was used to perform a correlation discrimination task using the monaural spike trains. The correlation discrimination thresholds derived from AVCN neurons were lower than those derived from AN fibers and sometimes as low as human psychophysical just noticeable differences. Importantly, low detection thresholds required comparisons of spike trains at small internal delays. Bandwidth dependence of neural decorrelation thresholds agreed with psychophysical data when large internal delays contributed to the detection. We conclude that, in the context of correlation discrimination, coding by AVCN fibers is superior to that by AN fibers and that these discriminations require a distribution of internal or best delays in binaural processing that differs from the predictions from studies of discrimination in interaural time delays.
Visual and Nonvisual Contributions to Three-Dimensional Heading Selectivity in the Medial Superior Temporal Area
Authors: Gu Yong , Watkins Paul V. , Angelaki Dora E. , DeAngelis Gregory C.
Published: January 2006

Robust perception of self-motion requires integration of visual motion signals with nonvisual cues. Neurons in the dorsal subdivision of the medial superior temporal area (MSTd) may be involved in this sensory integration, because they respond selectively to global patterns of optic flow, as well as translational motion in darkness. Using a virtual-reality system, we have characterized the three-dimensional (3D) tuning of MSTd neurons to heading directions defined by optic flow alone, inertial motion alone, and congruent combinations of the two cues. Among 255 MSTd neurons, 98% exhibited significant 3D heading tuning in response to optic flow, whereas 64% were selective for heading defined by inertial motion. Heading preferences for visual and inertial motion could be aligned but were just as frequently opposite. Moreover, heading selectivity in response to congruent visual/vestibular stimulation was typically weaker than that obtained using optic flow alone, and heading preferences under congruent stimulation were dominated by the visual input. Thus, MSTd neurons generally did not integrate visual and nonvisual cues to achieve better heading selectivity. A simple two-layer neural network, which received eye-centered visual inputs and head-centered vestibular inputs, reproduced the major features of the MSTd data. The network was trained to compute heading in a head-centered reference frame under all stimulus conditions, such that it performed a selective reference-frame transformation of visual, but not vestibular, signals. The similarity between network hidden units and MSTd neurons suggests that MSTd may be an early stage of sensory convergence involved in transforming optic flow information into a (head-centered) reference frame that facilitates integration with vestibular signals.
Attention Lights Up New Object Representations before the Old Ones Fade Away
Authors: Khayat Paul S. , Spekreijse Henk , Roelfsema Pieter R.
Published: January 2006

We investigated how attention shifts from one object to another by recording neuronal activity in the primary visual cortex. Monkeys performed a contour-grouping task in which they had to select a target curve and ignore a distractor curve. Some trials required a shift of attention, because the target and distractor curves were switched during the course of the trial. We monitored the dynamics of this attention shift in area V1, in which neuronal responses evoked by the target curve are stronger than those evoked by the distractor. The reallocation of attention was associated with a rapid and strong enhancement of responses to the newly attended curve, followed, after ∼60 ms, by a weaker suppression of responses to the curve from which attention was removed. We conclude that attention can be rapidly allocated to a new object before it disengages from the previously attended one.
Integration of Male Mating and Feeding Behaviors inCaenorhabditis elegans
Authors: Gruninger Todd R. , Gualberto Daisy G. , LeBoeuf Brigitte , Garcia L. Rene
Published: January 2006

TheCaenorhabditis elegansmale must integrate various environmental cues to ensure proper execution of mating. One step of male mating, the insertion of the male copulatory spicules into its mate, requires UNC-103 ERG (ether-a-go-go-related gene)-like K+channels.unc-103(lf)alleles cause males to protract their spicules spontaneously in the absence of mating cues. To identify proteins that work with UNC-103, we suppressedunc-103(lf)and isolatedlev-11(rg1). LEV-11 (tropomyosin) regulates the spicules directly by controlling the male sex muscles and indirectly by controlling the pharyngeal muscles.lev-11-mediated suppression requires the pharyngeal NSM neurosecretory motor neurons; ablating these neurons inlev-11(rg1); unc-103(lf)males restores spontaneous spicule protraction. Additionally,unc-103-induced spicule protraction can be suppressed by reducing a pharyngeal-specific troponin T. These observations demonstrate that non-genitalia cells involved in feeding also mediate male sexual behaviors.
Supraspinal Brain-Derived Neurotrophic Factor Signaling: A Novel Mechanism for Descending Pain Facilitation
Authors: Guo Wei , Robbins Meredith T. , Wei Feng , Zou Shiping , Dubner Ronald , Ren Ke
Published: January 2006

In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10–100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs).In vitrostudies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP3, PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.
Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α
Authors: Jin Xiaochun , Gereau Robert W.
Published: January 2006

Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNFα can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNFα itself. However, the speed with which TNFα induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNFα may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNFα induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptorTRPV1–/–mice. In contrast, TNFα produced equivalent mechanical hypersensitivity inTRPV1–/–mice and wild-type littermates, suggesting a role for TRPV1 in TNFα-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na+channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNFα on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNFα rapidly enhances TTX-resistant Na+currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNFα is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNFα is also significantly reduced by SB202190. These results suggest that TNFα may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na+channels.
Dystrophin Is Required for Appropriate Retrograde Control of Neurotransmitter Release at theDrosophilaNeuromuscular Junction
Authors: van der Plas Mariska C. , Pilgram Gonneke S. K. , Plomp Jaap J. , de Jong Anja , Fradkin Lee G. , Noordermeer Jasprina N.
Published: January 2006

Mutations in the humandystrophingene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles ofdystrophin-mediated signaling pathways remain unknown. To further our understanding of this aspect of the function ofdystrophin, we have generatedDrosophilamutants that lack the largedystrophinisoforms and analyzed their role in synapse function at the neuromuscular junction. In expression and rescue studies, we show that lack of the largedystrophinisoforms in the postsynaptic muscle cell leads to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence ofdystrophinresults in increased probability of release. Absence of the largedystrophinisoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. Our results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis.
Cholinergic Synaptic Transmission in AdultDrosophilaKenyon CellsIn Situ
Authors: Gu Huaiyu , O'Dowd Diane K.
Published: January 2006

Behavioral and genetic studies inDrosophilahave contributed to our understanding of molecular mechanisms that underlie the complex processes of learning and memory. Use of this model organism for exploration of the cellular mechanisms of memory formation requires the ability to monitor synaptic activity in the underlying neural networks, a challenging task in the tiny adult fly. Here, we describe an isolated whole-brain preparation in which it is possible to obtainin situwhole-cell recordings from adult Kenyon cells, key members of a neural circuit essential for olfactory associative learning inDrosophila. The presence of sodium action potential (AP)-dependent synaptic potentials and synaptic currents in >50% of the Kenyon cells shows that these neurons are members of a spontaneously active neural circuit in the isolated brain. The majority of sodium AP-dependent synaptic transmission is blocked by curare and by α-bungarotoxin (α-BTX). This demonstrates that nicotinic acetylcholine receptors (nAChRs) are responsible for most of the spontaneous excitatory drive in this circuit in the absence of normal sensory input. Furthermore, analysis of sodium AP-independent synaptic currents provides the first direct demonstration that α-BTX-sensitive nAChRs mediate fast excitatory synaptic transmission in Kenyon cells in the adultDrosophilabrain. This new preparation, in which whole-cell recordings and pharmacology can be combined with genetic approaches, will be critical in understanding the contribution of nAChR-mediated fast synaptic transmission to cellular plasticity in the neural circuits underlying olfactory associative learning.
β1-Integrins Are Required for Hippocampal AMPA Receptor-Dependent Synaptic Transmission, Synaptic Plasticity, and Working Memory
Authors: Chan Chi-Shing , Weeber Edwin J. , Zong Lin , Fuchs Elaine , Sweatt J. David , Davis Ronald L.
Published: January 2006

Integrins comprise a large family of cell adhesion receptors that mediate diverse biological events through cell–cell and cell–extracellular matrix interactions. Recent studies have shown that several integrins are localized to synapses with suggested roles in synaptic plasticity and memory formation. We generated a postnatal forebrain and excitatory neuron-specific knock-out of β1-integrin in the mouse. Electrophysiological studies demonstrated that these mutants have impaired synaptic transmission through AMPA receptors and diminished NMDA receptor-dependent long-term potentiation. Despite the impairment in hippocampal synaptic transmission, the mutants displayed normal hippocampal-dependent spatial and contextual memory but were impaired in a hippocampal-dependent, nonmatching-to-place working memory task. These phenotypes parallel those observed in animals carrying knock-outs of the GluR1 (glutamate receptor subunit 1) subunit of the AMPA receptor. These observations suggest a new function of β1-integrins as regulators of synaptic glutamate receptor function and working memory.
Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death
Authors: Martin Lee J. , Pan Yan , Price Ann C. , Sterling Wanda , Copeland Neal G. , Jenkins Nancy A. , Price Donald L. , Lee Michael K.
Published: January 2006

α-Synuclein (α-Syn) is enriched in nerve terminals. Two mutations in the α-Syngene (Ala53→ Thr and Ala30→ Pro) occur in autosomal dominant familial Parkinson's disease. Mice overexpressing the human A53T mutant α-Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human wild-type or familial Parkinson's disease-linked A53T or A30P mutant α-syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end-stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human α-syn and nitrated synuclein. Motor neurons were depleted (∼75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for humanα-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.
Silence as Sound: Handel's Sublime Pauses
Authors: HARRIS ELLEN T.
Published: January 2006

The notated absence of sound creates some of the most dramatic and compelling moments in Handel's mature music. Handel's practice can be traced to the word-based silences of the madrigal on one hand, and the rhetorical silences found in Corelli's trio sonatas on the other. By transferring Corelli's systematic use of silence to vocal music, Handel moved beyond word-painting to expressive text-setting. Some critics condemned these silences, which prove strikingly similar to the emotional pauses introduced later by Garrick into his theatrical roles, as incorrect. Others considered them sublime.
Savva Mamontov, Serge Diaghilev, and a Rocky Path to Modernism
Authors: HALDEY OLGA
Published: January 2006

The Ballets Russes of Serge Diaghilev has frequently been hailed as an emblem of 20th-century modernism, its productions created by a “committee” of directors, composers, and designers viewed as a realization of an elusive dream of art synthesis. Present research based on diverse unpublished sources traces the beginning of the transition toward modernism on stage to the earlier activities of the Moscow Private Opera directed by Savva Mamontov. An artist and a millionaire, Mamontov succeeded in realizing his ideal of opera as a synthesized art form by instigating major reforms in acting, directing, and design, all later adopted by Diaghilev. However, parallels between their two enterprises have always been dismissed as coincidental. New evidence reveals the existence of a mentor-student relationship between Mamontov and Diaghilev based on shared aesthetic views that earned both men a derogatory label of “decadents.” Intrigued by Mamontov's philosophy and collaborative methodology employed in creating productions such as Gluck's Orfeo and Rimsky-Korsakov's Sadko, Diaghilev studied organizational principles of his enterprise and modeled the Ballets Russes after them, while himself assuming the role of an artistic director similar to Mamontov's. Thus, Savva Mamontov paved the way for the modernist vision of theater presented to the world by Diaghilev's Ballets Russes.
Debussy and La Sonate cyclique
Authors: WHEELDON MARIANNE
Published: January 2006

In 1915, Debussy returned to the genre of chamber music for the first time since the String Quartet of 1893 and composed the only sonatas of his career. What draws these early and late chamber works together is that they are all cyclic in construction. While Debussy's quartet clearly bears the imprint of César Franck's cyclic procedures, his sonatas engage with this tradition more cautiously. Comparing the string quartet with the sonatas elucidates Debussy's uneasy rapprochement with a style he had formerly embraced. Debussy's underplaying of the cyclic tradition was motivated by what the cyclic sonata had come to represent in the intervening years, in particular its appropriation by Franck's student Vincent d'Indy. In his teachings and publications, d'Indy promulgated a nationalistic view of the cyclic sonata, one that declared Franck and the modern French school as the only comprehending heirs of Beethoven. Reluctant to participate in this particular heritage, Debussy diverted attention from the cyclic procedures used in the sonatas by explicitly emphasizing their stylistic affiliation with the French 18th century and by implicitly aligning himself with Franck rather than with d'Indy. In this way Debussy sought to carve out a place for his sonatas within a less contentious tradition.
“Nach dem Weltuntergang”: Adorno's Engagement with Postwar Music
Authors: ZAGORSKI MARCUS
Published: January 2006

Adorno's engagement with postwar music is reflected in the complex history of his reception among composers, theorists, and critics of the time. His work was seen both as pointing the way forward and as hopelessly outmoded, and his ideas were often eagerly adopted only to be transformed into something very nearly their opposite. This tangled and contradictory reception stems in part from misreadings of his texts, but it also parallels his changing positions on the music and ideas of the period. Changes and constants in Adorno's thinking can be seen by comparing two of his central essays on postwar music: “Das Altern der Neuen Musik” and “Vers une musique informelle.” Key concepts in these essays (and his music philosophy in general) include material, time, subjectivity, and the ethics of new music. An analysis of these essays and concepts reveals that despite relevant changes, Adorno's narrow reading of an Austro-German compositional tradition is a constant that defines the standard for his engagement with postwar music.