Dynamic oscillations of coupled domain walls.

In domain wall (DW) excitation experiments, nonlinearity (NL) intrinsic to the DW dynamics is often hard to distinguish from perturbation due to the confining potential or DW distortion. Here we numerically investigate the dynamic oscillations of magnetostatically coupled DWs: a system well understood in the quasistatic limit. NL is observed, even for a harmonic potential, due to the intrinsic DW motion. This behavior is principally dependent on terms normally associated with the DW canonical momentum and is in contrast with a NL restoring potential. This NL is not observable in quasistatic measurements, relatively insensitive to the confining potential, and may be tuned by the nanowire parameters. The shown NLs are present in any DW restoring potential and must be accounted for when probing DW potential landscapes.

Tunable remote pinning of domain walls in magnetic nanowires.

Domain wall (DW) pinning in ferromagnetic nanowires is in general a complex process. Distortions of the DW shape make quantitative agreement between modeling and experiment difficult. Here we demonstrate pinning using nanometer scale localized stray fields. This type of interaction gives well-characterized, tailorable potential landscapes that do not appreciably distort the DW. Our experimental results are in excellent quantitative agreement with an Arrhenius-Néel model of depinning--a result only possible when the modeled potential profile agrees fully with that experienced by the DW.

Fast domain wall motion in magnetic comb structures.

Modern fabrication technology has enabled the study of submicron ferromagnetic strips with a particularly simple domain structure, allowing single, well-defined domain walls to be isolated and characterized. However, these domain walls have complex field-driven dynamics. The wall velocity initially increases with field, but above a certain threshold the domain wall abruptly slows down, accompanied by periodic transformations of the domain wall structure. This behaviour is potentially detrimental to the speed and proper functioning of proposed domain-wall-based devices, and although methods for suppression of the breakdown have been demonstrated in simulations, a convincing experimental demonstration is lacking. Here, we show experimentally that a series of cross-shaped traps acts to prevent transformations of the domain wall structure and increase the domain wall velocity by a factor of four compared to the maximum velocity on a plain strip. Our results suggest a route to faster and more reliable domain wall devices for memory, logic and sensing.

Near-field interaction between domain walls in adjacent Permalloy nanowires.

The magnetostatic interaction between two oppositely charged transverse domain walls (TDWs) in adjacent Permalloy nanowires is experimentally demonstrated. The dependence of the pinning strength on wire separation is investigated for distances between 13 and 125 nm. The results can be described fully by considering the distribution of magnetic charge within rigid, isolated TDWs. Alternative DW internal structure cannot reproduce this observed dependence. Modeling suggests the TDW internal structure is not appreciably disturbed, and remains rigid although the pinning strength is significant.

Magnetization reversal in individual cobalt micro- and nanowires grown by focused-electron-beam-induced-deposition.

We systematically study individual micro- and nanometric polycrystalline cobalt wires grown by focused-electron-beam-induced-deposition. The deposits were grown in a range of aspect ratios varying from 1 up to 26. The minimum lateral dimension of the nanowires was 150 nm, for a thickness of 40 nm. Atomic force microscopy images show beam-current-dependent profiles, associated with different regimes of deposition. The magnetization reversal of individual nanowires is studied by means of the spatially resolved magneto-optical Kerr effect. Abrupt switching is observed, with a systematic dependence on the wire's dimensions. This dependence of the coercive field is understood in magnetostatic terms, and agrees well with previous results on cobalt wires grown with different techniques. The influence of compositional gradients along the structural profile on the magnetic reversal is studied by using micromagnetic simulations. This work demonstrates the feasibility of using this technique to fabricate highly pure magnetic nanostructures, and highlights the advantages and disadvantages of the technique with respect to more conventional ones.

Measuring domain wall fidelity lengths using a chirality filter.

The motion of transverse domain walls (DWs) in thin Permalloy nanowires has been studied by locally detecting the chirality of the moving DW, using a cross-shaped trap acting as a chirality filter. We find that structural changes of the DW occur over a characteristic minimum distance: the "DW fidelity length." The measured field dependence of the fidelity length is in good qualitative agreement with a 1D analytical model and with published results of numerical simulations and experiments. We also demonstrate extension of the fidelity length to meter length scales using a series of filters.

Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients.

Previously, a specific dietary supplement, selected vegetables (SV), was found to be associated with prolonged survival of stage III and IV non-small cell lung cancer (NSCLC) patients. In this study, several anticancer components in SV were measured; the anticancer activity of SV was assessed using a lung tumor model, line 1 in BALB/c mice. SV was also used in conjunction with conventional therapies by stage IIIB and IV NSCLC patients whose survival and clinical responses were evaluated. A daily portion (283 g) of SV was found to contain 63 mg of inositol hexaphosphate, 4.4 mg of daidzein, 2.6 mg of genistein, and 16 mg of coumestrol. Mouse food containing 5% SV (wt/wt) was associated with a 53-74% inhibition of tumor growth rate. Fourteen of the 18 patients who ingested SV daily for 2-46 months were included in the analyses; none showed evidence of toxicity. The first lead case remained tumor free for > 133 months; the second case showed complete regression of multiple brain lesions after using SV and radiotherapy. The median survival time of the remaining 12 patients was 33.5 months, and one-year survival was > 70%. The median survival time of the 16 "intent-to-treat" patients (including ineligible patients) was 20 months, and one-year survival was 55%. The Karnofsky performance status of eligible patients was 55 +/- 13 at entry but improved to 92 +/- 9 after use of SV for five months or longer (p < 0.01). Five patients had stable lesions for 30, 30, 20, 12, and 2 months; two of them, whose primary tumor was resected, used SV alone and demonstrated an objective response of their metastatic tumors. In addition to the two lead cases, eight patients had no new metastases after using SV. Three patients had complete regression of brain metastases after using radiotherapy and SV. In this study, daily ingestion of SV was associated with objective responses, prolonged survival, and attenuation of the normal pattern of progression of stage IIIB and IV NSCLC. A large randomized phase III clinical trial is needed to confirm the results observed in this pilot study.

N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: an extracellularly tumor-activated prodrug devoid of intravenous acute toxicity.

Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD(50) of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.

Cochlear nerve acoustic envelope response detection is improved by the addition of random-phased tonal stimuli.

We test Lowenstein's dc bias hypothesis as an alternative mechanism for the phenomenon sometimes called 'stochastic resonance'. Probe stimuli consisting of paired phase-locked tones at frequencies f(1) and f(2) (where f(2)-f(1)=800 Hz, f(1)>4.5 kHz) and at equal intensity were used to generate synchronous 800 Hz cochlear nerve activity (envelope responses). When a background tone of the same intensity, with a frequency halfway between f(1) and f(2), is presented simultaneously with the probe stimulus, the envelope response amplitude typically decreases. Consistent with Lowenstein's hypothesis, however, when the intensities of the probe and background tone are near the detection threshold of the envelope response (approximately 0-20 dB sound pressure level), the simultaneous presence of the background tone often increases the amplitude of the envelope response. At these same intensity levels, when the background tone precedes the probe stimulus, it decreases the amplitude of the response to the probe stimulus. The effects of simultaneous presentation of the probe and the background tone are frequency-dependent, becoming less pronounced or reversing as the frequency of the background tone departs from those of the probe stimuli.

Functional consequences of a novel middle ear adaptation in the central African frog Petropedetes parkeri (Ranidae).

During the breeding season, each tympanic membrane of males of the Old World treefrog Petropedetes parkeri is decorated with a single, prominent, fleshy tympanic papilla. The tympanic papilla, located dorsally on the tympanic membrane, is covered by an epidermal surface and is composed of non-ossified, spongiform tissue containing a number of globular, fluid-filled vesicles found at highest density near the papillar tip. These vesicles appear to have exit pores and are probably simple alveolar exocrine glands. Injecting sound into the pressurized vocal cavity of the male and measuring the vibration velocity response of the tympanic membrane revealed that from 0.3 to 2.0 kHz the tympanic papilla velocity amplitude is on average 20 dB lower than that of a point diametrically opposite on the ventral half of the tympanic membrane. The close agreement between the dominant frequency of the call and the frequency of the maximum spectral peak of the Fast Fourier Transform of the impulse response of the eardrum is consistent with the use of the eardrum in this species both as a call receiver and as a call radiator, similar to the function suggested for the eardrum of the male bullfrog Rana catesbeiana. Unexpectedly, surgically removing the tympanic papilla lowered the frequency of the peak vibrational amplitude, testifying to the importance of membrane tension as a dominant factor in the vibratory behavior of the eardrum. During normal positive-pressure breathing, the tympanic papillae move conspicuously, suggesting a possible rôle as a visual signal.

Enzyme-induced strain/distortion in the ground-state ES complex in beta-lactamase catalysis revealed by FTIR.

Class A beta-lactamases hydrolyze penicillins and other beta-lactams via an acyl-enzyme catalytic mechanism. Ser70 is the active site nucleophile. By constructing the S70A mutant, which is unable to form the acyl-enzyme intermediate, it was possible to make stable ES complexes with various substrates. The stability of such Michaelis complexes permitted acquisition of their infrared spectra. Comparison of the beta-lactam carbonyl stretch frequency (nu(CO)) in the free and enzyme-bound substrate revealed an average decrease of 13 cm(-)(1), indicating substantial strain/distortion of the lactam carbonyl when bound in the ES complex. Interestingly, regardless of the frequency of the C=O stretch in the free substrate, when complexed to Bacillus licheniformis beta-lactamase, the frequency was always 1755 +/- 2 cm(-)(1). This suggests the active site environment induces a similar conformation of the beta-lactam in all substrates when bound to the enzyme. Using deuterium substitution, it was shown that the "oxyanion hole", which involves hydrogen bonding to two backbone amides, is the major source of the enzyme-induced strain/distortion. The very weak catalytic activity of the S70A beta-lactamase suggests enzyme-facilitated hydrolysis due to substrate distortion on binding to the enzyme. Thus the binding of the substrate in the active site induces substantial strain and distortion that contribute significantly to the overall rate enhancement in beta-lactamase catalysis.

Essential roles of noise in neural coding and in studies of neural coding.

We present examples of results from our studies of auditory primary afferent nerve fibers and populations of such fibers in the frog and gerbil. We take advantage of the natural dithering effect of internal noise, where it is sufficient, to construct highly predictive descriptive models (based on the Wiener series with kernels derived from white-noise analysis). Where the internal noise is insufficient, we enhance dithering by applying external acoustic noise together with our stimuli. Using acoustic noise as a background sound, orthogonal to the stimulus waveform, we show that under some circumstances such background sound can enhance the ability of individual fibers and populations of fibers to encode the stimulus waveform.

Localization by interaural time difference (ITD): effects of interaural frequency mismatch.

A commonly accepted physiological model for lateralization of low-frequency sounds by interaural time delay (ITD) stipulates that binaural comparison neurons receive input from frequency-matched channels from each ear. Here, the effects of hypothetical interaural frequency mismatches on this model are reported. For this study, the cat's auditory system peripheral to the binaural comparison neurons was represented by a neurophysiologically derived model, and binaural comparison neurons were represented by cross-correlators. The results of the study indicate that, for binaural comparison neurons receiving input from one cochlear channel from each ear, interaural CF mismatches may serve to either augment or diminish the effective difference in ipsilateral and contralateral axonal time delays from the periphery to the binaural comparison neuron. The magnitude of this increase or decrease in the effective time delay difference can be up to 400 microseconds for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between 250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz, the 25-microsecond effective time delay difference caused by a 0.012-octave CF mismatch is equal to the ITD previously shown to be behaviorally sufficient for the cat to lateralize a low-frequency sound source.

Predicting the temporal responses of non-phase-locking bullfrog auditory units to complex acoustic waveforms.

Axons from the basilar papilla of the American bullfrog (Rana catesbeiana) do not phase lock to stimuli within an octave of their best frequencies. Nevertheless, they show consistent temporal patterns of instantaneous spike rate (as reflected in peristimulus time histograms) in response to repeated stimuli in that frequency range. We show that the second-order Wiener kernels for these axons, derived from the cross-correlation of continuous (non-repeating), broad-band noise stimulus with the spike train produced in response to that stimulus, can predict with considerable precision the temporal pattern of instantaneous spike rate in response to a novel, complex acoustic waveform (a repeated, 100-ms segment of noise, band-limited to cover the single octaves above and below best frequency). Furthermore, we show that most of this predictive power is retained when the second-order Wiener kernel is reduced to the highest-ranking pair of singular vectors derived from singular-value decomposition, that the retained pair of vectors corresponds to a single auditory filter followed by an envelope-detection process, and that the auditory filter itself predicts the characteristic frequency (CF) of the axon and the shape of the frequency-threshold tuning curve in the vicinity of CF.

A comparison of the linear tuning properties of two classes of axons in the bullfrog lagena.

Various vertebrate inner-ear end organs appear to have switched their sensory function between equilibrium sensing and acoustic sensing over the courses of various lines of evolution. It is possible that all that is required to make this transition is to provide an end organ with access to the appropriate stimulus mode and frequency range. If, as we believe, however, the adaptive advantage of an acoustic sensory system lies in its ability to sort the total acoustic input into components that correspond to individual acoustic sources, and the adaptive advantage of an equilibrium sensory system lies in its ability to compute the total orientation and motion of the head without regard to the individual sources contributing to that orientation and motion, then it is easy to argue that the differences between acoustic and equilibrium sensors should be more profound than simply access to the appropriate stimuli. Effective signal-sorting requires high resolution in both time and frequency; to achieve this resolution, a peripheral tuning structure must be one of high dynamic order (i.e., constructed from multiple independent energy storage elements). If the peripheral tuning structure simply converts head acceleration to head displacement, velocity, or jerk (i.e., provides one or two steps of integration or differentiation with respect to time, where one energy storage element per step is required), then high dynamic order is inappropriate. Because the bullfrog lagena possesses both acoustic and equilibrium sensitive regions, it is especially suited for comparing these two sensor types and addressing the question of dynamic order of tuning. In this paper we report observations of the linear tuning properties of bullfrog lagenar primary afferent nerve fibers obtained by stimulating the lagena with random, dorsoventral micromotion over the frequency range from 10 Hz to 1.0 kHz. Tuning curves obtained by reverse correlation analysis and discrete Fourier transformation were used to estimate the dynamic order of each fiber's associated peripheral tuning structure. We found two classes of lagenar afferent axons--those with lowpass amplitude tuning characteristics (44 units) and those with bandpass amplitude tuning characteristics (73 units). Lowpass units were found to originate at the equilibrium region of the macula, and they exhibited low dynamic order--summed low- and high-frequency slopes (absolute values) ranged from 10 dB/decade to 64 dB/decade, implying dynamic orders of less than one to three (the modal value was equal to one). Bandpass units were found to originate at the acoustic region of the macula, and they exhibited higher dynamic order than lowpass units--summed low- and high-frequency slopes (absolute values) ranged from 53 dB/decade to 185 dB/decade, implying dynamic orders of three to nine (the modal value was equal to five). It appears that while lagenar equilibrium and acoustic sensors both possess access to signals in the acoustic frequency range, lagenar acoustic sensors are tuned by means of peripheral structures with markedly greater dynamic order and consequently markedly greater physical complexity. These results suggest that steep-sloped (high-dynamic-order) tuning properties reflect special adaptations in acoustic sensors not found in equilibrium sensors, and that any evolutionary transition between the two sensor types must have involved profound structural changes.

Seismic communication between the burrows of kangaroo rats, Dipodomys spectabilis.

Banner-tailed kangaroo rats, Dipodomys spectabilis, footdrum to produce substrate-borne and airborne acoustic energy. Previous studies show that they communicate territorial ownership via airborne footdrumming signals. The research reported here used simulated footdrum patterns generated by an artificial 'thumper' to address the question of whether kangaroo rats communicate through seismic components of these acoustic signals. With microphones suspended in sealed burrows, we found that airborne sounds were attenuated by approximately 40 dB as they passed through the burrow wall into the burrow chamber. The substrate-borne vibrations from the thumper yielded sound approximately 40 dB greater in peak amplitude than the attenuated airborne sound. Thus, 99.9% of the peak power of the thumper was transmitted directly through the substrate into the burrow. The rats in sealed burrows timed their responses to playbacks of footdrums from the thumper and a loudspeaker so they did not initiate a drumming sequence during either the seismic or airborne signals. When these signals were masked by loud noise, the rats continued to drum to the seismic signal but drummed randomly during the airborne playback. These results suggest that the sealed burrow provides a quiet place in which D. spectabilis can listen for substrate-borne communications from conspecifics.

Multi-unit recording from regenerated bullfrog eighth nerve using implantable silicon-substrate microelectrodes.

Multi-microelectrode silicon devices were developed for extracellular recording from multiple axons in regenerated eighth cranial nerves of American bullfrogs. Each includes a photolithographically defined array of holes and adjacent metal microelectrodes. A device is implanted within a transected eighth nerve; regenerating fibers grow through the holes en route to the brainstem. Multiple spike trains were recorded from two animals at up to 21 weeks after implantation. Single units were tracked for over 8 h. Some responded to sound with tuning typical of fibers innervating the amphibian and basilar papillae. Units of vestibular origin also were recorded. Action potentials were 30-140 microV P-P amid noise of 5 10 microV RMS, an adequate signal-to-noise ratio for spike detection and sorting. Histology confirmed that bundles of myelinated fibers grew through holes near electrodes that recorded activity. The implantation success rate was low, due to surgical morbidity, device extrusion, and lack of nerve regeneration through some devices. Future designs will address these issues and incorporate transistor amplifiers on devices to increase signal-to-noise ratios. The potential of implanted silicon devices to simultaneously record from many axons offers an opportunity for multicellular studies of auditor, vestibular and seismic signal processing in the vertebrate inner ear.

A point mutation leads to altered product specificity in beta-lactamase catalysis.

beta-Lactamases are the primary cause of beta-lactam antibiotic resistance in many pathogenic organisms. The beta-lactamase catalytic mechanism has been shown to involve a covalent acyl-enzyme. Examination of the structure of the class A beta-lactamase from Bacillus licheniformis suggested that replacement of Asn-170 by leucine would disrupt the deacylation reaction by displacing the hydrolytic water molecule. When N170L beta-lactamase was reacted with penicillins, a novel product was formed. We postulate that with leucine at position 170 the acyl-enzyme undergoes deacylation by an intramolecular rearrangement (rather than hydrolysis) to form a thiazolidine-oxazolinone as the initial product. The oxazolinone subsequently undergoes rapid breakdown leading to the formation of N-phenylacetylglycine and N-formylpenicillamine. This appears to be the first reported case where a point mutation leads to a change in enzyme mechanism resulting in a substantially altered product, effectively changing the product specificity of beta-lactamase into that of D-Ala-D-Ala-carboxypeptidase interacting with benzylpenicillin.

The use of seismic signals by fossorial southern African mammals: a neuroethological gold mine.

Behavioral adaptations exhibited by two African fossorial mammals for the reception of vibrational signals are discussed. The Namib Desert golden mole (Eremitalpa granti namibensis) is a functionally blind, nocturnal insectivore in the family Chrysochloridae that surface forages nightly in the Namib desert. Both geophone and microphone recordings in the substrate suggest that the golden mole is able to detect termite colonies and other prey items solely using seismic cues. This animal exhibits a hypertrophied malleus, an adaptation favoring detection of low-frequency signals. In a field study of the Cape mole-rat (Georychus capensis), a subterranean rodent in the family Bathyergidae, both seismic and auditory signals were tested for their propagation characteristics. This solitary animal is entirely fossorial and apparently communicates with its conspecifics by drumming its hind legs on the burrow floor. Auditory signals attenuate rapidly in the substrate, whereas vibratory signals generated in one burrow are easily detectable in neighboring burrows. The sensitivity to substrate vibrations in two orders of burrowing mammals suggests that this sense is likely to be widespread within this taxon and may serve as a neuroethological model for understanding the evolution of vibrational communication. Neuroethological implications of these findings are discussed.

High-frequency tuning properties of bullfrog lagenar vestibular afferent fibers.

A common property of vertebrate acoustic sensors, including otoconial acoustic sensors in lower vertebrates, is steep slopes on the high- and low-frequency band edges of the amplitude tuning curves. Bullfrog otoconial acoustic fibers are responsive to sound and exquisitely responsive to substrate vibrations in the frequency range from 20 Hz to 300 Hz. The sum of the absolute values of the two band-edge slopes of the amplitude tuning curve of such a fiber typically ranges from 100 dB/decade to 160 dB/decade (sometimes as high as 220 dB/decade), implying typical dynamic order of at least five to eight. We wondered if such steep slopes and the high dynamic order implied by them reflect special adaptations in acoustic sensors or if they are inherent in all lower-vertebrate otoconial sensors excited in this frequency range. To address this question, we examined the amplitude tuning characteristics of afferent nerve fibers from a bullfrog otoconial vestibular sensor in the same frequency range. In this paper, we report observations of tuning for bullfrog lagenar vestibular fibers in the frequency range from 10 Hz to approximately 500 Hz. To make these observations, we stimulated the frog with random dorsoventral motion that exhibited Gaussian amplitude distribution and that was flat in velocity from 10 Hz to 1.0 kHz. For each afferent fiber studied, we used discrete cross-correlation (between stimulus waveform and axon spike train) and discrete Fourier transformation to compute an amplitude tuning curve. In contrast with the amplitude tuning curve. In contrast with the amplitude tuning curves from saccular and lagenar acoustic fibers, those from the lagenar vestibular fibers typically had band-edge slopes whose absolute values summed to approximately 20 dB/decade, implying typical dynamic order of one. We conclude that steep band-edge slopes and high dynamic order are indeed special features of acoustic sensors, not shared by vestibular sensors.