Automatic Construction of Predictive Neuron Models through Large Scale Assimilation of Electrophysiological Data.

We report on the construction of neuron models by assimilating electrophysiological data with large-scale constrained nonlinear optimization. The method implements interior point line parameter search to determine parameters from the responses to intracellular current injections of zebra finch HVC neurons. We incorporated these parameters into a nine ionic channel conductance model to obtain completed models which we then use to predict the state of the neuron under arbitrary current stimulation. Each model was validated by successfully predicting the dynamics of the membrane potential induced by 20-50 different current protocols. The dispersion of parameters extracted from different assimilation windows was studied. Differences in constraints from current protocols, stochastic variability in neuron output, and noise behave as a residual temperature which broadens the global minimum of the objective function to an ellipsoid domain whose principal axes follow an exponentially decaying distribution. The maximum likelihood expectation of extracted parameters was found to provide an excellent approximation of the global minimum and yields highly consistent kinetics for both neurons studied. Large scale assimilation absorbs the intrinsic variability of electrophysiological data over wide assimilation windows. It builds models in an automatic manner treating all data as equal quantities and requiring minimal additional insight

A Mechanism for Frequency Modulation in Songbirds Shared with Humans

In most animals that vocalize, control of fundamental frequency is a key element for effective communication. In humans, subglottal pressure controls vocal intensity but also influences fundamental frequency during phonation. Given the underlying similarities in the biomechanical mechanisms of vocalization in humans and songbirds, songbirds offer an attractive opportunity to study frequency modulation by pressure. Here, we present a novel technique for dynamic control of subsyringeal pressure in zebra finches. By regulating the opening of a custom-built fast valve connected to the air sac system, we achieved partial or total silencing of specific syllables, and could modify syllabic acoustics through more complex manipulations of air sac pressure. We also observed that more nuanced pressure variations over a limited interval during production of a syllable concomitantly affected the frequency of that syllable segment. These results can be explained in terms of a mathematical model for phonation that incorporates a nonlinear description for the vocal source capable of generating the observed frequency modulations induced by pressure variations. We conclude that the observed interaction between pressure and frequency was a feature of the source, not a result of feedback control. Our results indicate that, beyond regulating phonation or its absence, regulation of pressure is important for control of fundamental frequencies of vocalizations. Thus, although there are separate brainstem pathways for syringeal and respiratory control of song production, both can affect airflow and frequency. We hypothesize that the control of pressure and frequency is combined holistically at higher levels of the vocalization pathways.Fil: Amador, Ana. Universidad de Buenos Aires. Facultad de Cs.exactas y Naturales; Argentina;Fil: Margoliash, Daniel. University Of Chicago; Estados Unidos de América

Active Carboxylic Acid-Terminated Alkanethiol Self-Assembled Monolayers on Gold Bead Electrodes for Immobilization of Cytochromes c

It is extremely difficult to immobilize cytochrome c (cyt c) on carboxylic acid-terminated alkanethiol self-assembled monolayers (HOOC-SAM) on gold bead electrodes prepared in a hydrogen flame. We found that simple pretreatment of a HOOC-SAM/gold bead electrode by potential cycling in buffer solution in the range ±300 mV prior to immobilization of the protein facilitated stable cyt c binding to HOOC-SAMs. The stability of cyt c on the HOOC-SAMs is independent of the topology of the gold surface

The Redox Couple of the Cytochrome \u3cem\u3ec\u3c/em\u3e Cyanide Complex: The Contribution of Heme Iron Ligation to the Structural Stability, Chemical Reactivity, and Physiological Behavior of Horse Cytochrome \u3cem\u3ec\u3c/em\u3e

Contrary to most heme proteins, ferrous cytochrome c does not bind ligands such as cyanide and CO. In order to quantify this observation, the redox potential of the ferric/ferrous cytochrome c–cyanide redox couple was determined for the first time by cyclic voltammetry. Its E0′ was −240 mV versus SHE, equivalent to −23.2 kJ/mol. The entropy of reaction for the reduction of the cyanide complex was also determined. From a thermodynamic cycle that included this new value for the cyt c cyanide complex E0′, the binding constant of cyanide to the reduced protein was estimated to be 4.7 × 10−3 LM−1 or 13.4 kJ/mol (3.2 kcal/mol), which is 48.1 kJ/mol (11.5 kcal/mol) less favorable than the binding of cyanide to ferricytochrome c. For coordination of cyanide to ferrocytochrome c, the entropy change was earlier experimentally evaluated as 92.4 Jmol−1K−1 (22.1 e.u.) at 25 K, and the enthalpy change for the same net reaction was calculated to be 41.0 kJ/mol (9.8 kcal/mol). By taking these results into account, it was discovered that the major obstacle to cyanide coordination to ferrocytochrome c is enthalpic, due to the greater compactness of the reduced molecule or, alternatively, to a lower rate of conformational fluctuation caused by solvation, electrostatic, and structural factors. The biophysical consequences of the large difference in the stabilities of the closed crevice structures are discussed

The impact of short tandem repeat variation on gene expression.

Short tandem repeats (STRs) have been implicated in a variety of complex traits in humans. However, genome-wide studies of the effects of STRs on gene expression thus far have had limited power to detect associations and provide insights into putative mechanisms. Here, we leverage whole-genome sequencing and expression data for 17 tissues from the Genotype-Tissue Expression Project to identify more than 28,000 STRs for which repeat number is associated with expression of nearby genes (eSTRs). We use fine-mapping to quantify the probability that each eSTR is causal and characterize the top 1,400 fine-mapped eSTRs. We identify hundreds of eSTRs linked with published genome-wide association study signals and implicate specific eSTRs in complex traits, including height, schizophrenia, inflammatory bowel disease and intelligence. Overall, our results support the hypothesis that eSTRs contribute to a range of human phenotypes, and our data should serve as a valuable resource for future studies of complex traits

Songbirds, Grandmothers, Templates: A Neuroethological Approach

Songbirds such as the white-crowned sparrow memorize the song of conspecific adults during a critical period early in life, and later in life develop song by utilizing auditory feedback. Neurons in one of the telencephalic nuclei controlling song have recently been shown to respond to acoustic stimuli. I investigated the auditory response properties of units in this nucleus using a technique that permitted great flexibility in manipulating complex stimuli such as song. A few of the units exhibited considerable selectivity for the individual's own song. In wild-caught birds, song specific units exhibited intra-dialect selectivity. In those birds that sang abnormal songs due to laboratory manipulation of song exposure during the critical period for song learning, units were selective for the abnormal songs. By systematic modification of a song, and by construction of complex synthetic sounds mimicking song, the acoustic parameters responsible for the response selectivity were identified. Song specific units responded to sequences of two song parts, but not to the parts in isolation. Modification of the frequencies of either part of the sequence, or increasing the interval between the parts, varied the strength of the response. Thus, temporal as well as spectral parameters were important for the response. When sequences of synthetic sounds mimicking song were effective in evoking an excitatory response, the response was sensitive to the aforementioned manipulations. With these techniques it was possible to elucidate the acoustic parameters required to excite song specific units. All songs of the repertoire eliciting a strong excitatory response contained the appropriate parameters, which were missing from all weakly effective, ineffective, or inhibitory songs. These observations suggest that the ontogenetic modification of integrative neural mechanisms underlying song learning or song crystalization is reflected at the level of single neurons.</p

Probing Electron Tunneling Pathways: Electrochemical Study of Rat Heart Cytochromecand Its Mutant on Pyridine-Terminated SAMs

The electron-transfer rates between gold electrodes and adsorbed cytochromes are compared for native cytochrome c and its mutant (K13A) using two different immobilization strategies. A recent study by Niki (Niki, K.; Hardy, W. R.; Hill, M. G.; Li, H.; Sprinkle, J. R.; Margoliash, E.; Fujita, K.; Tanimura, R.; Nakamura, N.; Ohno, H.; Richards, J. H.; Gray, H. B. J. Phys. Chem. B 2003, 107, 9947) showed that the electron-transfer rate for a particular mutant cytochrome c (K13A) is orders of magnitude slower than the native form when electrostatically adsorbed on SAM-coated gold electrodes. The current study directly “links” the protein's heme unit to the SAM, thereby “short circuiting” the electron tunneling pathway. These findings demonstrate that the immobilization strategy can modify the electron-transfer rate by changing the tunneling pathway