Detection of Cochlear Amplification and Its Activation

The operation of the mammalian cochlea relies on a mechanical traveling wave that is actively boosted by electromechanical forces in sensory outer hair cells (OHCs). This active cochlear amplifier produces the impressive sensitivity and frequency resolution of mammalian hearing. The cochlear amplifier has inspired scientists since its discovery in the 1970s, and is still not well understood. To explore cochlear electromechanics at the sensory cell/tissue interface, sound-evoked intracochlear pressure and extracellular voltage were measured using a recently developed dual-sensor with a microelectrode attached to a micro-pressure sensor. The resulting coincident in vivo observations of OHC electrical activity, pressure at the basilar membrane and basilar membrane displacement gave direct evidence for power amplification in the cochlea. Moreover, the results showed a phase shift of voltage relative to mechanical responses at frequencies slightly below the peak, near the onset of amplification. Based on the voltage-force relationship of isolated OHCs, the shift would give rise to effective OHC pumping forces within the traveling wave peak. Thus, the shift activates the cochlear amplifier, serving to localize and thus sharpen the frequency region of amplification. These results are the most concrete evidence for cochlear power amplification to date and support OHC somatic forces as its source.     

Detection of Cochlear Amplification and Its Activation

The operation of the mammalian cochlea relies on a mechanical traveling wave that is actively boosted by electromechanical forces in sensory outer hair cells (OHCs). This active cochlear amplifier produces the impressive sensitivity and frequency resolution of mammalian hearing. The cochlear amplifier has inspired scientists since its discovery in the 1970s, and is still not well understood. To explore cochlear electromechanics at the sensory cell/tissue interface, sound-evoked intracochlear pressure and extracellular voltage were measured using a recently developed dual-sensor with a microelectrode attached to a micro-pressure sensor. The resulting coincident in vivo observations of OHC electrical activity, pressure at the basilar membrane and basilar membrane displacement gave direct evidence for power amplification in the cochlea. Moreover, the results showed a phase shift of voltage relative to mechanical responses at frequencies slightly below the peak, near the onset of amplification. Based on the voltage-force relationship of isolated OHCs, the shift would give rise to effective OHC pumping forces within the traveling wave peak. Thus, the shift activates the cochlear amplifier, serving to localize and thus sharpen the frequency region of amplification. These results are the most concrete evidence for cochlear power amplification to date and support OHC somatic forces as its source.     

Adaptation of Cochlear Amplification to Low Endocochlear Potential

Endocochlear potential (EP) is essential for cochlear amplification by providing the voltage source needed to drive outer hair cell (OHC) transducer current, which leads to OHC electromechanical force. An early study using furosemide to reversibly reduce EP showed that distortion product otoacoustic emissions (DPOAEs) recovered before EP. This indicated that cochlear amplification may be able to adjust to a new, lower EP. To investigate the mechanism of this adjustment, the extracellular OHC voltage, which we term local cochlear microphonic (LCM), was measured simultaneously with DPOAE and EP while using intraperitoneal (IP) and intravenous injection of furosemide to reversibly reduce EP. With IP injection, the DPOAEs recovered fully, whereas the EP was reduced, but LCM showed a similar time course as EP. The DPOAEs failed to accurately report the variation of cochlear amplification. With intravenous injection, for which both reduction and recovery of EP are known to occur relatively quickly compared to IP, the cochlear amplification observed in LCM could attain nearly full or even full recovery with reduced EP. This showed the cochlea has an ability to adjust to diminished operating condition. Furthermore, the cochlear amplifier and EP recovered with different time courses: cochlear amplification just started to recover after the EP was nearly fully recovered and stabilized. Using a Boltzmann model and the second harmonic of the LCM to estimate the mechanoelectric transducer channel operating point, we found that the recovery of cochlear amplification occurred with recentering of the operating point.     

An Active Oscillator Model Describes the Statistics of Spontaneous Otoacoustic Emissions

Even in the absence of external stimulation, the cochleas of most humans emit very faint sounds below the threshold of hearing, sounds that are known as spontaneous otoacoustic emissions. They are a signature of the active amplification mechanism in the cochlea. Emissions occur at frequencies that are unique for an individual and change little over time. The statistics of a population of ears exhibit characteristic features such as a preferred relative frequency distance between emissions (interemission intervals). We propose a simplified cochlea model comprising an array of active nonlinear oscillators coupled both hydrodynamically and viscoelastically. The oscillators are subject to a weak spatial disorder that lends individuality to the simulated cochlea. Our model captures basic statistical features of the emissions: distributions of 1), emission frequencies; 2), number of emissions per ear; and 3), interemission intervals. In addition, the model reproduces systematic changes of the interemission intervals with frequency. We show that the mechanism for the preferred interemission interval in our model is the occurrence of synchronized clusters of oscillators.     

An Active Oscillator Model Describes the Statistics of Spontaneous Otoacoustic Emissions

Even in the absence of external stimulation, the cochleas of most humans emit very faint sounds below the threshold of hearing, sounds that are known as spontaneous otoacoustic emissions. They are a signature of the active amplification mechanism in the cochlea. Emissions occur at frequencies that are unique for an individual and change little over time. The statistics of a population of ears exhibit characteristic features such as a preferred relative frequency distance between emissions (interemission intervals). We propose a simplified cochlea model comprising an array of active nonlinear oscillators coupled both hydrodynamically and viscoelastically. The oscillators are subject to a weak spatial disorder that lends individuality to the simulated cochlea. Our model captures basic statistical features of the emissions: distributions of 1), emission frequencies; 2), number of emissions per ear; and 3), interemission intervals. In addition, the model reproduces systematic changes of the interemission intervals with frequency. We show that the mechanism for the preferred interemission interval in our model is the occurrence of synchronized clusters of oscillators.     

Optimal Electrical Properties of Outer Hair Cells Ensure Cochlear Amplification

The organ of Corti (OC) is the auditory epithelium of the mammalian cochlea comprising sensory hair cells and supporting cells riding on the basilar membrane. The outer hair cells (OHCs) are cellular actuators that amplify small sound-induced vibrations for transmission to the inner hair cells. We developed a finite element model of the OC that incorporates the complex OC geometry and force generation by OHCs originating from active hair bundle motion due to gating of the transducer channels and somatic contractility due to the membrane protein prestin. The model also incorporates realistic OHC electrical properties. It explains the complex vibration modes of the OC and reproduces recent measurements of the phase difference between the top and the bottom surface vibrations of the OC. Simulations of an individual OHC show that the OHC somatic motility lags the hair bundle displacement by ∼90 degrees. Prestin-driven contractions of the OHCs cause the top and bottom surfaces of the OC to move in opposite directions. Combined with the OC mechanics, this results in ∼90 degrees phase difference between the OC top and bottom surface vibration. An appropriate electrical time constant for the OHC membrane is necessary to achieve the phase relationship between OC vibrations and OHC actuations. When the OHC electrical frequency characteristics are too high or too low, the OHCs do not exert force with the correct phase to the OC mechanics so that they cannot amplify. We conclude that the components of OHC forward and reverse transduction are crucial for setting the phase relations needed for amplification.     

一种改进的小波阈值法去除耳声发射中的伪迹

本文探讨了耳声发射及其分类、特性、目前存在的问题和相关研究方法,并提出一种改进的小波阈值处理方法,它是基于一种多分辨分析小波阈值去噪,在传统的软、硬阈值去噪基础上设立两个变量,通过调节这两个变量有效地达到去除噪声的效果。     

The Spatial Arrangement of the Wild-Type and Mutant Tobacco Mosaic Virus Coat Proteins Assessed by Tritium Planigraphy

Mutant ts21-66 of the tobacco mosaic virus (TMV) differs from the wild-type TMV-U1 by two mutations (Ile21 Thr and Asp66 Gly) in the coat protein (CP) gene and in symptoms produced in infected N" plants. The CP structure in TMV-U1 and ts21-66 virions was probed by tritium planigraphy. Compared with the wild-type CP, labeling of the N-terminal region of mutant CP was half as high and suggested its greater shielding. The role of this CP region in virus interactions with the N" resistance system is discussed.     

Interactions between Hair Cells Shape Spontaneous Otoacoustic Emissions in a Model of the Tokay Gecko's Cochlea

Background

The hearing of tetrapods including humans is enhanced by an active process that amplifies the mechanical inputs associated with sound, sharpens frequency selectivity, and compresses the range of responsiveness. The most striking manifestation of the active process is spontaneous otoacoustic emission, the unprovoked emergence of sound from an ear. Hair cells, the sensory receptors of the inner ear, are known to provide the energy for such emissions; it is unclear, though, how ensembles of such cells collude to power observable emissions.

Methodology and Principal Findings

We have measured and modeled spontaneous otoacoustic emissions from the ear of the tokay gecko, a convenient experimental subject that produces robust emissions. Using a van der Pol formulation to represent each cluster of hair cells within a tonotopic array, we have examined the factors that influence the cooperative interaction between oscillators.

Conclusions and Significance

A model that includes viscous interactions between adjacent hair cells fails to produce emissions similar to those observed experimentally. In contrast, elastic coupling yields realistic results, especially if the oscillators near the ends of the array are weakened so as to minimize boundary effects. Introducing stochastic irregularity in the strength of oscillators stabilizes peaks in the spectrum of modeled emissions, further increasing the similarity to the responses of actual ears. Finally, and again in agreement with experimental findings, the inclusion of a pure-tone external stimulus repels the spectral peaks of spontaneous emissions. Our results suggest that elastic coupling between oscillators of slightly differing strength explains several properties of the spontaneous otoacoustic emissions in the gecko.     

The Genetic Divergence of Sublines as Assessed by Histocompatibility Testing

The degree of genetic divergence which has occurred between a number of inbred strains of mice and between two sublines of inbred rats was assessed by determining the fate of inter-subline skin grafts. Sublines which had been separated for 29 and 42 generations possessed no detectable incompatibility, while three combinations of sublines judged to have been maintained apart for from 123 to 129 generations showed slight degrees of histoincompatibility. One pair of sublines which had been separated for 119 generations demonstrated a marked degree of incompatibility, and an F₂ test suggested that mutations had occurred at four or five histocompatibility loci.     

The Evolutionary History of Nitrogen Fixation, as Assessed by NifD

The evolutionary history of nitrogen fixation has been vigorously debated for almost two decades. Previous phylogenetic analyses of nitrogen fixation genes (nif) have shown support for either evolution by vertical descent or lateral transfer, depending on the specific nif gene examined and the method of analyses used. The debate centers on the placement and monophyly of the cyanobacteria, proteobacteria, and Gram-positive bacteria (actinobacteria and firmicutes). Some analyses place the cyanobacteria and actinobacteria within the proteobacteria, which suggests that the nif genes have been laterally transferred since this topology is incongruent with ribosomal phylogenies, the standard marker for comparison. Other nif analyses resolve and support the monophyly of the cyanobacteria, proteobacteria, and actinobacteria, supporting vertical descent. We have revisited these conflicting scenarios by analyzing nifD from an increased number of cyanobacteria, proteobacteria, and Gram-positive bacteria. Parsimony analyses of amino acid sequences and maximum likelihood analysis of nucleic acid sequences support the monophyly of the cyanobacteria and actinobacteria but not the proteobacteria, lending support for vertical descent. However, distance analysis of nucleic acid sequences placed the actinobacteria within the proteobacteria, supporting lateral transfer. We discuss evidence for both vertical descent and lateral transfer of nitrogen fixation.     

The Accuracy of Genomic Selection in Norwegian Red Cattle Assessed by Cross-Validation

Genomic Selection (GS) is a newly developed tool for the estimation of breeding values for quantitative traits through the use of dense markers covering the whole genome. For a successful application of GS, accuracy of the prediction of genomewide breeding value (GW-EBV) is a key issue to consider. Here we investigated the accuracy and possible bias of GW-EBV prediction, using real bovine SNP genotyping (18,991 SNPs) and phenotypic data of 500 Norwegian Red bulls. The study was performed on milk yield, fat yield, protein yield, first lactation mastitis traits, and calving ease. Three methods, best linear unbiased prediction (G-BLUP), Bayesian statistics (BayesB), and a mixture model approach (MIXTURE), were used to estimate marker effects, and their accuracy and bias were estimated by using cross-validation. The accuracies of the GW-EBV prediction were found to vary widely between 0.12 and 0.62. G-BLUP gave overall the highest accuracy. We observed a strong relationship between the accuracy of the prediction and the heritability of the trait. GW-EBV prediction for production traits with high heritability achieved higher accuracy and also lower bias than health traits with low heritability. To achieve a similar accuracy for the health traits probably more records will be needed.GENOMIC selection (GS) is a new technology that is expected to revolutionize animal breeding. It is distinct from traditional selection methods where phenotype and pedigree information is combined to predict breeding values and where at least one source is necessary for a prediction. Estimation of GS breeding value is based on the estimation of marker effects covering the whole genome and combines these estimates with the marker genotypes to obtain breeding value estimates. Given a sufficiently dense genomewide marker map, all the genetic variance is expected to be explained by the markers, and all quantitative trait loci (QTL) are in linkage disequilibrium (LD) with at least one marker (Calus et al. 2008). This allows GS to predict genomewide estimates of breeding values (GW-EBV) without the need of phenotyping the selection candidates. A potential cost reduction of up to 90% can be achieved for a breeding program by GS (Schaeffer 2006), because only a moderate number of individuals are required to have both known marker genotypes and phenotypes. These individuals form a reference data set for the estimation of GW-EBV. The knowledge obtained from the reference data set can be applied to the calculation of GW-EBV for the selection candidates on the basis of their marker genotypes, with an accuracy that is found in the validation of the prediction (Goddard and Hayes 2007).For a successful application of GS, based on a reference data set, to a usually much larger population of selection candidates without phenotypic records, accuracy of the prediction is a key issue to consider (Goddard and Hayes 2009). Since GS was first proposed by Meuwissen et al. (2001), many research works using simulated data have been performed on this issue (Calus and Veerkamp 2007; Habier et al. 2007; Kolbehdari et al. 2007; Calus et al. 2008; Solberg et al. 2008). The recent availability of genomewide dense SNP marker maps has made GS with real data feasible. Studies of the accuracy of genomic predictions have emerged in some animal species, including mice (Lee et al. 2008; Legarra et al. 2008), chickens (Gonzalez-Recio et al. 2009), and cattle (Hayes et al. 2009), and in plant species [for example, barley (Zhong et al. 2009)]. For GS applied to dairy cattle, accuracies for the GW-EBV have been reported in North American Holstein (VanRaden et al. 2009), Australian Holstein–Friesian (Hayes et al. 2009), and New Zealand Holstein–Friesian and Jersey dairy cattle (Harris et al. 2008).In the present work we applied GS to Norwegian Red dairy cattle to investigate the accuracy and possible bias of GW-EBV prediction for the phenotypes of milk production, clinical mastitis, and calving ease, by using real bovine genotyping data. Three methods, best linear unbiased prediction, Bayesian statistics, and a mixture model approach were used in the study, and their accuracies and biases of the GW-EBV were compared. To estimate the accuracy and bias of the GW-EBV the approach of cross-validation was employed, making use of estimates of breeding value from the Norwegian Red dairy cattle breeding scheme.     

Spatial Variation of the Gut Microbiota in Broiler Chickens as Affected by Dietary Available Phosphorus and Assessed by T-RFLP Analysis and 454 Pyrosequencing

Molecular fingerprinting and sequencing based techniques have been widely used to characterize microbial communities. Terminal restriction fragment length polymorphism (T-RFLP) and 454-pyrosequencing were used to determine the microorganisms present in the different sections of the chicken gastrointestinal tract (GIT) (crop, jejunum, ileum and caeca). Broilers fed with diets differing in phosphorous (P) and calcium (Ca) as well as in phytase levels were used to study the microbiota of the upper and lower part of the GIT. A database with terminal restriction fragments (T-RF) of the most important organism present in the different gastrointestinal sections was constructed. The analysis revealed a distinct microbial assemblage on each section. Regardless of the diet, crop, jejunum and ileum were mainly colonized by Lactobacillaceae, and caeca were the most diverse site. The correlation between Lactobacillus crispatus and L. reuteri was positive in the crop, but negative in the jejunum. In crop samples, higher P and Ca levels led to a shift in the abundance of L. reuteri and L. crispatus to L. salivarius and L. taiwanensis whereas in the ileum supplementation of phytase favored L. salivarius and L. taiwanensis but resulted in decreased abundance of L. crispatus. Both methods were correlating significantly, being T-RFLP a reliable fingerprinting method to rapidly analyze large numbers of samples in a cost-effective and rapid manner. Results are easy to interpret with no need of deep bioinformatics knowledge and can be integrated with taxonomic information.     

The Purity of Radioiodide-I131 Assessed by in Vivo and in Vitro Methods

Between 41 and 94% of the radioactivity of 24 preparations of I¹³¹ supplied without cysteine preservative was non-iodide on chromatographic analysis. Extraneous radio-activity was essentially absent from I¹³¹ supplied with cysteine. It was converted to iodide-I¹³¹ by 10^-3 M cysteine or iodide but not by incubation at pH 2. The average thyroid uptake of I¹³¹ containing extraneous radioactivity was significantly lower than the uptake of I¹³¹ free from non-iodide impurity in 16 human subjects measured under controlled conditions and in a random group of 669 patients. Incubation of samples of I¹³¹ containing non-iodide radioactivity with tyrosine and cupric chloride resulted in the non-enzymatic formation of monoiodotyrosine-I¹³¹ either in the presence or absence of thyroid homogenate. Enzymatic formation of monoiodotyrosine-I¹³¹ by thyroid homogenates could be demonstrated only when I¹³¹ free from extraneous activity was used.     

The Cochlear Duct of Lizards and Snakes

The gross morphology of the cochlear ducts of approximatelyhalf (150) of the living genera of lizards and a third (130)of the living genera of snakes have been studied. The differencesin the structure of the cochlear duct are related to both theacoustical capacities and the taxonomic relationships of certainlizards and snakes. The cochlear duct of lizards consists offairly well joined lagenar and limbic portions. By contrast,the cochlear duct of snakes consists of a lagenar sac somewhatconstricted from the limbus. Each family of lizards has a morphologicallycharacteristic cochlear duct, but taxonomic relationships areindicated by certain anatomical similarities. The cochlear ductof snakes is more primitive than that of lizards, and, unlikelizards, does not exhibit marked specializations of its variousparts. Differences in morphology of the cochlear duct in snakesare much more related to habitat than family. The limbus andpapilla basilaris of snakes regardless of family, are most elongatedin bin rowing species, are only moderately elongated or ovoidin terrestrial species, and are small or reduced in certainarboreal and aquatic species.     

The Evolutionary Origins of Hierarchy

Hierarchical organization—the recursive composition of sub-modules—is ubiquitous in biological networks, including neural, metabolic, ecological, and genetic regulatory networks, and in human-made systems, such as large organizations and the Internet. To date, most research on hierarchy in networks has been limited to quantifying this property. However, an open, important question in evolutionary biology is why hierarchical organization evolves in the first place. It has recently been shown that modularity evolves because of the presence of a cost for network connections. Here we investigate whether such connection costs also tend to cause a hierarchical organization of such modules. In computational simulations, we find that networks without a connection cost do not evolve to be hierarchical, even when the task has a hierarchical structure. However, with a connection cost, networks evolve to be both modular and hierarchical, and these networks exhibit higher overall performance and evolvability (i.e. faster adaptation to new environments). Additional analyses confirm that hierarchy independently improves adaptability after controlling for modularity. Overall, our results suggest that the same force–the cost of connections–promotes the evolution of both hierarchy and modularity, and that these properties are important drivers of network performance and adaptability. In addition to shedding light on the emergence of hierarchy across the many domains in which it appears, these findings will also accelerate future research into evolving more complex, intelligent computational brains in the fields of artificial intelligence and robotics.     

The Developmental Origins of Osteoporosis

Osteoporosis is one of the most prevalent skeletal disorders and has enormous public health consequences due to the morbidity and mortality of the resulting fractures. This article discusses the developmental origins of osteoporosis and outlines some of the modifiable and non-modifiable risk factors in both intrauterine and postnatal life that contribute to the later onset of osteoporosis. Evidence for the effects of birth size and early growth in both preterm and term born infants are discussed and the role of epigenetics within the programming hypothesis is highlighted. This review provides compelling evidence for the developmental origins of osteoporosis and highlights the importance of osteoporosis prevention at all stages of the life course.     

The Origins of Cellular Life

Understanding the origin of cellular life on Earth requires the discovery of plausible pathways for the transition from complex prebiotic chemistry to simple biology, defined as the emergence of chemical assemblies capable of Darwinian evolution. We have proposed that a simple primitive cell, or protocell, would consist of two key components: a protocell membrane that defines a spatially localized compartment, and an informational polymer that allows for the replication and inheritance of functional information. Recent studies of vesicles composed of fatty-acid membranes have shed considerable light on pathways for protocell growth and division, as well as means by which protocells could take up nutrients from their environment. Additional work with genetic polymers has provided insight into the potential for chemical genome replication and compatibility with membrane encapsulation. The integration of a dynamic fatty-acid compartment with robust, generalized genetic polymer replication would yield a laboratory model of a protocell with the potential for classical Darwinian biological evolution, and may help to evaluate potential pathways for the emergence of life on the early Earth. Here we discuss efforts to devise such an integrated protocell model.The emergence of the first cells on the early Earth was the culmination of a long history of prior chemical and geophysical processes. Although recognizing the many gaps in our knowledge of prebiotic chemistry and the early planetary setting in which life emerged, we will assume for the purpose of this review that the requisite chemical building blocks were available, in appropriate environmental settings. This assumption allows us to focus on the various spontaneous and catalyzed assembly processes that could have led to the formation of primitive membranes and early genetic polymers, their coassembly into membrane-encapsulated nucleic acids, and the chemical and physical processes that allowed for their replication. We will discuss recent progress toward the construction of laboratory models of a protocell (Fig. 1), evaluate the remaining steps that must be achieved before a complete protocell model can be constructed, and consider the prospects for the observation of spontaneous Darwinian evolution in laboratory protocells. Although such laboratory studies may not reflect the specific pathways that led to the origin of life on Earth, they are proving to be invaluable in uncovering surprising and unanticipated physical processes that help us to reconstruct plausible pathways and scenarios for the origin of life.Open in a separate windowFigure 1.A simple protocell model based on a replicating vesicle for compartmentalization, and a replicating genome to encode heritable information. A complex environment provides lipids, nucleotides capable of equilibrating across the membrane bilayer, and sources of energy (left), which leads to subsequent replication of the genetic material and growth of the protocell (middle), and finally protocellular division through physical and chemical processes (right). (Reproduced from Mansy et al. 2008 and reprinted with permission from Nature Publishing ©2008.)The term protocell has been used loosely to refer to primitive cells or to the first cells. Here we will use the term protocell to refer specifically to cell-like structures that are spatially delimited by a growing membrane boundary, and that contain replicating genetic information. A protocell differs from a true cell in that the evolution of genomically encoded advantageous functions has not yet occurred. With a genetic material such as RNA (or perhaps one of many other heteropolymers that could provide both heredity and function) and an appropriate environment, the continued replication of a population of protocells will lead inevitably to the spontaneous emergence of new coded functions by the classical mechanism of evolution through variation and natural selection. Once such genomically encoded and therefore heritable functions have evolved, we would consider the system to be a complete, living biological cell, albeit one much simpler than any modern cell (Szostak et al. 2001).