Realizing acoustic qubit analogues with nonlinearly tunable phi-bits in externally driven coupled acoustic waveguides.

Using experiments and theory, we investigate the behavior of nonlinear acoustic modes in a physical system composed of an array of three coupled acoustic waveguides, two of which are externally driven with two different frequencies. Nonlinear modes with frequency given by linear combinations of the driving frequencies are realizations of so-called logical phi-bits. A phi-bit is a two-state degree of freedom of an acoustic wave, which can be in a coherent superposition of states with complex amplitude coefficients, i.e., a qubit analogue. We demonstrate experimentally that phi-bit modes are supported in the array of waveguides. Using perturbation theory, we show that phi-bits may result from the intrinsic nonlinearity of the material used to couple the waveguides. We have also isolated possible effects on phi-bit states associated with the systems' electronics, transducers and ultrasonic coupling agents used to probe the array and that may introduce extrinsic nonlinearities. These extrinsic effects are shown to be easily separable from the intrinsic behavior. The intrinsic behavior includes sharp jumps in phi-bit phases occurring over very narrow ranges of driving frequency. These jumps may also exhibit hysteretic behavior dependent on the direction of driving frequency tuning. The intrinsic states of phi-bits and multiple nonlinearly correlated phi-bits may serve as foundation for robust and practical quantum-analogue information technologies.

Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: A resting state 1H-MRS study.

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ∼20-30 years have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN), which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 years underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, or in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk.

Exponentially Complex "Classically Entangled" States in Arrays of One-Dimensional Nonlinear Elastic Waveguides.

We demonstrate theoretically, using multiple-time-scale perturbation theory, the existence of nonseparable superpositions of elastic waves in an externally driven elastic system composed of three one-dimensional elastic wave guides coupled via nonlinear forces. The nonseparable states span a Hilbert space with exponential complexity. The amplitudes appearing in the nonseparable superposition of elastic states are complex quantities dependent on the frequency of the external driver. By tuning these complex amplitudes, we can navigate the state's Hilbert space. This nonlinear elastic system is analogous to a two-partite two-level quantum system.

Evidence for hidden order in a nonlinear model elastic system.

Hidden order may arise in strongly correlated systems even if there is an apparent lack of long-range order as measured by local order parameters. This phenomenon has been essentially associated with topological order in quantum systems. Here, we demonstrate the emergence of hidden order in a 1D non-linear classical mechanical system that supports rotational degrees of freedom. The potential energy of the model system creates a bistable system for which hidden order emerges with the introduction of a biquadratic term. To our surprise, we discover that varying the strength of the biquadratic term leads to four distinct phases quantified by the behaviors of the Néel and string order parameters. Three of these phases are locally disordered. Hidden order is identified by a string order parameter that shows correlations with significantly longer range than the Néel order parameter. The hidden order correlation length diverges as the kinetic energy of the system is lowered with a critical exponent ~0.5. The observation of hidden order in a mechanical system reveals that instability and non-linearity may play critical roles in the generation of nonlocal long-range correlations in apparently locally disordered systems.

Giant frequency down-conversion of the dancing acoustic bubble.

We have demonstrated experimentally the existence of a giant frequency down-conversion of the translational oscillatory motion of individual submillimeter acoustic bubbles in water in the presence of a high frequency (500 kHz) ultrasonic standing wave. The frequency of the translational oscillations (~170 Hz) is more than three orders of magnitude smaller than that of the driving acoustic wave. We elucidate the mechanism of this very slow oscillation with an analytical model leading to an equation of translational motion of a bubble taking the form of Mathieu's equation. This equation illuminates the origin of the giant down conversion in frequency as arising from an unstable equilibrium. We also show that bubbles that form chains along the direction of the acoustic standing wave due to radiation interaction forces exhibit also translation oscillations that form a spectral band. This band extends approximately from 130 Hz up to nearly 370 Hz, a frequency range that is still at least three orders of magnitude lower than the frequency of the driving acoustic wave.

Effect of sound on gap-junction-based intercellular signaling: Calcium waves under acoustic irradiation.

We present a previously unrecognized effect of sound waves on gap-junction-based intercellular signaling such as in biological tissues composed of endothelial cells. We suggest that sound irradiation may, through temporal and spatial modulation of cell-to-cell conductance, create intercellular calcium waves with unidirectional signal propagation associated with nonconventional topologies. Nonreciprocity in calcium wave propagation induced by sound wave irradiation is demonstrated in the case of a linear and a nonlinear reaction-diffusion model. This demonstration should be applicable to other types of gap-junction-based intercellular signals, and it is thought that it should be of help in interpreting a broad range of biological phenomena associated with the beneficial therapeutic effects of sound irradiation and possibly the harmful effects of sound waves on health.

Phase-controlling phononic crystals: realization of acoustic Boolean logic gates.

A phononic crystal (PC) consisting of a square array of cylindrical polyvinylchloride inclusions in air is used to construct a variety of acoustic logic gates. In a certain range of operating frequencies, the PC band structure shows square-like equi-frequency contours centered off the gamma point. This attribute allows for the realization of non-collinear wave and group velocity vectors in the PC wave vector space. This feature can be utilized to control with great precision, the relative phase between propagating acoustic waves in the PC. By altering the incidence angle of the impinging acoustic beams or varying the PC thickness, interferences occur between acoustic wave pairs. It is recognized that information can be encoded with this mechanism (e.g., wave amplitudes/interference patterns) and accordingly to construct a series of logic gates emulating Boolean functions. The NAND, XOR, and NOT gates are demonstrated with finite-difference time-domain simulations of acoustic waves impinging upon the PC.

The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.

Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins and in defining vitamin K nutriture have led to a substantial revision in our understanding of vitamin K physiology. The only unequivocal function for vitamin K is as a cofactor for the carboxylation of VKD proteins which renders them active. While vitamin K was originally associated only with hepatic VKD proteins that participate in hemostasis, VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet and their contribution to hepatic vs. non-hepatic tissue. New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional hemostasis, the undercarboxylation of at least one non-hemostatic protein is frequently observed in the general population. The advances in defining VKD protein function and vitamin K nutriture are described, as is the potential impact of VKD proteins on atherosclerosis. Many of the VKD proteins contribute to atherogenesis. Recent studies suggest involvement in arterial calcification, which may be influenced by dietary levels of vitamin K and by anticoagulant drugs such as warfarin that antagonize vitamin K action.

Frontal lobe dysfunctions in Korsakoff's syndrome and chronic alcoholism: continuity or discontinuity?

The effect of long-term heavy alcohol consumption on brain functions is still under debate. The authors investigated a sample of 17 Korsakoff amnesics, 23 alcoholics without Korsakoff's syndrome, and 21 controls with peripheral nerve diseases, matched for intelligence and education. Executive functions were examined for word fluency, the modified Wisconsin Card Sorting Test, an alternate response task, and an "n-back" working memory task. Korsakoff amnesics, but not alcoholics, showed a marked memory impairment. They also scored lower in each of the executive tasks-the alcoholics only in the alternate response task. This task also correlated with the years of the alcohol dependency. First, the authors conclude that Korsakoff's syndrome is associated not only with a memory impairment but also with a global executive deficit. Second, the decline in the ability to alternate between different responses argues for a restricted neurotoxic effect of alcohol on some frontal lobe areas.

Photonic polymers:a new class of photonic wire structure from intersecting polymer-blend microspheres.

We report a new kind of photonic wire structure made from the sequential attachment of polymer-blend microparticles. Using a linear quadrupole to manipulate the particles in space, we are able to take advantage of a modified surface structure in the blend particle to actively assemble particles in programmable two- or three-dimensional architectures. Strong resonance features in fluorescence are observed near the intersection of linked spheres that cannot be interpreted with a two-dimensional (equatorial plane) model. Three-dimensional ray optics calculations show long-lived periodic trajectories that propagate in great circles linked at an angle with respect to the plane containing the sphere centers.

Yeast telomerase appears to frequently copy the entire template in vivo.

Telomeres derived from the same formation event in wild type strains of Saccharomyces cerevisiae possess the same, precise TG(1-3) sequence for the most internal approximately 100 bp of the 250-350 bp TG(1-3) repeats. The conservation of this internal domain is thought to reflect the fact that telomere lengthening and shortening, and thus alteration of the precise TG(1-3) sequence, is confined to the terminal region of the telomere. The internal domains of telomeres from yku70 and tel1 mutants, whose entire telomeres are only approximately 100 bp, were examined by analyzing 5.1 kb of cloned TG(1-3) sequences from telomeres formed during transformation of wild type, yku70 and tel1 cells. The internal domains were 97-137 bp in wild type cells, 27-36 bp in yku70 cells and 7-9 bp in tel1 cells. These data suggest that the majority of the tel1 cell TG(1-3) repeats may be resynthesized during shortening and lengthening reactions while a portion of the yku70 cell telomeres are protected. TG(1-3) sequences are synthesized by telomerase repeatedly copying an internal RNA template, which introduces a sequence bias into TG(1-3) repeats. Analysis of in vivo-derived telomeres revealed that of the many possible high affinity binding sites for the telomere protein Rap1p in TG(1-3) repeats, only those consistent with telomere hybridization to the ACACAC in the 3'-region of the telomerase RNA template followed by copying of most of the template were present. Copies of the telomerase RNA template made up 40-60% of the TG(1-3) sequences from each strain and could be found in long, tandem repeats. The data suggest that in vivo yeast telomerase frequently allows telomeres to hybridize to the 3'-region of RNA template and copy most of it prior to dissociation, or that in vivo telomere processing events result in the production of TG(1-3) sequences that mimic this process.

Two paralogs involved in transcriptional silencing that antagonistically control yeast life span.

In the yeast Saccharomyces cerevisiae, one determinant of aging or life span is the accumulation of extrachromosomal copies of rDNA circles in old mother cells [1]. The production of rDNA circles depends upon intrachromosomal recombination within the rDNA tandem array, a process regulated by the protein Sir2 (Sir2p). Together with Sir1p, Sir3p, Sir4p and Orc1p, Sir2p is also involved in transcriptional silencing of genes at the silent mating-type cassettes, in the rDNA array, and at telomeres. Using a 'triple silencer' strain that can monitor an increase or decrease in gene expression at these three loci, we found that deletion of the ZDS1 gene caused an increase in silencing in the rDNA and at a silent mating-type cassette at the expense of telomere silencing. The zds1 deletion also resulted in an increase in life span and a decrease in Sir3p phosphorylation. In contrast, deletion of its paralog ZDS2 caused a decrease in rDNA silencing, a decrease in life span and an increase in Sir3p phosphorylation. As Zds2p, but not Zds1p, had strong two-hybrid interactions with Orc1p and the four Sir proteins, Zds1p might indirectly control Sir3p through a Sir3p kinase.

Varying the number of telomere-bound proteins does not alter telomere length in tel1Delta cells.

Yeast telomere DNA consists of a continuous, approximately 330-bp tract of the heterogeneous repeat TG(1-3) with irregularly spaced, high affinity sites for the protein Rap1p. Yeast monitor, or count, the number of telomeric Rap1p C termini in a negative feedback mechanism to modulate the length of the terminal TG(1-3) repeats, and synthetic telomeres that tether Rap1p molecules adjacent to the TG(1-3) tract cause wild-type cells to maintain a shorter TG(1-3) tract. To identify trans-acting proteins required to count Rap1p molecules, these same synthetic telomeres were placed in two short telomere mutants: yku70Delta (which lack the yeast Ku70 protein) and tel1Delta (which lack the yeast ortholog of ATM). Although both mutants maintain telomeres with approximately 100 bp of TG(1-3), only yku70Delta cells maintained shorter TG(1-3) repeats in response to internal Rap1p molecules. This distinct response to internal Rap1p molecules was not caused by a variation in Rap1p site density in the TG(1-3) repeats as sequencing of tel1Delta and yku70Delta telomeres showed that both strains have only five to six Rap1p sites per 100-bp telomere. In addition, the tel1Delta short telomere phenotype was epistatic to the unregulated telomere length caused by deletion of the Rap1p C-terminal domain. Thus, the length of the TG(1-3) repeats in tel1Delta cells was independent of the number of the Rap1p C termini at the telomere. These data indicate that tel1Delta cells use an alternative mechanism to regulate telomere length that is distinct from monitoring the number of telomere binding proteins.

Tel2p, a regulator of yeast telomeric length in vivo, binds to single-stranded telomeric DNA in vitro.

The telomeres of the yeast Saccharomyces cerevisiae consist of a duplex region of TG(1-3) repeats that acquire a single-stranded 3' extension of the TG(1-3) strand at the end of S-phase. The length of these repeats is kept within a defined range by regulators such as the TEL2-encoded protein (Tel2p). Here we show that Tel2p can specifically bind to single-stranded TG(1-3). Tel2p binding produced several shifted bands; however, only the slowest migrating band contained Tel2p. Methylation protection and interference experiments as well as gel shift experiments using inosine-containing probes indicated that the faster migrating bands resulted from Tel2p-mediated formation of DNA secondary structures held together by G-G interactions. Tel2p bound to single-stranded substrates that were at least 19 bases in length and contained 14 bases of TG(1-3), and also to double-stranded/single-stranded hybrid substrates with a 3' TG(1-3) overhang. Tel2p binding to a hybrid substrate with a 24 base single-stranded TG(1-3) extension also produced a band characteristic of G-G-mediated secondary structures. These data suggest that Tel2p could regulate telomeric length by binding to the 3' single-stranded TG(1-3) extension present at yeast telomeres.

The ZDS1 and ZDS2 proteins require the Sir3p component of yeast silent chromatin to enhance the stability of short linear centromeric plasmids.

Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a centromere, origin of replication, two telomeres and a >50 kb insert of DNA are maintained as normal yeast chromosomes. However, short linear centromeric plasmids of 10-15 kb in size (short YACs) are missegregated at a much higher frequency than long YACs or 10-15 kb circular centromeric plasmids. A search for genes that stabilized short linear centromeric plasmids when present in multiple copies per cell uncovered ZDS1, which reduced the rate at which cells lost the short YAC, increased the fraction of cells that maintained the short YAC and decreased the number of short YACs per cell. Multiple copies of ZDS2, a homolog of ZDS1, had similar effects. Genes near yeast telomeres are transcriptionally silenced by the recruitment of proteins encoded by the SIR2, SIR3 and SIR4 genes (Sir2p, Sir3p and Sir4p). Multiple copies of ZDS1 and ZDS2 caused an increase in telomeric silencing. In addition, ZDS1 and ZDS2 both required the open reading frame encoding the N-terminal 174 amino acids of Sir3p to stabilize short YACs. Thus, the short YAC stability assay revealed a silencing-independent function for the Sir3p N-terminus. Two-hybrid analysis indicated that Zds1p and Zds2p interact with Sir2p, Sir3p, Sir4p or the yeast telomere binding protein Rap1p. Deletion of both ZDS1 and ZDS2 made short YACs, but not a 100 kb YAC, extremely unstable and also caused a 70 bp increase in the length of the telomeric TG1-3 repeats. These data indicate that short YACs can be stabilized by trans-acting factors and suggest that the proteins encoded by ZDS1 and ZDS2 alter short YAC stability by interacting with proteins that function at the telomere.

The yeast telomere length counting machinery is sensitive to sequences at the telomere-nontelomere junction.

Saccharomyces cerevisiae telomeres consist of a continuous 325 +/- 75-bp tract of the heterogeneous repeat TG1-3 which contains irregularly spaced, high-affinity sites for the protein Rap1p. Yeast cells monitor or count the number of telomeric Rap1p molecules in a negative feedback mechanism which modulates telomere length. To investigate the mechanism by which Rap1p molecules are counted, the continuous telomeric TG1-3 sequences were divided into internal TG1-3 sequences and a terminal tract separated by nontelomeric spacers of different lengths. While all of the internal sequences were counted as part of the terminal tract across a 38-bp spacer, a 138-bp disruption completely prevented the internal TG1-3 sequences from being considered part of the telomere and defined the terminal tract as a discrete entity separate from the subtelomeric sequences. We also used regularly spaced arrays of six Rap1p sites internal to the terminal TG1-3 repeats to show that each Rap1p molecule was counted as about 19 bp of TG1-3 in vivo and that cells could count Rap1p molecules with different spacings between tandem sites. As previous in vitro experiments had shown that telomeric Rap1p sites occur about once every 18 bp, all Rap1p molecules at the junction of telomeric and nontelomeric chromatin (the telomere-nontelomere junction) must participate in telomere length measurement. The conserved arrangement of these six Rap1p molecules at the telomere-nontelomere junction in independent transformants also caused the elongated TG1-3 tracts to be maintained at nearly identical lengths, showing that sequences at the telomere-nontelomere junction had an effect on length regulation. These results can be explained by a model in which telomeres beyond a threshold length form a folded structure that links the chromosome terminus to the telomere-nontelomere junction and prevents telomere elongation.

The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.

TEL2 is required for telomere length regulation and viability in Saccharomyces cerevisiae. To investigate the mechanism by which Tel2p regulates telomere length, the majority (65%) of the TEL2 ORF was fused to the 3'-end of the gene for maltose binding protein, expressed in bacteria and the purified protein used in DNA binding studies. Rap1p, the major yeast telomere binding protein, recognizes a 13 bp duplex site 5'-GGTGTGTGGGTGT-3' in yeast telomeric DNA with high affinity. Gel shift experiments revealed that the MBP-Tel2p fusion binds the double-stranded yeast telomeric Rap1p site in a sequence-specific manner. Analysis of mutated sites showed that MBP-Tel2p could bind 5'-GTGTGTGG-3' within this 13 bp site. Methylation interference analysis revealed that Tel2p contacts the 5'-terminal guanine in the major groove. MBP-Tel2p did not bind duplex telomeric DNA repeats from vertebrates, Tetrahymena or Oxytricha. These results suggest that Tel2p is a DNA binding protein that recognizes yeast telomeric DNA.

The C terminus of the major yeast telomere binding protein Rap1p enhances telomere formation.

The telomeres of most organisms consist of short repeated sequences that can be elongated by telomerase, a reverse transcriptase complex that contains its own RNA template for the synthesis of telomere repeats. In Saccharomyces cerevisiae, the RAP1 gene encodes the major telomere binding protein Rap1p. Here we use a quantitative telomere formation assay to demonstrate that Rap1p C termini can enhance telomere formation more than 30-fold when they are located at internal sites. This stimulation is distinct from protection from degradation. Enhancement of formation required the gene for telomerase RNA but not Sir1p, Sir2p, Sir3p, Sir4p, Tel1p, or the Rif1p binding site in the Raplp C terminus. Our data suggest that Rap1p C termini enhance telomere formation by attracting or increasing the activity of telomerase near telomeres. Earlier work suggests that Rap1p molecules at the chromosome terminus inhibit the elongation of long telomeres by blocking the access of telomerase. Our results suggest a model where a balance between internal Rap1p increasing telomerase activity and Rap1p at the termini of long telomeres controlling telomerase access maintains telomeres at a constant length.

[Is Candida septicemia in premature infants a nosocomial infection?]. / Ist die Candida-Septikämie bei Frühgeborenen eine nosokomiale Infektion?

Yeast colonization of the vagina is found in about 30% of all pregnant women. Premature infants are severely endangered by generalized fungal infections due to their immature immune system. The objective of this study was to elucidate the relationship between vaginal yeast colonization of the mothers and Candida septicemia in their premature babies. In a prospective study, running from 12/1994 to 8/1996, 176 mothers, facing probable premature birth, were investigated, when hospitalized, for vaginal yeast colonization. 150 premature infants (birth weights ranging from 550 to 2390 g) of these mothers were culturally examined for yeasts in specimens from the mouth, ear, stool and urine immediately after birth as well as once weekly in the following weeks. The patients were divided into two groups. In group A, oral prophylaxis with nystatin was practiced only in infants with at least one positive yeast culture. In group B, all patients received nystatin prophylaxis. Candida septicemia developed one or two weeks after birth mainly in infants with birth weights below 1000 g. Primary oral prophylaxis with nystatin lowers considerably the risk of developing Candida infection.