Quantum Lissajous Scars.

A quantum scar-an enhancement of a quantum probability density in the vicinity of a classical periodic orbit-is a fundamental phenomenon connecting quantum and classical mechanics. Here we demonstrate that some of the eigenstates of the perturbed two-dimensional anisotropic (elliptic) harmonic oscillator are strongly scarred by the Lissajous orbits of the unperturbed classical counterpart. In particular, we show that the occurrence and geometry of these quantum Lissajous scars are connected to the anisotropy of the harmonic confinement, but unlike the classical Lissajous orbits the scars survive under a small perturbation of the potential. This Lissajous scarring is caused by the combined effect of the quantum (near) degeneracies in the unperturbed system and the localized character of the perturbation. Furthermore, we discuss experimental schemes to observe this perturbation-induced scarring.

Alcohol metabolism contributes to brain histone acetylation.

Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, and implicates specific metabolic factors in neural functions that drive behaviour1. In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)2. Notably, the breakdown of alcohol in the liver leads to a rapid increase in levels of blood acetate3, and alcohol is therefore a major source of acetate in the body. Histone acetylation in neurons may thus be under the influence of acetate that is derived from alcohol4, with potential effects on alcohol-induced gene expression in the brain, and on behaviour5. Here, using in vivo stable-isotope labelling in mice, we show that the metabolism of alcohol contributes to rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of acetyl groups that are derived from alcohol onto histones in an ACSS2-dependent manner. A similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo. In a pregnant mouse, exposure to labelled alcohol resulted in the incorporation of labelled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced transcriptional programs related to learning and memory, which were sensitive to ACSS2 inhibition. We show that alcohol-related associative learning requires ACSS2 in vivo. These findings suggest that there is a direct link between alcohol metabolism and gene regulation, through the ACSS2-dependent acetylation of histones in the brain.

Single sample sequencing (S3EQ) of epigenome and transcriptome in nucleus accumbens.

BACKGROUND: High-throughput sequencing has been widely applied to uncover the molecular mechanisms underlying neurological and psychiatric disorders. The large body of data support the role of epigenetic mechanisms in neurological function of both human and animals. Yet, the existing data is limited by the fact that epigenetic and transcriptomic changes have only been measured in separate cohorts. This has limited precise correlation of epigenetic changes in gene expression. NEW METHOD: Single Sample Sequencing (S3EQ) is an innovative approach to analyze both epigenetic and transcriptomic regulation within a single neuronal sample. Using this method, we analyzed chromatin immunoprecipitation (ChIP)- and RNA-sequencing data from the nucleus accumbens (NAc) of the same animal. RESULTS: ChIP-S3EQ of neuronal nuclei reliably identified hPTM enrichment in the adult mouse NAc with high precision. Comparing cellular compartments, we found that the spliceosome of whole cell RNA-seq was more closely recapitulated by cytosolic RNA-S3EQ than nuclear RNA-seq. Finally, S3EQ showed increased sensitivity for correlating chromatin modifications with gene expression, especially for lowly expressed transcripts. COMPARISON WITH EXISTING METHODS: S3EQ accurately generates both RNA- and ChIP-seq from a single sample, providing a clear advantage over existing methods which require two samples. ChIP-S3EQ performance was comparable to ChIP-seq, while RNA-S3EQ generated an almost identical expression profile to nuclear-enriched and whole cell RNA-seq. Finally, we directly compared RNA-seq by cellular compartments, addressing a limitation of RNA-seq studies limited to neuronal nuclei. CONCLUSION: The S3EQ method can be applied to improve the correlative power of transcriptomic and epigenomic studies in neuronal tissue.

Dynamical tunneling versus fast diffusion for a non-convex Hamiltonian.

This paper attempts to resolve the issue of the nature of the 0.01-0.1 cm(-1) peak splittings observed in high-resolution IR spectra of polyatomic molecules. One hypothesis is that these splittings are caused by dynamical tunneling, a quantum-mechanical phenomenon whereby energy flows between two disconnected regions of phase-space across dynamical barriers. However, a competing classical mechanism for energy flow is Arnol'd diffusion, which connects different regions of phase-space by a resonance network known as the Arnol'd web. The speed of diffusion is bounded by the Nekhoroshev theorem, which guarantees stability on exponentially long time scales if the Hamiltonian is steep. Here we consider a non-convex Hamiltonian that contains the characteristics of a molecular Hamiltonian, but does not satisfy the Nekhoroshev theorem. The diffusion along the Arnol'd web is expected to be fast for a non-convex Hamiltonian. While fast diffusion is an unlikely competitor for longtime energy flow in molecules, we show how dynamical tunneling dominates compared to fast diffusion in the nearly integrable regime for a non-convex Hamiltonian, as well as present a new kind of dynamical tunneling.

Optimized polypeptide for a subunit vaccine against avian reovirus.

Avian reovirus (ARV) is a disease-causing agent. The disease is prevented by vaccination with a genotype-specific vaccine while many variants of ARV exist in the field worldwide. Production of new attenuated vaccines is a long-term process and in the case of fast-mutating viruses, an impractical one. In the era of molecular biology, vaccines may be produced by using only the relevant protein for induction of neutralizing antibodies, enabling fast adjustment to the emergence of new genetic strains. Sigma C (SC) protein of ARV is a homotrimer that facilitates host-cell attachment and induce the production and secretion of neutralizing antibodies. The aim of this study was to identify the region of SC that will elicit a protective immune response. Full-length (residues 1-326) and two partial fragments of SC (residues 122-326 and 192-326) were produced in Escherichia coli. The SC fragment of residues 122-326 include the globular head, shaft and hinge domains, while eliminating intra-capsular region. This fragment induces significantly higher levels of anti-ARV antibodies than the shorter fragment or full length SC, which neutralized embryos infection by the virulent strain to a higher extent compared with the antibodies produced in response to the whole virus vaccine. Residues 122-326 fragment is assumed to be folded correctly, exposing linear as well as conformational epitopes that are identical to those of the native protein, while possibly excluding suppressor sequences. The results of this study may serve for the development of a recombinant subunit vaccine for ARV.

The Degree of Ergodicity of ortho- and para-Aminobenzonitrile in an Electric Field.

We study the dynamics of the two molecules ortho-aminobenzonitrile (OABN) and para-aminobenzonitrile (PABN). They are structural isomers, with differing asymmetries and dipole moments. In this paper, we show that the dynamics of the system strongly depends on the region of phase space of the initial rotational state, the asymmetry of the molecule, and on the direction of the dipole. We also show that the ergodicity of the system varies gradually with energy, except where the rotational energy of the initial state is much less than the Stark interaction. In this regime, the projection of the dipole along the lab-frame z-axis varies linearly with increasing energy and follows the microcanonical ergodic estimate. Both molecules are far from full chaos for total angular momentum quanta J ∈ [0,45]. However, the initial rotational states in OABN access much more of the available phase space than in PABN. We show that this is a likely cause for the experimental discrepancies in molecular beam deflection experiments.

Fractal dynamics in chaotic quantum transport.

Despite several experiments on chaotic quantum transport in two-dimensional systems such as semiconductor quantum dots, corresponding quantum simulations within a real-space model have been out of reach so far. Here we carry out quantum transport calculations in real space and real time for a two-dimensional stadium cavity that shows chaotic dynamics. By applying a large set of magnetic fields we obtain a complete picture of magnetoconductance that indicates fractal scaling. In the calculations of the fractality we use detrended fluctuation analysis-a widely used method in time-series analysis-and show its usefulness in the interpretation of the conductance curves. Comparison with a standard method to extract the fractal dimension leads to consistent results that in turn qualitatively agree with the previous experimental data.

[Focal liver lesions in patients with malignant haematological disease: value of B-mode ultrasound in comparison to contrast-enhanced ultrasound--a retrospective study with N = 61 patients]. / Stellenwert der kontrastunterstützten Sonografie im Vergleich zur B-Bild-Sonografie in der Charakterisierung fokaler Leberläsionen bei zugrunde liegender maligner hämatologischer Erkrankung: Eine retrospektive Studie mit n = 61 Patienten.

PURPOSE: The aim of the retrospective study is to illustrate the role of contrast-enhanced ultrasound (CEUS) in the dignity assessment of focal liver lesions compared to B-mode ultrasound (US) in patients with malignant haematological diseases (MHD). PATIENTS AND METHODS: Focal liver lesions were diagnosed in n = 61 patients (24 female, 37 male) with MHD via US within the period from November 2005 to February 2009. After the presentation of a not clearly cystic liver lesion (n = 48), CEUS was performed and documented in addition to US. The underlying diagnoses were stem cell diseases (n = 31) and malignant lymphomas (n = 30). The detection of a lesion was documented in n = 17 patients with at this time point primary diagnosed haematological disease, n = 13 patients were in relapse and n = 31 in complete remission (CR). The diagnoses of the liver pathology were confirmed through sonographic follow-up studies and clinical courses (n = 22), CT/MRI (n = 18) and histology (n = 21). RESULTS: In total 67 % of the cases were diagnosed as benign and 33 % as malignant liver lesions. Regarding the therapeutic state, the numbers of benign lesions differ from those of malignant lesions: primary diagnosis 53 vs. 47 %, relapse 69 vs. 31 %, CR 90 vs. 10 %. The frequency distributions of benign versus malignant lesions were 94 vs. 6 % in patients with stem cell diseases and 40 vs. 60 % in patients with malignant lymphomas. Regarding dignity assessment of focal liver lesions, CEUS showed a sensitivity of 90 vs. 45 % and specificity of 96 vs. 18 % (p < 0.0001) compared to US. CONCLUSION: CEUS possesses a significant diagnostic value in the characterization of focal liver lesions and should be used in the context of staging procedures in patients with MHD.

The impact of PEGylation on protein immunogenicity.

Covalent attachment of PEG (PEGylation) is widely used to improve the pharmaceutical properties of therapeutic proteins. The applicability and safety of this method have been proven by the use of various PEGylated pharmaceutical proteins approved by the Food and Drug Administration (FDA). One of the properties attributed to PEGylation is immunogenicity reduction of the PEGylated protein. In this study, the impact of PEGylation on immunogenicity was tested and compared for two proteins (chicken IgY and horse IgG) in two strains of mice (Balb/c and C57BL/6) for two routes of administration (i.v. and i.m.) and two sizes of PEG (5 kD and 20 kD). The influence of PEG was shown to be inconsistent between the mouse strains and routes of administration, even with the same tested protein. Consequently, immunogenicity reduction by PEGylation cannot be predicted or assumed; it must be tested on an individual case basis.

Sesamoid complex disruption as a cause of hallux valgus: report of three cases.

Hallux valgus is perhaps the most common forefoot deformity, usually related to genetic factors, gender and footwear habits. The current cases represent an unusual etiology of the syndrome due to sesamoid ligamentary damage and inter-sesamoid ligament rupture. One of the cases was treated surgically by excision of the non-united lateral sesamoid and reconstruction of the intermetatarsal ligament. Another one was treated by a Wilson-like osteotomy. The third one was conservatively treated by casting. In these cases the hallux valgus angle declined following treatment.

Wide-range protection against avian reovirus conferred by vaccination with representatives of four defined genotypes.

Many isolates of the contagious avian reovirus have been characterized, mainly based on the sequence of their sigma C protein. These isolates have been classified into four genotypes. Currently available vaccines are of limited effectiveness, likely due to the existence of many variants. The aim of this study was to test the efficacy of a vaccine consisting of a mixture of prototypes (representatives) of the four defined genotypic groups of avian reovirus. The prototypes were selected based on their distance from the isolates within each genotype. All prototypes were found to be virulent. Antibodies produced against each of the prototypes neutralized all members of its genotype. Birds were then vaccinated with a mixture of the four prototypes. Results suggest that the 4-valent vaccine can prevent disease and confer broad protection against field isolates of avian reovirus.

Differentiating infected from vaccinated animals, and among virulent prototypes of reovirus.

Birds are most susceptible to infection by avian reovirus, genus Orthoreovirus family Reoviridae, at a young age. Although chicks are protected by antibodies transferred from vaccinated maternal flocks, due to the many variants in the field, the efficiency of the vaccines is limited. The level of antibodies against viruses is generally determined by enzyme-linked immunosorbent assay (ELISA), using the whole virus as the antigen. This has some disadvantages: first, the test measures antibodies against all capsid proteins, most of which are irrelevant for neutralizing the virus, and as such does not reflect the real protection status; second, it is impossible to distinguish between vaccine- and infection-derived antibodies. In the case of a virus that changes frequently, a third disadvantage is the inability to distinguish among serotypes. The aim of this study was to develop a test that would address these concerns. Four prototypes of the avian reovirus protein sigma C were used as antigens on the ELISA plate. Sigma C is the main protein inducing neutralizing antibodies and the most variable among strains and isolates, and it is used for reovirus classification. This differentiating ELISA enabled distinguishing between vaccine and field strains of the virus, identifying the infection source, and in the case of vaccination, exclusively determining the level of protective antibodies. Whereas the whole virus detected antibodies against all strains, differentiating ELISA enabled differentiating between infected and vaccinated animals (DIVA) and in most cases, identifying the sigma C genotype. In a field study, a correlation was found between disease symptoms and antibodies identified against virulent strains in the flock. Thus virulent strains can be identified in the field, enabling adjustment of the relevant vaccines.

Coated cross-species antibodies by mannosamine-biotin adduct confer protection against snake venom without eliciting humoral immune response.

Passive immunization with cross-species antibodies triggers the patient's immune response, thereby preventing repeated treatment. Mannosamine-biotin adduct (MBA) has been described as a masking agent for immunogenic reduction and here, the immunogenicity and biological activity of MBA-coated horse anti-viper venom (hsIgG) were compared to those of uncoated or PEGylated hsIgG. In in vitro tests, hsIgG binding was not affected by MBA conjugation. The immune response to hsIgG-MBA was about 8-fold and 32-fold lower than to PEG-coated and uncoated hsIgG, respectively. In vivo, hsIgG-MBA showed efficient venom-neutralization activity. We thus demonstrate the feasibility of using MBA as a masking agent for passive immunization with cross-species antibodies.

Imaging coherent transport in graphene. Part I: mapping universal conductance fluctuations.

Graphene provides a fascinating testbed for new physics and exciting opportunities for future applications based on quantum phenomena. To understand the coherent flow of electrons through a graphene device, we employ a nanoscale probe that can access the relevant length scales--the tip of a liquid-He-cooled scanning probe microscope (SPM) capacitively couples to the graphene device below, creating a movable scatterer for electron waves. At sufficiently low temperatures and small size scales, the diffusive transport of electrons through graphene becomes coherent, leading to universal conductance fluctuations (UCF). By scanning the tip over a device, we map these conductance fluctuations versus scatterer position. We find that the conductance is highly sensitive to the tip position, producing delta G approximately e(2)/h fluctuations when the tip is displaced by a distance comparable to half the Fermi wavelength. These measurements are in good agreement with detailed quantum simulations of the imaging experiment and demonstrate the value of a cooled SPM for probing coherent transport in graphene.

Freak waves in the linear regime: a microwave study.

Microwave transport experiments have been performed in a quasi-two-dimensional resonator with randomly distributed conical scatterers. At high frequencies, the flow shows branching structures similar to those observed in stationary imaging of electron flow. Semiclassical simulations confirm that caustics in the ray dynamics are responsible for these structures. At lower frequencies, large deviations from Rayleigh's law for the wave height distribution are observed, which can only partially be described by existing multiple-scattering theories. In particular, there are "hot spots" with intensities far beyond those expected in a random wave field. The results are analogous to flow patterns observed in the ocean in the presence of spatially varying currents or depth variations in the sea floor, where branches and hot spots lead to an enhanced frequency of freak or rogue wave formation.

Differences in genetic background influence the induction of innate and acquired immune responses in chickens depending on the virulence of the infecting infectious bursal disease virus (IBDV) strain.

Previous studies and field observations have suggested that genetic background influences infectious bursal disease virus (IBDV) pathogenesis. However, the influence of the virulence of the infecting IBDV strain and the mechanisms underlying the differences in susceptibility are not known. In the present study IBDV pathogenesis was compared between specific-pathogen-free layer-type (LT) chickens, which are the most susceptible chicken for IBDV and have been used as the model for pathogenesis studies, and broiler-type (BT) chickens, which are known to be less susceptible to clinical infectious bursal disease (IBD). The innate and acquired immune responses were investigated after inoculation of an intermediate (i), virulent (v) or very virulent (vv) strain of IBDV. IBDV pathogenesis was comparable among genetic backgrounds after infection with iIBDV. After infection with vIBDV and vvIBDV, LT birds showed severe clinical disease and mortality, higher bursal lesion scores and IBDV-antigen load relative to BT birds. Circulating cytokine induction varied significantly in both timing and quantity between LT and BT birds and among virus strains (P<0.05). Evaluation of different immune cell populations by flow-cytometric analysis in the bursa of Fabricius provided circumstantial evidence of a stronger local T cell response in BT birds vs. LT birds after infection with the virulent strain. On the other hand, LT birds showed a more significant increase in circulating macrophage-derived immune mediators such as total interferon (IFN) and serum nitrite than BT birds on days 2 and 3 post-vIBDV infection (P<0.05). Stronger stimulation of innate immune reactions especially after vIBDV infection in the early phase may lead to faster and more severe lesion development accompanied by clinical disease and death in LT chickens relative to BT chickens. Interestingly, no significant differences were seen between genetic backgrounds in induction of the IBDV-specific humoral response: timing of IBDV-antibody induction and antibody levels were comparable between BT and LT birds. This study clearly demonstrates a significant influence of chickens' genetic background on disease outcome. The difference between backgrounds in IBDV susceptibility is further influenced by the virulence of the infecting virus strain.

Unique co-expression of immune cell-related genes in IBDV resistant chickens indicates the activation of specific cellular host-response mechanisms.

Infectious bursal disease virus (IBDV) causes highly contagious, immunosuppressive disease that leads to high mortality in young chickens. The purpose of this study was to look for the genetic regulation of the immune acute immune response to IBDV in our selected lines. Chicks of a F2 generation of two lines divergently selected for early high (HH) or low (LL) antibody (Ab) response to Escherichia coLi vaccination were challenged with virulent IBDV. Viral load in infected bursae was used to determine resistant (R) and susceptible (S) birds. By using a 13K chicken cDNA microarray, and pooled spleen mRNA of R, S and non-challenged, control (C) chicks, several genes were identified with differential expression associated with host resistance to IBDV. These genes were also subjected to RT-PCR on individual samples to verify the results obtained from microarrays. The major finding was the co-upregulation of seven genes--ETS2, H963, RGS1, ABIN-2, CREM/ICER, DUSP1 and CXCR4- in several R, but not S or C individuals, and characterized by a high correlation of expression levels. Resistance also generally coincided with reduced transcript levels of acute-phase serum amyloid A (A-SAA) and increased levels of IL-8. Based on reported functions of these genes, these findings suggest that resistance was mediated by the activation of specific cellular mechanisms, indicated by increased activity of splenic macrophages and T-lymphocytes 3 days post-challenge.

Identification of a bovine mastitis Escherichia coli subset.

Eleven Escherichia coli isolates from clinical bovine mastitis cases (mastitic strains) and 11 from the cowshed environment (environmental strains) were compared, to determine if the former were a subset of the latter. The mastitic and environmental strains could not be distinguished according to O antigen and antibiotic sensitivity. All mastitic isolates showed significantly (P<0.0001) faster growth in milk and faster lactose fermentation than most (approximately 64%) environmental strains, but growth rates in nutrient broth did not differ. The rates of lactose fermentation and growth in milk were positively correlated. Adhesion and phagocytosis of mastitic strains by bovine PMN were significantly (P<0.0001) lower than those of environmental strains, and correlated negatively with growth in milk and lactose fermentation. The average percentages of killing by bovine leukocytes in the two sources were not statistically different. All mastitic strains were serum sensitive, whereas most ( approximately 72%) environmental ones were resistant. Finally, pulse-field gel electrophoresis revealed two main pulse type clusters, sharing a similarity coefficient of 79%. Cluster 1 comprised only environmental strains, whereas cluster 2 comprised mostly mastitic strains and only three environmental ones. Four mastitic strains shared a similarity coefficient of less than 74% with the other strains and were not included in the clusters. Our results suggest that clinical bovine mastitis E. coli isolates may form a subset of the general environmental E. coli population; they seem better able to multiply in the udder medium and to evade the host cellular innate immune response, and are genetically distinct from most environmental strains.

Beta cell function, insulin resistance and plasma adiponectin concentrations are predictors for the change of postprandial glucose in non-diabetic subjects at risk for type 2 diabetes.

Insulin resistance, impaired insulin secretion, and low adiponectin levels have been shown to be predictors for type 2 diabetes. However, it is not yet clear whether these associations (1) are independent of changes in body weight, or (2) are valid for changes in glucose tolerance in the prediabetic state. Sixty-two non-diabetics (50 with normal glucose tolerance) aged 41 +/- 11 years, BMI 30.5 +/- 5.3 kg/m2 (mean +/- SD) were studied twice with a standard oral glucose tolerance test (oGTT, mean follow-up time 3.0 +/- 1.8 years (mean +/- SD) [range 0.5-6.5 years]). Insulin sensitivity and insulin secretion were estimated from oGTT using validated indices. Two-hour blood glucose during oGTT deteriorated over time (baseline 2 h glucose 6.32 +/- 0.21 VS. follow-up 2 h glucose 7.14 +/- 0.22 mM, p < 0.001) while the percentage body fat did not change (32.7 +/- 1.2 VS. 32.6 +/- 1.2%, p = 0.46). Follow-up 2 h blood glucose was predicted by adiponectin (p = 0.01), baseline insulin sensitivity (p = 0.02) and baseline insulin secretion relative to insulin sensitivity (p = 0.03) independent of sex, age, baseline 2 h blood glucose or change in percentage body fat. Our results suggest that low adiponectin levels, insulin resistance and low beta cell function predict the continuous deterioration of glucose tolerance in early prediabetic states, independent of changes in adiposity. Therefore, the early influence of these parameters should be the subject of future prevention programs to prevent deterioration of glucose tolerance.

Guided Gaussian wave packets.

We discuss several semiclassical Gaussian wave packet approaches with emphasis on one that is not very well-known, that is, the off-center guiding approach. Off-center guiding of (thawed) Gaussian wave packets uses the same information as other Gaussian propagation schemes, that is, the full van Vleck determinant and multiple trajectories. It retains the well-known caustic smoothing property of Gaussians. The off-center guiding of Gaussians can handle hard chaos and other highly nonlinear situations, where the van Vleck propagator, for example, has over 30,000 separate branches.