Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy

We present an approach to quantify drug-target engagement using in vivo fluorescence endomicroscopy, validated with in vitro measurements. Doxorubicin binding to chromatin changes the fluorescence lifetime of histone-GFP fusions that we measure in vivo at single-cell resolution using a confocal laparo/endomicroscope. We measure both intra- and inter-tumor heterogeneity in doxorubicin chromatin engagement in a model of peritoneal metastasis of ovarian cancer, revealing striking variation in the efficacy of doxorubicin-chromatin binding depending on intra-peritoneal or intravenous delivery. Further, we observe significant variations in doxorubicin-chromatin binding between different metastases in the same mouse and between different regions of the same metastasis. The quantitative nature of fluorescence lifetime imaging enables direct comparison of drug-target engagement for different drug delivery routes and between in vitro and in vivo experiments. This uncovers different rates of cell killing for the same level of doxorubicin binding in vitro and in vivo

Single photon quantum non-demolition in the presence of inhomogeneous broadening

Electromagnetically induced transparency (EIT) has been often proposed for generating nonlinear optical effects at the single photon level; in particular, as a means to effect a quantum non-demolition measurement of a single photon field. Previous treatments have usually considered homogeneously broadened samples, but realisations in any medium will have to contend with inhomogeneous broadening. Here we reappraise an earlier scheme [Munro \textit{et al.} Phys. Rev. A \textbf{71}, 033819 (2005)] with respect to inhomogeneities and show an alternative mode of operation that is preferred in an inhomogeneous environment. We further show the implications of these results on a potential implementation in diamond containing nitrogen-vacancy colour centres. Our modelling shows that single mode waveguide structures of length $200 \mu\mathrm{m}$ in single-crystal diamond containing a dilute ensemble of NV$^-$ of only 200 centres are sufficient for quantum non-demolition measurements using EIT-based weak nonlinear interactions.Comment: 21 pages, 9 figures (some in colour) at low resolution for arXiv purpose

Quantum Computation by Communication

We present a new approach to scalable quantum computing--a ``qubus computer''--which realises qubit measurement and quantum gates through interacting qubits with a quantum communication bus mode. The qubits could be ``static'' matter qubits or ``flying'' optical qubits, but the scheme we focus on here is particularly suited to matter qubits. There is no requirement for direct interaction between the qubits. Universal two-qubit quantum gates may be effected by schemes which involve measurement of the bus mode, or by schemes where the bus disentangles automatically and no measurement is needed. In effect, the approach integrates together qubit degrees of freedom for computation with quantum continuous variables for communication and interaction.Comment: final published versio

Highly non-Gaussian states created via cross-Kerr nonlinearity

We propose a feasible scheme for generation of strongly non-Gaussian states using the cross-Kerr nonlinearity. The resultant states are highly non-classical states of electromagnetic field and exhibit negativity of their Wigner function, sub-Poissonian photon statistics, and amplitude squeezing. Furthermore, the Wigner function has a distinctly pronounced ``banana'' or ``crescent'' shape specific for the Kerr-type interactions, which so far was not demonstrated experimentally. We show that creating and detecting such states should be possible with the present technology using electromagnetically induced transparency in a four-level atomic system in N-configuration.Comment: 12 pages, 7 figure

Macroscopically distinct quantum superposition states as a bosonic code for amplitude damping

We show how macroscopically distinct quantum superposition states (Schroedinger cat states) may be used as logical qubit encodings for the correction of spontaneous emission errors. Spontaneous emission causes a bit flip error which is easily corrected by a standard error correction circuit. The method works arbitrarily well as the distance between the amplitudes of the superposed coherent states increases.Comment: 4 pages, 2 postscript figures, LaTeX2e, RevTeX, minor changes, 1 reference adde

Quantum Dynamics of Three Coupled Atomic Bose-Einstein Condensates

The simplest model of three coupled Bose-Einstein Condensates (BEC) is investigated using a group theoretical method. The stationary solutions are determined using the SU(3) group under the mean field approximation. This semiclassical analysis using the system symmetries shows a transition in the dynamics of the system from self trapping to delocalization at a critical value for the coupling between the condensates. The global dynamics are investigated by examination of the stable points and our analysis shows the structure of the stable points depends on the ratio of the condensate coupling to the particle-particle interaction, undergoes bifurcations as this ratio is varied. This semiclassical model is compared to a full quantum treatment, which also displays the dynamical transition. The quantum case has collapse and revival sequences superposed on the semiclassical dynamics reflecting the underlying discreteness of the spectrum. Non-zero circular current states are also demonstrated as one of the higher dimensional effects displayed in this system.Comment: Accepted to PR

Native Speaker Perceptions of Accented Speech: The English Pronunciation of Macedonian EFL Learners

The paper reports on the results of a study that aimed to describe the vocalic and consonantal features of the English pronunciation of Macedonian EFL learners as perceived by native speakers of English and to find out whether native speakers who speak different standard variants of English perceive the same segments as non-native. A specially designed computer web application was employed to gather two types of data: a) quantitative (frequency of segment variables and global foreign accent ratings on a 5-point scale), and b) qualitative (open-ended questions). The result analysis points out to three most frequent markers of foreign accent in the English speech of Macedonian EFL learners: final obstruent devoicing, vowel shortening and substitution of English dental fricatives with Macedonian dental plosives. It also reflects additional phonetic aspects poorly explained in the available reference literature such as allophonic distributional differences between the two languages and intonational mismatch

Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons

Background: The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer’s disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L. Methods and results: We generated antibodies against SEZ6 and SEZ6L and validated these proteins as BACE1 substrates in vitro and in vivo. Levels of the soluble, BACE1-cleaved ectodomain of both proteins (sSEZ6, sSEZ6L) were strongly reduced upon BACE1 inhibition in primary neurons and also in vivo in brains of BACE1-deficient mice. BACE1 inhibition increased neuronal surface levels of SEZ6 and SEZ6L as shown by cell surface biotinylation, demonstrating that BACE1 controls surface expression of both proteins. Moreover, mass spectrometric analysis revealed that the BACE1 cleavage site in SEZ6 is located in close proximity to the membrane, similar to the corresponding cleavage site in SEZ6L. Finally, an improved method was developed for the proteomic analysis of murine cerebrospinal fluid (CSF) and was applied to CSF from BACE-deficient mice. Hereby, SEZ6 and SEZ6L were validated as BACE1 substrates in vivo by strongly reduced levels in the CSF of BACE1-deficient mice. Conclusions: This study demonstrates that SEZ6 and SEZ6L are physiological BACE1 substrates in the murine brain and suggests that sSEZ6 and sSEZ6L levels in CSF are suitable markers to monitor BACE1 inhibition in mice