Extinction of metastable stochastic populations

We investigate extinction of a long-lived self-regulating stochastic population, caused by intrinsic (demographic) noise. Extinction typically occurs via one of two scenarios depending on whether the absorbing state n=0 is a repelling (scenario A) or attracting (scenario B) point of the deterministic rate equation. In scenario A the metastable stochastic population resides in the vicinity of an attracting fixed point next to the repelling point n=0. In scenario B there is an intermediate repelling point n=n_1 between the attracting point n=0 and another attracting point n=n_2 in the vicinity of which the metastable population resides. The crux of the theory is WKB method which assumes that the typical population size in the metastable state is large. Starting from the master equation, we calculate the quasi-stationary probability distribution of the population sizes and the (exponentially long) mean time to extinction for each of the two scenarios. When necessary, the WKB approximation is complemented (i) by a recursive solution of the quasi-stationary master equation at small n and (ii) by the van Kampen system-size expansion, valid near the fixed points of the deterministic rate equation. The theory yields both entropic barriers to extinction and pre-exponential factors, and holds for a general set of multi-step processes when detailed balance is broken. The results simplify considerably for single-step processes and near the characteristic bifurcations of scenarios A and B.Comment: 19 pages, 7 figure

Measuring Entangled Qutrits and Their Use for Quantum Bit Commitment

We produce and holographically measure entangled qudits encoded in transverse spatial modes of single photons. With the novel use of a quantum state tomography method that only requires two-state superpositions, we achieve the most complete characterisation of entangled qutrits to date. Ideally, entangled qutrits provide better security than qubits in quantum bit-commitment: we model the sensitivity of this to mixture and show experimentally and theoretically that qutrits with even a small amount of decoherence cannot offer increased security over qubits.Comment: Paper updated to match published version; 5 pages, 4 figures, images have been included at slightly lower quality for the archiv

Microglia modulate hippocampal neural precursor activity in response to exercise and aging

Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX(3)CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX(3)CL1 receptor, CX(3)CR1, but not control IgG, dramatically reduced the neurosphere formation frequency in mice that had exercised. While an increase in soluble CX(3)CL1 was observed following running, reduced levels of this chemokine were found in the aged brain. Lower levels of CX(3)CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could be partially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX(3)CL1-CX(3)CR1 axis critically contributes toward this process

Female genital tuberculosis in Pakistan - A retrospective review of 10-year laboratory data and analysis of 32 cases

Background: Female genital tuberculosis (FGTB) is an underobserved clinical entity owing to diagnostic challenges stemming from difficulty of obtaining diagnostic specimens and paucibacillary nature of the disease. Yet, FGTB is a cause of infertility, pelvic pain, or menstrual irregularities in high-burden countries. To assess laboratory and microbiology diagnostic utilization for FGTB in Pakistan, we have collected data from 2007 to 2016 to inform the need for improved laboratory diagnostics. The objectives of this study were to determine the proportion of FGTB as culture-confirmed extrapulmonary tuberculosis (EPTB) and to describe the characteristics of women with culture-confirmed FGTB in a nationwide laboratory network in Pakistan.Method: A retrospective database was established by accessing laboratory archives and analyzed by sex and source to determine extrapulmonary cases among women. Data were checked for quality, and after removing patient identifiers and duplicate samples, frequencies were calculated in MS Excel. Clinical characteristics of patients were derived from a linked hospital database for those patients who were diagnosed and managed at the affiliated university hospital in Karachi, Pakistan.Results: Over 10 years, 410,748 mycobacterial cultures were received from multiple geographic sites throughout Pakistan and processed at the study laboratory. The overall mean culture positivity rate was 5.9% ± 3.5%, while the mean culture positivity rate among females was 2.8% ± 0.8%. Among female culture-confirmed tuberculosis cases, the pulmonary-to-EPTB ratio of infection was 5. Over 10 years, a total of 32 FGTB cases were reported on the basis of positive cultures for Mycobacterium tuberculosis; 3 (9.4%) were rifampin resistant.Conclusions: FGTB currently constitutes a small but significant proportion of culture-confirmed EPTB. A fewer number of laboratory requisitions suggest the need to increase awareness and testing. The advent of high-sensitivity molecular testing on extrapulmonary specimens has the potential to improve diagnostic accuracy and improved detection of FGTB cases in high-burden regions

Large fluctuations in stochastic population dynamics: momentum space calculations

Momentum-space representation renders an interesting perspective to theory of large fluctuations in populations undergoing Markovian stochastic gain-loss processes. This representation is obtained when the master equation for the probability distribution of the population size is transformed into an evolution equation for the probability generating function. Spectral decomposition then brings about an eigenvalue problem for a non-Hermitian linear differential operator. The ground-state eigenmode encodes the stationary distribution of the population size. For long-lived metastable populations which exhibit extinction or escape to another metastable state, the quasi-stationary distribution and the mean time to extinction or escape are encoded by the eigenmode and eigenvalue of the lowest excited state. If the average population size in the stationary or quasi-stationary state is large, the corresponding eigenvalue problem can be solved via WKB approximation amended by other asymptotic methods. We illustrate these ideas in several model examples.Comment: 20 pages, 9 figures, to appear in JSTA

Using Cluster Abundances and Peculiar Velocities to Test the Gaussianity of the Cosmological Density Field

(Abridged) By comparing the frequency of typical events with that of unusual events, one can test whether the cosmological density distribution function is consistent with the normally made assumption of Gaussianity. To this end, we compare the consistency of the tail-inferred (from clusters) and measured values (from large-scale flows) of the rms level of mass fluctuations for two distribution functions: a Gaussian, and a texture (positively-skewed) PDF. Averaging the recent large-scale flow measurements, we find that observations of the rms and the tail at the 10 h^-1 Mpc scale disfavor a texture PDF at ~1.5 sigma in all cases. However, taking only the most recent measurement of the rms, that from Willick et al. (1997b), the comparison disfavors textures for low Omega_0=0.3, and disfavors Gaussian models if Omega_0=1 (again at ~1.5 sigma). Predictions for evolution of high temperature clusters can also be made for the models considered, and strongly disfavor Omega_0=1 in Gaussian models and marginally disfavor Omega_0=1 in texture models. Only Omega_0=0.3 Gaussian models are consistent with all the data considered.Comment: 34 pg incl. 8 embedded figures, LaTeX, aaspp4.sty, submitted to Ap

Entangled Qutrits: Production and Characterisation

We produce and measure entangled qubits and qutrits, two- and three-level quantum systems, realised using transverse spatial modes of the optical field. Photons encoded in these modes are manipulated and analysed by a combination of holograms and single-mode fibres. Using quantum state tomography, we achieve the most complete characterisation of entangled qutrits to date. Ideally, entangled qutrits provide better security than qubits in quantum bit-commitment and coin-flipping protocols: we show that to reach this regime places stringent requirements on the initial state

Modeling of Stardust Entry at High Altitude, Part 1: Flowfield Analysis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83562/1/AIAA-37360-273.pd

Targeting melanoma growth and viability reveals dualistic functionality of the phosphonothionate analogue of carba cyclic phosphatidic acid

<p>Abstract</p> <p>Background</p> <p>Although the incidence of melanoma in the U.S. is rising faster than any other cancer, the FDA-approved chemotherapies lack efficacy for advanced disease, which results in poor overall survival. Lysophosphatidic acid (LPA), autotaxin (ATX), the enzyme that produces LPA, and the LPA receptors represent an emerging group of therapeutic targets in cancer, although it is not known which of these is most effective.</p> <p>Results</p> <p>Herein we demonstrate that thio-ccPA 18:1, a stabilized phosphonothionate analogue of carba cyclic phosphatidic acid, ATX inhibitor and LPA1/3 receptor antagonist, induced a marked reduction in the viability of B16F10 metastatic melanoma cells compared with PBS-treated control by 80-100%. Exogenous LPA 18:1 or D-sn-1-O-oleoyl-2-O-methylglyceryl-3-phosphothioate did not reverse the effect of thio-ccPA 18:1. The reduction in viability mediated by thio-ccPA 18:1 was also observed in A375 and MeWo melanoma cell lines, suggesting that the effects are generalizable. Interestingly, siRNA to LPA3 (siLPA3) but not other LPA receptors recapitulated the effects of thio-ccPA 18:1 on viability, suggesting that inhibition of the LPA3 receptor is an important dualistic function of the compound. In addition, siLPA3 reduced proliferation, plasma membrane integrity and altered morphology of A375 cells. Another experimental compound designed to antagonize the LPA1/3 receptors significantly reduced viability in MeWo cells, which predominantly express the LPA3 receptor.</p> <p>Conclusions</p> <p>Thus the ability of thio-ccPA 18:1 to inhibit the LPA3 receptor and ATX are key to its molecular mechanism, particularly in melanoma cells that predominantly express the LPA3 receptor. These observations necessitate further exploration and exploitation of these targets in melanoma.</p

Intelligent Liver Function Testing (iLFT):A trial of automated diagnosis and staging of liver disease in Primary Care

Background: Liver function tests (LFTs) are frequently requested blood tests which may indicate liver disease. LFTs are commonly abnormal, the causes of which can be complex and frequently under investigated. This can lead to missed opportunities to diagnose and treat liver disease at an early stage. We developed an automated investigation algorithm, which would maximise early diagnosis of liver related diseases. Our aim was to determine whether this new pathway of care, Intelligent Liver Function testing (iLFT) increased diagnosis of liver disease and was cost-effective. Methods: We developed an automated system that further investigated abnormal LFTs on initial testing samples to generate a probable diagnosis and management plan. We integrated an automated investigation algorithm into the laboratory management system, based on minimal diagnostic criteria, liver fibrosis estimation, and reflex testing for causes of liver disease. This algorithm then generated a diagnosis and/or management plan. A stepped-wedged trial design was utilised to compare LFT outcomes in General Practices in the 6 months before and after introduction of the iLFT system. Diagnostic outcomes were collated and compared. Results: Using iLFT, the diagnosis of liver disease was increased by 43%. It was cost-effective with a low initial incremental cost-effectiveness ratio (ICER) of £284 per correct diagnosis, and a saving to the NHS of £3,216 per patient lifetime. Conclusions: iLFT increases liver diagnosis, improves quality of care, and is highly cost-effective. This can be achieved with minor changes to working practices and exploitation of functionality existing within modern laboratory diagnostics systems. Lay Summary: There is a growing epidemic of advanced liver disease, this could be offset by early detection and management. Checking liver blood tests (LFTs) should be an opportunity diagnose liver problems, but abnormal results are often incompletely investigated. In this study we were able to substantially increase the diagnostic yield of the abnormal LFTs using the automated iLFT system. With the addition of referral recommendations and management plans, this strategy provides optimum investigation and management of LFTs and is cost saving to the NHS