Extreme non-linear response of ultra-narrow optical transitions in cavity QED for laser stabilization

We explore the potential of direct spectroscopy of ultra-narrow optical transitions of atoms localized in an optical cavity. In contrast to stabilization against a reference cavity, which is the approach currently used for the most highly stabilized lasers, stabilization against an atomic transition does not suffer from Brownian thermal noise. Spectroscopy of ultra-narrow optical transitions in a cavity operates in a very highly saturated regime in which non-linear effects such as bistability play an important role. From the universal behavior of the Jaynes-Cummings model with dissipation, we derive the fundamental limits for laser stabilization using direct spectroscopy of ultra-narrow atomic lines. We find that with current lattice clock experiments, laser linewidths of about 1 mHz can be achieved in principle, and the ultimate limitations of this technique are at the 1 $\mu$ Hz level.Comment: 5 pages, 4 figure

Blinding Trachoma: Systematic Review of Rates and Risk Factors for Progressive Disease.

BACKGROUND: Sight loss from trachoma is the end result of a scarring disease process starting in early childhood and characterised by repeated episodes of conjunctival inflammation (active trachoma). Subsequently, the conjunctiva becomes scarred, causing the eyelashes to turn inwards and scratch the cornea (trichiasis), damaging the corneal surface and leading to corneal opacification and visual impairment. It is thought that this process is initiated and driven by repeated infection with Chlamydia trachomatis. We review published longitudinal studies to re-examine the disease process, its progression rates and risk factors. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed for studies presenting incidence and progression data for the different stages of trachoma natural history. We only included studies reporting longitudinal data and identified 11 publications meeting this criterion. The studies were very heterogeneous in design, disease stage, duration, size and location, precluding meta-analysis. Severe conjunctival inflammation was consistently associated with incident and progressive scarring in five studies in which this was examined. One study reported an association between C. trachomatis infection and incident scarring. No studies have yet demonstrated an association between C. trachomatis infection and progressive scarring. Several studies conducted in regions with low prevalence active disease and C. trachomatis infection found evidence of on-going scarring progression. CONCLUSIONS/SIGNIFICANCE: Overall, there are few longitudinal studies that provide estimates of progression rates and risk factors, reflecting the challenges of conducting such studies. Our understanding of this disease process and the long-term impact of control measures is partial. Intense conjunctival inflammation was consistently associated with scarring, however, direct evidence demonstrating an association between C. trachomatis and progression is limited. This suggests that on-going chlamydial reinfection may not be mandatory for progression of established scarring, indicating that sight threatening trichiasis may continue to evolve in older people in formerly endemic populations, that will require service provision for years after active disease is controlled

Ultrashort echo time (UTE) imaging using gradient pre-equalization and compressed sensing.

Ultrashort echo time (UTE) imaging is a well-known technique used in medical MRI, however, the implementation of the sequence remains non-trivial. This paper introduces UTE for non-medical applications and outlines a method for the implementation of UTE to enable accurate slice selection and short acquisition times. Slice selection in UTE requires fast, accurate switching of the gradient and r.f. pulses. Here a gradient "pre-equalization" technique is used to optimize the gradient switching and achieve an effective echo time of 10μs. In order to minimize the echo time, k-space is sampled radially. A compressed sensing approach is used to minimize the total acquisition time. Using the corrections for slice selection and acquisition along with novel image reconstruction techniques, UTE is shown to be a viable method to study samples of cork and rubber with a shorter signal lifetime than can typically be measured. Further, the compressed sensing image reconstruction algorithm is shown to provide accurate images of the samples with as little as 12.5% of the full k-space data set, potentially permitting real time imaging of short T2(*) materials.HTF would like to acknowledge the financial support of the Gates-Cambridge Trust and all authors of the EPSRC (EP/K008218/1). In addition, we would like to thank SoftPoint Industries Inc. for providing samples of rubber.This version is final published version, distributed under a Creative Commons Attribution License 2.0. This can also be viewed on the publisher's website at: http://www.sciencedirect.com/science/article/pii/S1090780714001840

Systemic Effector and Regulatory Immune Responses to Chlamydial Antigens in Trachomatous Trichiasis

Trachomatous trichiasis (TT) caused by repeated or chronic ocular infection with Chlamydia trachomatis is the result of a pro-fibrotic ocular immune response. At the conjunctiva, the increased expression of both inflammatory (IL1B, TNF) and regulatory cytokines (IL10) have been associated with adverse clinical outcomes. We measured in vitro immune responses of peripheral blood to a number of chlamydial antigens. Peripheral blood effector cells (CD4, CD69, IFNγ, IL-10) and regulatory cells (CD4, CD25, FOXP3, CTLA4/GITR) were readily stimulated by C. trachomatis antigens but neither the magnitude (frequency or stimulation index) or the breadth and amount of cytokines produced in vitro [IL-5, IL-10, IL-12 (p70), IL-13, IFNγ, and TNFα] were significantly different between TT cases and their non-diseased controls. Interestingly we observed that CD4+ T cells account for <50% of the IFNγ positive cells induced following stimulation. Further investigation in individuals selected from communities where exposure to ocular infection with C. trachomatis is endemic indicated that CD3−CD56+ (classical natural killer cells) were a major early source of IFNγ production in response to C. trachomatis elementary body stimulation and that the magnitude of this response increased with age. Future efforts to unravel the contribution of the adaptive immune response to conjunctival fibrosis should focus on the early events following infection and the interaction with innate immune mediated mechanisms of inflammation in the conjunctiva

Synergistic cross-scale coupling of turbulence in a tokamak plasma

For the first time, nonlinear gyrokinetic simulations spanning both the ion and electron spatio-temporal scales have been performed with realistic electron mass ratio ((m[subscript D] [over m [subscript e])[superscript 1 over 2] = 60.0), realistic geometry, and all experimental inputs, demonstrating the coexistence and synergy of ion (k[subscript θρs] ~O(1.0)) and electron-scale (k[subscript θρe] ~O(1.0)) turbulence in the core of a tokamak plasma. All multi-scale simulations utilized the GYRO code [J. Candy and R. E. Waltz, J. Comput. Phys. 186, 545 (2003)] to study the coupling of ion and electron-scale turbulence in the core (r/a = 0.6) of an Alcator C-Mod L-mode discharge shown previously to exhibit an under-prediction of the electron heat flux when using simulations only including ion-scale turbulence. Electron-scale turbulence is found to play a dominant role in setting the electron heat flux level and radially elongated (k[subscript r] ≪ k[subscript θ]) “streamers” are found to coexist with ion-scale eddies in experimental plasma conditions. Inclusion of electron-scale turbulence in these simulations is found to increase both ion and electron heat flux levels by enhancing the transport at the ion-scale while also driving electron heat flux at sub-ρ[subscript i] scales. The combined increases in the low and high-k driven electron heat flux may explain previously observed discrepancies between simulated and experimental electron heat fluxes and indicates a complex interaction of short and long wavelength turbulence.United States. Dept. of Energy. Office of Science (Contract DE-AC02-05CH11231)United States. Dept. of Energy (Contract DE-FC02-99ER54512-CMOD)United States. Dept. of Energy. Fusion Energy Postdoctoral Research Program (Oak Ridge Institute for Science and Education

Evaluation of a Chlamydia trachomatis-specific, commercial, real-time PCR for use with ocular swabs.

BACKGROUND: Trachoma, the leading infectious cause of blindness worldwide, is caused by conjunctival Chlamydia trachomatis infection. Trachoma is diagnosed clinically by observation of conjunctival inflammation and/or scarring; however, there is evidence that monitoring C. trachomatis infection may be required for elimination programmes. There are many commercial and 'in-house' nucleic acid amplification tests for the detection of C. trachomatis DNA, but the majority have not been validated for use with ocular swabs. This study evaluated a commercial assay, the Fast-Track Vaginal swab kit, using conjunctival samples from trachoma-endemic areas. An objective, biostatistical-based method for binary classification of continuous PCR data was developed, to limit potential user-bias in diagnostic settings. METHODS: The Fast-Track Vaginal swab assay was run on 210 ocular swab samples from Guinea-Bissau and Tanzania. Fit of individual amplification curves to exponential or sigmoid models, derivative and second derivative of the curves and final fluorescence value were examined for utility in thresholding for determining positivity. The results from the Fast-Track Vaginal swab assay were evaluated against a commercial test (Amplicor CT/NG) and a non-commercial test (in-house droplet digital PCR), both of whose performance has previously been evaluated. RESULTS: Significant evidence of exponential amplification (R2 > 0.99) and final fluorescence > 0.15 were combined for thresholding. This objective approach identified a population of positive samples, however there were a subset of samples that amplified towards the end of the cycling protocol (at or later than 35 cycles), which were less clearly defined. The Fast-Track Vaginal swab assay showed good sensitivity against the commercial (95.71) and non-commercial (97.18) tests. Specificity was lower against both (90.00 and 96.55, respectively). CONCLUSIONS: This study defined a simple, automated protocol for binary classification of continuous, real-time qPCR data, for use in an end-point diagnostic test. This method identified a population of positive samples, however, as with manual thresholding, a subset of samples that amplified towards the end of the cycling program were less easily classified. When used with ocular swabs, the Fast-Track Vaginal swab assay had good sensitivity for C. trachomatis detection, but lower specificity than the commercial and non-commercial assays it was evaluated against, possibly leading to false positives

miRNAs that associate with conjunctival inflammation and ocular Chlamydia trachomatis infection do not predict progressive disease.

We previously showed that conjunctival miR-147b and miR-1285 were upregulated in Gambian adults with inflammatory scarring trachoma, and miR-155 and miR-184 expression was strongly associated with conjunctival inflammation and ocular Chlamydia trachomatis infection in children from Guinea-Bissau. We investigated whether the single or combined expression of miR-147b, miR-1285, miR-155 and miR-184 was able to identify individuals with increased risk of incident or progressive scarring trachoma. Conjunctival swab samples were collected from 506 children between the ages of 4 and 12 living in northern Tanzania. These 506 samples formed the baseline sample set of a 4-year longitudinal study. Chlamydia trachomatis infection was diagnosed by droplet digital PCR and expression of miR-155, miR-184, miR-1285 and miR-147b was tested by qPCR. Individuals were assessed for incidence and progression of conjunctival scarring by comparison of conjunctival photographs taken at baseline and 4 years later. miR-184 and miR-155 were strongly associated with inflammation and infection at baseline; however, no miR was associated with 4-year scarring incidence or progression. miR-184 expression was more strongly downregulated during inflammation in non-progressors relative to progressors, suggesting that a disequilibrium in the efficiency of wound healing is a significant determinant of progressive conjunctival fibrosis

An outbreak of acute haemorrhagic conjunctivitis associated with coxsackievirus A24 variant in The Gambia, West Africa.

OBJECTIVE: An outbreak of acute haemorrhagic conjunctivitis occurred in The Gambia, West Africa in 2011. Affected individuals presented with conjunctival haemorrhages, swelling and ocular discharge. In an effort to identify a causative agent of the disease, ocular swabs were taken from patients during the acute and convalescent phases. Total RNA was extracted from all samples and reverse-transcriptase PCR performed using primers specific for all enteroviruses. Resulting amplicons were sequenced and data compared to known sequences using the BLAST algorithm. RESULTS: Forty-eight swabs were included in the analysis. Of these, 21 acute and 9 convalescent swabs (65% of the total) gave positive PCR results. Sequence analysis of the resulting amplicons indicated 99% sequence identity with coxsackievirus A24 variant identified during independent outbreaks of acute haemorrhagic conjunctivitis around the world and suggest the Gambian outbreak was due to this virus

Multi-scale gyrokinetic simulations: Comparison with experiment and implications for predicting turbulence and transport

To better understand the role of cross-scale coupling in experimental conditions, a series of multi-scale gyrokinetic simulations were performed on Alcator C-Mod, L-mode plasmas. These simulations, performed using all experimental inputs and realistic ion to electron mass ratio ((mi/me)1∕2 = 60.0), simultaneously capture turbulence at the ion (kθρs∼(1.0)) and electron-scales (kθρe∼(1.0)). Direct comparison with experimental heat fluxes and electron profile stiffness indicates that Electron Temperature Gradient (ETG) streamers and strong cross-scale turbulence coupling likely exist in both of the experimental conditions studied. The coupling between ion and electron-scales exists in the form of energy cascades, modification of zonal flow dynamics, and the effective shearing of ETG turbulence by long wavelength, Ion Temperature Gradient (ITG) turbulence. The tightly coupled nature of ITG and ETG turbulence in these realistic plasma conditions is shown to have significant implications for the interpretation of experimental transport and fluctuations. Initial attempts are made to develop a “rule of thumb” based on linear physics, to help predict when cross-scale coupling plays an important role and to inform future modeling of experimental discharges. The details of the simulations, comparisons with experimental measurements, and implications for both modeling and experimental interpretation are discussed.United States. Department of Energy (DE-AC02-05CH11231)United States. Department of Energy (DE-FC02-99ER54512-CMOD)United States. Department of Energy (DE-SC0006957)United States. Department of Energy (DE-FG02-06ER54871

Simulations and Design of a Single-Photon CMOS Imaging Pixel Using Multiple Non-Destructive Signal Sampling

A single-photon CMOS image sensor (CIS) design based on pinned photodiode (PPD) with multiple charge transfers and sampling is described. In the proposed pixel architecture, the photogenerated signal is sampled non-destructively multiple times and the results are averaged. Each signal measurement is statistically independent and by averaging, the electronic readout noise is reduced to a level where single photons can be distinguished reliably. A pixel design using this method was simulated in TCAD and several layouts were generated for a 180-nm CMOS image sensor process. Using simulations, the noise performance of the pixel was determined as a function of the number of samples, sense node capacitance, sampling rate and transistor characteristics. The strengths and limitations of the proposed design are discussed in detail, including the trade-off between noise performance and readout rate and the impact of charge transfer inefficiency (CTI). The projected performance of our first prototype device indicates that single-photon imaging is within reach and could enable ground-breaking performances in many scientific and industrial imaging applications