The Rsb phosphoregulatory network controls availability of the primary sigma factor in Chlamydia trachomatis and influences the kinetics of growth and development

Chlamydia trachomatis is the leading cause of both bacterial sexually transmitted infection and infection-derived blindness world-wide. No vaccine has proven protective to date in humans. C. trachomatis only replicates from inside a host cell, and has evolved to acquire a variety of nutrients directly from its host. However, a typical human immune response will normally limit the availability of a variety of essential nutrients. Thus, it is thought that the success of C. trachomatis as a human pathogen may lie in its ability to survive these immunological stress situations by slowing growth and development until conditions in the cell have improved. This mode of growth is known as persistence and how C. trachomatis senses stress and responds in this manner is an important area of research. Our report characterizes a complete signaling module, the Rsb network, that is capable of controlling the growth rate or infectivity of Chlamydia. By manipulating the levels of different pathway components, we were able to accelerate and restrict the growth and development of this pathogen. Our results suggest a mechanism by which Chlamydia can tailor its growth rate to the conditions within the host cell. The disruption of this pathway could generate a strain incapable of surviving a typical human immune response and would represent an attractive candidate as an attenuated growth vaccine

Frame dragging with optical vortices

General Relativistic calculations in the linear regime have been made for electromagnetic beams of radiation known as optical vortices. These exotic beams of light carry a physical quantity known as optical orbital angular momentum (OAM). It is found that when a massive spinning neutral particle is placed along the optical axis, a phenomenon known as inertial frame dragging occurs. Our results are compared with those found previously for a ring laser and an order of magnitude estimate of the laser intensity needed for a precession frequency of 1 Hz is given for these "steady" beams of light.Comment: 13 pages, 2 figure

Scaling laws and simulation results for the self--organized critical forest--fire model

We discuss the properties of a self--organized critical forest--fire model which has been introduced recently. We derive scaling laws and define critical exponents. The values of these critical exponents are determined by computer simulations in 1 to 8 dimensions. The simulations suggest a critical dimension $d_c=6$ above which the critical exponents assume their mean--field values. Changing the lattice symmetry and allowing trees to be immune against fire, we show that the critical exponents are universal.Comment: 12 pages, postscript uuencoded, figures included, to appear in Phys. Rev.

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Distortions of Subjective Time Perception Within and Across Senses

Background: The ability to estimate the passage of time is of fundamental importance for perceptual and cognitive processes. One experience of time is the perception of duration, which is not isomorphic to physical duration and can be distorted by a number of factors. Yet, the critical features generating these perceptual shifts in subjective duration are not understood. Methodology/Findings: We used prospective duration judgments within and across sensory modalities to examine the effect of stimulus predictability and feature change on the perception of duration. First, we found robust distortions of perceived duration in auditory, visual and auditory-visual presentations despite the predictability of the feature changes in the stimuli. For example, a looming disc embedded in a series of steady discs led to time dilation, whereas a steady disc embedded in a series of looming discs led to time compression. Second, we addressed whether visual (auditory) inputs could alter the perception of duration of auditory (visual) inputs. When participants were presented with incongruent audio-visual stimuli, the perceived duration of auditory events could be shortened or lengthened by the presence of conflicting visual information; however, the perceived duration of visual events was seldom distorted by the presence of auditory information and was never perceived shorter than their actual durations. Conclusions/Significance: These results support the existence of multisensory interactions in the perception of duration and, importantly, suggest that vision can modify auditory temporal perception in a pure timing task. Insofar as distortions in subjective duration can neither be accounted for by the unpredictability of an auditory, visual or auditory-visual event, we propose that it is the intrinsic features of the stimulus that critically affect subjective time distortions

On the Perturbative Stability of Quantum Field Theories in de Sitter Space

We use a field theoretic generalization of the Wigner-Weisskopf method to study the stability of the Bunch-Davies vacuum state for a massless, conformally coupled interacting test field in de Sitter space. We find that in $\lambda \phi^4$ theory the vacuum does {\em not} decay, while in non-conformally invariant models, the vacuum decays as a consequence of a vacuum wave function renormalization that depends \emph{singularly} on (conformal) time and is proportional to the spatial volume. In a particular regularization scheme the vacuum wave function renormalization is the same as in Minkowski spacetime, but in terms of the \emph{physical volume}, which leads to an interpretation of the decay. A simple example of the impact of vacuum decay upon a non-gaussian correlation is discussed. Single particle excitations also decay into two particle states, leading to particle production that hastens the exiting of modes from the de Sitter horizon resulting in the production of \emph{entangled superhorizon pairs} with a population consistent with unitary evolution. We find a non-perturbative, self-consistent "screening" mechanism that shuts off vacuum decay asymptotically, leading to a stationary vacuum state in a manner not unlike the approach to a fixed point in the space of states.Comment: 36 pages, 4 figures. Version to appear in JHEP, more explanation

Testing foundations of quantum mechanics with photons

The foundational ideas of quantum mechanics continue to give rise to counterintuitive theories and physical effects that are in conflict with a classical description of Nature. Experiments with light at the single photon level have historically been at the forefront of tests of fundamental quantum theory and new developments in photonics engineering continue to enable new experiments. Here we review recent photonic experiments to test two foundational themes in quantum mechanics: wave-particle duality, central to recent complementarity and delayed-choice experiments; and Bell nonlocality where recent theoretical and technological advances have allowed all controversial loopholes to be separately addressed in different photonics experiments.Comment: 10 pages, 5 figures, published as a Nature Physics Insight review articl

Null Models of Economic Networks: The Case of the World Trade Web

In all empirical-network studies, the observed properties of economic networks are informative only if compared with a well-defined null model that can quantitatively predict the behavior of such properties in constrained graphs. However, predictions of the available null-model methods can be derived analytically only under assumptions (e.g., sparseness of the network) that are unrealistic for most economic networks like the World Trade Web (WTW). In this paper we study the evolution of the WTW using a recently-proposed family of null network models. The method allows to analytically obtain the expected value of any network statistic across the ensemble of networks that preserve on average some local properties, and are otherwise fully random. We compare expected and observed properties of the WTW in the period 1950-2000, when either the expected number of trade partners or total country trade is kept fixed and equal to observed quantities. We show that, in the binary WTW, node-degree sequences are sufficient to explain higher-order network properties such as disassortativity and clustering-degree correlation, especially in the last part of the sample. Conversely, in the weighted WTW, the observed sequence of total country imports and exports are not sufficient to predict higher-order patterns of the WTW. We discuss some important implications of these findings for international-trade models.Comment: 39 pages, 46 figures, 2 table

Management of Small Urethrocutaneous Fistula by Tight Ligation with Fulguration of the External Epithelium of the Tract

Background/Purpose: Urethrocutaneous fistula (UCF) is the most common reported complication of hypospadias repair. The success of the operative technique is usually measured by its effectiveness in reduction of the incidence of UCF. Materials &amp; Methods: In a prospective study, 11 patients with 12 small caliber fistulae were included. After identifying the fistulous opening, the fistula tract was circumferentially and meticulously dissected ,then the dissected tract was lifted up and the base was ligated tightly with 5/0 vicryl, the external epithelium of the dissected tract was fulgurated with the diathermy, then a second layer of local soft tissue was secured over the ligated fistula with 6/0 vicryl, followed by overlapping skin closure over the ligated stump with 5/0 vicryl rapid . Dressing with fucidin -tull and pressure dressing was applied to be removed after 24h with removal of the urethral catheter. Meatal stenosis and urethral stricture distal to the fistula was excluded in all the patients, except in one patient who was having meatal stenosis who had meatoplasty in the same time. Results: All fistulae healed nicely with no recurrence over 6 months follow up period. Conclusion: tight ligation of the UCF with fulguration of the epithelium of its tract is effective and successful in treating the small caliber UCF. It is non-time consuming, and not associated with any urethral stenosis or obstruction at the site of the ligated fistula.Index Word: Penile fistula, urethra-cutaneous fistula, ligation, hypospadias

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs