Boundary States and Black Hole Entropy

Black hole entropy is derived from a sum over boundary states. The boundary states are labeled by energy and momentum surface densities, and parametrized by the boundary metric. The sum over state labels is expressed as a functional integral with measure determined by the density of states. The sum over metrics is expressed as a functional integral with measure determined by the universal expression for the inverse temperature gradient at the horizon. The analysis applies to any stationary, nonextreme black hole in any theory of gravitational and matter fields.Comment: 4 pages, Revte

Robustness from flexibility in the fungal circadian clock

Background Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa. Results The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq) gene inhibits its transcriptional activator white collar-1 (wc-1), interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on the circuit by the interlocking loop structure. Conclusions Our model shows that the behaviour of the fungal clock in light-dark cycles can be accounted for by a transcription-translation feedback model of the central FRQ-WC oscillator. More generally, we provide an example of a biological circuit in which greater flexibility yields improved robustness, while also introducing novel sensitivity analysis techniques applicable to a broader range of cellular oscillators

Increased hazard of myocardial infarction with insulin‐provision therapy in actively smoking patients with diabetes mellitus and stable ischemic heart disease: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial

Background In the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, randomization of diabetic patients with stable ischemic heart disease to insulin provision ( IP ) therapy, as opposed to insulin sensitization ( IS ) therapy, resulted in biochemical evidence of impaired fibrinolysis but no increase in adverse clinical outcomes. We hypothesized that the prothrombotic effect of IP therapy in combination with the hypercoagulable state induced by active smoking would result in an increased risk of myocardial infarction ( MI ). Methods and Results We analyzed BARI 2D patients who were active smokers randomized to IP or IS therapy. The primary end point was fatal or nonfatal MI . PAI ‐1 (plasminogen activator inhibitor 1) activity was analyzed at 1, 3, and 5 years. Of 295 active smokers, MI occurred in 15.4% randomized to IP and in 6.8% randomized to IS over the 5.3 years ( P =0.023). IP therapy was associated with a 3.2‐fold increase in the hazard of MI compared with IS therapy (hazard ratio: 3.23; 95% confidence interval, 1.43–7.28; P =0.005). Baseline PAI ‐1 activity (19.0 versus 17.5 Au/mL, P =0.70) was similar in actively smoking patients randomized to IP or IS therapy. However, IP therapy resulted in significantly increased PAI ‐1 activity at 1 year (23.0 versus 16.0 Au/mL, P =0.001), 3 years (24.0 versus 18.0 Au/mL, P =0.049), and 5 years (29.0 versus 15.0 Au/mL, P =0.004) compared with IS therapy. Conclusions Among diabetic patients with stable ischemic heart disease who were actively smoking, IP therapy was independently associated with a significantly increased hazard of MI . This finding may be explained by higher PAI ‐1 activity in active smokers treated with IP therapy. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00006305. </jats:sec

Microwave Dielectric Heating of Drops in Microfluidic Devices

We present a technique to locally and rapidly heat water drops in microfluidic devices with microwave dielectric heating. Water absorbs microwave power more efficiently than polymers, glass, and oils due to its permanent molecular dipole moment that has a large dielectric loss at GHz frequencies. The relevant heat capacity of the system is a single thermally isolated picoliter drop of water and this enables very fast thermal cycling. We demonstrate microwave dielectric heating in a microfluidic device that integrates a flow-focusing drop maker, drop splitters, and metal electrodes to locally deliver microwave power from an inexpensive, commercially available 3.0 GHz source and amplifier. The temperature of the drops is measured by observing the temperature dependent fluorescence intensity of cadmium selenide nanocrystals suspended in the water drops. We demonstrate characteristic heating times as short as 15 ms to steady-state temperatures as large as 30 degrees C above the base temperature of the microfluidic device. Many common biological and chemical applications require rapid and local control of temperature, such as PCR amplification of DNA, and can benefit from this new technique.Comment: 6 pages, 4 figure

The Midpoint Rule as a Variational--Symplectic Integrator. I. Hamiltonian Systems

Numerical algorithms based on variational and symplectic integrators exhibit special features that make them promising candidates for application to general relativity and other constrained Hamiltonian systems. This paper lays part of the foundation for such applications. The midpoint rule for Hamilton's equations is examined from the perspectives of variational and symplectic integrators. It is shown that the midpoint rule preserves the symplectic form, conserves Noether charges, and exhibits excellent long--term energy behavior. The energy behavior is explained by the result, shown here, that the midpoint rule exactly conserves a phase space function that is close to the Hamiltonian. The presentation includes several examples.Comment: 11 pages, 8 figures, REVTe

Action Principle for the Generalized Harmonic Formulation of General Relativity

An action principle for the generalized harmonic formulation of general relativity is presented. The action is a functional of the spacetime metric and the gauge source vector. An action principle for the Z4 formulation of general relativity has been proposed recently by Bona, Bona--Casas and Palenzuela (BBP). The relationship between the generalized harmonic action and the BBP action is discussed in detail.Comment: This version is contains more thorough presentations and discussions of the key results. To be published in PRD. (8 pages, no figures

Trumpet slices of the Schwarzschild-Tangherlini spacetime

We study families of time-independent maximal and 1+log foliations of the Schwarzschild-Tangherlini spacetime, the spherically-symmetric vacuum black hole solution in D spacetime dimensions, for D >= 4. We identify special members of these families for which the spatial slices display a trumpet geometry. Using a generalization of the 1+log slicing condition that is parametrized by a constant n we recover the results of Nakao, Abe, Yoshino and Shibata in the limit of maximal slicing. We also construct a numerical code that evolves the BSSN equations for D=5 in spherical symmetry using moving-puncture coordinates, and demonstrate that these simulations settle down to the trumpet solutions.Comment: 11 pages, 6 figures, submitted to PR

Whole genome sequence analysis reveals the broad distribution of the RtxA type 1 secretion system and four novel putative type 1 secretion systems throughout the Legionella genus.

Type 1 secretion systems (T1SSs) are broadly distributed among bacteria and translocate effectors with diverse function across the bacterial cell membrane. Legionella pneumophila, the species most commonly associated with Legionellosis, encodes a T1SS at the lssXYZABD locus which is responsible for the secretion of the virulence factor RtxA. Many investigations have failed to detect lssD, the gene encoding the membrane fusion protein of the RtxA T1SS, in non-pneumophila Legionella, which has led to the assumption that this system is a virulence factor exclusively possessed by L. pneumophila. Here we discovered RtxA and its associated T1SS in a novel Legionella taurinensis strain, leading us to question whether this system may be more widespread than previously thought. Through a bioinformatic analysis of publicly available data, we classified and determined the distribution of four T1SSs including the RtxA T1SS and four novel T1SSs among diverse Legionella spp. The ABC transporter of the novel Legionella T1SS Legionella repeat protein secretion system shares structural similarity to those of diverse T1SS families, including the alkaline protease T1SS in Pseudomonas aeruginosa. The Legionella bacteriocin (1-3) secretion systems T1SSs are novel putative bacteriocin transporting T1SSs as their ABC transporters include C-39 peptidase domains in their N-terminal regions, with LB2SS and LB3SS likely constituting a nitrile hydratase leader peptide transport T1SSs. The LB1SS is more closely related to the colicin V T1SS in Escherichia coli. Of 45 Legionella spp. whole genomes examined, 19 (42%) were determined to possess lssB and lssD homologs. Of these 19, only 7 (37%) are known pathogens. There was no difference in the proportions of disease associated and non-disease associated species that possessed the RtxA T1SS (p = 0.4), contrary to the current consensus regarding the RtxA T1SS. These results draw into question the nature of RtxA and its T1SS as a singular virulence factor. Future studies should investigate mechanistic explanations for the association of RtxA with virulence

Tidal interactions at the edge of the Local Group: New evidence for tidal features in the Antlia Dwarf Galaxy

Using deep B band imaging down to mu_{B} = 26 mag arcsec^{-2}, we present evidence for tidal tails in the Antlia Dwarf galaxy, one of the most distant members of the Local Group. This elongation is in the direction of Antlia's nearest neighbor, the Magellanic-type NGC 3109. The tail is offset by less than 10 degrees from a vector linking the centers of the two galaxies, indicative of interactions between the pair. Combined with the warped disc previously identified in NGC 3109, Antlia and NGC 3109 must be at a small separation for tidal features to be present in Antlia. We calculate that Antlia cannot be completely disrupted by NGC 3109 in a single interaction unless its orbit pericenter is less than 6 kpc, however multiple interactions could significantly alter its morphology. Therefore despite being located right at the edge of the Local Group, environmental effects are playing an important role in Antlia's evolution.Comment: 8 pages, 4 figures, accepted for publication in ApJ

Dissecting interferon-induced transcriptional programs in human peripheral blood cells

Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings