Simulation-based reachability analysis for nonlinear systems using componentwise contraction properties

A shortcoming of existing reachability approaches for nonlinear systems is the poor scalability with the number of continuous state variables. To mitigate this problem we present a simulation-based approach where we first sample a number of trajectories of the system and next establish bounds on the convergence or divergence between the samples and neighboring trajectories. We compute these bounds using contraction theory and reduce the conservatism by partitioning the state vector into several components and analyzing contraction properties separately in each direction. Among other benefits this allows us to analyze the effect of constant but uncertain parameters by treating them as state variables and partitioning them into a separate direction. We next present a numerical procedure to search for weighted norms that yield a prescribed contraction rate, which can be incorporated in the reachability algorithm to adjust the weights to minimize the growth of the reachable set

EHMTI-0026. Neuroprolotherapy and acupuncture for clinical trial of acute and chronic migraine treatment

Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca2+-mobilizing messengers important for modulating cardiac excitation–contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase family, catalyzes synthesis of both NAADP and cADPR in vitro. However, it remains unclear whether this is the main enzyme for their production under physiological conditions. Here we show that membrane fractions from WT but not CD38−/− mouse hearts supported NAADP and cADPR synthesis. Membrane permeabilization of cardiac myocytes with saponin and/or Triton X-100 increased NAADP synthesis, indicating that intracellular CD38 contributes to NAADP production. The permeabilization also permitted immunostaining of CD38, with a striated pattern in WT myocytes, whereas CD38−/− myocytes and nonpermeabilized WT myocytes showed little or no staining, without striation. A component of β-adrenoreceptor signaling in the heart involves NAADP and lysosomes. Accordingly, in the presence of isoproterenol, Ca2+ transients and contraction amplitudes were smaller in CD38−/− myocytes than in the WT. In addition, suppressing lysosomal function with bafilomycin A1 reduced the isoproterenol-induced increase in Ca2+ transients in cardiac myocytes from WT but not CD38−/− mice. Whole hearts isolated from CD38−/− mice and exposed to isoproterenol showed reduced arrhythmias. SAN4825, an ADP-ribosyl cyclase inhibitor that reduces cADPR and NAADP synthesis in mouse membrane fractions, was shown to bind to CD38 in docking simulations and reduced the isoproterenol-induced arrhythmias in WT hearts. These observations support generation of NAADP and cADPR by intracellular CD38, which contributes to effects of β-adrenoreceptor stimulation to increase both Ca2+ transients and the tendency to disturb heart rhythm

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

The early X-ray afterglows of optically bright and dark Gamma-Ray Bursts

A systematical study on the early X-ray afterglows of both optically bright and dark gamma-ray bursts (B-GRBs and D-GRBs) observed by Swift has been presented. Our sample includes 25 GRBs. Among them 13 are B-GRBs and 12 are D-GRBs. Our results show that the distributions of the X-ray afterglow fluxes ($F_{X}$), the gamma-ray fluxes ($S_{\gamma}$), and the ratio ($R_{\gamma, X}$) for both the D-GRBs and B-GRBs are similar. The differences of these distributions for the two kinds of GRBs should be statistical fluctuation. These results indicate that the progenitors of the two kinds of GRBs are the same population. Their total energy explosions are comparable. The suppression of the optical emissions from D-GRBs should results from circumburst but not their central engine.Comment: 10 pages, 3 figures, 1 table; accepted by ChJA

Constraints on Fluid Dynamics from Equilibrium Partition Functions

We study the thermal partition function of quantum field theories on arbitrary stationary background spacetime, and with arbitrary stationary background gauge fields, in the long wavelength expansion. We demonstrate that the equations of relativistic hydrodynamics are significantly constrained by the requirement of consistency with any partition function. In examples at low orders in the derivative expansion we demonstrate that these constraints coincide precisely with the equalities between hydrodynamical transport coefficients that follow from the local form of the second law of thermodynamics. In particular we recover the results of Son and Surowka on the chiral magnetic and chiral vorticity flows, starting from a local partition function that manifestly reproduces the field theory anomaly, without making any reference to an entropy current. We conjecture that the relations between transport coefficients that follow from the second law of thermodynamics agree to all orders in the derivative expansion with the constraints described in this paper.Comment: Typos corrected, References adde

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

Background: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner

Characterisation of feline renal cortical fibroblast cultures and their transcriptional response to transforming growth factor beta 1

Chronic kidney disease (CKD) is common in geriatric cats, and the most prevalent pathology is chronic tubulointerstitial inflammation and fibrosis. The cell type predominantly responsible for the production of extra-cellular matrix in renal fibrosis is the myofibroblast, and fibroblast to myofibroblast differentiation is probably a crucial event. The cytokine TGF-β1 is reportedly the most important regulator of myofibroblastic differentiation in other species. The aim of this study was to isolate and characterise renal fibroblasts from cadaverous kidney tissue of cats with and without CKD, and to investigate the transcriptional response to TGF-β1

Multivalued SK-contractions with respect to b-generalized pseudodistances

A new class of multivalued non-self-mappings, called SK-contractions with respect to b-generalized pseudodistances, is introduced and used to investigate the existence of best proximity points by using an appropriate geometric property. Some new fixed point results in b-metric spaces are also obtained. Examples are given to support the usability of our main result

Exoplanets and SETI

The discovery of exoplanets has both focused and expanded the search for extraterrestrial intelligence. The consideration of Earth as an exoplanet, the knowledge of the orbital parameters of individual exoplanets, and our new understanding of the prevalence of exoplanets throughout the galaxy have all altered the search strategies of communication SETI efforts, by inspiring new "Schelling points" (i.e. optimal search strategies for beacons). Future efforts to characterize individual planets photometrically and spectroscopically, with imaging and via transit, will also allow for searches for a variety of technosignatures on their surfaces, in their atmospheres, and in orbit around them. In the near-term, searches for new planetary systems might even turn up free-floating megastructures.Comment: 9 page invited review. v2 adds some references and v3 has other minor additions and modification

Constraints on Superfluid Hydrodynamics from Equilibrium Partition Functions

Following up on recent work in the context of ordinary fluids, we study the equilibrium partition function of a 3+1 dimensional superfluid on an arbitrary stationary background spacetime, and with arbitrary stationary background gauge fields, in the long wavelength expansion. We argue that this partition function is generated by a 3 dimensional Euclidean effective action for the massless Goldstone field. We parameterize the general form of this action at first order in the derivative expansion. We demonstrate that the constitutive relations of relativistic superfluid hydrodynamics are significantly constrained by the requirement of consistency with such an effective action. At first order in the derivative expansion we demonstrate that the resultant constraints on constitutive relations coincide precisely with the equalities between hydrodynamical transport coefficients recently derived from the second law of thermodynamics.Comment: 46 page