On the global evolution problem in 2+1 gravity

Existence of global CMC foliations of constant curvature 3-dimensional maximal globally hyperbolic Lorentzian manifolds, containing a constant mean curvature hypersurface with \genus(\Sigma) > 1 is proved. Constant curvature 3-dimensional Lorentzian manifolds can be viewed as solutions to the 2+1 vacuum Einstein equations with a cosmological constant. The proof is based on the reduction of the corresponding Hamiltonian system in constant mean curvature gauge to a time dependent Hamiltonian system on the cotangent bundle of Teichm\"uller space. Estimates of the Dirichlet energy of the induced metric play an essential role in the proof.Comment: 14 pages, amsar

Chronic Exposure to Triclosan Sustains Microbial Community Shifts and Alters Antibiotic Resistance Gene Levels in Anaerobic Digesters

Triclosan, an antimicrobial chemical found in consumer personal care products, has been shown to stimulate antibiotic resistance in pathogenic bacteria. Although many studies focus on antibiotic resistance pertinent to medical scenarios, resistance developed in natural and engineered environments is less studied and has become an emerging concern for human health. In this study, the impacts of chronic triclosan (TCS) exposure on antibiotic resistance genes (ARGs) and microbial community structure were assessed in lab-scale anaerobic digesters. TCS concentrations from below detection to 2500 mg kg−1 dry solids were amended into anaerobic digesters over 110 days and acclimated for \u3e3 solid retention time values. Four steady state TCS concentrations were chosen (30–2500 mg kg−1). Relative abundance of mexB, a gene coding for a component of a multidrug efflux pump, was significantly higher in all TCS-amended digesters (30 mg kg−1 or higher) relative to the control. TCS selected for bacteria carrying tet(L) and against those carrying erm(F) at concentrations which inhibited digester function; the pH decrease associated with digester failure was suspected to cause this selection. Little to no impact of TCS was observed on intI1 relative abundance. Microbial communities were also surveyed by high-throughput 16S rRNA gene sequencing. Compared to the control digesters, significant shifts in community structure towards clades containing commensal and pathogenic bacteria were observed in digesters containing TCS. Based on these results, TCS should be included in studies and risk assessments that attempt to elucidate relationships between chemical stressors (e.g. antibiotics), antibiotic resistance genes, and public health

Inhibiting Translesion DNA Synthesis as an Approach to Combat Drug Resistance to DNA Damaging Agents

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using click chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anticancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine

Theoretical Basis for Estimated Test Times and Conditions for Drop Tower and Space-Based Droplet Burning Experiments With Methanol and N-Heptane

In order to develop an extensive envelope of test conditions for NASA's space-based Droplet Combustion Experiment (DCE) as well those droplet experiments which can be performed using a drop tower, the transient vaporization and combustion of methanol and n-heptane droplets were simulated using a recently developed fully time-dependent, spherically symmetric droplet combustion model. The transient vaporization of methanol and n-heptane was modeled to characterize the instantaneous gas phase composition surrounding the droplet prior to the introduction of an ignition source. The results for methanol/air showed that the entire gas phase surrounding a 2 mm methanol droplet deployed in zero-g .quickly falls outside the lean flammability limit. The gas phase surrounding an identically-sized n-heptane droplet, on the other hand, remains flammable. The combustion of methanol was then modeled considering a detailed gas phase chemical kinetic mechanism (168 steps, 26 species) and the effect of the dissolution of flame-generated water into the liquid droplet. These results were used to determine the critical ignition diameter required to achieve quasi-steady droplet combustion in a given oxidizing environment. For droplet diameters greater than the critical ignition diameter, the model predicted a finite diameter at which the flame would extinguish. These extinction diameters were found to vary significantly with initial droplet diameter. This phenomenon appears to be unique to the transient heat transfer, mass transfer and chemical kinetics of the system and thus has not been reported elsewhere to date. The extinction diameter was also shown to vary significantly with the liquid phase Lewis number since the amount of water present in the droplet at extinction is largely governed by the rate at which water is transported into the droplet via mass diffusion. Finally, the numerical results for n-heptane combustion were obtained using both 2 step and 96 step semi-emperical chemical kinetic mechanisms. Neither mechanism exhibited the variation of extinction diameter with initial diameter

A mixture of U.S. Food and Drug Administration-approved monoaminergic drugs protects the retina from light damage in diverse models of night blindness

Purpose: The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors. Methods: Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (α1-receptor antagonist) before bright light exposure. Light damage was primarily assessed with optical coherence tomography and inspection of cone population in retinal whole mounts. Retinal inflammation was assessed in a subset of experiments using autofluorescence imaging by scanning laser ophthalmoscopy and by postmortem inspection of microglia and astrocyte activity. Results: The Gnat1-/- mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2-/- mice were very resistant. The Arr1-/- and Grk1-/- mice were sensitive for both rod and cone light damage and showed robust retinal inflammation 7 days after bright light exposure. Pretreatment with metoprolol + bromocriptine + tamsulosin rescued the retina in all genetic backgrounds, starting at doses of 0.2 mg/kg metoprolol, 0.02 mg/kg bromocriptine, and 0.01 mg/kg tamsulosin in the Gnat1-/- mice. The therapeutic drug doses increased in parallel with light-damage severity. Conclusions: Our results suggest that congenital stationary night blindness and Oguchi disease patients can be at an elevated risk of the toxic effects of bright light. Furthermore, systems pharmacology drug regimens that stimulate Gi signaling and attenuate Gs and Gq signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases

Life Limiting Behavior in Interlaminar Shear of Continuous Fiber-Reinforced Ceramic Matrix Composites at Elevated Temperatures

Interlaminar shear strength of four different fiber-reinforced ceramic matrix composites was determined with doublenotch shear test specimens as a function of test rate at elevated temperatures ranging from 1100 to 1316 C in air. Life limiting behavior, represented as interlaminar shear strength degradation with decreasing test rate, was significant for 2-D crossplied SiC/MAS-5 and 2-D plain-woven C/SiC composites, but insignificant for 2-D plain-woven SiC/SiC and 2-D woven Sylramic (Dow Corning, Midland, Michigan) SiC/SiC composites. A phenomenological, power-law delayed failure model was proposed to account for and to quantify the rate dependency of interlaminar shear strength of the composites. Additional stress rupture testing in interlaminar shear was conducted at elevated temperatures to validate the proposed model. The model was in good agreement with SiC/MAS-5 and C/SiC composites, but in poor to reasonable agreement with Sylramic SiC/SiC. Constant shear stress-rate testing was proposed as a possible means of life prediction testing methodology for ceramic matrix composites subjected to interlaminar shear at elevated temperatures when short lifetimes are expected

Intercontinental transport of pollution manifested in the variability and seasonal trend of springtime O3 at northern middle and high latitudes

Observations (0–8 km) from the Tropospheric Ozone Production about the Spring Equinox (TOPSE) experiment are analyzed to examine air masses contributing to the observed variability of springtime O3 and its seasonal increase at 40°–85°N over North America. Factor analysis using the positive matrix factorization and principal component analysis methods is applied to the data set with 14 chemical tracers (O3, NOy, PAN, CO, CH4, C2H2, C3H8, CH3Cl, CH3Br, C2Cl4, CFC-11, HCFC-141B, Halon-1211, and 7Be) and one dynamic tracer (potential temperature). Our analysis results are biased by the measurements at 5–8 km (70% of the data) due to the availability of 7Be measurements. The identified tracer characteristics for seven factors are generally consistent with the geographical origins derived from their 10 day back trajectories. Stratospherically influenced air accounts for 14 ppbv (35–40%) of the observed O3 variability for data with O3concentrations \u3c100 ppbv at middle and high latitudes. It accounts for about 2.5 ppbv/month (40%) of the seasonal O3 trend at midlatitudes but for only 0.8 ppbv/month (\u3c20%) at high latitudes, likely reflecting more vigorous midlatitude dynamical systems in spring. At midlatitudes, reactive nitrogen-rich air masses transported through Asia are much more significant (11 ppbv in variability and 3.5 ppbv/month in trend) than other tropospheric contributors. At high latitudes the O3 variability is significantly influenced by air masses transported from lower latitudes (11 ppbv), which are poor in reactive nitrogen. The O3 trend, in contrast, is largely defined by air masses rich in reactive nitrogen transported through Asia and Europe across the Pacific or the Arctic (3 ppbv/month). The influence from the stratospheric source is more apparent at 6–8 km, while the effect of O3 production and transport within the troposphere is more apparent at lower altitudes. The overall effect of tropospheric photochemical production, through long-range transport, on the observed O3 variability and its seasonal trend is more important at high latitudes relative to more photochemically active midlatitudes

Cyclometalated Iridium(III) Complexes with Deoxyribose Substituents

Fundamental study of enzymatic nucleoside transport suffers for lack of optical probes that can be tracked noninvasively. Nucleoside transporters are integral membrane glycoproteins that mediate the salvage of nucleosides and their passage across cell membranes. The substrate recognition site is the deoxyribose sugar, often with little distinction among nucleobases. Reported here are nucleoside analogues in which emissive, cyclometalated iridium(III) complexes are “clicked” to C-1 of deoxyribose in place of canonical nucleobases. The resulting complexes show visible luminescence at room temperature and 77 K with microsecond-length triplet lifetimes. A representative complex is crystallographically characterized. Transport and luminescence are demonstrated in cultured human carcinoma (KB3-1) cells

Cyclometalated Iridium(III) Complexes with Deoxyribose Substituents

Fundamental study of enzymatic nucleoside transport suffers for lack of optical probes that can be tracked noninvasively. Nucleoside transporters are integral membrane glycoproteins that mediate the salvage of nucleosides and their passage across cell membranes. The substrate recognition site is the deoxyribose sugar, often with little distinction among nucleobases. Reported here are nucleoside analogues in which emissive, cyclometalated iridium(III) complexes are “clicked” to C-1 of deoxyribose in place of canonical nucleobases. The resulting complexes show visible luminescence at room temperature and 77 K with microsecond-length triplet lifetimes. A representative complex is crystallographically characterized. Transport and luminescence are demonstrated in cultured human carcinoma (KB3-1) cells