Photoswitchable Nanoparticles for Triggered Tissue Penetration and Drug Delivery

We report a novel nanoparticulate drug delivery system that undergoes reversible volume change from 150 to 40 nm upon phototriggering with UV light. The volume change of these monodisperse nanoparticles comprising spiropyran, which undergoes reversible photoisomerization, and PEGylated lipid enables repetitive dosing from a single administration and enhances tissue penetration. The photoswitching allows particles to fluoresce and release drugs inside cells when illuminated with UV light. The mechanism of the light-induced size switching and triggered-release is studied. These particles provide spatiotemporal control of drug release and enhanced tissue penetration, useful properties in many disease states including cancer

Scattering theory for Klein-Gordon equations with non-positive energy

We study the scattering theory for charged Klein-Gordon equations: \{{array}{l} (\p_{t}- \i v(x))^{2}\phi(t,x) \epsilon^{2}(x, D_{x})\phi(t,x)=0,[2mm] \phi(0, x)= f_{0}, [2mm] \i^{-1} \p_{t}\phi(0, x)= f_{1}, {array}. where: \epsilon^{2}(x, D_{x})= \sum_{1\leq j, k\leq n}(\p_{x_{j}} \i b_{j}(x))A^{jk}(x)(\p_{x_{k}} \i b_{k}(x))+ m^{2}(x), describing a Klein-Gordon field minimally coupled to an external electromagnetic field described by the electric potential $v(x)$ and magnetic potential $\vec{b}(x)$. The flow of the Klein-Gordon equation preserves the energy: h[f, f]:= \int_{\rr^{n}}\bar{f}_{1}(x) f_{1}(x)+ \bar{f}_{0}(x)\epsilon^{2}(x, D_{x})f_{0}(x) - \bar{f}_{0}(x) v^{2}(x) f_{0}(x) \d x. We consider the situation when the energy is not positive. In this case the flow cannot be written as a unitary group on a Hilbert space, and the Klein-Gordon equation may have complex eigenfrequencies. Using the theory of definitizable operators on Krein spaces and time-dependent methods, we prove the existence and completeness of wave operators, both in the short- and long-range cases. The range of the wave operators are characterized in terms of the spectral theory of the generator, as in the usual Hilbert space case

Starburst99: Synthesis Models for Galaxies with Active Star Formation

Starburst99 is a comprehensive set of model predictions for spectrophotometric and related properties of galaxies with active star formation. The models are an improved and extended version of the data set previously published by Leitherer & Heckman (1995). We have upgraded our code by implementing the latest set of stellar evolution models of the Geneva group and the model atmosphere grid compiled by Lejeune et al. (1997). Several predictions which were not included in the previous publication are shown here for the first time. The models are presented in a homogeneous way for five metallicities between Z = 0.040 and 0.001 and three choices of the initial mass function. The age coverage is 10^6 to 10^9 yr. We also show the spectral energy distributions which are used to compute colors and other quantities. The full data set is available for retrieval at http://www.stsci.edu/science/starburst99/. This website allows users to run specific models with non-standard parameters as well. We also make the source code available to the community.Comment: 32 pages, LaTeX. All the Figures and the summary Table are located at http://www.stsci.edu/science/starburst99/, ApJ accepte

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results

Polar Smectic Films

We report on a new experimental procedure for forming and studying polar smectic liquid crystal films. A free standing smectic film is put in contact with a liquid drop, so that the film has one liquid crystal/liquid interface and one liquid crystal/air interface. This polar environment results in changes in the textures observed in the film, including a boojum texture and a previously unobserved spiral texture in which the winding direction of the spiral reverses at a finite radius from its center. Some aspects of these textures are explained by the presence of a Ksb term in the bulk elastic free energy density that favors a combination of splay and bend deformations.Comment: 4 pages, REVTeX, 3 figures, submitted to PR

The Escape Problem for Irreversible Systems

The problem of noise-induced escape from a metastable state arises in physics, chemistry, biology, systems engineering, and other areas. The problem is well understood when the underlying dynamics of the system obey detailed balance. When this assumption fails many of the results of classical transition-rate theory no longer apply, and no general method exists for computing the weak-noise asymptotics of fundamental quantities such as the mean escape time. In this paper we present a general technique for analysing the weak-noise limit of a wide range of stochastically perturbed continuous-time nonlinear dynamical systems. We simplify the original problem, which involves solving a partial differential equation, into one in which only ordinary differential equations need be solved. This allows us to resolve some old issues for the case when detailed balance holds. When it does not hold, we show how the formula for the mean escape time asymptotics depends on the dynamics of the system along the most probable escape path. We also present new results on short-time behavior and discuss the possibility of focusing along the escape path.Comment: 24 pages, APS revtex macros (version 2.1) now available from PBB via `get oldrevtex.sty

Nanowired three-dimensional cardiac patches

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds1, 2, 3. These biomaterials, which are usually made of either biological polymers such as alginate4 or synthetic polymers such as poly(lactic acid) (PLA)5, help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit6. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.National Institutes of Health (U.S.) (NIH, grant GM073626)National Institutes of Health (U.S.) (NIH, grant DE13023)National Institutes of Health (U.S.) (NIH, grant DE016516)American Heart Association (Postdoctoral Fellowship)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award (no. F32GM096546)

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

Episodic mass loss in binary evolution to the Wolf-Rayet phase: Keck and HST proper motions of RY Scuti's nebula

Binary mass transfer via Roche-lobe overflow (RLOF) is a key channel for producing stripped-envelope Wolf-Rayet (WR) stars and may be critical to account for SN Ib/c progenitors. RY Scuti is an extremely rare example of a massive binary star caught in this brief but important phase. Its toroidal nebula indicates equatorial mass loss during RLOF, while the mass-gaining star is apparently embedded in an opaque accretion disk. RY Scuti's toroidal nebula has two components: an inner ionised double-ring system, and an outer dust torus that is twice the size of the ionised rings. We present two epochs of Lband Keck NGS-AO images of the dust torus, plus three epochs of HST images of the ionised gas rings. Proper motions show that the inner ionised rings and the outer dust torus came from two separate ejection events roughly 130 and 250 yr ago. This suggests that RLOF in massive contact binaries can be accompanied by eruptive and episodic burst of mass loss, reminiscent of LBVs. We speculate that the repeating outbursts may arise in the mass gainer from instabilities associated with a high accretion rate. If discrete mass-loss episodes in other RLOF binaries are accompanied by luminous outbursts, they might contribute to the population of extragalactic optical transients. When RLOF ends for RY Scuti, the overluminous mass gainer, currently surrounded by an accretion disk, will probably become a B[e] supergiant and may outshine the hotter mass-donor star that should die as a Type Ib/c supernova.Comment: 15 pages, 7 figures, submitted to MNRA