Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O2 •–) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O2 consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O2 •– through type-I photochemistry, and the generated O2 •– can further trigger a biocascade to reduce the PDT’s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O2-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.

(2015). A classical treatment of optical tunneling in plasmonic gaps: extending the quantum corrected model to practical situations. Faraday Discussions, 178, The optical response of plasmonic nanogaps is challenging to address when the separation between the two nanoparticles forming the gap is reduced to a few nanometers or even subnanometer distances. We have compared results of the plasmon response within different levels of approximation, and identified a classical local regime, a nonlocal regime and a quantum regime of interaction. For separations of a fewÅngstroms, in the quantum regime, optical tunneling can occur, strongly modifying the optics of the nanogap. We have considered a classical effective model, so called Quantum Corrected Model (QCM), that has been introduced to correctly describe the main features of optical transport in plasmonic nanogaps. The basics of this model are explained in detail, and its implementation is extended to include nonlocal effects and address practical situations involving different materials and temperatures of operation.

Semi-classical non-local optics based on the hydrodynamic description of conduction electrons might be an adequate tool to study complex phenomena in the emerging field of nanoplasmonics. With the aim of confirming this idea, we obtain the local and non-local optical absorption spectra in a model nanoplasmonic device in which there are spatial gaps between the components at nanometric and sub-nanometric scales. After a comparison against time-dependent density functional calculations, we conclude that hydrodynamic non-local optics provides absorption spectra exhibiting qualitative agreement but not quantitative accuracy. This lack of accuracy, which is manifest even in the limit where induced electric currents are not established between the constituents of the device, is mainly due to the poor description of induced electron densities.

We present an ab initio study of the hybridization of localized surface plasmons in a metal nanoparticle dimer. The atomic structure, which is often neglected in theoretical studies of quantum nanoplasmonics, has a strong impact on the optical absorption properties when subnanometric gaps between the nanoparticles are considered. We demonstrate that this influences the hybridization of optical resonances of the dimer, and leads to significantly smaller electric field enhancements as compared to the standard jellium model. In addition, we show that the corrugation of the metal surface at a microscopic scale becomes as important as other well-known quantum corrections to the plasmonic response, implying that the atomic structure has to be taken into account to obtain quantitative predictions for realistic nanoplasmonic devices. There is a growing interest in the development and implementation of nanoplasmonic devices such as nanosensors [1,2], nanophotonic lasers [3][4][5], optoelectronic [6,7] and light-harvesting [8,9] structures, and nanoantennas [10,11]. Therefore, it is essential to have theoretical techniques with a sufficient predictive value to understand the physical processes of light-matter interactions at the nanoscale. In this regime, the standard analysis of the plasmonic response to external electromagnetic (EM) fields using the classical macroscopic Maxwell equations must be undertaken with caution. Indeed, genuine quantum effects such as the nonlocal nature of the electron-density response, the inhomogeneity of the conduction-electron density, or the possibility of charge transfer by tunneling have to be considered [12]. These effects can be incorporated into Maxwell equations in an approximate manner using, e.g., nonlocal dielectric functions [13][14][15][16][17][18][19] or the ad hoc inclusion of "virtual" dielectric materials [20][21][22]. While these semiclassical approximations have been successfully applied in many cases, they do not achieve the precision provided by first-principle calculations.A number of recent publications [20,[23][24][25][26][27] have treated the electronic response of plasmonic structures using stateof-the-art time-dependent density functional theory (TDDFT) [28,29]. However, the ionic structure is typically neglected and replaced by a homogeneous jellium background or by an unstructured effective potential. Although this approximation is sometimes justified by the collective nature of plasmon excitations [30,31], the charge oscillations associated with a localized surface plasmon (LSP) are mainly concentrated on the metal-vacuum interface. One may thus expect that the ionic structure in this region will have a quantitative and even qualitative impact. Therefore, there is a need to address the influence of the atomic configuration in the plasmonic response at the nanoscale. In this Rapid Communication we present ab initio calculations including the atomic structure, in accordance with the current paradigm in computational condensed matter physics [32] and physical chem...

The transcription factor PU.1 is an important regulator of hematopoiesis; precise expression levels are critical for normal hematopoietic development and suppression of leukemia. We show here that noncoding antisense RNAs are important modulators of proper dosages of PU.1. Antisense and sense RNAs are regulated by shared evolutionarily conserved cis-regulatory elements, and we can show that antisense RNAs inhibit PU.1 expression by modulating mRNA translation. We propose that such antisense RNAs will likely be important in the regulation of many genes and may be the reason for the large number of overlapping complementary transcripts with so far unknown function.[Keywords: Noncoding antisense RNA; upstream and intronic regulatory elements; coordinated expression of the target and regulator; translation stalling] Supplemental material is available at http://www.genesdev.org.

We present a transformation-optics approach which sheds analytical insight into the impact that spatial dispersion has on the optical response of separated dimers of metallic nanowires. We show that nonlocal effects are apparent at interparticle distances one order of magnitude larger than the longitudinal plasmon decay length, which coincides with the spatial regime where electron tunneling phenomena occur. Our method also clarifies the interplay between nonlocal and radiation effects taking place in the nanostructure, yielding the dimer dimensions that optimize its light harvesting capabilities. The impact of spatial nonlocality in the optical properties of metal nanoparticles is currently attracting great research attention. The presence of subnanometric geometric features in these nanostructures enables them to support extremely localized surface plasmon (SP) resonances. Classical electrodynamics predicts that the focusing ability of SPs is pushed to its maximum efficiency at these diminutive decorations, 1 where the extent of the electromagnetic fields become comparable to the Coulomb screening length ( ∼ 0.1 nm for noble metals). However, the local constitutive relations of macroscopic Maxwell's equations do not reflect the occurrence of significant electron-electron interactions in this spatial regime. Thus, a nonlocal treatment of the dielectric characteristics of metals, 2 beyond the free-electron Drude model, is required to clarify the limitations and guide the optimization of plasmonic devices.Although spatial dispersion in the permittivity of metals has been intensively studied in the past, 3-6 its experimental exploration has not been possible until very recently. Current fabrication and optical characterization techniques allow the probing of SP resonances below the nanometer, 7-10 which has renewed the theoretical interest in the nonlocal response of metallic nanostructures.11-13 Nanoparticle dimers are probably the system most thoroughly investigated in this context. [14][15][16] In this Rapid Communication, we revisit this geometry using a quasianalytical transformation-optics (TO) approach, 17 which was first developed within the local approximation.18-21 Lately, this method has been used to describe nonlocal effects in touching nanowires. 22 Here, we extend this TO framework to separated dimers, clarifying how spatial dispersion affects the light harvesting properties of these devices. Figure 1(a) depicts a pair of metal nanowires of radius R separated by a gap distance d, illuminated by an electric field polarized along the dimer axis. Under the logarithmic transformation indicated, the dimer maps into the metalinsulator-metal structure shown in Fig. 1(b). 18 The incident electric field maps into an array of dipole sources located at x = 0 with period 2π . The transformed parameters can be expressed in terms of the original ones as g = 4R √ ρ(1 + ρ) and a = 2 ln(is the relative gap size. The permittivity tensor of the dimer is described using the hydrodynamical model.2 Thus, the transverse co...

Dysfunction in thyroid regulation can cause menstrual and ovulatory disturbances, the mechanism of which is not clear. The distribution and activity of the thyroid-stimulating hormone (TSHR), and the thyroid hormone receptors (TR) alpha1, alpha2 and beta1 in human ovarian tissue and in granulosa cells was studied using immunohistochemistry, reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative PCR and immunoassays. Strong immunostaining of TSHR, TRalpha1 and TRbeta1 was observed in ovarian surface epithelium and in oocytes of primordial, primary and secondary follicles, with minimal staining in granulosa cells of secondary follicles. Granulosa cells of antral follicles expressed TSHR, TRalpha1 and TRbeta1 proteins. Messenger RNA for all receptors was present in ovarian tissue. Mature human granulosa cells expressed transcripts for 5' deiodinases types 2 and 3, but not type 1, indicating the possibility of conversion of peripheral thyroid hormone thyroxin (T(4)). Granulosa cells stimulated with TSH showed a significant increase in cAMP concentrations after 2 h of culture (P = 0.047), indicating activation through TSHR. Stimulation with T(4) resulted in increased extracellular signal-regulated kinase 1 and 2 activation after 10, 30, 60 min and 24 h. These data demonstrate that TSH and thyroid hormone receptors may participate in the regulation of ovarian function.

Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies.