Spontaneous Symmetry Breaking in a Coherently Driven Nanophotonic Bose-Hubbard Dimer.

We report on the first experimental observation of spontaneous mirror symmetry breaking (SSB) in coherently driven-dissipative coupled optical cavities. SSB is observed as the breaking of the spatial or mirror Z_{2} symmetry between two symmetrically pumped and evanescently coupled photonic crystal nanocavities, and manifests itself as random intensity localization in one of the two cavities. We show that, in a system featuring repulsive boson interactions (U>0), the observation of a pure pitchfork bifurcation requires negative photon hopping energies (J<0), which we have realized in our photonic crystal molecule. SSB is observed over a wide range of the two-dimensional parameter space of driving intensity and detuning, where we also find a region that exhibits bistable symmetric behavior. Our results pave the way for the experimental study of limit cycles and deterministic chaos arising from SSB, as well as the study of nonclassical photon correlations close to SSB transitions.

Identification of a novel, fast-acting GABAergic antidepressant.

Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl-gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response-binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.

Strong Coupling between Self-Assembled Molecules and Surface Plasmon Polaritons.

We experimentally demonstrate strong coupling between self-assembled PTCDI-C7 organic molecules and the electromagnetic mode generated by surface plasmon polaritons (SPPs). The system consists of a dense self-assembly of ordered molecules evaporated directly on a thin gold film, which stack perpendicularly to the metal surface to form H-aggregates, without a host matrix. Experimental wavevector-resolved reflectance spectra show the formation of hybrid states that display a clear anticrossing, attesting the strong coupling regime with a Rabi splitting energy of ΩR ≃ 102 meV at room temperature. We demonstrate that the strength of the observed strong coupling regime derives from the high degree of organization of the dense layers of self-assembled molecules at the nanoscale that results in the concentration of the oscillator strength in a charge-transfer Frenkel exciton, with a dipole moment parallel to the direction of the maximum electric field. We compare our results to numerical simulations of a transfer matrix model and reach good qualitative agreement with the experimental findings. In our nanophotonic system, the use of self-assembled molecules opens interesting prospects in the context of strong coupling regimes with molecular systems.

Calorically restricted diets decrease PCSK9 in overweight adolescents.

BACKGROUND AND AIMS: Nutritional therapy is the first line approach to treatment of hyperlipidemia in childhood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of plasma cholesterol levels and a target of novel lipid-lowering pharmacotherapies. We examined the effects of an intensive nutritional intervention on PCSK9 levels in overweight adolescents with cardiovascular disease (CVD) risk factors. METHODS AND RESULTS: Twenty seven obese and overweight adolescents with CVD risk factors were assigned to either a low fat or low glycemic load diet. During an 8-week "Intensive Phase," assigned meals were delivered to the home, and all participants received weekly in-person home nutrition counseling and phone calls. The subjects then underwent a 4-month "Maintenance Phase" without food provision and with no in-person contact. Anthropometric measurements, laboratory data, and serum PCSK9 protein levels were measured at baseline, 8 weeks, and 6 months. PCSK9 decreased by 16.5% at 8 weeks (201.2 ± 56.3 vs 165.6 ± 58.4 ng/mL; p < 0.001); PCSK9 levels returned to baseline levels at 6 months, after the Maintenance Phase. Change in PCSK9 was associated with change in fasting insulin, HOMA-IR, and AUC insulin, independent of weight loss. CONCLUSIONS: PCSK9 decreased in youth participating in an intensive dietary intervention. Change in HOMA-IR was associated with change in PCSK9, independent of weight loss, suggesting an important relationship with insulin sensitivity. ClinicalTrials.gov Identifier: NCT01080339.

Segmented waveguide arrays: deriving discrete diffraction relations in a square lattice photonic crystal.

Segmented strip-loaded waveguide arrays are investigated within a rigorous square lattice photonic crystal model. We derive a full multiband discrete diffraction approach for near-axial injection in the direction of a lattice vector. We obtain an effective waveguide array picture, with quasi-linear dependence on the segmentation ratio in a simplified single-band scheme. Our results are validated by beam deviation experiments. Such a diffraction framework allows for efficient shaping of the phase map in waveguide arrays and enriches the engineering toolkit of photonic crystals with the in-plane free propagation structures of discrete photonics.

Millisecond Photon Lifetime in a Slow-Light Microcavity.

Optical microcavities with ultralong photon storage times are of central importance for integrated nanophotonics. To date, record quality (Q) factors up to 10^{11} have been measured in millimetric-size single-crystal whispering-gallery-mode (WGM) resonators, and 10^{10} in silica or glass microresonators. We show that, by introducing slow-light effects in an active WGM microresonator, it is possible to enhance the photon lifetime by several orders of magnitude, thus circumventing both fabrication imperfections and residual absorption. The slow-light effect is obtained from coherent population oscillations in an erbium-doped fluoride glass microsphere, producing strong dispersion of the WGM (group index n_{g}∼10^{6}). As a result, a photon lifetime up to 2.5 ms at room temperature has been measured, corresponding to a Q factor of 3×10^{12} at 1530 nm. This system could yield a new type of optical memory microarray with ultralong storage times.

Distinct ethanol drinking microstructures in two replicate lines of mice selected for drinking to intoxication.

The High Drinking in the Dark (HDID) mice have been selectively bred for reaching high blood ethanol concentrations (BECs) following the limited access Drinking in the Dark (DID) test. We have shown previously that mice from the first HDID replicate line (HDID-1) drink in larger, but not longer, ethanol drinking bouts than the low-drinking HS/Npt control mice when consuming modest amounts in the DID test. Here, we assessed drinking microstructure in HDID-1 mice during binge-like levels of ethanol intake using a lickometer system. Mice from both HDID replicates (HDID-1 and -2) and HS mice were also given three DID tests (single-bottle ethanol, two-bottle choice and single-bottle saccharin) using a continuously recording BioDAQ system to determine whether there are selection-dependent changes in drinking microstructure. Larger ethanol bout size in the HDID-1 mice than the HS mice was found to be due to a larger lick volume in these mice. HDID-1 and HDID-2 mice were also seen to have different drinking microstructures that both resulted in high intake and high BECs. The HDID-1 mice drank in larger ethanol bouts than HS, whereas HDID-2 mice drank in more frequent bouts. This pattern was also seen in two-bottle choice DID. The HDID-2 mice had a high bout frequency for all fluid types tested, whereas the large bout size phenotype of the HDID-1 mice was specific to alcohol. These findings suggest that selection for drinking to intoxication has resulted in two distinct drinking microstructures, both of which lead to high BECs and high ethanol intake.

Progress in a replicated selection for elevated blood ethanol concentrations in HDID mice.

Drinking in the dark (DID) is a limited access ethanol-drinking phenotype in mice. High Drinking in the Dark (HDID-1) mice have been bred for 27 selected generations (S27) for elevated blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol. A second replicate line (HDID-2) was started later from the same founder population and is currently in S20. An initial report of response to selection in HDID-1 was published after S11. This article reports genetic and behavioral characteristics of both lines in comparison with the HS controls. Heritability is low in both replicates (h(2) = 0.09) but the lines have shown 4-5 fold increases in BEC since S0; 80% of HDID-1 and 60% of HDID-2 mice reach BECs greater than 1.0 mg/ml. Several hours after a DID test, HDID mice show mild signs of withdrawal. Although not considered during selection, intake of ethanol (g/kg) during the DID test increased by approximately 80% in HDID-1 and 60% in HDID-2. Common genetic influences were more important than environmental influences in determining the similarity between BEC and intake for HDID mice. Analysis of the partitioning of intake showed that 60% of intake is concentrated in the last 2 h of the 4 h session. However, this has not changed during selection. Hourly BECs during the DID test reach peak levels after 3 or 4 h of drinking. HDID mice do not differ from HS mice in their rate of elimination of an acute dose of alcohol.

Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype.

In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.

Continuous-wave operation of photonic band-edge laser near 1.55 microm on silicon wafer.

We report on the continuous-wave operation of a band edge laser at room temperature near 1.55 mum in an InGaAs/InP photonic crystal. A flat dispersion band-edge photonic mode is used for surface normal operation. The photonic crystal slab is integrated onto a Silicon chip by means of Au/In bonding technology, which combines two advantages, efficient heat sinking and broad band reflectivity.

Tuning a two-dimensional photonic crystal resonance via optical carrier injection.

We report on wide wavelength tuning through optical injection of carriers of a photonic resonance observed in reflectivity at 1543 nm in an InP-based two-dimensional photonic crystal slab. An 8-nm blueshift, which represents 20 times the resonance linewidth, is observed when a 4-kW/cm2 intense optical pump is incident on the sample. An analytical model that we developed, based on a coupled-mode nonlinear approach, allows us to describe this phenomenon in detail.

Preparation of F-18 labeled annexin V: a potential PET radiopharmaceutical for imaging cell death.

The clinical response to antitumor therapy is measured using imaging, such as CT or MRI, 6-12 weeks following chemotherapy treatment. The images at that time reflect both tumor cell death and new growth. Therefore, the amount of tumor cell death caused by chemotherapy cannot be efficiently quantified with current imaging modalities. A quantitative measurement of tumor cell death immediately following chemotherapy is needed to help validate both new agents and to optimize administration of existing therapies. Annexin V is a 36kD protein that binds to exposed phosphatidylserine (PS) on dying cells. In order to synthesize a probe that can detect cell death in vivo, the positron emitter F-18 was conjugated to annexin V via the compound N- succinimidyl-4-[18F]fluorobenzoate, [18F]SFB. The decay corrected radiochemical yield of F-18 labeled annexin V from 18F fluoride was 17.6 +/- 5.6% (n = 4) in three hours. The stepwise radiochemical yield of the conjugation step with annexin V was as high as 70% when a protein concentration of 5 mg/ml was used. Cancer cells treated with the chemotherapeutic agent, etoposide, showed an 88% increase in the binding of F-18 labeled annexin V compared to untreated cells. We conclude that [18F] labeled annexin V can be readily prepared by the conjugation of annexin V with [18F]SFB and that the positron-emitting compound is biologically active in detecting apoptosis.

Second-harmonic generation in one-dimensional photonic edge waveguides.

Diffraction losses in one-dimensional photonic crystal (PC) waveguides are the primary limitation on second-harmonic (SH) conversion efficiency. By using a finite difference time domain (FDTD) code taking into account second-order nonlinear polarization, we investigated these losses numerically, particularly at the SH wavelength. We propose an efficient SH conversion scheme in Al(x)Ga(1-x)As/air-etched waveguides. An analytical model is used to extrapolate the conversion efficiency to a number of periods for which time consumption makes the FDTD codes unsuitable.

Molecular classification of selective oestrogen receptor modulators on the basis of gene expression profiles of breast cancer cells expressing oestrogen receptor alpha.

The purpose of this study was to classify selective oestrogen receptor modulators based on gene expression profiles produced in breast cancer cells expressing either wtERalpha or mutant(351)ERalpha. In total, 54 microarray experiments were carried out by using a commercially available Atlas cDNA Expression Arrays (Clontech), containing 588 cancer-related genes. Nine sets of data were generated for each cell line following 24 h of treatment: expression data were obtained for cells treated with vehicle EtOH (Control); with 10(-9) or 10(-8) M oestradiol; with 10(-6) M 4-hydroxytamoxifen; with 10(-6) M raloxifene; with 10(-6) M idoxifene, with 10(-6) M EM 652, with 10(-6) M GW 7604; with 5 x 10(-5) M resveratrol and with 10(-6) M ICI 182,780. We developed a new algorithm 'Expression Signatures' to classify compounds on the basis of differential gene expression profiles. We created dendrograms for each cell line, in which branches represent relationships between compounds. Additionally, clustering analysis was performed using different subsets of genes to assess the robustness of the analysis. In general, only small differences between gene expression profiles treated with compounds were observed with correlation coefficients ranged from 0.83 to 0.98. This observation may be explained by the use of the same cell context for treatments with compounds that essentially belong to the same class of drugs with oestrogen receptors related mechanisms. The most surprising observation was that ICI 182,780 clustered together with oestrodiol and raloxifene for cells expressing wtERalpha and clustered together with EM 652 for cells expressing mutant(351)ERalpha. These data provide a rationale for a more precise and elaborate study in which custom made oligonucleotide arrays can be used with comprehensive sets of genes known to have consensus and putative oestrogen response elements in their promoter regions.

Phase-matched frequency doubling at photonic band edges: efficiency scaling as the fifth power of the length.

By exploiting the unique properties of periodic stratified media we demonstrate simultaneously phase matching and enhancement of the optical field under second order nonlinear interaction. This leads to a second harmonic efficiency growth faster than the fifth power of the structure length, far better than the usual quadratic behavior associated with second order nonlinear effects.

Estrogen receptor alpha mediated induction of the transforming growth factor alpha gene by estradiol and 4-hydroxytamoxifen in MDA-MB-231 breast cancer cells.

The selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT) is a full agonist at the transforming growth factor (TGF) alpha gene in ER negative breast cancer cells stably transfected with ER alpha cDNA (Levenson et al., Br. J. Cancer 77 (1998) 1812-1819). E(2) and 4-OHT increase TGF alpha mRNA and protein in a concentration dependent manner. The responses to E(2) and 4-OHT are blocked by the pure antiestrogen ICI 182,780, which does not induce TGF alpha. Transfected MDA-MB-231 cells contain functional ER alpha but no ER beta function was detected. Neo transfected cells that did not express ER alpha or cells stably transfected with the DNA binding domain mutant C202R/E203V which prevents gene activation did not induce TGF alpha mRNA after either E(2) or 4-OHT treatment. An examination of the time course for either 10 nM E(2) or 1 microM 4-OHT for MDA-MB-231 cells stably transfected with cDNA for ER alpha showed increases in TGF alpha mRNA within 2 or 3 h respectively. Cells pretreated with cycloheximide (1 microg/ml) showed induced TGF alpha mRNA in response to E(2) or 4-OHT but TGF alpha mRNA induction was blocked by actinomycin D (1 microg/ml). We conclude that both E(2) and 4-OHT induce TGF alpha by direct interaction of ER alpha with DNA and that ER beta is not involved in the estrogen-like response to 4-OHT in the MDA-MB-231 cells.

Molecular classification of estrogens.

Estrogens are involved in a multiplicity of programmed events in target tissues e.g.: uterus, breast, and pituitary gland, and hormone-responsive tumors occur at these target sites. We have addressed the possibility that all of the estrogens do not produce the same conformation of estrogen receptor alpha (ER). A novel assay in vitro was used to activate the transforming growth factor alpha (TGF-alpha) gene in situ in MDA-MB-231 cells stably transfected with cDNA for D351 ER or D351G ER. Three estrogen types were used: estradiol, diethylstilbestrol, and a triphenylethylene (TPE) derivative of tamoxifen without the antiestrogenic side chain. Computer molecular modeling was used to interpret data. A flat estrogen such as estradiol or diethylstilbestrol can induce TGF-alpha through a correctly positioned activating function 2 (AF2) and bind SRC-1. The TPE did not activate AF2 but activated the TGF-alpha gene through AF2b. This was demonstrated because D351 but not D351G ER activated the TGF-alpha gene with the TPE. We propose two classes of estrogens with different ER complexes that may incorporate different coactivators to function. Phytoestrogens and environmental xenoestrogens will fall into different classes based on structure and may exhibit selective actions and carcinogenic potential based on different ER conformations.

Control of the estrogen-like actions of the tamoxifen-estrogen receptor complex by the surface amino acid at position 351.

Tamoxifen is a valuable therapeutic agent with applications in the treatment and prevention of breast cancer. However, the development of drug resistance limits the usefulness of tamoxifen therapy. One form of drug resistance in breast cancer is tamoxifen-stimulated growth. We have addressed a mechanism how the tamoxifen-estrogen receptor (ER) complex can convert from being a blocking to stimulatory signal in breast cancer. We have described an effective assay system to study the action of antiestrogen-ER complex through the activation of transforming growth factor alpha gene in situ. The MDA-MB-231 breast cancer cells were stably transfected with cDNAs for wtER (D351), mutant Asp351Tyr ER (D351Y) and mutant Asp351Gly ER (D351G). The D351Y ER can enhance the estrogenic properties of 4OHT and change the pharmacology of raloxifene by converting it from antiestrogen to estrogen. We hypothesized that alterations in the charge of amino acid (aa) 351, and changes in the interaction with the side chain of an antiestrogen, are critical for the subsequent estrogenicity of the complex. Our goal was (1) to modulate the estrogenicity of the antiestrogen-ER complex by different aa substitutions at position 351 and (2) to examine the role of alterations in the side chain of antiestrogens on the estrogenicity of the complex. Substitution of tyrosine for aspartate at aa351 results in increased estrogenicity for a series of tamoxifen derivatives-ER complexes and the conversion of EM 652-ER and GW 7604-ER complexes from antiestrogenic to estrogen-like. Substitution of glycine for aspartate at aa 351 results in the conversion of 4OHT-ER complex from estrogen-like to antiestrogenic. We propose that the side chain of antiestrogens either neutralizes or displaces the charge at aspartate 351 thereby removing a charged site for the opportunistic binding of a novel coactivator. If no charge is present (D351G) then no coactivator can bind and the complex with any antiestrogen is not estrogen-like. However, if the charge is extended beyond the reach of an antiestrogen side chain (D351Y), then the coactivators bind and compounds are estrogen-like. The establishment of a relationship between the structure of the antiestrogen-ER complex and its function will enhance the development of novel compounds with unique biological activities and potentially avoid premature drug resistance.

Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3.

Transforming growth factor-beta (TGF-beta) stimulates the transcription of the alpha2(I) procollagen gene (COL1A2). The intracellular mediators involved in this response remain poorly understood. In this study, we demonstrate that primary human skin fibroblasts express Smads, a novel family of signaling molecules, in vitro in the absence of TGF-beta. The levels of Smad 7 mRNA was rapidly and transiently increased by TGF-beta. Transient overexpression of Smad 3 and Smad 4, but not Smad 1 or Smad 2, caused trans-activation of a CAT reporter gene driven by a 772 bp segment of the human COL1A2 promoter containing putative TGF-beta response elements. Smad stimulation of promoter activity was ligand independent, but was further enhanced by TGF-beta. Overexpression of a phosphorylation-deficient Smad 3 mutant or wild-type Smad 7, which lacks the carboxy-terminal phosphorylation motif, specifically inhibited TGF-beta-induced activation of COL1A2 promoter. A CAGACA sequence shown to be a functional Smad-binding element in the plasminogen activator inhibitor-1 gene promoter was found within the TGF-beta-response region of the proximal COL1A2 promoter. Gel mobility shift assays showed protein phosphorylation-dependent binding activity in fibroblast nuclear extracts specific for this sequence; TGF-beta treatment strongly stimulated the formation of this DNA-protein complex. Smad was identified as a component of the CAGACA-binding transcription complex in TGF-beta-treated fibroblasts by antibody supershifting. These results demonstrate that (i) Smad 3 transmits TGF-beta signals from the receptor to the COL1A2 promoter in human fibroblasts, and is likely to play an important role in stimulation of COL1A2 promoter activity elicited by TGF-beta; (ii) in fibroblasts, Smads appear to function as inducible DNA-binding transcription factors; and (iii) Smad 7 may be involved in autocrine negative feedback in the regulation of COL1A2 promoter activity by TGF-beta.