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.

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.

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.

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.

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.

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.

The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor.

The crystallization of the ligand-binding domain (LBD) of the estrogen receptor (ER) with 17beta-estradiol and raloxifene [A. M. Brzozowski et al., Nature (Lond.), 389: 753-758, 1997] now provides a molecular basis for the biological activity of complexes as either agonists or antagonists. It is well established that the critical structural feature of antiestrogens is a correctly positioned alkylaminoethoxy side chain. The X-ray crystallography clearly shows that the alkylaminoethoxy side chain of raloxifene causes a specific and inappropriate molecular perturbation of the LBD and that the nitrogen in the side chain must hydrogen bond with aspartate 351 in the LBD of ER. We previously identified and characterized a naturally occurring mutation in the ER from a tamoxifen-stimulated transplantable human breast tumor line. The mutation is at AA351 of LBD, where the aspartate is changed to tyrosine (Asp351Tyr). In this report, we compared and contrasted the pharmacology of raloxifene to block or induce E2-stimulated increase in TGF-alpha mRNA in stable transfectants of ER-negative human breast cancer cells with the cDNAs from wild-type, mutant-amino acid (AA) 400 ER and mutant-AA 351 ER. Our results show that the mutation at AA 351 that replaces aspartate by tyrosine specifically changes the pharmacology of raloxifene from an antiestrogen to an estrogen. By contrast, a mutation at AA 400 does not, and the antiestrogenic properties of raloxifene are retained. These data and the fact that the nitrogen in the side chain must specifically interact with aspartate 351 makes this the key to the antiestrogenic activity of raloxifene.

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.

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.

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.

The growth of investor-owned psychiatric hospitals.

The number of investor-owned (proprietary) psychiatric hospitals in the United States has increased substantially in the past decade: these facilities now account for well over half of the nation's nongovernmental psychiatric hospitals. One of the reasons for this development has been the growth of multihospital chains, and another factor has been the economic advantages enjoyed by all investor-owned hospitals. These factors are likely to bring about further growth among investor-owned psychiatric hospitals in the future. Investor-owned hospitals in general, however, have become a subject of considerable controversy. Investor-owned psychiatric hospitals warrant specific consideration with respect to this controversy, particularly with respect to questions about quality of care.

Selective oestrogen receptor modulation: molecular pharmacology for the millennium.

Knowledge of the mechanism of action and pharmacology of tamoxifen and raloxifene, for the prevention of breast cancer and osteoporosis respectively, has opened the door for the discovery of multifunctional medicines. There is now the potential to prevent osteoporosis, coronary heart disease, breast and endometrial cancer in postmenopausal women with elevated risk factors.

Selective oestrogen receptor modulation: molecular pharmacology for the millennium.

Knowledge of the mechanism of action and pharmacology of tamoxifen and raloxifene, for the prevention of breast cancer and osteoporosis respectively, has opened the door for the discovery of multifunctional medicines. There is now the potential to prevent osteoporosis, coronary heart disease, breast and endometrial cancer in postmenopausal women with elevated risk factors.

Agonist activity of antiestrogen-receptor complexes to regulate urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression in breast cancer cells.

We have shown that 4-hydroxytamoxifen (4-OHT) has estrogen-like effects on induction of TGFalpha mRNA in estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells, transfected with either wildtype (S30 cells) or a codon 351asp-->tyr mutant ER (BC-2 cells). The mutant receptor used to produce the stable transfectants was identified in a tamoxifen-stimulated human breast tumor. We have also demonstrated that raloxifene exhibits a gene-specific estrogen-like effect with mutant ER (BC-2 cells) but not with wildtype ER (S30 cells) (Levenson, A.S., Catherino, W.H. and Jordan, V.C. (1997) Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor. J. Steroid Biochem. Mol. Biol., 60, 261-268). We now describe the regulation of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) endogenous gene expression by estradiol (E2) and different antiestrogens in BC-2 cells. Northern blot analyses revealed that 4-OHT and raloxifene have concentration-dependent agonistic (E2-like) effects on the regulation of these genes. In contrast, the pure antiestrogen ICI 182780 alone had no effect but could block the action of E2, 4-OHT and raloxifene. The E2-like effects of non-steroidal antiestrogens in this model system cannot be explained by the mutation in the ER alone because 4-OHT acts as an agonist with wildtype receptor as well. We propose that the clear cut biological expression of estrogen-like qualities with different antiestrogens will in the future serve as an important model to dissect the signal transduction pathway.

Prevention of psychiatric recidivism: a model service.

This article describes the patient-care activities of a medical school multidisciplinary section on geriatric psychiatry. The main treatment goal is the prevention of psychiatric recidivism. An index of this prevention is the re-admission rate, since the risks of institutionalization and recidivism tend to rise with each successive admission. The Section reported a re-admission rate of 4 percent for the first year of operation, a rate significantly less than that reported in the literature. The Section's achievement is predicated upon compliance with the requirements for optimal mental health care of the elderly. The protocol is presented in the hope that it may help others who wish to start such a service.

Gerontologic and geriatric training in medical school: curricular preferences shown by medical students, educators, and general practitioners.

The need for incorporating gerontologic and geriatric training into the education of medical students is evident. Two main obstacles are the lack of educator knowledge in planning such training, and negative attitudes toward aging and the aged. Curriculum planning requires a design for the goals/objectives, the content, and the delivery vehicles. This article concerns chiefly the delivery vehicles, a subject which has received little attention in the literature. Negative attitudes on the part of students and their educators may defeat the incorporation of geriatric training into the curriculum. To assist in reducing these obstacles, a study was conducted for the purpose of providing data to educators which might facilitate the design of a delivery component for a medical student curriculum in gerontology and geriatrics. Senior medical students, their educators, and some general practitioners were surveyed in randomized groups, to determine: 1) their preferences for delivery vehicles in such a curriculum, 2) their attitudes toward aging and the aged, and 3) relevant demographic variables. The results are discussed from the viewpoint of the potential impact of these factors on their preferences and on the creation of obstacles to curriculum incorporation.

Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines.

Estrogen responsiveness of breast tumors can be correlated with the presence or absence of the estrogen receptor (ER). Breast cancer cells that contain ER are, in general, responsive to stimulation by estrogen both in vivo and in vitro; therefore hormonal control is possible. Breast tumors that lose the ER, and become hormone-independent are refractory to the direct effect of estrogens and antiestrogens. It is therefore of interest to determine whether the re-expression of the ER will be sufficient to make ER-negative cells sensitive to the growth effect of estrogen. Transfection experiments with wild type and mutant ER cDNAs into different mammalian cell lines have been performed to re-establish hormonal control over hormone-independent cells. Paradoxically, introduction of exogenous ER into ER-negative cells and treatment with estrogen leads to growth inhibition rather than growth promotion. The activation of a number of estrogen-regulated genes has been examined in ER-transfectants but gene regulation is often variable. It is clear that the transfection of the ER gene into cells lacking this protein does not simply re-create the native ER-positive phenotype. Studies need to be extended to identify either the transcription factors that interact with ER to cause the negative effects of estrogen indirectly ("squelching") or the precise target genes that cause growth inhibition directly.

Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptor.

The estrogen receptor (ER) functions as a ligand-activated transcription factor which mediates the actions of estrogens and antiestrogens in target tissues. Other investigators have shown that artificial point mutations in the transcriptional activation domain AF-2 of the ligand binding domain (LBD) of the ER can increase the estrogenic properties of antiestrogens, determined by transcriptional activation of estrogen-responsive reporter constructs cotransfected into cells. Although these data provide valuable information about ER function there is no evidence that these mutations occur naturally. We have taken a different approach and examined the naturally occurring codon 351 asp --> tyr mutation in the LBD of ER to stimulate the expression of an endogenous target gene. This approach avoids dependence on artificial reporter constructs and their idealized estrogen response elements (EREs). In this report we describe the regulation of transforming growth factor alpha (TGF alpha) mRNA by estradiol and the antiestrogens keoxifene and ICI 182,780 in our stable transfectants of ER-negative MDA-MB-231 breast cancer cells, which express either the wild-type (S30 cells) or codon 351 asp --> tyr mutant ER (BC-2 cells). The mutant receptor was identified in a tamoxifen-stimulated human breast tumor. Our results demonstrate, for the first time, that a naturally occurring mutation in the ER changes the pharmacology of the antiestrogen keoxifene by increasing estrogenic activity, and that keoxifene exhibits a gene-specific estrogen-like effect with mutant ER but not with wild-type ER. The pure antiestrogen ICI 182,780 maintained complete antagonistic activities in both ER transfectants, demonstrating that its action is unaffected by the mutation.

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.