A community based intervention program to enhance neighborhood cohesion: The Learning Families Project in Hong Kong

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High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor–Gs Coupling Underlying Opioid Tolerance and Dependence

Ultra-low-dose opioid antagonists enhance opioid analgesia and reduce analgesic tolerance and dependence by preventing a G protein coupling switch (Gi/o to Gs) by the mu opioid receptor (MOR), although the binding site of such ultra-low-dose opioid antagonists was previously unknown. Here we show that with approximately 200-fold higher affinity than for the mu opioid receptor, naloxone binds a pentapeptide segment of the scaffolding protein filamin A, known to interact with the mu opioid receptor, to disrupt its chronic opioid-induced Gs coupling. Naloxone binding to filamin A is demonstrated by the absence of [3H]-and FITC-naloxone binding in the melanoma M2 cell line that does not contain filamin or MOR, contrasting with strong [3H]naloxone binding to its filamin A-transfected subclone A7 or to immunopurified filamin A. Naloxone binding to A7 cells was displaced by naltrexone but not by morphine, indicating a target distinct from opioid receptors and perhaps unique to naloxone and its analogs. The intracellular location of this binding site was confirmed by FITC-NLX binding in intact A7 cells. Overlapping peptide fragments from c-terminal filamin A revealed filamin A2561-2565 as the binding site, and an alanine scan of this pentapeptide revealed an essential mid-point lysine. Finally, in organotypic striatal slice cultures, peptide fragments containing filamin A2561-2565 abolished the prevention by 10 pM naloxone of both the chronic morphine-induced mu opioid receptor–Gs coupling and the downstream cAMP excitatory signal. These results establish filamin A as the target for ultra-low-dose opioid antagonists previously shown to enhance opioid analgesia and to prevent opioid tolerance and dependence

Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin

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Ultrafast control of donor-bound electron spins with single detuned optical pulses

The ability to control spins in semiconductors is important in a variety of fields including spintronics and quantum information processing. Due to the potentially fast dephasing times of spins in the solid state [1-3], spin control operating on the picosecond or faster timescale may be necessary. Such speeds, which are not possible to attain with standard electron spin resonance (ESR) techniques based on microwave sources, can be attained with broadband optical pulses. One promising ultrafast technique utilizes single broadband pulses detuned from resonance in a three-level Lambda system [4]. This attractive technique is robust against optical pulse imperfections and does not require a fixed optical reference phase. Here we demonstrate the principle of coherent manipulation of spins theoretically and experimentally. Using this technique, donor-bound electron spin rotations with single-pulse areas exceeding pi/4 and two-pulses areas exceeding pi/2 are demonstrated. We believe the maximum pulse areas attained do not reflect a fundamental limit of the technique and larger pulse areas could be achieved in other material systems. This technique has applications from basic solid-state ESR spectroscopy to arbitrary single-qubit rotations [4, 5] and bang-bang control[6] for quantum computation.Comment: 15 pages, 4 figures, submitted 12/2008. Since the submission of this work we have become aware of related work: J. Berezovsky, M. H. Mikkelsen, N. G. Stoltz, L. A. Coldren, and D. D. Awschalom, Science 320: 349-352 (2008

Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)

The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, high-stringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities KD∼1 μM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy. © 2013 Shen et al

Calmodulin-like proteins localized to the conoid regulate motility and cell invasion by Toxoplasma gondii

Toxoplasma gondii contains an expanded number of calmodulin (CaM)-like proteins whose functions are poorly understood. Using a combination of CRISPR/Cas9-mediated gene editing and a plant-like auxin-induced degron (AID) system, we examined the roles of three apically localized CaMs. CaM1 and CaM2 were individually dispensable, but loss of both resulted in a synthetic lethal phenotype. CaM3 was refractory to deletion, suggesting it is essential. Consistent with this prediction auxin-induced degradation of CaM3 blocked growth. Phenotypic analysis revealed that all three CaMs contribute to parasite motility, invasion, and egress from host cells, and that they act downstream of microneme and rhoptry secretion. Super-resolution microscopy localized all three CaMs to the conoid where they overlap with myosin H (MyoH), a motor protein that is required for invasion. Biotinylation using BirA fusions with the CaMs labeled a number of apical proteins including MyoH and its light chain MLC7, suggesting they may interact. Consistent with this hypothesis, disruption of MyoH led to degradation of CaM3, or redistribution of CaM1 and CaM2. Collectively, our findings suggest these CaMs may interact with MyoH to control motility and cell invasion

Qualidade de vida no trabalho nivel de estresse dos profissionais das UBS do Distrito Leste do Município de Foz do Iguaçu-PR

Trabalho de conclusão de Residência apresentado ao Programa Multiprofissional em Saúde da Família da Universidade Federal da Integração Latino-Americana, como requisito para obtenção do título de Especialista em Saúde da Família na modalidade de Residência. Orientador: Prof. Dr Thiago Luis de Andrade Barbosa Co-orientador: Prof. Ms. Gilberto Garcia da RochaObjetivo: Avaliar a qualidade de vida no trabalho (QVT) e nível de estresse dos trabalhadores da Atenção Primária à Saúde (APS) do distrito leste de Foz do Iguaçu-PR. Metodologia: Trata-se de estudo transversal no qual participaram 120 profissionais da APS pertencentes a 06 UBS do referido distrito. Os profissionais responderam questionários sociodemográfico, de QVT abreviado (QWLQ-Bref) e Escala do Estresse Percebido (PSS 13). Verificou-se associação da QVT e dos níveis de estresse com variáveis sociodemográficas com uso do teste t de Student, ANOVA, Mann-Whitney e Kruskal-Wallis. Nível de significância adotado foi de 5%. Resultados: A avaliação da QVT dos profissionais foi 62,8±10,0 e associou-se com sexo (p=0,016), idade (p=0,042), presença de dor (p=0,029) e satisfação com trabalho (p=0,002). Em relação aos domínios avaliados da QVT, houve associação com presença de dor e satisfação laboral. O escore total médio de estresse percebido dos participantes foi 24,5±6,0. Notou-se relação com as variáveis percepção quanto à alimentação saudável (p=0,013), presença de dor (p=0,002), dor relacionada ao trabalho (p=0,004) e satisfação com trabalho (p=0,001). Conclusão: Constatou-se satisfatória QVT e níveis médios de estresse dos profissionais o que demanda ações preventivas que melhorem esse panorama na APS do municípioObjective: To evaluate the quality of working life (QWL) and stress level of workers at Primary Health Care (PHC) in the east district of Foz do Iguaçu-PR. Methodology: Cross- sectional study with 120 PHC professionals from 06 basic health units of this district. Professionals answered sociodemographic questionnaire, abbreviated QLW (QWLQ-Bref) and Perceived Stress Scale (PSS 13). We verified the association of QWL and stress levels with sociodemographic variables using Student's t-test, ANOVA, Mann-Whitney and Kruskal-Wallis. Level of significance was 5%. Results: The professional QWL assessment was 62.8 ± 10.0 and was associated with gender (p=0.016), age (p=0.042), presence of pain (p = 0.029) and work satisfaction (p=0.002). In relation to the evaluated domains of QWL, there was an association with presence of pain and job satisfaction. The mean total perceived stress score of the participants was 24.5 ± 6.0. There was a relationship with the variables of perception regarding healthy eating (p=0.013), presence of pain (p=0.002), pain related to work (p=0.004) and satisfaction with work (p=0.001). Conclusion: We observed satisfactory QWL and mean levels of stress of PHC workers that demand improvement of this situationObjetivo: Evaluar la calidad de vida en el trabajo (QVT) y nivel de estrés de los trabajadores de la Atención Primaria a la Salud (APS) del distrito este de Foz do Iguaçu-PR. Metodología: Se trata de un estudio transversal en el que participaron 120 profesionales de la APS pertenecientes a 06 UBS de dicho distrito. Los profesionales respondieron cuestionarios sociodemográficos, de QVT abreviado (QWLQ-Bref) y Escala del estrés percibido (PSS 13). Se verificó asociación de QVT y de los niveles de estrés con variables sociodemográficas con el uso del test t de Student, ANOVA, Mann-Whitney y Kruskal-Wallis. El nivel de significancia adoptado fue del 5%. Resultados: La evaluación de la QVT de los profesionales fue de 62,8 ± 10,0 y se asoció con sexo (p=0,016), edad (p=0,042), presencia de dolor (p=0,029) y satisfacción con el trabajo (p=0,029) 0,002). En relación a los ámbitos evaluados de la QVT, hubo asociación con presencia de dolor y satisfacción laboral. La puntuación total promedio de estrés percibido de los participantes fue de 24,5 ± 6,0. Se observó relación con las variables percepción en cuanto a la alimentación sana (p=0,013), presencia de dolor (p=0,002), dolor relacionado al trabajo (p=0,004) y satisfacción con el trabajo (p=0,001). Conclusión: Se constató satisfactoria QVT y niveles medios de estrés de los profesionales lo que demanda acciones preventivas que mejoren ese panorama en la APS del municipi

Electric-field-induced alignment of electrically neutral disk-like particles: modelling and calculation

This work reveals a torque from electric field to electrically neutral flakes that are suspended in a higher electrical conductive matrix. The torque tends to rotate the particles toward an orientation with its long axis parallel to the electric current flow. The alignment enables the anisotropic properties of tiny particles to integrate together and generate desirable macroscale anisotropic properties. The torque was obtained from thermodynamic calculation of electric current free energy at various microstructure configurations. It is significant even when the electrical potential gradient becomes as low as 100 v/m. The changes of electrical, electroplastic and thermal properties during particles alignment were discussed

Association between the c.*229C>T polymorphism of the topoisomerase IIb binding protein 1 (TopBP1) gene and breast cancer

Topoisomerase IIb binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 30UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific Top- BP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95 % confidence interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer

The role of magnetic anisotropy in the Kondo effect

In the Kondo effect, a localized magnetic moment is screened by forming a correlated electron system with the surrounding conduction electrons of a non-magnetic host. Spin S=1/2 Kondo systems have been investigated extensively in theory and experiments, but magnetic atoms often have a larger spin. Larger spins are subject to the influence of magnetocrystalline anisotropy, which describes the dependence of the magnetic moment's energy on the orientation of the spin relative to its surrounding atomic environment. Here we demonstrate the decisive role of magnetic anisotropy in the physics of Kondo screening. A scanning tunnelling microscope is used to simultaneously determine the magnitude of the spin, the magnetic anisotropy and the Kondo properties of individual magnetic atoms on a surface. We find that a Kondo resonance emerges for large-spin atoms only when the magnetic anisotropy creates degenerate ground-state levels that are connected by the spin flip of a screening electron. The magnetic anisotropy also determines how the Kondo resonance evolves in a magnetic field: the resonance peak splits at rates that are strongly direction dependent. These rates are well described by the energies of the underlying unscreened spin states.Comment: 14 pages, 4 figures, published in Nature Physic