NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content.

In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission

Cigarette Smoking, Body Mass and Other Risk Factors for Fractures of the Hip in Women

Determinants of hip fractures were assessed using data from a network of hospital-based case-control studies from northern Italy. For the present analysis, cases were 209 women with fractures of the hip/proximal femur (aged 29 to 74, median age 62) admitted to a network of teaching and general hospitals in the greater Milan area; controls were 1449 women, aged 25 to 74 (median age 55), admitted for non-traumatic, acute conditions to the same network of hospitals. There was a strong direct association with smoking, the relative risk (RR) being significantly and similarly elevated both in ex-and in current smokers (RR 1.7 and 1.5 respectively) which rose to 2.4 for 25 or over cigarettes per day. The risk was associated with duration of smoking and apparently greater in post-menopausal women. Two factors showed significant inverse associations with hip fractures: relative weight, with relative risks of 0.5, 0.4 and 0.3 in subsequent categories of body mass index as compared with thinner ones, and the use of oestrogen replacement treatment (multi-variate RR = 0.4, 95% confidence interval (CI): 0.2-1.1). No association was observed with education or social class, selected indicator foods or alcohol consumption (RR for the highest consumption level = 1.0). The effects of smoking and body mass index appeared independent: compared with never smoking heavier women, the RR for smoking thin women was 4.6. Thus, this case-control study of hip fractures in a predominantly post-menopausal population of Italian women showed a strong association with smoking and appreciable protection from heavier body mass index and the use of oestrogen replacement treatmen

A New Extension of the Binomial Error Model for Responses to Items of Varying Difficulty in Educational Testing and Attitude Surveys

We put forward a new item response model which is an extension of the binomial error model first introduced by Keats and Lord. Like the binomial error model, the basic latent variable can be interpreted as a probability of responding in a certain way to an arbitrarily specified item. For a set of dichotomous items, this model gives predictions that are similar to other single parameter IRT models (such as the Rasch model) but has certain advantages in more complex cases. The first is that in specifying a flexible two-parameter Beta distribution for the latent variable, it is easy to formulate models for randomized experiments in which there is no reason to believe that either the latent variable or its distribution vary over randomly composed experimental groups. Second, the elementary response function is such that extensions to more complex cases (e.g., polychotomous responses, unfolding scales) are straightforward. Third, the probability metric of the latent trait allows tractable extensions to cover a wide variety of stochastic response processes

Quasistationary binary inspiral. I. Einstein equations for the two Killing vector spacetime

The geometry of two infinitely long lines of mass moving in a fixed circular orbit is considered as a toy model for the inspiral of a binary system of compact objects due to gravitational radiation. The two Killing fields in the toy model are used, according to a formalism introduced by Geroch, to describe the geometry entirely in terms of a set of tensor fields on the two-manifold of Killing vector orbits. Geroch's derivation of the Einstein equations in this formalism is streamlined and generalized. The explicit Einstein equations for the toy model spacetime are derived in terms of the degrees of freedom which remain after a particular choice of gauge.Comment: 37 pages, REVTeX, one PostScript Figure included with epsfig; minor formatting changes and copyright notice added for journal publicatio

Smoking Habits and Risk of Benign Breast Disease

The relationship between smoking habits and the risk of benign breast disease (BBD) was analyzed using data from a case-control study conducted between 1981 and 1983 in the greater Milan area, Northern Italy. Cases (n = 288) were women with histologically confirmed BBD (203 dysplasia, 85 benign tumours) referred to the National Cancer Institute of Milan for biopsies. Controls were women (n = 291) seen on selected days for a cytological smear for cervical cancer in outpatient clinics of the same Institute. No consistent association emerged between various indicators of smoking habits (smoking status, number of cigarettes smoked per day, duration of smoking) and the risk of BBD. Compared with never smokers the relative risk (RR) of all BBD combined was 0.7 (95% confidence interval, Cl: 0.4-1.3) in exsmokers, 1.4 (95% Cl: 0.8-2.5) in smokers of less than 10 cigarettes per day, and 1.1 (95% Cl: 0.7-1.7) in smokers of 10 or more cigarettes per day. There was some suggestion that the risk may be below unity post-menopause, but the relative risks for smokers were not statistically different in pre- (RR = 1.2; 95% Cl: 0.8-1.8) and post-menopausal (RR = 0.6; 95% Cl: 0.2-1.7) women. The risk of benign tumours (chiefly fibradenoma) was higher in current smokers, but this finding was not statistically significant (RR = 1.5; 95% Cl: 0.9-2.6) and the highest risks were observed in the strata of lighter smokers and those with shorter duration of smoking. Overall these results fail to support a negative association between smoking habits and benign breast diseas

Smoking Habits and Risk of Benign Breast Disease

The relationship between smoking habits and the risk of benign breast disease (BBD) was analyzed using data from a case-control study conducted between 1981 and 1983 in the greater Milan area, Northern Italy. Cases (n = 288) were women with histologically confirmed BBD (203 dysplasia, 85 benign tumours) referred to the National Cancer Institute of Milan for biopsies. Controls were women (n = 291) seen on selected days for a cytological smear for cervical cancer in outpatient clinics of the same Institute. No consistent association emerged between various indicators of smoking habits (smoking status, number of cigarettes smoked per day, duration of smoking) and the risk of BBD. Compared with never smokers the relative risk (RR) of all BBD combined was 0.7 (95% confidence interval, Cl: 0.4-1.3) in exsmokers, 1.4 (95% Cl: 0.8-2.5) in smokers of less than 10 cigarettes per day, and 1.1 (95% Cl: 0.7-1.7) in smokers of 10 or more cigarettes per day. There was some suggestion that the risk may be below unity post-menopause, but the relative risks for smokers were not statistically different in pre- (RR = 1.2; 95% Cl: 0.8-1.8) and post-menopausal (RR = 0.6; 95% Cl: 0.2-1.7) women. The risk of benign tumours (chiefly fibradenoma) was higher in current smokers, but this finding was not statistically significant (RR = 1.5; 95% Cl: 0.9-2.6) and the highest risks were observed in the strata of lighter smokers and those with shorter duration of smoking. Overall these results fail to support a negative association between smoking habits and benign breast disease

A status report on the observability of cosmic bubble collisions

In the picture of eternal inflation as driven by a scalar potential with multiple minima, our observable universe resides inside one of many bubbles formed from transitions out of a false vacuum. These bubbles necessarily collide, upsetting the homogeneity and isotropy of our bubble interior, and possibly leading to detectable signatures in the observable portion of our bubble, potentially in the Cosmic Microwave Background or other precision cosmological probes. This constitutes a direct experimental test of eternal inflation and the landscape of string theory vacua. Assessing this possibility roughly splits into answering three questions: What happens in a generic bubble collision? What observational effects might be expected? How likely are we to observe a collision? In this review we report the current progress on each of these questions, improve upon a few of the existing results, and attempt to lay out directions for future work.Comment: Review article; comments very welcome. 24 pages + 4 appendices; 19 color figures. (Revised version adds two figures, minor edits.

Live Cell Imaging Unveils Multiple Domain Requirements for In Vivo Dimerization of the Glucocorticoid Receptor

Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects.Fil: Presman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Ogara, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Stortz, Martin Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Alvarez, Lautaro Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Pooley, John R.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados Unidos. University of Bristol; Reino UnidoFil: Schiltz, R. Louis. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Grøntved, Lars. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Johnson, Thomas A.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Mittelstadt, Paul R.. National Cancer Institute. Laboratory of Immune Cell Biology; Estados UnidosFil: Ashwell, Jonathan D.. National Cancer Institute. Laboratory of Immune Cell Biology; Estados UnidosFil: Ganesan, Sundar. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados Unidos. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Burton, Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Levi, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Hager, Gordon L.. National Cancer Institute. Laboratory of Receptor Biology and Gene Expression; Estados UnidosFil: Pecci, Adali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin