Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons

PSD-95 (postsynaptic density 95) is a postsynaptic scaffolding protein that links NMDA receptors to the cytoskeleton and signaling molecules. The N-terminal domain of PSD-95 is involved in the synaptic targeting and clustering of PSD-95 and in the clustering of NMDA receptors at synapses. The N-terminal domain of PSD-95 contains three consensus phosphorylation sites for cyclin-dependent kinase 5 (cdk5), a proline-directed serine-threonine kinase essential for brain development and implicated in synaptic plasticity, dopamine signaling, cocaine addiction, and neurodegenerative disorders. We report that PSD-95 is phosphorylated in the N-terminal domain by cdk5 in vitro and in vivo, and that this phosphorylation is not detectable in brain lysates of cdk5-/- mice. N-terminal phosphorylated PSD-95 is found in PSD fractions together with cdk5 and its activator, p35, suggesting a role for phosphorylated PSD-95 at synapses. In heterologous cells, coexpression of active cdk5 reduces the ability of PSD-95 to multimerize and to cluster neuronal ion channels, two functions attributed to the N-terminal domain of PSD-95. Consistent with these observations, the lack of cdk5 activity in cultured neurons results in larger clusters of PSD-95. In cdk5-/- cortical neurons, more prominent PSD-95 immunostained clusters are observed than in wild-type neurons. In hippocampal neurons, the expression of DNcdk5 (inactive form of cdk5) or of the triple alanine mutant (T19A, S25A, S35A) full-length PSD-95 results in increased PSD-95 cluster size. These results identify cdk5-dependent phosphorylation of the N-terminal domain of PSD-95 as a novel mechanism for regulating the clustering of PSD-95. Moreover, these observations support the possibility that cdk5-dependent phosphorylation of PSD-95 dynamically regulates the clustering of PSD-95/NMDA receptors at synapses, thus providing a possible mechanism for rapid changes in density and/or number of receptor at synapses

What Obstetrician-Gynecologists Think of Preconception Care

Objectives: To describe obstetrician-gynecolog-ists’ opinions of preconception care (PCC) and ascertain patient uptake for this service. Methods: A questionnaire was mailed to 1105 ACOG members in August 2004. Results: There was a 60% response rate. Most physicians think PCC is important (87%) and almost always recommend it to women planning a pregnancy (94%); 54% do so with women who are sexually active. Around a third (34%) thought their patients usually do not plan their pregnancies and 49% said very few pregnant patients came in for PCC. Of those who obtain PCC, they were believed to do so more likely to assure a healthy pregnancy (83%) than because of an elevated risk for birth defects (20%). Of 11 issues presented, cigarette smoking and folic acid supplementation were rated the most important for PCC counseling; exercise and environmental concerns were the least important. Conclusions: Physicians are willing to provide PCC but few patients are accessing such services

Using the internet to seek information about genetic and rare diseases: A case study comparing data from 2006 and 2011

BACKGROUND: The Genetic and Rare Disease Information Center (GARD) is a major provider of Web-based information on genetic and rare diseases. Little is known about the type of Web-based information individuals seek about genetic and rare diseases or their reasons for seeking. OBJECTIVE: The objective of this paper is to describe the types of Web-based information sought about genetic and rare diseases and the reasons for seeking it from GARD by examining inquiries from 2006 and 2011. METHODS: There were 278 English-language email and Web-based inquiries posed to GARD by lay individuals (ie, patients, parents, and relatives), which were randomly selected from inquiries in 2006 (n=68) and 2011 (n=210) and examined using content analysis. RESULTS: Most often in both years, individuals sought basic disease information (51/68, 75.0% and 132/210, 62.8%; P=.067) and information about treatment (17/51, 33.3% and 62/132, 47.0%; P=.095). Specifically, inquirers requested information about their disease prognosis (6/51, 11.8% and 23/132, 17.4%; P=.347) and made requests for specialists (8/68, 11.8% and 31/210, 14.8%; P=.536). In both 2006 and 2011, a substantial subset of inquirers requested information related to undiagnosed symptoms, representing 16.2% (11/68) and 11.9% (25/210; P=.362) of inquiries, respectively. Inquirers were significantly more likely to have seen a health care provider before contacting GARD (99/210, 47.1% vs 20/68, 29.4%; P=.010) and to ask about clinical research studies in 2011 than in 2006 (24/210, 11.4% vs 2/68, 2.9%; P=.037). In the 2011 data set, the majority of the inquirers were women (201/210, 95.7%). In our 2006 sample, men were the majority source of inquiries (54/68, 79.4%). CONCLUSIONS: Findings from this study indicate that lay people contacting a genetic and rare disease information center most often seek information about disease prognosis, finding a specialist, and obtaining a diagnosis for symptoms. Unique characteristics of individuals searching the Internet for genetic and rare diseases information, includes a growing interest in participating in clinical research studies and a desire to supplement or better understand information discussed during a visit with a health care provider. These efforts represent advancements in patient self-advocacy

Unilateral heat accelerates bone elongation and lengthens extremities of growing mice

Linear growth failure results from a broad spectrum of systemic and local disorders that can generate chronic musculoskeletal disability. Current bone lengthening protocols involve invasive surgeries or drug regimens, which are only partially effective. Exposure to warm ambient temperature during growth increases limb length, suggesting that targeted heat could noninvasively enhance bone elongation. We tested the hypothesis that daily heat exposure on one side of the body unilaterally increases femoral and tibial lengths. Mice (N = 20) were treated with 40 °C unilateral heat for 40 min/day for 14 days post-weaning. Non-treated mice (N = 6) served as controls. Unilateral increases in ear (8.8%), hindfoot (3.5%), femoral (1.3%), and tibial (1.5%) lengths were obtained. Tibial elongation rate was \u3e 12% greater (15 μm/day) on the heat-treated side. Extremity lengthening correlated with temperature during treatment. Body mass and humeral length were unaffected. To test whether differences persisted in adults, mice were examined 7-weeks post-treatment. Ear area, hindfoot, femoral, and tibial lengths were still significantly increased ∼6%, 3.5%, 1%, and 1%, respectively, on the heat-treated side. Left-right differences were absent in non-treated controls, ruling out inherent side asymmetry. This model is important for designing noninvasive heat-based therapies to potentially combat a range of debilitating growth impediments in children

PMN J1838-3427: A new gravitationally lensed quasar

We report the discovery of a new double-image quasar that was found during a search for gravitational lenses in the southern sky. Radio source PMN J1838-3427 is composed of two flat-spectrum components with separation 1", flux density ratio 14:1 and matching spectral indices, in VLA and VLBA images. Ground-based BRI images show the optical counterpart (total I=18.6) is also double with the same separation and position angle as the radio components. An HST/WFPC2 image reveals the lens galaxy. The optical flux ratio (27:1) is higher than the radio value probably due to differential extinction of the components by the lens galaxy. An optical spectrum of the bright component contains quasar emission lines at z=2.78 and several absorption features, including prominent Ly-alpha absorption. The lens galaxy redshift could not be measured but is estimated to be z=0.36 +/- 0.08. The image configuration is consistent with the simplest plausible models for the lens potential. The flat radio spectrum and observed variability of PMN J1838-3427 suggest the time delay between flux variations of the components is measurable, and could thus provide an independent measurement of H_0.Comment: 23 pages, incl. 6 figures, to appear in A.J.; replaced with accepted version; minor changes to text, improved figure

Individualized decision aid for diverse women with lupus nephritis (IDEA-WON): A randomized controlled trial.

BackgroundTreatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus nephritis.Methods and findingsIn a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of <$40,000, and 36% had a high school education or less. Compared with the provision of the ACR lupus pamphlet (n = 147), participants randomized to the decision aid (n = 151) had (1) a clinically meaningful and statistically significant reduction in decisional conflict, 21.8 (standard error [SE], 2.5) versus 12.7 (SE, 2.0; p = 0.005) and (2) no difference in informed choice in the main analysis, 41% versus 31% (p = 0.08), but clinically meaningful and statistically significant difference in sensitivity analysis (net values for immunosuppressives positive [in favor] versus negative [against]), 50% versus 35% (p = 0.006). Unresolved decisional conflict was lower in the decision aid versus pamphlet groups, 22% versus 44% (p < 0.001). Significantly more patients in the decision aid versus pamphlet group rated information to be excellent for understanding lupus nephritis (49% versus 33%), risk factors (43% versus 27%), medication options (50% versus 33%; p ≤ 0.003 for all); and the ease of use of materials was higher in the decision aid versus pamphlet groups (51% versus 38%; p = 0.006). Key study limitations were the exclusion of men, short follow-up, and the lack of clinical outcomes, including medication adherence.ConclusionsAn individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis.Trial registrationClinicaltrials.gov, NCT02319525

Nonequilibrium Dynamics of Optical Lattice-Loaded BEC Atoms: Beyond HFB Approximation

In this work a two-particle irreducible (2PI) closed-time-path (CTP) effective action is used to describe the nonequilibrium dynamics of a Bose Einstein condensate (BEC) selectively loaded into every third site of a one-dimensional optical lattice. The motivation of this work is the recent experimental realization of this system at National Institute of Standards and Technology (NIST) where the placement of atoms in an optical lattice is controlled by using an intermediate superlattice. Under the 2PI CTP scheme with this initial configuration, three different approximations are considered: a) the Hartree-Fock-Bogoliubov (HFB) approximation, b) the next-to-leading order 1/$\mathcal{N}$ expansion of the 2PI effective action up to second order in the interaction strength and c) a second order perturbative expansion in the interaction strength. We present detailed comparisons between these approximations and determine their range of validity by contrasting them with the exact many body solution for a moderate number of atoms and wells. As a general feature we observe that because the second order 2PI approximations include multi-particle scattering in a systematic way, they are able to capture damping effects exhibited in the exact solution that a mean field collisionless approach fails to produce. While the second order approximations show a clear improvement over the HFB approximation our numerical result shows that they do not work so well at late times, when interaction effects are significant.Comment: 34 pages, 7 figure

Displaying the Heterogeneity of the SN 2002cx-like Subclass of Type Ia Supernovae with Observations of the Pan-STARRS-1 Discovered SN2009ku

SN2009ku, discovered by Pan-STARRS-1, is a Type Ia supernova (SNIa), and a member of the distinct SN2002cx-like class of SNeIa. Its light curves are similar to the prototypical SN2002cx, but are slightly broader and have a later rise to maximum in g. SN2009ku is brighter (~0.6 mag) than other SN2002cx-like objects, peaking at M_V = -18.4 mag - which is still significantly fainter than typical SNeIa. SN2009ku, which had an ejecta velocity of ~2000 kms^-1 at 18 days after maximum brightness is spectroscopically most similar to SN2008ha, which also had extremely low-velocity ejecta. However, SN2008ha had an exceedingly low luminosity, peaking at M_V = -14.2 mag, ~4 mag fainter than SN2009ku. The contrast of high luminosity and low ejecta velocity for SN2009ku is contrary to an emerging trend seen for the SN2002cx class. SN2009ku is a counter-example of a previously held belief that the class was more homogeneous than typical SNeIa, indicating that the class has a diverse progenitor population and/or complicated explosion physics. As the first example of a member of this class of objects from the new generation of transient surveys, SN2009ku is an indication of the potential for these surveys to find rare and interesting objects.Comment: 7 pages, 3 figure

Phosphorylation of CRN2 by CK2 regulates F-actin and Arp2/3 interaction and inhibits cell migration

CRN2 (synonyms: coronin 1C, coronin 3) functions in the re-organization of the actin network and is implicated in cellular processes like protrusion formation, secretion, migration and invasion. We demonstrate that CRN2 is a binding partner and substrate of protein kinase CK2, which phosphorylates CRN2 at S463 in its C-terminal coiled coil domain. Phosphomimetic S463D CRN2 loses the wild-type CRN2 ability to inhibit actin polymerization, to bundle F-actin, and to bind to the Arp2/3 complex. As a consequence, S463D mutant CRN2 changes the morphology of the F-actin network in the front of lamellipodia. Our data imply that CK2-dependent phosphorylation of CRN2 is involved in the modulation of the local morphology of complex actin structures and thereby inhibits cell migration

Uptake routes and toxicokinetics of silver nanoparticles and silver ions in the earthworm Lumbricus rubellus

Current bioavailability models, such as the free ion activity model and biotic ligand model, explicitly consider that metal exposure will be mainly to the dissolved metal in ionic form. With the rise of nanotechnology products and the increasing release of metal-based nanoparticles (NPs) to the environment, such models may increasingly be applied to support risk assessment. It is not immediately clear, however, whether the assumption of metal ion exposure will be relevant for NPs. Using an established approach of oral gluing, a toxicokinetics study was conducted to investigate the routes of silver nanoparticles (AgNPs) and Ag+ ion uptake in the soil-dwelling earthworm Lumbricus rubellus. The results indicated that a significant part of the Ag uptake in the earthworms is through oral/gut uptake for both Ag+ ions and NPs. Thus, sealing the mouth reduced Ag uptake by between 40% and 75%. An X-ray analysis of the internal distribution of Ag in transverse sections confirmed the presence of increased Ag concentrations in exposed earthworm tissues. For the AgNPs but not the Ag+ ions, high concentrations were associated with the gut wall, liver-like chloragogenous tissue, and nephridia, which suggest a pathway for AgNP uptake, detoxification, and excretion via these organs. Overall, the results indicate that Ag in the ionic and NP forms is assimilated and internally distributed in earthworms and that this uptake occurs predominantly via the gut epithelium and less so via the body wall. The importance of oral exposure questions the application of current metal bioavailability models, which implicitly consider that the dominant route of exposure is via the soil solution, for bioavailability assessment and modeling of metal-based NPs