CK2 Is the Regulator of SIRT1 Substrate-Binding Affinity, Deacetylase Activity and Cellular Response to DNA-Damage

SIRT1, an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase, protects cells from stress-induced apoptosis, and its orthologues delay aging in lower eukaryotes. SIRT1 increases survival in response to stress such as DNA damage by deacetylating a number of substrates including pro-apoptotic protein p53. The molecular mechanism by which DNA-damage activates SIRT1 is not known. By screening a kinase inhibitor library, we identified CK2 as a SIRT1 kinase. CK2 is a pleiotropic kinase with more than 300 substrates and well-known anti-apoptotic and pro-growth activities. We find that CK2 is recruited to SIRT1 after ionizing radiation (IR) and phosphorylates conserved residues Ser 154, 649, 651 and 683 in the N- and C-terminal domains of mouse SIRT1. Phosphorylation of SIRT1 increases its deacetylation rate but not if the four Ser residues are mutated. In addition, phosphorylation of SIRT1 increases its substrate-binding affinity. CK2-mediated phosphorylation increases the ability of SIRT1 to deacetylate p53 and protect cells from apoptosis after DNA damage. Based on these findings, we propose that CK2 protects against IR-induced apoptosis partly by phosphorylating and activating SIRT1. Thus, this work suggests that SIRT1 is a component of the expansive anti-apoptotic network controlled by CK2. Since expression of both CK2 and SIRT1 is upregulated with tumorigenesis and downregulated with senescence, the CK2-SIRT1 link sheds new light on how CK2 may regulate cancer development and aging

Multi-Frequency-Aware Patch Adversarial Learning for Neural Point Cloud Rendering

We present a neural point cloud rendering pipeline through a novel multi-frequency-aware patch adversarial learning framework. The proposed approach aims to improve the rendering realness by minimizing the spectrum discrepancy between real and synthesized images, especially on the high-frequency localized sharpness information which causes image blur visually. Specifically, a patch multi-discriminator scheme is proposed for the adversarial learning, which combines both spectral domain (Fourier Transform and Discrete Wavelet Transform) discriminators as well as the spatial (RGB) domain discriminator to force the generator to capture global and local spectral distributions of the real images. The proposed multi-discriminator scheme not only helps to improve rendering realness, but also enhance the convergence speed and stability of adversarial learning. Moreover, we introduce a noise-resistant voxelisation approach by utilizing both the appearance distance and spatial distance to exclude the spatial outlier points caused by depth noise. Our entire architecture is fully differentiable and can be learned in an end-to-end fashion. Extensive experiments show that our method produces state-of-the-art results for neural point cloud rendering by a significant margin. Our source code will be made public at a later date.Comment: 8 pages, 4 figure

Advances in targeting cyclic nucleotide phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants

Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study

Study Objectives: To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables. Methods: Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant. Results: Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of 9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset. Conclusions: Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy

Multi-Wavelength Observations Of A New Redback Millisecond Pulsar 4FGL J1910.7-5320

We present the study of multi-wavelength observations of an unidentified Fermi Large Area Telescope (LAT) source, 4FGL J1910.7-5320, a new candidate redback millisecond pulsar binary. In the 4FGL 95% error region of 4FGL J1910.7-5320, we find a possible binary with a 8.36-hr orbital period from the Catalina Real-Time Transient Survey (CRTS), confirmed by optical spectroscopy using the SOAR telescope. This optical source was recently independently discovered as a redback pulsar by the TRAPUM project, confirming our prediction. We fit the optical spectral energy distributions of 4FGL J1910.7-5320 with a blackbody model, inferring a maximum distance of 4.1 kpc by assuming that the companion fills its Roche-lobe with a radius of R = 0.7R_sun. Using a 12.6 ks Chandra X-ray observation, we identified an X-ray counterpart for 4FGL J1910.7-5320, with a spectrum that can be described by an absorbed power-law with a photon index of 1.0+/-0.4. The spectrally hard X-ray emission shows tentative evidence for orbital variability. Using more than 12 years of Fermi-LAT data, we refined the position of the {\gamma}-ray source, and the optical candidate still lies within the 68% positional error circle. In addition to 4FGL J1910.7-5320, we find a variable optical source with a periodic signal of 4.28-hr inside the 4FGL catalog 95% error region of another unidentified Fermi source, 4FGL J2029.5-4237. However, the {\gamma}-ray source does not have a significant X-ray counterpart in a 11.7 ks Chandra observation, with a 3-{\sigma} flux upper limit of 2.4*10^-14 erg cm^-2 s^-1 (0.3-7 keV). Moreover, the optical source is outside our updated Fermi-LAT 95% error circle. These observational facts all suggest that this new redback millisecond pulsar powers the {\gamma}-ray source 4FGL J1910.7-5320 while 4FGL J2029.5-4237 is unlikely the {\gamma}-ray counterpart to the 4.28-hr variable.Comment: Accepted for publication in Ap

Chemical Beam Epitaxy of Compound Semiconductors

Contains reports on three research projects and a list of publications.3M Company Faculty Development GrantAT&T Research Foundation Special Purpose GrantCharles S. Draper Laboratories Contract DL-H-418484Defense Advanced Research Projects Agency Subcontract 216-25013Defense Advanced Research Projects Agency Subcontract 542383Joint Services Electronics Program Contract DAAL03-89-C-0001Joint Services Electronics Program Contract DAAL03-92-C-0001National Science Foundation Grant ECS 88-46919National Science Foundation Grant ECS 89-05909Defense Advanced Research Projects Agency Subcontract 5300716-07U.S. Navy - Office of Naval Research Contract N00014-88-K-0564Defense Advanced Research Projects Agency Subcontract 530-0716-07National Science Foundation Subcontract DMR 90-0789

A Domain-Specific Language for Incremental and Modular Design of Large-Scale Verifiably-Safe Flow Networks (Preliminary Report)

We define a domain-specific language (DSL) to inductively assemble flow networks from small networks or modules to produce arbitrarily large ones, with interchangeable functionally-equivalent parts. Our small networks or modules are "small" only as the building blocks in this inductive definition (there is no limit on their size). Associated with our DSL is a type theory, a system of formal annotations to express desirable properties of flow networks together with rules that enforce them as invariants across their interfaces, i.e, the rules guarantee the properties are preserved as we build larger networks from smaller ones. A prerequisite for a type theory is a formal semantics, i.e, a rigorous definition of the entities that qualify as feasible flows through the networks, possibly restricted to satisfy additional efficiency or safety requirements. This can be carried out in one of two ways, as a denotational semantics or as an operational (or reduction) semantics; we choose the first in preference to the second, partly to avoid exponential-growth rewriting in the operational approach. We set up a typing system and prove its soundness for our DSL.Comment: In Proceedings DSL 2011, arXiv:1109.032

Gravitational physics with antimatter

The production of low-energy antimatter provides unique opportunities to search for new physics in an unexplored regime. Testing gravitational interactions with antimatter is one such opportunity. Here a scenario based on Lorentz and CPT violation in the Standard- Model Extension is considered in which anomalous gravitational effects in antimatter could arise.Comment: 5 pages, presented at the International Conference on Exotic Atoms (EXA 2008) and the 9th International Conference on Low Energy Antiproton Physics (LEAP 2008), Vienna, Austria, September 200

Objectively measured short sleep duration and later sleep midpoint in pregnancy are associated with a higher risk of gestational diabetes

BACKGROUND: Experimental and epidemiologic data suggest that among nonpregnant adults, sleep duration may be an important risk factor for chronic disease. Although pregnant women commonly report poor sleep, few studies objectively evaluated the quality of sleep in pregnancy or explored the relationship between sleep disturbances and maternal and perinatal outcomes. OBJECTIVE: Our objective was to examine the relationship between objectively assessed sleep duration, timing, and continuity (measured via wrist actigraphy) and maternal cardiovascular and metabolic morbidity specific to pregnancy. STUDY DESIGN: This was a prospective cohort study of nulliparous women. Women were recruited between 16 0/7 and 21 6/7 weeks' gestation. They were asked to wear a wrist actigraphy monitor and complete a daily sleep log for a period of 7 consecutive days. The primary sleep exposure variables were the averages of the following over the total valid nights (minimum 5, maximum 7 nights): short sleep duration during the primary sleep period (5 am), and top quartile of minutes of wake time after sleep onset and sleep fragmentation index. The primary outcomes of interest were a composite of hypertensive disorders of pregnancy (mild, severe, or superimposed preeclampsia; eclampsia; or antepartum gestational hypertension) and gestational diabetes mellitus. We used χ2 tests to assess associations between sleep variables and categorical baseline characteristics. Crude odds ratios and 95% confidence intervals were estimated from univariate logistic regression models to characterize the magnitude of the relationship between sleep characteristics and hypertensive disorders of pregnancy and gestational diabetes. For associations significant in univariate analysis, multiple logistic regression was used to explore further the association of sleep characteristics with pregnancy outcomes. RESULTS: In all, 901 eligible women consented to participate; 782 submitted valid actigraphy studies. Short sleep duration and a later sleep midpoint were associated with an increased risk of gestational diabetes (odds ratio, 2.24; 95% confidence interval, 1.11-4.53; and odds ratio, 2.58; 95% confidence interval, 1.24-5.36, respectively) but not of hypertensive disorders. A model with both sleep duration and sleep midpoint as well as their interaction term revealed that while there was no significant interaction between these exposures, the main effects of both short sleep duration and later sleep midpoint with gestational diabetes remained significant (adjusted odds ratio, 2.06; 95% confidence interval, 1.01-4.19; and adjusted odds ratio, 2.37; 95% confidence interval, 1.13-4.97, respectively). Additionally, after adjusting separately for age, body mass index, and race/ethnicity, both short sleep duration and later sleep midpoint remained associated with gestational diabetes. No associations were demonstrated between the sleep quality measures (wake after sleep onset, sleep fragmentation) and hypertensive disorders or gestational diabetes. CONCLUSION: Our results demonstrate a relationship between short sleep duration and later sleep midpoint with gestational diabetes. Our data suggest independent contributions of these 2 sleep characteristics to the risk for gestational diabetes in nulliparous women