The Pericentrion: Identification, Characterization, and Function of a Novel cPKC-Dependent Compartment

Members of the protein kinase C (PKC) superfamily transduce a myriad of transmembrane signals initiated by the formation of sn-l ,2-diacylglycerol (DAG). As the primary physiological agonist for C] domain containing PKC isoenzymes, DAG functions to regulate the spatial and temporal parameters of PKC activity. It is now recognized that cellular DAG levels can vary from minutes to hours and even days. These observations have suggested a division of PKC functions that correlate to the duration of the cellular DAG signal. In their classical role, cPKCs respond acutely to the short-lived (1-2 min) DAG generated at the plasma membrane by the phospholipase C-mediated turnover of phosphoinositides. In contrast, a more persistent DAG signal can be produced through a variety of physiologic as well as pathologic mechanisms, and this DAG has also been proposed to regulate PKC activity. Currently, there are conflicting data on this issue and the specific subcellular localization of cPKC during prolonged DAG is unknown. To investigate the target of PKC during sustained activation, green fluorescent protein (GFP) technology was utilized to monitor the subcellular traffic of various PKC isoenzymes in response to treatment with either DAG-mimicking phorbol esters or DAG-generating agonists (e.g. platelet-derived growth factor). In response to a persistent elevation of DAG, cPKC isoenzymes, α and βII, translocated to the plasma membrane and to a juxtanuclear location in a variety of cell lines examined. Characterization of this compartment revealed that it overlapped/co-localized with a rab II-positive subcompartment of recycling endosomes concentrated around the MTOC/centrosome. The cPKC compartment was distinguish from the rab II-positive compartment by several features including a requirement for kinase and phospholipase D activity, an enrichment of lipid raft components, and the independence of microtubules and temperature for maintenance of the structure. Investigation into the significance of this compartment revealed that cPKC translocation coincided with the attendant sequestration of membrane recycling components. Given these distinctions, it was proposed that this novel cPKC-compartment be named the pericentrion in order to distinguish it from the rab 11 subcompartment of recycling endosomes. Subsequent analysis of a disease model wherein cPKC is maintained in a persistently active state, in this case chronic hyperglycemia associated with type I and type II diabetes, revealed a possible role for cPKC in the dysregulation of GLUT4 trafficking in response to insulin. These studies identify a novel site for cPKC translocation and function in response to a physiological and pathological elevation of DAG

Precise Localization of the Soft Gamma Repeater SGR 1627-41 and the Anomalous X-ray Pulsar AXP 1E1841-045 with Chandra

We present precise localizations of AXP 1E1841-045 and SGR 1627-41 with Chandra. We obtained new infrared observations of SGR 1627-41 and reanalyzed archival observations of AXP 1E1841-045 in order to refine their positions and search for infrared counterparts. A faint source is detected inside the error circle of AXP 1E1841-045. In the case of SGR 1627-41, several sources are located within the error radius of the X-ray position and we discuss the likelihood of one of them being the counterpart. We compare the properties of our candidates to those of other known AXP and SGR counterparts. We find that the counterpart candidates for SGR 1627-41 and SGR 1806-20 would have to be intrinsically much brighter than AXPs to have detectable counterparts with the observational limits currently available for these sources. To confirm the reported counterpart of SGR 1806-20, we obtained new IR observations during the July 2003 burst activation of the source. No brightening of the suggested counterpart is detected, implying that the counterpart of SGR 1806-20 remains yet to be identified.Comment: 29 pages, 4 figures, accepted for publication in Ap

Nontelomeric TRF2-REST Interaction Modulates Neuronal Gene Silencing and Fate of Tumor and Stem Cells

SummaryRemoval of TRF2, a telomere shelterin protein, recapitulates key aspects of telomere attrition including the DNA-damage response and cell-cycle arrest [1]. Distinct from the response of proliferating cells to loss of TRF2 [2, 3], in rodent noncycling cells, TRF2 inhibition promotes differentiation and growth [4, 5]. However, the mechanism that couples telomere gene-silencing features [6–8] to differentiation programs has yet to be elucidated. Here we describe an extratelomeric function of TRF2 in the regulation of neuronal genes mediated by the interaction of TRF2 with repressor element 1-silencing transcription factor (REST), a master repressor of gene networks devoted to neuronal functions [9–12]. TRF2-REST complexes are readily detected by coimmunoprecipitation assays and are localized to aggregated PML-nuclear bodies in undifferentiated pluripotent human NTera2 stem cells. Inhibition of TRF2, either by a dominant-negative mutant or by RNA interference, dissociates TRF2-REST complexes resulting in ubiquitin-proteasomal degradation of REST. Consequentially, REST-targeted neural genes (L1CAM, β3-tubulin, synaptophysin, and others) are derepressed, resulting in acquisition of neuronal phenotypes. Notably, selective damage to telomeres without affecting TRF2 levels causes neither REST degradation nor cell differentiation. Thus, in addition to protecting telomeres, TRF2 possesses a novel role in stabilization of REST thereby controlling neural tumor and stem cell fate

Comparative study of the modulation of fructose/sucrose-induced hepatic steatosis by mixed lipid formulations varying in unsaturated fatty acid content

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. The etiology of NAFLD remains unclear but is thought to relate to increased fatty acid flux within the liver that results in toxic fatty acid metabolite production. One source of increased fatty acid flux is fructose/sucrose-induced hepatic lipogenesis. Current treatment for NAFLD encompasses dietary modifications. However, little scientific evidence exists on which to base many dietary recommendations, especially the intake of different types of carbohydrates and fats. We hypothesized that lipid mixtures of unsaturated fatty acids would inhibit lipogenesis and subsequent hepatic steatosis induced by high carbohydrate diets. The aim of this study was to examine the effects of different complex mixtures of fatty acids upon the development of fructose/sucrose-induced hepatic steatosis. METHODS: C57BL/6 mice were randomized to normocaloric chow-based diets that varied in the type of carbohydrate (starch, sucrose, fructose). Animals in each carbohydrate group were further randomized to diets that varied in lipid type (no additional lipid, soybean oil, fish oil, olive/soybean oil, macadamia nut oil). These oils were chosen based upon their content of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, or omega-7 monounsaturated fatty acids. Fatty acid flux in the liver was determine by assessing hepatic lipid content (steatosis). We also assessed fatty acid levels in the plasma and liver of the animals, hepatic lipogenesis activity, hepatic stearoyl-CoA-1 desaturase activity, and hepatic elongase activity. RESULTS: Animals consumed similar amounts of the diets and maintained normal body weights throughout the study. Both sucrose and fructose induced hepatic lipogenesis and steatosis, with fructose being more potent. All mixed lipids similarly inhibited steatosis, limiting lipid content to levels found in the control (starch) animals. Lipogenesis and stearoyl-CoA-1 desaturase activity were increased in the sucrose and fructose groups. Levels of these enzymatic processes remained at baseline in all of the lipid groups. CONCLUSION: This is the first study to compare various complex lipid mixtures, based upon dietary oils with different types of long-chain fatty acids, upon development of sucrose/fructose-induced steatosis. Both carbohydrate source and lipid content appear important for the modulation of steatosis. Moderate intake of complex lipids with high unsaturated to saturated fatty acid ratios inhibited both lipogenesis and steatosis

Characterizing the Cool KOIs. VI. H- and K-band Spectra of Kepler M Dwarf Planet-Candidate Hosts

We present H- and K-band spectra for late-type Kepler Objects of Interest (the "Cool KOIs"): low-mass stars with transiting-planet candidates discovered by NASA's Kepler Mission that are listed on the NASA Exoplanet Archive. We acquired spectra of 103 Cool KOIs and used the indices and calibrations of Rojas-Ayala et al. to determine their spectral types, stellar effective temperatures and metallicities, significantly augmenting previously published values. We interpolate our measured effective temperatures and metallicities onto evolutionary isochrones to determine stellar masses, radii, luminosities and distances, assuming the stars have settled onto the main-sequence. As a choice of isochrones, we use a new suite of Dartmouth predictions that reliably include mid-to-late M dwarf stars. We identify five M4V stars: KOI-961 (confirmed as Kepler 42), KOI-2704, KOI-2842, KOI-4290, and the secondary component to visual binary KOI-1725, which we call KOI-1725 B. We also identify a peculiar star, KOI-3497, which has a Na and Ca lines consistent with a dwarf star but CO lines consistent with a giant. Visible-wavelength adaptive optics imaging reveals two objects within a 1 arc second diameter; however, the objects' colors are peculiar. The spectra and properties presented in this paper serve as a resource for prioritizing follow-up observations and planet validation efforts for the Cool KOIs, and are all available for download online using the "data behind the figure" feature.Comment: Accepted for publication in the Astrophysical Journal Supplement Series (ApJS). Data and table are available in the sourc

Understanding the Effect of Chiral NN Parametrization on Nuclear Shapes From an Ab Initio Perspective

The ab initio symmetry-adapted no-core shell model naturally describes nuclear deformation and collectivity, and is therefore well-suited to studying the dynamics and coexistence of shapes in atomic nuclei. For the first time, we analyze how these features in low-lying states of 6Li and 12C are impacted by the underlying realistic nucleon-nucleon interaction. We find that the interaction parametrization has a notable but limited effect on collective shapes in the lowest 6Li and 12C states, while collective structures in the excited 2+ state of 12C are significantly more sensitive to the interaction parameters and exhibits emergent shape coexistence.Comment: 4 pages + references, 3 figures, CGS17 (2023) conference proceedings contributio

Genetic and environmental pathways to complex diseases

<p>Abstract</p> <p>Background</p> <p>Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches.</p> <p>Results</p> <p>Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes.</p> <p>Conclusion</p> <p>Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.</p

Galaxy Zoo: dust lane early-type galaxies are tracers of recent, gas-rich minor mergers

We present the second of two papers concerning the origin and evolution of local early-type galaxies exhibiting dust features. We use optical and radio data to examine the nature of active galactic nucleus (AGN) activity in these objects, and compare these with a carefully constructed control sample. We find that dust lane early-type galaxies are much more likely to host emission-line AGN than the control sample galaxies. Moreover, there is a strong correlation between radio and emission-line AGN activity in dust lane early-types, but not the control sample. Dust lane early-type galaxies show the same distribution of AGN properties in rich and poor environments, suggesting a similar triggering mechanism. By contrast, this is not the case for early-types with no dust features. These findings strongly suggest that dust lane early-type galaxies are starburst systems formed in gas-rich mergers. Further evidence in support of this scenario is provided by enhanced star formation and black hole accretion rates in these objects. Dust lane early-types therefore represent an evolutionary stage between starbursting and quiescent galaxies. In these objects, the AGN has already been triggered but has not as yet completely destroyed the gas reservoir required for star formation.Comment: 11 pages, 18 figures, 4 tables, MNRAS (Accepted for publication- 2012 January 19

Spectroscopy of High-Redshift Supernovae from the ESSENCE Project: The First Two Years

We present the results of spectroscopic observations of targets discovered during the first two years of the ESSENCE project. The goal of ESSENCE is to use a sample of ~200 Type Ia supernovae (SNe Ia) at moderate redshifts (0.2 < z < 0.8) to place constraints on the equation of state of the Universe. Spectroscopy not only provides the redshifts of the objects, but also confirms that some of the discoveries are indeed SNe Ia. This confirmation is critical to the project, as techniques developed to determine luminosity distances to SNe Ia depend upon the knowledge that the objects at high redshift are the same as the ones at low redshift. We describe the methods of target selection and prioritization, the telescopes and detectors, and the software used to identify objects. The redshifts deduced from spectral matching of high-redshift SNe Ia with low-redshift SNe Ia are consistent with those determined from host-galaxy spectra. We show that the high-redshift SNe Ia match well with low-redshift templates. We include all spectra obtained by the ESSENCE project, including 52 SNe Ia, 5 core-collapse SNe, 12 active galactic nuclei, 19 galaxies, 4 possibly variable stars, and 16 objects with uncertain identifications.Comment: 38 pages, 9 figures (many with multiple parts), submitted to A

Role of tyrosine M210 in the initial charge separation of reaction centers of Rhodobacter sphaeroides

Femtosecond spectroscopy was used in combination with site-directed mutagenesis to study the influence of tyrosine M210 (YM210) on the primary electron transfer in the reaction center of Rhodobacter sphaeroides. The exchange of YM210 to phenylalanine caused the time constant of primary electron transfer to increase from 3.5 f 0.4 ps to 16 f 6 ps while the exchange to leucine increased the time constant even more to 22 f 8 ps. The results suggest that tyrosine M210 is important for the fast rate of the primary electron transfer