Apolipoprotein D in Lipid Metabolism and Its Functional Implication in Atherosclerosis and Aging

Dyslipidemia is characterized by increased triglyceride and low-density lipoprotein (LDL) levels, and decreased high-density lipoprotein (HDL) levels. Such an atherogenic lipid profile often predisposes an at risk individual to coronary artery disease with incompletely understood mechanisms. Apolipoprotein D (apoD) is an atypical apolipoprotein. Unlike canonical apolipoproteins that are produced mainly in liver and intestine, apoD is expressed widely in mammalian tissues. ApoD does not share significant degrees of homology in amino acid sequence with other apolipoproteins. Instead, apoD is structurally similar to lipocalins, a diverse family of lipid-binding proteins that are responsible for transporting lipids and other small hydrophobic molecules for metabolism. Plasma ApoD is present mainly in HDL and to a lesser extent in low density lipoproteins (LDL) and very low-density lipoproteins (VLDL). Genetic variants of apoD are associated with abnormal lipid metabolism and increased risk of developing metabolic syndrome. Increased apoD deposition is detectable in atherosclerotic lesions of humans with established cardiovascular disease as well as mice with premature atherosclerosis. Moreover, apoD is associated with anti-oxidation and anti-stress activities, contributing to lifespan expansion in fruit flies. Elderly subjects and patients with Alzheimer exhibit markedly elevated apoD production in the brain. Thus, apoD is emerged as a significant player in lipid metabolism and aging. Here we focus our review on recent advances toward our understanding of apoD in lipid metabolism and address whether apoD dysregulation contributes to the pathogenesis of dyslipidemia and atherosclerosis. We will also discuss the functional implication of apoD in aging

An Ultracool Star's Candidate Planet

We report here the discovery of the first planet around an ultracool dwarf star. It is also the first extrasolar giant planet (EGP) astrometrically discovered around a main-sequence star. The statistical significance of the detection is shown in two ways. First, there is a 2 x 10^-8 probability that the astrometric motion fits a parallax-and-proper-motion-only model. Second, periodogram analysis shows a false alarm probability of 3 x 10^-5 that the discovered period is randomly generated. The planetary mass is M2 = 6.4 (+2.6,-3.1) Jupiter-masses (MJ), and the orbital period is P = 0.744 (+0.013,-0.008) yr in the most likely model. In less likely models, companion masses that are higher than the 13 MJ planetary mass limit are ruled out by past radial velocity measurements unless the system radial velocity is more than twice the current upper limits and the near-periastron orbital phase was never observed. This new planetary system is remarkable, in part, because its star, VB 10, is near the lower mass limit for a star. Our astrometric observations provide a dynamical mass measurement and will in time allow us to confront the theoretical models of formation and evolution of such systems and their members. We thus add to the diversity of planetary systems and to the small number of known M-dwarf planets. Planets such as VB 10b could be the most numerous type of planets because M stars comprise >70% of all stars. To date they have remained hidden since the dominant radial-velocity (RV) planet-discovery technique is relatively insensitive to these dim, red systems.Comment: 1 30 page pdf file, 9 figures, accepted for publication in The Astrophysical Journa

A Mechanistic Study of Carbonic Anhydrase Enhanced Calcite Dissolution

Carbonic anhydrase (CA) has been shown to promote calcite dissolution (Liu, 2001, https://doi.org/10.1111/j.1755-6724.2001.tb00531.x; Subhas et al., 2017, https://doi.org/10.1073/pnas.1703604114), and understanding the catalytic mechanism will facilitate our understanding of the oceanic alkalinity cycle. We use atomic force microscopy (AFM) to directly observe calcite dissolution in CA‐bearing solution. CA is found to etch the calcite surface only when in extreme proximity (~1 nm) to the mineral. Subsequently, the CA‐induced etch pits create step edges that serve as active dissolution sites. The possible catalytic mechanism is through the adsorption of CA on the calcite surface, followed by proton transfer from the CA catalytic center to the calcite surface during CO2 hydration. This study shows that the accessibility of CA to particulate inorganic carbon (PIC) in the ocean is critical in properly estimating oceanic CaCO3 and alkalinity cycles

A Mechanistic Study of Carbonic Anhydrase Enhanced Calcite Dissolution

Carbonic anhydrase (CA) has been shown to promote calcite dissolution (Liu, 2001, https://doi.org/10.1111/j.1755-6724.2001.tb00531.x; Subhas et al., 2017, https://doi.org/10.1073/pnas.1703604114), and understanding the catalytic mechanism will facilitate our understanding of the oceanic alkalinity cycle. We use atomic force microscopy (AFM) to directly observe calcite dissolution in CA‐bearing solution. CA is found to etch the calcite surface only when in extreme proximity (~1 nm) to the mineral. Subsequently, the CA‐induced etch pits create step edges that serve as active dissolution sites. The possible catalytic mechanism is through the adsorption of CA on the calcite surface, followed by proton transfer from the CA catalytic center to the calcite surface during CO2 hydration. This study shows that the accessibility of CA to particulate inorganic carbon (PIC) in the ocean is critical in properly estimating oceanic CaCO3 and alkalinity cycles

Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism.

OBJECTIVE: Brown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa). METHODS: In order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses. RESULTS: A subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor γ coactivator 1 α (Pgc1α) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1 nor Pgc1α mRNA expression. CONCLUSION: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMH(ACh)-Rpa(5-HT) pathway may mediate physiological heat-defense responses to elevated environmental temperature.We thank Althea Cavanaugh and Licheng Wu for technical supports. This work was supported by NIDDK (RO1DK092246) to Y.-H.J. and New York obesity nutrition research center to J.H.J.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2212877815000617

An Atomic Force Microscopy Study of Calcite Dissolution in Seawater

We present the first examination of calcite dissolution in seawater using Atomic Force Microscopy (AFM). We quantify step retreat velocity and etch pit density to compare dissolution in seawater to low ionic strength water, and also to compare calcite dissolution under AFM conditions to those conducted in bulk solution experiments (e.g. Subhas et al., 2015, Dong et al., 2018). Bulk dissolution rates and step retreat velocities are slower at high and mid-saturation state (Ω) values and become comparable to low ionic strength water rates at low Ω. The onset of defect-assisted etch pit formation in seawater is at Ω ∼ 0.85 (defined as Ω_(critical)), higher than in low ionic strength water (Ω ∼ 0.54). There is an abrupt increase in etch pit density (from ∼10⁶ cm⁻² to ∼10⁸ cm⁻²) occurring when Ω falls below 0.7 in seawater, compared to Ω ∼ 0.1 in low ionic strength water, suggesting a transition from defect-assisted dissolution to homogeneous dissolution much closer to equilibrium in seawater. The step retreat velocity (v) does not scale linearly with undersaturation (1-Ω) across an Ω range of 0.4 to 0.9 in seawater, potentially indicating a high order correlation between kink rate and Ω for non-Kossel crystals such as calcite, or surface complexation processes during calcite dissolution in seawater

An Atomic Force Microscopy Study of Calcite Dissolution in Seawater

We present the first examination of calcite dissolution in seawater using Atomic Force Microscopy (AFM). We quantify step retreat velocity and etch pit density to compare dissolution in seawater to low ionic strength water, and also to compare calcite dissolution under AFM conditions to those conducted in bulk solution experiments (e.g. Subhas et al., 2015, Dong et al., 2018). Bulk dissolution rates and step retreat velocities are slower at high and mid-saturation state (Ω) values and become comparable to low ionic strength water rates at low Ω. The onset of defect-assisted etch pit formation in seawater is at Ω ∼ 0.85 (defined as Ω_(critical)), higher than in low ionic strength water (Ω ∼ 0.54). There is an abrupt increase in etch pit density (from ∼10⁶ cm⁻² to ∼10⁸ cm⁻²) occurring when Ω falls below 0.7 in seawater, compared to Ω ∼ 0.1 in low ionic strength water, suggesting a transition from defect-assisted dissolution to homogeneous dissolution much closer to equilibrium in seawater. The step retreat velocity (v) does not scale linearly with undersaturation (1-Ω) across an Ω range of 0.4 to 0.9 in seawater, potentially indicating a high order correlation between kink rate and Ω for non-Kossel crystals such as calcite, or surface complexation processes during calcite dissolution in seawater

52-week efficacy and safety of telbivudine with conditional tenofovir intensification at week 24 in HBeAg-positive chronic Hepatitis B

Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration: ClinicalTrials.gov NCT0065120

Submicron Structures Fabrication and Research

Contains reports on thirteen research projects.Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908)National Science Foundation (Grant ECS82-05701)I.B.M. (PO No. 90305-QPSA-559)U.S. Department of Energy (Contract DE-AC02-82-ER13019)Lawrence Livermore Laboratory (Contract 2069209