Lysosomal acid lipase-driven cholesterol ester hydrolysis promotes cancer aggressiveness

Aberrant cholesterol ester (CE) accumulation in various cancer is well documented, while abrogation of cholesterol esterification can effectively suppress cancer aggressiveness. However, the exact role of CE in cancer progression remains elusive. To understand the function of CE in cancer development, we sought to identify the key regulator and functional products of CE hydrolysis and elucidate its specific function and mechanisms in cancer. Here, we found that Lysosomal Acid Lipase (LIPA) was upregulated and correlated with unfavorable prognosis in many cancers by bioinformatics analysis. Combining with experiment results, we found that CE hydrolysis is mediated by LIPA in cancer cells. The inhibition of LIPA significantly increased lipid accumulation into lipid droplets (LDs), which contain a high level of CE and the most variable CE was cholesteryl arachidonate. Besides, both genetic and pharmacologic suppression of LIPA impaired cell migration, instead of proliferation. According to the prediction bioinformatics analysis using TCGA dataset, epithelial-mesenchymal transition (EMT), PI3K-AKT, and NF-kB signaling pathways might be involved in LIPA-driven cancer progression. Finally, we further validated that knockdown of LIPA impaired the expression levels of EMT markers. Collectively, LIPA-driven CE hydrolysis is an important metabolic process in cancer progression by contributing to cancer aggressiveness

NSNO: Neumann Series Neural Operator for Solving Helmholtz Equations in Inhomogeneous Medium

In this paper, we propose Neumann Series Neural Operator (NSNO) to learn the solution operator of Helmholtz equation from inhomogeneity coefficients and source terms to solutions. Helmholtz equation is a crucial partial differential equation (PDE) with applications in various scientific and engineering fields. However, efficient solver of Helmholtz equation is still a big challenge especially in the case of high wavenumber. Recently, deep learning has shown great potential in solving PDEs especially in learning solution operators. Inspired by Neumann series in Helmholtz equation, we design a novel network architecture in which U-Net is embedded inside to capture the multiscale feature. Extensive experiments show that the proposed NSNO significantly outperforms the state-of-the-art FNO with at least 60\% lower relative $L^2$-error, especially in the large wavenumber case, and has 50\% lower computational cost and less data requirement. Moreover, NSNO can be used as the surrogate model in inverse scattering problems. Numerical tests show that NSNO is able to give comparable results with traditional finite difference forward solver while the computational cost is reduced tremendously

Bond-Selective Intensity Diffraction Tomography

Recovering molecular information remains a grand challenge in the widely used holographic and computational imaging technologies. To address this challenge, we developed a computational mid-infrared photothermal microscope, termed Bond-selective Intensity Diffraction Tomography (BS-IDT). Based on a low-cost brightfield microscope with an add-on pulsed light source, BS-IDT recovers both infrared spectra and bond-selective 3D refractive index maps from intensity-only measurements. High-fidelity infrared fingerprint spectra extraction is validated. Volumetric chemical imaging of biological cells is demonstrated at a speed of ~20 seconds per volume, with a lateral and axial resolution of ~350 nm and ~1.1 micron, respectively. BS-IDT's application potential is investigated by chemically quantifying lipids stored in cancer cells and volumetric chemical imaging on Caenorhabditis elegans with a large field of view (~100 micron X 100 micron)

MicroRNA regulation of endothelial homeostasis and commitment—implications for vascular regeneration strategies using stem cell therapies

Human embryonic (hESC) and induced pluripotent (hiPSC) stem cells have broad therapeutic potential in the treatment of a range of diseases, including those of the vascular system. Both hESCs and hiPSCs have the capacity for indefinite self-renewal, in addition to their ability to differentiate into any adult cell type. These cells could provide a potentially unlimited source of cells for transplantation and, therefore, provide novel treatments, e.g. in the production of endothelial cells for vascular regeneration. MicroRNAs are short, noncoding RNAs that act posttranscriptionally to control gene expression and thereby exert influence over a wide range of cellular processes, including maintenance of pluripotency and differentiation. Expression patterns of these small RNAs are tissue specific, and changes in microRNA levels have often been associated with disease states in humans, including vascular pathologies. Here, we review the roles of microRNAs in endothelial cell function and vascular disease, as well as their role in the differentiation of pluripotent stem cells to the vascular endothelial lineage. Furthermore, we discuss the therapeutic potential of stem cells and how knowledge and manipulation of microRNAs in stem cells may enhance their capacity for vascular regeneration

Methyl 7-meth­oxy-9-oxo-9H-xanthene-2-carboxyl­ate

The crystal structure of the title compound, C16H12O5, is stabilized by C—H⋯O hydrogen bonds and C=O⋯π inter­actions; π–π inter­actions are also present. With respective average deviations from planarity of 0.003 (2) and 0.002 (1) Å, the xanthone and ester fragments are oriented at an angle of 2.8 (2)° with respect to each other. The mean planes of the xanthone skeleton lie either parallel to each other or are inclined at an angle of 85.5 (2)° in the crystal structure

Proteomic Analysis of Rhesus Macaque Brain Explants Treated With Borrelia burgdorferi Identifies Host GAP-43 as a Potential Factor Associated With Lyme Neuroborreliosis

BackgroundLyme neuroborreliosis (LNB) is one of the most dangerous manifestations of Lyme disease, but the pathogenesis and inflammatory mechanisms are not fully understood.MethodsCultured explants from the frontal cortex of rhesus monkey brain (n=3) were treated with live Borrelia burgdorferi (Bb) or phosphate-buffered saline (PBS) for 6, 12, and 24 h. Total protein was collected for sequencing and bioinformatics analysis. In addition, changes in protein expression in the explants over time following Bb treatment were screened.ResultsWe identified 1237 differentially expressed proteins (DEPs; fold change ≥1.5 or ≤0.67, P-value ≤0.05). One of these, growth-associated protein 43 (GAP-43), was highly expressed at all time points in the explants. The results of the protein-protein interaction network analysis of DEPs suggested that GAP-43 plays a role in the neuroinflammation associated with LNB. In HMC3 cells incubated with live Bb or PBS for 6, 12, and 24 h, real-time PCR and western blot analyses confirmed the increase of GAP-43 mRNA and protein, respectively.ConclusionsElevated GAP-43 expression is a potential marker for LNB that may be useful for diagnosis or treatment

Transsternal Maximal Thymectomy is Effective for Extirpation of Cervical Ectopic Thymic Tissue in the Treatment of Myasthenia Gravis

PURPOSE: Extensive extirpation of cervico-mediastinal adipose tissue increases the chance of removing ectopic thymic tissues, thus potentially improving the prognosis of myasthenia gravis after thymectomy. We sought to increase efficacy and safety of transsternal maximal thymectomy (TSMT). MATERIALS AND METHODS: Twenty four patients who underwent TSMT from July 2006 to June 2007 were retrospectively reviewed and compared with 73 patients who underwent transsternal extended thymectomy (TSET) from January 2004 to May 2006. Ectopic thymic tissue in additionally excised cervicomediastinal fat tissue was examined histologically. RESULTS: In TSMT group, operation time, amount of cumulative drainage and duration of drainage were significantly higher than TSET group. However, the difference in hemoglobin count, amount of transfusion, duration of intensive care, postoperative hospital stay, and complication rates were not statistically different. There was no operative mortality in either group. Ectopic thymic tissue was found in 50% of patients. All patients had ectopic thymic tissues in the cervical area. Two patients had additional ectopic tissue in the aortopulmonary window, and 1 patient had ectopic tissue at posterior of the left bracheocephalic vein and lateral of the right phrenic nerve. CONCLUSION: TSMT is more effective in the extirpation of ectopic thymic tissues than TSET without significant impairment of safety, especially in the cervical area.ope

Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia

Caveolae regulate many cardiovascular functions and thus could be of interest in relation to pre-eclampsia, a pregnancy specific disorder characterised by hypertension and proteinuria. We examined placental mRNA and protein expression/localisation of the caveolae components Caveolin 1-3, Cavin 1-4 as well as eNOS/ iNOS in normotensive control (n=24) and pre-eclamptic pregnancies (n=19). Placental mRNA expression of caveolin-1, cavin 1-3, was lower and eNOS expression was increased in pre-eclampsia (P<0.05 for all). Additionally Caveolin-1 protein expression was also reduced in pre-eclampsia (P=0.007); this could be an adaptive response in pre-eclampsia, possibly to attenuate the oxidative stress/inflammation

Expression of NAD(P)H Oxidase Subunits and Their Contribution to Cardiovascular Damage in Aldosterone/Salt-Induced Hypertensive Rat

NAD(P)H oxidase plays an important role in hypertension and its complication in aldosterone-salt rat. We questioned whether NAD(P)H oxidase subunit expression and activity are modulated by aldosterone and whether this is associated with target-organ damage. Rats were infused with aldosterone (0.75 µg/hr/day) for 6 weeks and were given 0.9% NaCl±losartan (30 mg/kg/day), spironolactone (200 mg/kg/day), and apocynin (1.5 mM/L). Aldosterone-salt hypertension was prevented completely by spironolactone and modestly by losartan and apocynin. Aldosterone increased aortic NAD(P)H oxidase activity by 34% and spironolactone and losartan inhibited the activity. Aortic expression of the subunits p47phox, gp91phox, and p22phox increased in aldosterone-infused rats by 5.5, 4.7, and 3.2-fold, respectively, which was decreased completely by spironolactone and partially by losartan and apocynin. Therefore, the increased expression of NAD(P)H oxidase may contribute to cardiovascular damage in aldosterone-salt hypertension through the increased expression of each subunit

Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function

Supplementary information accompanies this paper at http://www.nature.com/srepCopper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.SS is a British Heart Foundation (BHF) PhD student; GDA is BHF Chair in cardiac surgery and NIHR Senior Investigator; CE is a BHF Senior Research Fellow. Sources of Funding: This research was supported by NIH R01 HL070187 (T.F.), Department of Veterans Affairs Merit Review grant 1I01BX001232 (T.F.), R01HL116976 (T.F., M.U.-F.), NIH R01 HL077524 and HL077524-S1, R21HL112293 (to M.U.-F.), Ruth L. Kirschstein-National Service Research Award (Kirschstein-NRSA) T32 Training Grant (to G-F.C.), AHA Post-doctoral Fellowship 09POST2250151 (to N.U.), and 11POST5740006 (to V.S.).Peer-reviewedPublisher Versio