A novel family of evolutionally conserved neuronal guidance cues, including ligands (i.e., Slit, netrin, epherin, and semaphorin) and their corresponding receptors (i.e., Robo, DCC/Unc5, Eph and plexin/ neuropilin), has been identified to play a crucial role in axon pathfinding and branching as well as neuronal cell migration. The presence of commonalities in both neural and vascular developments has led to some exciting discoveries recently, which have extended the functions of these systems to vascular formation (vasculogenesis) and development (angiogenesis). Some of these ligands and receptors have been found to be expressed in the vasculature and surrounding tissues in physiological and pathological conditions. It is postulated that they regulate the formation and integrity of blood vessels. In particular, it has been shown that the Slit/Robo pair plays a novel role in angiogenesis during tumorigenesis and vascular formation during embryogenesis. Herein we summarize briefly the characteristics of this family of neuronal guidance molecules and discuss the extra-neural expression and function of the Slit/Robo pair in angiogenesis in physiological and pathological settings. We report expression of Robo1 protein in capillary endothelium and co-expression of Slit2 and Robo1 proteins in syncytiotrophoblast in healthy term human placental villi. These cellular expression patterns implicate that the Slit/Robo signaling plays an autocrine and/or paracrine role in angiogenesis and trophoblast functions. We also speculate a possible role of this system in pathophysiological placental angiogenesis.

In a quasi-particle model of QCD matter at finite temperature with thermal masses for quarks and gluons from hard thermal loops, the equation of state (EOS) can be described by an effective temperature dependence of the strong coupling g(T). Assuming the same effective coupling between the exchanged gluon and thermal partons, the EOS can also be related to parton energy loss. Based on the quasi-particle linear Boltzmann transport (QLBT) model coupled to a (3+1)-dimensional viscous hydrodynamic model of the quark-gluon plasma (QGP) evolution and a hybrid fragmentation-coalescence model for heavy quark hadronization, we perform a Bayesian analysis of the experimental data on D meson suppression RAA and anisotropy v2 at RHIC and the LHC. We achieve a simultaneous constraint on the QGP EOS and the heavy quark transport coefficient, both consistent with the lattice QCD results.

To study the bulk properties of quark-gluon plasma produced at beam-energy scan (BES) energies at the Relativistic Heavy Ion Collider (RHIC), we extend the (3+1)-dimensional viscous hydrodynamics clvisc to include net baryon number conservation and Israel-Stewart-like equations for baryon diffusion with the neos-bqs equation of state, fluctuating initial conditions from the Monte Carlo Glauber model and the afterburner smash. This integrated framework is shown to provide a good description of identified particle spectra, mean transverse momenta, and anisotropic flows for different centralities and over a wide range of collision energies (7.7-62.4 GeV). It is found that the mean momenta of identified particles and anisotropic flows increase mildly with the collision energy due to larger radial flow. We further compute the multiple-particle cumulant ratio v2{4}/v2{2} of elliptic flow across BES energies, and find that the relative fluctuations of elliptic flow are insensitive to the collision energy, consistent with the preliminary STAR data. Our model provides a benchmark for understanding the RHIC-BES data and studying the critical properties and phase structure of hot and dense QCD matter.

We study the longitudinal decorrelations of elliptic, triangular and quadrangular flows in heavy-ion collisions at the LHC and RHIC energies. The event-by-event CLVisc (3+1)-dimensional hydrodynamics model, combined with the fully fluctuating AMPT initial conditions, is utilized to simulate the space-time evolution of the strongly-coupled quark-gluon plasma. Detailed analysis is performed for the longitudinal decorrelations of flow vectors, flow magnitudes and flow orientations. We find strong correlations between final-state longitudinal decorrelations of anisotropic flows and initial-state longitudinal structures and collision geometry: while the decorrelation of elliptic flow shows a non- monotonic centrality dependence due to initial elliptic geometry, typically the longitudinal flow decorrelations are larger in lower energy and less central collisions where the mean lengths of the string structure are shorter in the initial states.

The CLVisc (3+1)D viscous hydrodynamic model is extended to include the equation of net baryon conservation and the Israel-Stewart-like equations for dissipative baryon current. Using the NEOSB equation of state, we simulate the dynamical evolution and collectivity of the quark-gluon plasma with finite chemical potential, assuming smooth energy density and net baryon density distributions at the initial proper time. Numerical results are shown for the impact of net-baryon dissipation on particle yields and pT spectra in heavy-ion collisions at beam energy scan energies.

Preeclampsia is characterized by dysfunctional endothelium and impaired angiogenesis. Recent studies suggest that the neuronal guidance SLIT/ROBO system regulates tumor angiogenesis. This study investigated if SLIT and ROBO are differentially expressed in healthy term and preeclamptic placentas and if hypoxia regulates SLIT and ROBO expression in placental trophoblast and endothelial cells. Total RNA and protein were extracted from placental tissues of healthy term (n = 5) and preeclamptic (n = 6) pregnancies and used for SLIT/ROBO expression analyses with reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative-PCR, and immunoblotting. Paraffin-embedded tissues were processed to localize SLIT/ROBO proteins in placental villi by immunohistochemistry. BeWo choriocarcinoma cells and human umbilical vein endothelial cells (HUVEC) were treated with 2% or 10% oxygen or the hypoxia mimetic deferoxamine mesylate (100 μM) to test if hypoxia regulates SLIT/ROBO expression. SLIT2, SLIT3, ROBO1, and ROBO4 mRNA and proteins were detected in the placenta. SLIT2 and ROBO1 proteins localized in the syncytiotrophoblast, and SLIT3, ROBO1, and ROBO4 in capillary endothelium of the placental villi. Levels of ROBO1 and ROBO4 as well as sFLT1 (soluble fms-like tyrosine kinase-1) proteins were significantly greater in preeclamptic placentas compared to normal controls. Hypoxia significantly increased both mRNA and protein levels of SLIT2 in BeWo cells and of SLIT3, ROBO1, and ROBB4 in HUVEC. Thus, trophoblast and endothelial coexpression of SLIT/ROBO suggests an autocrine/paracrine regulatory system for regulating placental function. Differential expression of SLITs and ROBOs in healthy term and preeclamptic placentas and hypoxia regulation of their expressions in placental cells implicate a potential pathophysiological role for this system in preeclampsia.

Currently, no single marker is sensitive and specific enough to be considered a reliable biomarker for prenatal alcohol exposure. To identify a proteomic signature profile for maternal alcohol consumption, we carried out high-throughput proteomics on maternal endothelial caveolae exposed to moderate binge-like alcohol conditions. In these specialized lipid-ordered microdomains that contain a rich assembly of proteins, we demonstrate that moderate binge-like alcohol resulted in a distinctive maternal caveolar proteomic signature with important proteins being dramatically decreased/knocked out in the alcoholic profile. These proteins span from histones and basic structural proteins like α tubulin to proteins involved in trafficking, deubiquitination, cell signaling, and cell-cell adhesion. The profile also suggests an important role for the mother and the uteroplacental compartment in the pathogenesis of fetal alcohol spectrum disorders (FASD). These data demonstrate that the caveolar proteomic signature created by alcohol shows a promising direction for early detection of FASD.

ATP leads to endothelial NO synthase (eNOS)/NO-mediated vasodilation, a process hypothesized to depend on the endothelial caveolar eNOS partitioning and subcellular domain-specific multisite phosphorylation state. We demonstrate herein that, in both the absence and presence of ATP, the uterine artery endothelial caveolae contain specific protein machinery related to subcellular partitioning and act as specific focal "hubs" for NO- and ATP-related proteins. ATP-induced eNOS regulation showed a complex set of multisite posttranslational phosphorylation events that were closely associated with the enzyme's partitioning between caveolar and noncaveolar endothelial subcellular domains. The comprehensive model that we present demonstrates that ATP repartitioned eNOS between the caveolar and noncaveolar subcellular domains; specifically, the stimulatory (PSer635)eNOS was substantially higher in the caveolar pool with subcellular domain-independent increased levels on ATP treatment. The stimulatory (PSer1179)eNOS was not altered by ATP treatment. However, the inhibitory (PThr495)eNOS was regulated predominantly in the caveolar domain with decreased levels on ATP action. In contrast, the agonist-specific (PSer114)eNOS was localized in the noncaveolar pool with increased levels on ATP stimulation. Thus, the endothelial caveolar membrane system plays a pivotal role(s) in ATP-associated subcellular partitioning and possesses the relevant protein machinery for ATP-induced NO regulation. Furthermore, these subcellular domain-specific phosphorylation/dephosphorylation events provide evidence relating to eNOS spatio-temporal dynamics.

Crystallographic preferred orientation (CPO) of post-perovskite (Mg,Fe)SiO₃ (pPv) has been believed to be one potential source of the seismic anisotropic layer at the bottom of the lower mantle (D″ layer). However, the natural CPO of pPv remains ambiguous in the D″ layer. Here we have carried out the deformation experiments of pPv-(Mg_0.75,Fe_0.25)SiO₃ using synchrotron radial X-ray diffraction in a membrane-driven laser-heated diamond anvil cell from 135 GPa and 2,500 K to 154 GPa and 3,000 K. Our results show that the intrinsic texture of pPv-(Mg_0.75,Fe_0.25)SiO₃ should be (001) at realistic P-T conditions of the D″ layer, which can produce a shear wave splitting anisotropy of ∼3.7% with V_SH>V_SV. Considering the combined effect of both pPv and ferropericlase, we suggest that 50% or less of deformation is sufficient to explain the origin of the shear wave anisotropy observed seismically in the D″ layer beneath the circum-Pacific rim.

Covalent adduction of a nitrosyl group to cysteines [S-nitrosylation (S-NO)] is emerging as a key route for nitric oxide (NO) to directly modulate protein functions. Here, we studied the effects of estrogens on endothelial protein S-NO and analyzed the nitrosyl-proteomes by biotin/CyDye switch technique combined with two-dimensional fluorescence difference gel electrophoresis and identified nitrosoproteins by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Estradiol-17beta (E2) rapidly stimulated protein S-NO in human umbilical vein endothelial cells, maximizing within 10- to 30-min post-E2 (10 nm) exposure. E2-BSA also rapidly stimulated protein S-NO. Both E2 and E2-BSA-induced protein S-NO was blocked by ICI 182,780 and N-nitro-l-arginine-methylester. Human umbilical vein endothelial cells expressed estrogen receptor (ER)alpha and ERbeta; both seemed to be required for E2 stimulation of protein S-NO because: 1) neither ERalpha or ERbeta agonist alone, but their combination, stimulated protein S-NO; and 2) either ERalpha or ERbeta antagonist blocked E2-induced protein S-NO. Numerous nitrosoproteins (spots) were observed on two-dimensional fluorescence difference gel. One hundred spots of interest were picked up; 58 were identified and, of which 15 were novel nitrosoproteins, 28 were up-regulated, 11 were decreased, and the rest were unchanged by E2. Pathway analysis suggested that nitrosoproteins are involved in regulating various endothelial functions, including apoptosis, cell structure and metabolism, redox homeostasis, etc. Thus, estrogens stimulate dynamic endothelial protein S-NO via mechanisms linked to specific ERs possibly on the plasma membrane and endogenous NO. These findings signify a critical next step for the understanding of the biological targets of enhanced NO production by estrogens.