Brain homeostasis : VEGF receptor 1 and 2 ; two unequal brothers in mind

Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis

From 3D hydrodynamic simulations of common-envelope interaction to gravitational-wave mergers

Modeling the evolution of progenitors of gravitational-wave merger events in binary stars faces two major uncertainties: the common-envelope phase and supernova kicks. These two processes are critical for the final orbital configuration of double compact-object systems with neutron stars and black holes. Predictive one-dimensional models of common-envelope interaction are lacking and multidimensional simulations are challenged by the vast range of relevant spatial and temporal scales. Here, we present three-dimensional hydrodynamic simulations of the common-envelope interaction of an initially $10\,M_{\odot}$ red supergiant primary star with a black-hole and a neutron-star companion. We show that the high-mass regime is accessible to full ab-initio simulations. Nearly complete envelope ejection is reached assuming that all recombination energy still available at the end of our simulation continues to help unbinding the envelope. In contrast to previous assumptions, we find that the dynamical plunge-in of both companions terminates at orbital separations too wide for gravitational waves to merge the systems in a Hubble time. We discuss the further evolution of the system based on analytical estimates. A subsequent mass-transfer episode from the remaining $3\,M_{\odot}$ core of the supergiant to the compact companion does not shrink the orbit sufficiently either. A neutron-star--neutron-star and neutron-star--black-hole merger is still expected for a fraction of the systems if the supernova kick aligns favorably with the orbital motion. For double neutron star (neutron-star--black-hole) systems we estimate mergers in about $9 \%$ ($1 \%$) of cases while about $77 \%$ ($94 \%$) of binaries are disrupted, i.e., supernova kicks actually enable gravitational-wave mergers in our cases; however, we expect a reduction in predicted gravitational-wave merger events. (abbr.)Comment: 16 pages, 11 figures, accepted by A&

Thermal Emission from Warm Dust in the Most Distant Quasars

We report new continuum observations of fourteen z~6 quasars at 250 GHz and fourteen quasars at 1.4 GHz. We summarize all recent millimeter and radio observations of the sample of the thirty-three quasars known with 5.71<=z<=6.43, and present a study of the rest frame far-infrared (FIR) properties of this sample. These quasars were observed with the Max Plank Millimeter Bolometer Array (MAMBO) at 250 GHz with mJy sensitivity, and 30% of them were detected. We also recover the average 250 GHz flux density of the MAMBO undetected sources at 4 sigma, by stacking the on-source measurements. The derived mean radio-to-UV spectral energy distributions (SEDs) of the full sample and the 250 GHz non-detections show no significant difference from that of lower-redshift optical quasars. Obvious FIR excesses are seen in the individual SEDs of the strong 250 GHz detections, with FIR-to-radio emission ratios consistent with that of typical star forming galaxies. Most 250 GHz-detected sources follow the L_{FIR}--L_{bol} relationship derived from a sample of local IR luminous quasars (L_{IR}>10^{12}L_{\odot}), while the average L_{FIR}/L_{bol} ratio of the non-detections is consistent with that of the optically-selected PG quasars. The MAMBO detections also tend to have weaker Ly\alpha emission than the non-detected sources. We discuss possible FIR dust heating sources, and critically assess the possibility of active star formation in the host galaxies of the z~6 quasars. The average star formation rate of the MAMBO non-detections is likely to be less than a few hundred M_{\odot} yr^{-1}, but in the strong detections, the host galaxy star formation is probably at a rate of \gtrsim10^{3} M_{\odot} yr^{-1}, which dominates the FIR dust heating.Comment: 32 pages with 6 figures; ApJ, in press; Added references; Corrected typo

Gravitational wave emission from dynamical stellar interactions

We are witnessing the dawn of gravitational wave (GW) astronomy. With currently available detectors, observations are restricted to GW frequencies in the range between ${\sim} 10\,\mathrm{Hz}$ and $10\,\mathrm{kHz}$, which covers the signals from mergers of compact objects. The launch of the space observatory LISA will open up a new frequency band for the detection of stellar interactions at lower frequencies. In this work, we predict the shape and strength of the GW signals associated with common-envelope interaction and merger events in binary stars, and we discuss their detectability. Previous studies estimated these characteristics based on semi-analytical models. In contrast, we used detailed three-dimensional magnetohydrodynamic simulations to compute the GW signals. We show that for the studied models, the dynamical phase of common-envelope events and mergers between main-sequence stars lies outside of the detectability band of the LISA mission. We find, however, that the final stages of common-envelope interactions leading to mergers of the stellar cores fall into the frequency band in which the sensitivity of LISA peaks, making them promising candidates for detection. These detections can constrain the enigmatic common-envelope dynamics. Furthermore, future decihertz observatories such as DECIGO or BBO would also be able to observe this final stage and the post-merger signal, through which we might be able to detect the formation of Thorne-\.Zytkow objects.Comment: Accepted for publication in A&A, 12 pages, 8 figure

SIRT1 regulates Mxd1 during malignant melanoma progression

In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, gamma H2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.FAPESP [2011/0166-38, 2011/12306-1, 2014/13663-0, 2015/07925-5, 2016/06488-3]DAAD [PKZ A/12/79134]FAPESP/BAYLAT [2012/51300-7]Univ Fed Sao Paulo UNIFESP, Dept Pharmacol, Ontogeny & Epigenet Lab, Sao Paulo, SP, BrazilUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP, BrazilFriedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Expt Tumorpathol, Erlangen, GermanyFriedrich Alexander Univ Erlangen Nurnberg FAU, Dept Pediat & Adolescent Med, Erlangen, GermanyUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Ontogeny & Epigenet Lab, Sao Paulo, SP, BrazilFAPESP [2011/0166-38, 2011/12306-1, 2014/13663-0, 2015/07925-5, 2016/06488-3]DAAD [PKZ A/12/79134]FAPESP/BAYLAT [2012/51300-7]Web of Scienc

High-Redshift Quasars Found in Sloan Digital Sky Survey Commissioning Data II: The Spring Equatorial Stripe

This is the second paper in a series aimed at finding high-redshift quasars from five-color (u'g'r'i'z') imaging data taken along the Celestial Equator by the Sloan Digital Sky Survey (SDSS) during its commissioning phase. In this paper, we present 22 high-redshift quasars (z>3.6) discovered from ~250 deg^2 of data in the spring Equatorial Stripe, plus photometry for two previously known high-redshift quasars in the same region of sky. Our success rate of identifying high-redshift quasars is 68%. Five of the newly discovered quasars have redshifts higher than 4.6 (z=4.62, 4.69, 4.70, 4.92 and 5.03). All the quasars have i* < 20.2 with absolute magnitude -28.8 < M_B < -26.1 (h=0.5, q_0=0.5). Several of the quasars show unusual emission and absorption features in their spectra, including an object at z=4.62 without detectable emission lines, and a Broad Absorption Line (BAL) quasar at z=4.92.Comment: 28 pages, AJ in press (Jan 2000), final version with minor changes; high resolution finding charts available at http://www.astro.princeton.edu/~fan/paper/qso2.htm

Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer

Background Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ. Methods Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability/apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV/PI staining were employed. Interactions between PAK1 and ERK1/2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ´s effects on PAK1 scaffold function. Results Of the 104 proteins identified, 50 were upregulated ≥2 fold by TQ and included molecules in the AKT-MEK-ERK1/2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAKThr212 followed by late increase in pPAKThr423. TQ induced an increase of pERK1/2 and triggered the early formation of an ERK1/2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAKThr423 and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAKThr423, finally inhibiting MEK-ERK1/2 signaling and disrupting its prosurvival function. pERK1/2 loss was also validated in vivo. Conclusions Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. Because TQ affects the central RAF/MEK/ERK1/2 pathway, the combination of TQ with targeted therapies is worth considering for future anticancer treatments

Twist angle dependent interlayer transfer of valley polarization from excitons to free charge carriers in WSe2/MoSe2 heterobilayers

Transition metal dichalcogenides (TMDs) have attracted much attention in the fields of valley- and spintronics due to their property of forming valley-polarized excitons when illuminated by circularly polarized light. In TMD-heterostructures it was shown that these electron-hole pairs can scatter into valley-polarized interlayer exciton states, which exhibit long lifetimes and a twist-angle dependence. However, the question how to create a valley polarization of free charge carriers in these heterostructures after a valley selective optical excitation is unexplored, despite its relevance for opto-electronic devices. Here, we identify an interlayer transfer mechanism in twisted WSe2/MoSe2 heterobilayers that transfers the valley polarization from excitons in WSe2 to free charge carriers in MoSe2 with valley lifetimes of up to 12 ns. This mechanism is most efficient at large twist angles, whereas the valley lifetimes of free charge carriers are surprisingly short for small twist angles, despite the occurrence of interlayer excitons