Mechanistic target of rapamycin complex 1 signaling links hypoxia to increased igfbp-1 phosphorylation in primary human decidualized endometrial stromal cells

Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion/phosphorylation are poorly understood. Using decidualized primary human endometrial stromal cells (HESCs) from first-trimester placenta, we tested the hypothesis that mTORC1 signaling mechanistically links hypoxia to decidual IGFBP-1 secretion/phosphorylation. Hypoxia inhibited mechanistic target of rapamycin (mTORC1) (p-P70-S6K/Thr389, −47%, p = 0.038; p-4E-BP1/Thr70, −55%, p = 0.012) and increased IGFBP-1 (total, +35%, p = 0.005; phosphorylated, Ser101/+82%, p = 0.018; Ser119/+88%, p = 0.039; Ser 169/+157%, p = 0.019). Targeted parallel reaction monitoring-mass spectrometry (PRM-MS) additionally demonstrated markedly increased dual IGFBP-1 phosphorylation (pSer98+Ser101; pSer169+Ser174) in hypoxia. IGFBP-1 hyperphosphorylation inhibited IGF-1 receptor autophosphorylation/ Tyr1135 (−29%, p = 0.002). Furthermore, silencing of tuberous sclerosis complex 2 (TSC2) activated mTORC1 (p-P70-S6K/Thr389, +68%, p = 0.038; p-4E-BP1/Thr70, +30%, p = 0.002) and reduced total/site-specific IGFBP-1 phosphorylation. Importantly, TSC2 siRNA prevented inhibition of mTORC1 and the increase in secretion/site-specific IGFBP-1 phosphorylation in hypoxia. PRM-MS indicated concomitant changes in protein kinase autophosphorylation (CK2/Tyr182; PKC/Thr497; PKC/Ser657). Overall, mTORC1 signaling mechanistically links hypoxia to IGFBP-1 secretion/phosphorylation in primary HESC, implicating decidual mTORC1 inhibition as a novel mechanism linking uteroplacental hypoxia to fetal growth restriction

Preclinical formulation for the pharmacokinetics and efficacy of GBO-006, a selective polo like kinase 2 (PLK2) inhibitor for the treatment of triple negative breast cancer

GBO-006 was shown to be a highly specific and selective PLK2 inhibitor that promoted mitotic arrest in various cancer cell lines, subsequently resulting in their apoptotic death. Intraperitoneal alternate day dosing of GBO-006 using 100 % DMSO as formulation showed significant tumor regression in xenograft models, demonstrating proof of concept of PLK2 inhibition in vivo. These studies necessitated the development of a suitable and GRAS (generally considered as safe) preformulation for pharmacokinetic and efficacy studies. GBO-006 possesses challenging physicochemical and biopharmaceutical properties like poor solubility in aqueous media, low permeability and a crystalline nature. Different methods like cosolvency, complexation and micellar solubilization were employed to improve the solubility of GBO-006. A strategy of co-solvency is used to solubilize the GBO-006 up to 10 mg/mL. A formulation with 20 % DMSO, 40 % PEG 400, 30 % of 100 mM citrate buffer (pH 3.0) and 10 % solutol displayed clear solution without any visual precipitation of the drug even after 2 weeks of storage. GBO-006 showed moderate clearance in rat and high systemic clearance in mouse and dog. It showed poor oral bioavailability across all species. Intraperitoneal dosing of GBO-006 demonstrated the linear exposure. GBO-006 showed significant inhibition of tumor progression

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism

T Cell Receptor Engagement Leads to the Recruitment of IBP, a Novel Guanine Nucleotide Exchange Factor, to the Immunological Synapse

Reorganization of the actin cytoskeleton is crucial to the formation and function of the immunological synapse. Rho GTPases are critical mediators of cytoskeletal reorganization, and their activity at the synapse is likely to be stringently regulated. Guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins represent one major class of proteins that regulate the activity of Rho GTPases. Here we demonstrate that IBP, a homologue of SWAP-70, is a novel GEF for Rac1 and Cdc42 in T lymphocytes, which is recruited to the immunological synapse upon engagement of the antigen receptor. Mutational analysis supports a model whereby IBP is inactive in unstimulated cells. Upon engagement of the T cell receptor, its GEF activity is enhanced by tyrosine phosphorylation, as well as by binding newly generated phosphatidylinositol 3,4,5-trisphosphate. Although it is known that T cell receptor engagement leads to the recruitment of Vav to the immunological synapse, these findings indicate that other GEFs, such as IBP, also relocalize to this intercellular region. The recruitment and activation of distinct classes of GEFs may allow for precise control of Rho GTPase function at the crucial interface between T cells and antigen presenting cells

Optical variability properties of high luminosity AGN classes

We present the results of a comparative study of the intra-night optical variability (INOV) characteristics of radio-loud and radio-quiet quasars, which involves a systematic intra-night optical monitoring of seven sets of high luminosity AGNs covering the redshift range {\it z} $\simeq 0.2$ to {\it z} $\simeq 2.2$. The sample, matched in the optical luminosity -- redshift (M$_B$ -- z) plane, consists of seven radio-quiet quasars (RQQs), eight radio lobe-dominated quasars (LDQs), six radio core-dominated quasars (CDQs) and five BL Lac objects (BLs). Systematic CCD observations, aided by a careful data analysis procedure, have allowed us to detect INOV with amplitudes as low as 1%. Present observations cover a total of 113 nights (720 hours) with only a single quasar monitored as continuously as possible on a night. Considering cases of only unambiguous detections of INOV we have estimated duty cycles (DCs) of 17%, 12%, 20% and 72% respectively for RQQs, LDQs, CDQs, and BLs. The low amplitude and low DC of INOV shown by RQQs compared to BLs can be understood in terms of their having optical synchrotron jets which are modestly misdirected from us. From our fairly extensive dataset, no unambiguous general trend of a correlation between the INOV amplitude and the apparent optical brightness of the quasar is noticed.Comment: 36 pages, 14 Figures, due to large size Fig. 5,6,11 and 12 are not included. Intersted people contact to [email protected]. Submitted to Journal of Astrophysics and Astronom

Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for study of the liver

Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30-45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health-related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party

Centrality and transverse momentum dependence of elliptic flow of multi-strange hadrons and ϕ\phi meson in Au+Au collisions at sNN\sqrt{s_{NN}} = 200 GeV

We present high precision measurements of elliptic flow near midrapidity ($|y|<1.0$) for multi-strange hadrons and $\phi$ meson as a function of centrality and transverse momentum in Au+Au collisions at center of mass energy $\sqrt{s_{NN}}=$ 200 GeV. We observe that the transverse momentum dependence of $\phi$ and $\Omega$ $v_{2}$ is similar to that of $\pi$ and $p$, respectively, which may indicate that the heavier strange quark flows as strongly as the lighter up and down quarks. This observation constitutes a clear piece of evidence for the development of partonic collectivity in heavy-ion collisions at the top RHIC energy. Number of constituent quark scaling is found to hold within statistical uncertainty for both 0-30$\%$ and 30-80$\%$ collision centrality. There is an indication of the breakdown of previously observed mass ordering between $\phi$ and proton $v_{2}$ at low transverse momentum in the 0-30$\%$ centrality range, possibly indicating late hadronic interactions affecting the proton $v_{2}$.Comment: 7 pages and 4 figures, Accepted for publication in Physical Review Letter

Observation of charge asymmetry dependence of pion elliptic flow and the possible chiral magnetic wave in heavy-ion collisions

We present measurements of $\pi^-$ and $\pi^+$ elliptic flow, $v_2$, at midrapidity in Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200, 62.4, 39, 27, 19.6, 11.5 and 7.7 GeV, as a function of event-by-event charge asymmetry, $A_{ch}$, based on data from the STAR experiment at RHIC. We find that $\pi^-$ ($\pi^+$) elliptic flow linearly increases (decreases) with charge asymmetry for most centrality bins at $\sqrt{s_{_{\rm NN}}} = \text{27 GeV}$ and higher. At $\sqrt{s_{_{\rm NN}}} = \text{200 GeV}$, the slope of the difference of $v_2$ between $\pi^-$ and $\pi^+$ as a function of $A_{ch}$ exhibits a centrality dependence, which is qualitatively similar to calculations that incorporate a chiral magnetic wave effect. Similar centrality dependence is also observed at lower energies.Comment: 6 pages, 4 figure

Azimuthal anisotropy in U+U and Au+Au collisions at RHIC

Collisions between prolate uranium nuclei are used to study how particle production and azimuthal anisotropies depend on initial geometry in heavy-ion collisions. We report the two- and four-particle cumulants, $v_2\{2\}$ and $v_2\{4\}$, for charged hadrons from U+U collisions at $\sqrt{s_{\rm NN}}$ = 193 GeV and Au+Au collisions at $\sqrt{s_{\rm NN}}$ = 200 GeV. Nearly fully overlapping collisions are selected based on the amount of energy deposited by spectators in the STAR Zero Degree Calorimeters (ZDCs). Within this sample, the observed dependence of $v_2\{2\}$ on multiplicity demonstrates that ZDC information combined with multiplicity can preferentially select different overlap configurations in U+U collisions. An initial-state model with gluon saturation describes the slope of $v_2\{2\}$ as a function of multiplicity in central collisions better than one based on Glauber with a two-component multiplicity model.Comment: Final paper version accepted for publication in Phys. Rev. Lett. New version includes comparisons to a constituent quark glauber mode

Observation of Transverse Spin-Dependent Azimuthal Correlations of Charged Pion Pairs in p↑+pp^\uparrow+p at s=200\sqrt{s}=200 GeV

We report the observation of transverse polarization-dependent azimuthal correlations in charged pion pair production with the STAR experiment in $p^\uparrow+p$ collisions at RHIC. These correlations directly probe quark transversity distributions. We measure signals in excess of five standard deviations at high transverse momenta, at high pseudorapidities eta>0.5, and for pair masses around the mass of the rho-meson. This is the first direct transversity measurement in p+p collisions. Comparing the results to data from lepton-nucleon scattering will test the universality of these spin-dependent quantities.Comment: 11 pages, 5 figures, 15 tables. Submitted to PR