Investigating Cepheid ℓ\ell Carinae's Cycle-to-cycle Variations via Contemporaneous Velocimetry and Interferometry

Baade-Wesselink-type (BW) techniques enable geometric distance measurements of Cepheid variable stars in the Galaxy and the Magellanic clouds. The leading uncertainties involved concern projection factors required to translate observed radial velocities (RVs) to pulsational velocities and recently discovered modulated variability. We carried out an unprecedented observational campaign involving long-baseline interferometry (VLTI/PIONIER) and spectroscopy (Euler/Coralie) to search for modulated variability in the long-period (P $\sim$ 35.5 d) Cepheid Carinae. We determine highly precise angular diameters from squared visibilities and investigate possible differences between two consecutive maximal diameters, $\Delta_{\rm{max}} \Theta$. We characterize the modulated variability along the line-of-sight using 360 high-precision RVs. Here we report tentative evidence for modulated angular variability and confirm cycle-to-cycle differences of $\ell$ Carinae's RV variability. Two successive maxima yield $\Delta_{\rm{max}} \Theta$ = 13.1 $\pm$ 0.7 (stat.) {\mu}as for uniform disk models and 22.5 $\pm$ 1.4 (stat.) {\mu}as (4% of the total angular variation) for limb-darkened models. By comparing new RVs with 2014 RVs we show modulation to vary in strength. Barring confirmation, our results suggest the optical continuum (traced by interferometry) to be differently affected by modulation than gas motions (traced by spectroscopy). This implies a previously unknown time-dependence of projection factors, which can vary by 5% between consecutive cycles of expansion and contraction. Additional interferometric data are required to confirm modulated angular diameter variations. By understanding the origin of modulated variability and monitoring its long-term behavior, we aim to improve the accuracy of BW distances and further the understanding of stellar pulsations.Comment: Accepted for publication in MNRAS. 19 pages, 13 figures, 10 table

Spectral analysis of Kepler SPB and Beta Cep candidate stars

We determine the fundamental parameters of SPB and Beta Cep candidate stars observed by the Kepler satellite mission and estimate the expected types of non-radial pulsators by comparing newly obtained high-resolution spectra with synthetic spectra computed on a grid of stellar parameters assuming LTE and check for NLTE effects for the hottest stars. For comparison, we determine Teff independently from fitting the spectral energy distribution of the stars obtained from the available photometry. We determine Teff, log(g), micro-turbulent velocity, vsin(i), metallicity, and elemental abundance for 14 of the 16 candidate stars, two of the stars are spectroscopic binaries. No significant influence of NLTE effects on the results could be found. For hot stars, we find systematic deviations of the determined effective temperatures from those given in the Kepler Input Catalogue. The deviations are confirmed by the results obtained from ground-based photometry. Five stars show reduced metallicity, two stars are He-strong, one is He-weak, and one is Si-strong. Two of the stars could be Beta Cep/SPB hybrid pulsators, four SPB pulsators, and five more stars are located close to the borders of the SPB instability region.Comment: 10 pages, 10 figures, 10 table

MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs

Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide. Current medical therapy for HCC has limited efficacy. The present study tests the hypothesis that human cerebral endothelial cell-derived exosomes carrying elevated miR-214 (hCEC-Exo-214) can amplify the efficacy of anti-cancer drugs on HCC cells. Treatment of HepG2 and Hep3B cells with hCEC-Exo-214 in combination with anti-cancer agents, oxaliplatin or sorafenib, significantly reduced cancer cell viability and invasion compared with monotherapy with either drug. Additionally, the therapeutic effect of the combination therapy was detected in primary tumor cells derived from patients with HCC. The ability of hCEC-Exo-214 in sensitizing HCC cells to anti-cancer drugs was specific, in that combination therapy did not affect the viability and invasion of human liver epithelial cells and non-cancer primary cells. Furthermore, compared to monotherapy with oxaliplatin and sorafenib, hCEC-Exo-214 in combination with either drug substantially reduced protein levels of P-glycoprotein (P-gp) and splicing factor 3B subunit 3 (SF3B3) in HCC cells. P-gp and SF3B3 are among miR-214 target genes and are known to mediate drug resistance and cancer cell proliferation, respectively. In conclusion, the present in vitro study provides evidence that hCEC-Exo-214 significantly enhances the anti-tumor efficacy of oxaliplatin and sorafenib on HCC cells

Identification of a novel class of autotaxin inhibitors through cross-screening

Three novel series were generated in order to mimic the pharmacophoric features displayed by lead compound AM095, a Lysophosphatidic acid (LPA1) receptor antagonist. Biological evaluation of this array of putative LPA1 antagonists led us to the discovery of three novel series of inhibitors of the ecto-enzyme Autotaxin (ATX), responsible for LPA production in blood, with potencies in the range 1 – 4 μM accompanied with good (> 100 μg/mL) solubility

Lack of functional GABA receptors alters Kiss1 , Gnrh1 and Gad1 mRNA expression in the medial basal hypothalamus at postnatal day 4

Background/Aims: Adult mice lacking functional GABAB receptors (GABAB1KO) show altered Gnrh1 and Gad1 expressions in the preoptic area-anterior hypothalamus (POA-AH) and females display disruption of cyclicity and fertility. Here we addressed whether sexual differentiation of the brain and the proper wiring of the GnRH and kisspeptin systems were already disturbed in postnatal day 4 (PND4) GABAB1KO mice. Methods: PND4 wild-type (WT) and GABAB1KO mice of both sexes were sacrificed; tissues were collected to determine mRNA expression (qPCR), amino acids (HPLC), and hormones (RIA and/or IHC). Results: GnRH neuron number (IHC) did not differ among groups in olfactory bulbs or OVLT-POA. Gnrh1 mRNA (qPCR) in POA-AH was similar among groups. Gnrh1 mRNA in medial basal hypothalamus (MBH) was similar in WTs but was increased in GABAB1KO females compared to GABAB1KO males. Hypothalamic GnRH (RIA) was sexually different in WTs (males < females), but this sex difference was lost in GABAB1KOs; the same pattern was observed when analyzing only the MBH, but not in the POA-AH. Arcuate nucleus Kiss1 mRNA (micropunch-qPCR) was higher in WT females than in WT males and GABAB1KO females. Gad1 mRNA in MBH was increased in GABAB1KO females compared to GABAB1KO males. Serum LH and gonadal estradiol content were also increased in GABAB1KOs. Conclusion: We demonstrate that GABABRs participate in the sexual differentiation of the ARC/MBH, because sex differences in several reproductive genes, such as Gad1, Kiss1 and Gnrh1, are critically disturbed in GABAB1KO mice at PND4, probably altering the organization and development of neural circuits governing the reproductive axis. (c) 2013 S. Karger AG, Basel

Electromagnetic navigation transthoracic needle aspiration for the diagnosis of pulmonary nodules: A safety and feasibility pilot study

BACKGROUND: Pulmonary nodules remain a diagnostic challenge for physicians. Minimally invasive biopsy methods include bronchoscopy and CT guided transthoracic needle aspiration (TTNA). A novel electromagnetic guidance transthoracic needle aspiration (ETTNA) procedure which can be combined with navigational bronchoscopy (NB) and endobronchial ultrasound (EBUS) in a single setting has become available. METHODS: A prospective pilot study examining the safety, feasibility and diagnostic yield of ETTNA in a single procedural setting. All patients enrolled underwent EBUS for lung cancer staging followed by NB and ETTNA. Feasibility of performing ETTNA and a safety assessment by recording procedural related complications including pneumothorax or bleeding was performed. Diagnostic yield of ETTNA defined by a definitive pathologic tissue diagnosis was recorded. An additional diagnostic yield analysis was performed using a cohort analysis of combined interventions (EBUS + NB + ETTNA). All non-diagnostic biopsies were either followed with radiographic imaging or a surgical biopsy was performed. RESULTS: Twenty-four subjects were enrolled. ETTNA was feasible in 96% of cases. No bleeding events occurred. There were five pneumothoraces (21%) of which only two (8%) subjects required drainage. The diagnostic yield for ETTNA alone was 83% and increased to 87% (P=0.0016) when ETTNA was combined with NB. When ETTNA and NB were performed with EBUS for complete staging, the diagnostic yield increased further to 92% (P=0.0001). CONCLUSIONS: This is the first human pilot study demonstrating an acceptable safety and feasibility profile with a novel ETTNA system. Further studies are needed to investigate the increased diagnostic yield from this pilot study

Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Sulforaphane (SFN), an isothiocyanate phytochemical present predominantly in cruciferous vegetables such as brussels sprout and broccoli, is considered a promising chemo-preventive agent against cancer. In-vitro exposure to SFN appears to result in the induction of apoptosis and cell-cycle arrest in a variety of tumor types. However, the molecular mechanisms leading to the inhibition of cell cycle progression by SFN are poorly understood in epithelial ovarian cancer cells (EOC). The aim of this study is to understand the signaling mechanisms through which SFN influences the cell growth and proliferation in EOC.</p> <p>Results</p> <p>SFN at concentrations of 5 - 20 μM induced a dose-dependent suppression of growth in cell lines MDAH 2774 and SkOV-3 with an IC50 of ~8 μM after a 3 day exposure. Combination treatment with chemotherapeutic agent, paclitaxel, resulted in additive growth suppression. SFN at ~8 μM decreased growth by 40% and 20% on day 1 in MDAH 2774 and SkOV-3, respectively. Cells treated with cytotoxic concentrations of SFN have reduced cell migration and increased apoptotic cell death via an increase in Bak/Bcl-2 ratio and cleavage of procaspase-9 and poly (ADP-ribose)-polymerase (PARP). Gene expression profile analysis of cell cycle regulated proteins demonstrated increased levels of tumor suppressor retinoblastoma protein (RB) and decreased levels of E2F-1 transcription factor. SFN treatment resulted in G1 cell cycle arrest through down modulation of RB phosphorylation and by protecting the RB-E2F-1 complex.</p> <p>Conclusions</p> <p>SFN induces growth arrest and apoptosis in EOC cells. Inhibition of retinoblastoma (RB) phosphorylation and reduction in levels of free E2F-1 appear to play an important role in EOC growth arrest.</p

Increasing prevalence of overweight and obesity among Tanzanian women of reproductive age intending to conceive: evidence from three Demographic Health Surveys, 2004-2016

# Background The prevalence of people who are overweight or obese is increasing globally, especially in low- and middle-income countries. High body mass index (BMI) among women of reproductive age is a risk factor for various adverse reproductive and pregnancy outcomes. This study aims to describe trends over time in the distribution of BMI among Tanzanian women of reproductive age intending to conceive between 2004/5 and 2015/16, and identify factors associated with high BMI. # Methods We used data on 20,819 women of reproductive age (15-49 years) intending to conceive who participated in the Tanzania Demographic and Health Surveys in 2004/5, 2010 and 2015/16. We estimated the prevalence of high BMI (being overweight \[≥25 to <30 kg/m^2^] and obesity \[≥30kg/m^2^) and trends in the prevalence of high BMI across the three surveys. Using survey-weighted multivariable logistic regression, we used the most recent 2015/16 survey data to identify factors associated with high BMI. # Results Median BMI increased from 21.7kg/m^2^ (inter-quartile range, IQR=19.9-24.1 kg/m^2^) in 2004/5 to 22.0 kg/m^2^ (IQR=20.0-24.8 kg/m^2^) in 2010 to 22.7 kg/m^2^ (IQR=20.4-26.0 kg/m^2^) in 2015/16. The prevalence of overweight women increased from 11.1% in 2004/5 to 15.8% in 2015 (P <0.001). The prevalence of obesity increased from 3.1% in 2004/5 to 8.0% in 2015/16 (P<0.001). Women in the highest wealth quintile had higher odds (adjusted odds ratio, aOR= 4.5; 95%CI 3.4-6.3, P<0.001) of high BMI than women in the lowest quintile. The odds of high BMI were about four times greater (aOR=3.9; 95%CI=2.9-5.4, P<0.001) for women 40-44 years compared to 20–24-year-olds. Women in the high-paying occupations had greater odds of high BMI than those working in agriculture (aOR=1.5; 95% CI=1.1-2.2, P=0.002). Women residing in the Southern zone had 1.9 (95%CI=1.5-2.5, P<0.001) greater odds of high BMI than Lake zone residents. # Conclusions In Tanzania, high BMI affects almost 1 in 4 women of reproductive age who intend to conceive. This contributes to the burden of poor maternal and reproductive health outcomes. We recommend developing and implementing health-system strategies for addressing high BMI, tailored to the modifiable risk factors identified among women of reproductive age

The apoptotic response in HCT116BAX-/- cancer cells becomes rapidly saturated with increasing expression of a GFP-BAX fusion protein

Abstract Background Many chemotherapeutic agents promote tumor cell death by activating the intrinsic pathway of apoptosis. Intrinsic apoptosis involves permeabilization of the mitochondrial outer membrane and the release of cytochrome c, a process that is controlled by proteins of the BCL2 gene family. Chemoresistance is often associated with abnormalities in concentrations of BCL2 family proteins. Although stoichiometirc interactions between anti-apoptotic and BH3-only BCL2 family proteins have been well documented as affecting cell death, the association between changes in BAX concentration and intrinsic apoptosis are poorly understood. Methods Exogenous GFP-murine Bax fusion constructs were transfected into BAX-deficient HCT116 cells. To titrate the expression of the fusion protein, GFP-BAX was cloned into a tetracycline sensitive expression cassette and cotransfected with a plasmid expressing the rtTA transcription factor into HCT116 BAX-/- cells. Linear expression of the fusion gene was induced with doxycycline and monitored by quantitative PCR and immunoblotting. Cell death was assayed by DAPI staining cells after exposure to indomethacin, and scoring nuclei for condensed chromatin and fragmented nuclei. Results HCT116 BAX-/- cells were resistant to indomethacin, but susceptibility could be recovered in cells expressing a GFP-BAX fusion protein. Titration of GFP-BAX expression revealed that the concentration of BAX required to induce a saturating apoptosis response from baseline, was rapidly achieved. Increased levels of GFP-BAX were unable to stimulate higher levels of cell death. Examination of GFP-BAX distribution before and after indomethacin treatment indicated that BAX protein did not form aggregates when present at sub-lethal concentrations. Conclusion Within the limitations of this experimental system, BAX-dependent apoptosis in HCT116 cells exhibits an all-or-none response depending on the level of BAX protein present. The lack of BAX aggregation at sub-saturation levels suggests that the translocation step of BAX activation may be impaired