Wnt/beta-catenin signaling controls development of the blood–brain barrier

The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/beta-catenin (beta-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of beta-cat in vivo enhances barrier maturation, whereas inactivation of beta-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of beta-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of beta-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of beta-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown

Emission Line Metallicities From The Faint Infrared Grism Survey and VLT/MUSE

We derive direct measurement gas-phase metallicities of $7.4 < 12 + \log(O/H) < 8.4$ for 14 low-mass Emission Line Galaxies (ELGs) at $0.3 < z < 0.8$ identified in the Faint Infrared Grism Survey (FIGS). We use deep slitless G102 grism spectroscopy of the Hubble Ultra Deep Field (HUDF), dispersing light from all objects in the field at wavelengths between 0.85 and 1.15 microns. We run an automatic search routine on these spectra to robustly identify 71 emission line sources, using archival data from VLT/MUSE to measure additional lines and confirm redshifts. We identify 14 objects with $0.3 < z < 0.8$ with measurable O[III]$\lambda$4363 \AA\ emission lines in matching VLT/MUSE spectra. For these galaxies, we derive direct electron-temperature gas-phase metallicities with a range of $7.4 < 12 + \log(O/H) < 8.4$. With matching stellar masses in the range of $10^{7.9} M_{\odot} < M_{\star} < 10^{10.4} M_{\odot}$, we construct a mass-metallicity (MZ) relation and find that the relation is offset to lower metallicities compared to metallicities derived from alternative methods (e.g.,$R_{23}$, O3N2, N2O2) and continuum selected samples. Using star formation rates (SFR) derived from the $H\alpha$ emission line, we calculate our galaxies' position on the Fundamental Metallicity Relation (FMR), where we also find an offset toward lower metallicities. This demonstrates that this emission-line-selected sample probes objects of low stellar masses but even lower metallicities than many comparable surveys. We detect a trend suggesting galaxies with higher Specific Star Formation (SSFR) are more likely to have lower metallicity. This could be due to cold accretion of metal-poor gas that drives star formation, or could be because outflows of metal-rich stellar winds and SNe ejecta are more common in galaxies with higher SSFR.Comment: 14 pages, 11 figures, accepted in Ap

FIGS -- Faint Infrared Grism Survey: Description and Data Reduction

The Faint Infrared Grism Survey (FIGS) is a deep Hubble Space Telescope (HST) WFC3/IR (Wide Field Camera 3 Infrared) slitless spectroscopic survey of four deep fields. Two fields are located in the Great Observatories Origins Deep Survey-North (GOODS-N) area and two fields are located in the Great Observatories Origins Deep Survey-South (GOODS-S) area. One of the southern fields selected is the Hubble Ultra Deep Field. Each of these four fields were observed using the WFC3/G102 grism (0.8$\mu m$-1.15$\mu m$ continuous coverage) with a total exposure time of 40 orbits (~ 100 kilo-seconds) per field. This reaches a 3 sigma continuum depth of ~26 AB magnitudes and probes emission lines to $\approx 10^{-17}\ erg\ s^{-1} \ cm^{-2}$. This paper details the four FIGS fields and the overall observational strategy of the project. A detailed description of the Simulation Based Extraction (SBE) method used to extract and combine over 10000 spectra of over 2000 distinct sources brighter than m_F105W=26.5 mag is provided. High fidelity simulations of the observations is shown to significantly improve the background subtraction process, the spectral contamination estimates, and the final flux calibration. This allows for the combination of multiple spectra to produce a final high quality, deep, 1D-spectra for each object in the survey.Comment: 21 Pages. 17 Figures. To appear in Ap

Emission-Line Galaxies from the Hubble Space Telescope Probing Evolution and Reionization Spectroscopically (PEARS) Grism Survey. II: The Complete Sample

We present a full analysis of the Probing Evolution And Reionization Spectroscopically (PEARS) slitess grism spectroscopic data obtained with the Advanced Camera for Surveys on HST. PEARS covers fields within both the Great Observatories Origins Deep Survey (GOODS) North and South fields, making it ideal as a random survey of galaxies, as well as the availability of a wide variety of ancillary observations to support the spectroscopic results. Using the PEARS data we are able to identify star forming galaxies within the redshift volume 0< z<1.5. Star forming regions in the PEARS survey are pinpointed independently of the host galaxy. This method allows us to detect the presence of multiple emission line regions (ELRs) within a single galaxy. 1162 Ha, [OIII] and/or [OII] emission lines have been identified in the PEARS sample of ~906 galaxies down to a limiting flux of ~1e-18 erg/s/cm^2. The ELRs have also been compared to the properties of the host galaxy, including morphology, luminosity, and mass. From this analysis we find three key results: 1) The computed line luminosities show evidence of a flattening in the luminosity function with increasing redshift; 2) The star forming systems show evidence of disturbed morphologies, with star formation occurring predominantly within one effective (half-light) radius. However, the morphologies show no correlation with host stellar mass; and 3) The number density of star forming galaxies with M_* > 1e9} M_sun decreases by an order of magnitude at z<0.5 relative to the number at 0.5<z<0.9 in support of the argument for galaxy downsizing.Comment: Submitted. 48 pages. 19 figures. Accepted to Ap

Wnt/β-catenin signaling controls development of the blood–brain barrier

The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/β-catenin (β-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of β-cat in vivo enhances barrier maturation, whereas inactivation of β-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of β-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of β-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of β-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown

Do new matrix formulations improve resin composite resistance to degradation processes?

The aim of this study was to determine the degradation resistance of three new formulations-silorane-, Ormocer- and dimer-acid-based materials-and compare them to the traditional dimethacrylate-based materials. One silorane- (Filtek P90, P90), one Ormocer- (Ceram-X, CX), one dimer-acid- (N'Durance, ND) and two dimethacrylate-based (Filtek P60, P60; Tetric Ceram, TC) materials were investigated. Water sorption (Wsp) and solubility (Wsl) were determined after the materials were immersed in water for 28 days. Knoop hardness (KH) was determined before and after 24 h immersion in pure ethanol. The flexural-strength (FS) was determined by the bending test after one-week storage in a dry environment or after one-week immersion in pure ethanol. Data were submitted to analysis of variance (ANOVA) and Tukey's test (95%). The three new formulations showed lower Wsp than the dimethacrylate-based formulation. CX (0.50 &#177; 0.17%) and ND (0.72 &#177; 0.19%) exhibited the lowest Wsp, whereas P90 (0.02 &#177; 0.03%) and P60 (0.04 &#177; 0.03%) showed the lowest Wsl. All resins showed reduced Knoop hardness number (KHN) after ethanol immersion. P60 presented the lowest decrease in KH value (19 &#177; 5%). TC (48 &#177; 3%) and P90 (39 &#177; 9%) showed the highest KHN decrease after ethanol storage. The FS of CX, ND and TC were affected by ethanol storage. The new formulations did not improve the degradation resistance, as compared with the traditional methacrylate-based materials.41041

Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition. METHODS: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort. RESULTS: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events. CONCLUSION: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP

Brucella suis urease encoded by ure1 but not ure2 is necessary for intestinal infection of BALB/c mice

BACKGROUND: In prokaryotes, the ureases are multi-subunit, nickel-containing enzymes that catalyze the hydrolysis of urea to carbon dioxide and ammonia. The Brucella genomes contain two urease operons designated as ure1 and ure2. We investigated the role of the two Brucella suis urease operons on the infection, intracellular persistence, growth, and resistance to low-pH killing. RESULTS: The deduced amino acid sequence of urease-α subunits of operons-1 and -2 exhibited substantial identity with the structural ureases of alpha- and beta-proteobacteria, Gram-positive and Gram-negative bacteria, fungi, and higher plants. Four ure deficient strains were generated by deleting one or more of the genes encoding urease subunits of B. suis strain 1330 by allelic exchange: strain 1330Δure1K (generated by deleting ureD and ureA in ure1 operon), strain 1330Δure2K (ureB and ureC in ure2 operon), strain 1330Δure2C (ureA, ureB, and ureC in ure2 operon), and strain 1330Δure1KΔure2C (ureD and ureA in ure1 operon and ureA, ureB, and ureC in ure2 operon). When grown in urease test broth, strains 1330, 1330Δure2K and 1330Δure2C displayed maximal urease enzyme activity within 24 hours, whereas, strains 1330Δure1K and 1330Δure1KΔure2C exhibited zero urease activity even 96 h after inoculation. Strains 1330Δure1K and 1330Δure1KΔure2C exhibited slower growth rates in tryptic soy broth relative to the wild type strain 1330. When the BALB/c mice were infected intraperitoneally with the strains, six weeks after inoculation, the splenic recovery of the ure deficient strains did not differ from the wild type. In contrast, when the mice were inoculated by gavage, one week after inoculation, strain 1330Δure1KΔure2C was cleared from livers and spleens while the wild type strain 1330 was still present. All B. suis strains were killed when they were incubated in-vitro at pH 2.0. When the strains were incubated at pH 2.0 supplemented with 10 mM urea, strain 1330Δure1K was completely killed, strain 1330Δure2C was partially killed, but strains 1330 and 1330Δure2K were not killed. CONCLUSION: These findings suggest that the ure1 operon is necessary for optimal growth in culture, urease activity, resistance against low-pH killing, and in vivo persistence of B. suis when inoculated by gavage. The ure2 operon apparently enhances the resistance to low-pH killing in-vitro

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup