Abstract
Type Ia supernovae (SNe Ia) are more precise standardizable candles when measured in the near-infrared (NIR) than in the optical. With this motivation, from 2012 to 2017 we embarked on the ...RAISIN program with the Hubble Space Telescope (HST) to obtain rest-frame NIR light curves for a cosmologically distant sample of 37 SNe Ia (0.2 ≲
z
≲ 0.6) discovered by Pan-STARRS and the Dark Energy Survey. By comparing higher-
z
HST data with 42 SNe Ia at
z
< 0.1 observed in the NIR by the Carnegie Supernova Project, we construct a Hubble diagram from NIR observations (with only time of maximum light and some selection cuts from optical photometry) to pursue a unique avenue to constrain the dark energy equation-of-state parameter,
w
. We analyze the dependence of the full set of Hubble residuals on the SN Ia host galaxy mass and find Hubble residual steps of size ∼0.06-0.1 mag with 1.5
σ
−2.5
σ
significance depending on the method and step location used. Combining our NIR sample with cosmic microwave background constraints, we find 1 +
w
= −0.17 ± 0.12 (statistical + systematic errors). The largest systematic errors are the redshift-dependent SN selection biases and the properties of the NIR mass step. We also use these data to measure
H
0
= 75.9 ± 2.2 km s
−1
Mpc
−1
from stars with geometric distance calibration in the hosts of eight SNe Ia observed in the NIR versus
H
0
= 71.2 ± 3.8 km s
−1
Mpc
−1
using an inverse distance ladder approach tied to Planck. Using optical data, we find 1 +
w
= −0.10 ± 0.09, and with optical and NIR data combined, we find 1 +
w
= −0.06 ± 0.07; these shifts of up to ∼0.11 in
w
could point to inconsistency in the optical versus NIR SN models. There will be many opportunities to improve this NIR measurement and better understand systematic uncertainties through larger low-
z
samples, new light-curve models, calibration improvements, and eventually by building high-
z
samples from the Roman Space Telescope.
A reduced protein diet (RPD) is known to increase the level of intramuscular lipid in pig meat with a smaller effect on the amount of subcutaneous adipose tissue. This might be due to tissue-specific ...activation of the expression of lipogenic enzymes by the RPD. The present study investigated the effect of a RPD, containing palm kernel oil, soyabean oil or palm oil on the activity and expression of one of the major lipogenic enzymes, stearoyl-CoA desaturase (SCD) and on the level of total lipids and the fatty acid composition of muscle and subcutaneous adipose tissue in pigs. The RPD significantly increased SCD protein expression and activity in muscle but not in subcutaneous adipose tissue. The level of MUFA and total fatty acids in muscle was also elevated when the RPD was fed, with only small changes in subcutaneous adipose tissue. A positive significant correlation between SCD protein expression and total fatty acids in muscle was found. The results suggest that an increase in intramuscular but not subcutaneous adipose tissue fatty acids under the influence of a RPD is related to tissue-specific activation of SCD expression. It is suggested that the SCD isoform spectra in pig subcutaneous adipose tissue and muscle might be different.
MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody ...conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE).
This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2mg/kg) or weekly (Q1W, 0.8–1.6mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken.
Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC.
DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required.
NCT01335958.
Bats constitute a reservoir of zoonotic infections and some bat paramyxoviruses are capable of cross-species transmission, often with fatal consequences. Determining the level of viral diversity in ...reservoir populations is fundamental to understanding and predicting viral emergence. This is particularly relevant for RNA viruses where the adaptive mutations required for cross-species transmission can be present in the reservoir host. We report the use of non-invasively collected, pooled, neat urine samples as a robust sample type for investigating paramyxoviruses in bat populations. Using consensus PCR assays we have detected a high incidence and genetic diversity of novel paramyxoviruses in an urban fruit bat population over a short period of time. This may suggest a similarly unique relationship between bats and the members of the family Paramyxoviridae as proposed for some other viral families. Additionally, the high rate of bat–human contact at the study site calls for the zoonotic potential of the detected viruses to be investigated further.
Here, we present precise phase-connected pulse timing solutions for 16 γ-ray-selected pulsars recently discovered using the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope plus one ...very faint radio pulsar (PSR J1124–5916) that is more effectively timed with the LAT. We describe the analysis techniques including a maximum likelihood method for determining pulse times of arrival from unbinned photon data. A major result of this work is improved position determinations, which are crucial for multiwavelength follow-up. For most of the pulsars, we overlay the timing localizations on X-ray images from Swift and describe the status of X-ray counterpart associations. We report glitches measured in PSRs J0007+7303, J1124–5916, and J1813–1246. We analyze a new 20 ks Chandra ACIS observation of PSR J0633+0632 that reveals an arcminute-scale X-ray nebula extending to the south of the pulsar. We were also able to precisely localize the X-ray point source counterpart to the pulsar and find a spectrum that can be described by an absorbed blackbody or neutron star atmosphere with a hard power-law component. Another Chandra ACIS image of PSR J1732–3131 reveals a faint X-ray point source at a location consistent with the timing position of the pulsar. Finally, we present a compilation of new and archival searches for radio pulsations from each of the γ-ray-selected pulsars as well as a new Parkes radio observation of PSR J1124–5916 to establish the γ-ray to radio phase offset.
Background and Purpose
Endocannabinoids such as anandamide (AEA) are important lipid ligands regulating cell proliferation, differentiation and apoptosis. Their levels are regulated by hydrolase ...enzymes, the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Here, we investigated whether FAAH or AEA are involved in NF (erythroid‐derived 2)‐like 2 (Nrf2)/antioxidant responsive element (ARE) pathway.
Experimental Approach
The aim of this study was to analyse the effects of AEA or FAAH inhibition by the URB597 inhibitor or FAAH/siRNA on the activation of Nrf2‐ARE signalling pathway and heme oxygenase‐1 (HO‐1) induction and transcription.
Key Results
Endogenous AEA was detected in the immortalized human mammary epithelial MCF‐10A cells (0.034 ng per 106 cells) but not in MCF‐7 or MDA‐MB‐231 breast cancer cells. Because breast tumour cells express FAAH abundantly, we examined the effects of FAAH on Nrf2/antioxidant pathway. We found that inhibition of FAAH by the URB597 inhibitor induced antioxidant HO‐1 in breast cancer cells and MCF‐10A cells. RNAi‐mediated knockdown of FAAH or treatment with AEA‐activated ARE‐containing reporter induced HO‐1 mRNA and protein expression, independent of the cannabinoid receptors, CB1, CB2 or TRPV1. Furthermore, URB597, AEA and siRNA‐FAAH treatments induced the nuclear translocation of Nrf2, while siRNA‐Nrf2 treatment and Keap1 expression blocked AEA, URB597 and si‐FAAH from activation of ARE reporter and HO‐1 induction. siRNA‐HO‐1 treatment decreased the viability of breast cancer cells and MCF‐10A cells.
Conclusions and Implications
These data uncovered a novel mechanism by which inhibition of FAAH or exposure to AEA induced HO‐1 transcripts and implicating AEA and FAAH as direct modifiers in signalling mediated activation of Nrf2‐HO‐1 pathway, independent of cannabinoid receptors.
The cementite phase of Fe3C has been studied by high‐resolution neutron powder diffraction at 4.2 K and at 20 K intervals between 20 and 600 K. The crystal structure remains orthorhombic (Pnma) ...throughout, with the fractional coordinates of all atoms varying only slightly (the magnetic structure of the ferromagnetic phase could not be determined). The ferromagnetic phase transition, with Tc≃ 480 K, greatly affects the thermal expansion coefficient of the material. The average volumetric coefficient of thermal expansion above Tc was found to be 4.1 (1) × 10−5 K−1; below Tc it is considerably lower (< 1.8 × 10−5 K−1) and varies greatly with temperature. The behaviour of the volume over the full temperature range of the experiment may be modelled by a third‐order Grüneisen approximation to the zero‐pressure equation of state, combined with a magnetostrictive correction based on mean‐field theory.
Sixteen pulsars have been discovered so far in blind searches of photons collected with the Large Area Telescope on the Fermi Gamma-ray Space Telescope. We here report the discovery of radio ...pulsations from two of them. PSR J1741-2054, with period P = 413 ms, was detected in archival Parkes telescope data and subsequently has been detected at the Green Bank Telescope (GBT). Its received flux varies greatly due to interstellar scintillation and it has a very small dispersion measure of DM = 4.7 pc cm-3, implying a distance of 0.4 kpc and possibly the smallest luminosity of any known radio pulsar. At this distance, for isotropic emission, its gamma-ray luminosity above 0.1 GeV corresponds to 28% of the spin-down luminosity of erg s-1. The gamma-ray profile occupies 1/3 of pulse phase and has three closely spaced peaks with the first peak lagging the radio pulse by Delta *d = 0.29 P. We have also identified a soft Swift source that is the likely X-ray counterpart. In many respects PSR J1741-2054 resembles the Geminga pulsar. The second source, PSR J2032+4127, was detected at the GBT. It has P = 143 ms, and its DM = 115 pc cm-3 suggests a distance of 3.6 kpc, but we consider it likely that it is located within the Cyg OB2 stellar association at half that distance. The radio emission is nearly 100% linearly polarized, and the main radio peak precedes by Delta *d = 0.15 P the first of two narrow gamma-ray peaks that are separated by Delta *D = 0.50 P. The second peak has a harder spectrum than the first one, following a trend observed in young gamma-ray pulsars. Faint, diffuse X-ray emission in a Chandra image is possibly its pulsar wind nebula. The wind of PSR J2032+4127 is responsible for the formerly unidentified HEGRA source TeV J2032+4130. PSR J2032+4127 is coincident in projection with MT91 213, a Be star in Cyg OB2, although apparently not a binary companion of it.
The complications of obesity extend beyond the periphery to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. ...Preclinical studies support this concept, including studies that have examined the effects of a high-fat diet (HFD) on depressive-like behaviors. Although women are approximately two-fold more likely to develop depressive illness compared to men, most preclinical studies have focused on the effects of HFD in male rodents. Accordingly, the goal of this study was to examine depressive-like behaviors in male and female rats provided access to a HFD. In agreement with prior studies, male and female rats provided a HFD segregate into an obesity phenotype (i.e., diet-induced obesity; DIO) or a diet resistant (DR) phenotype. Upon confirmation of the DR and DIO phenotypes, behavioral assays were performed in control chow, DR, and DIO rats. In the sucrose preference test, male DIO rats exhibited significant decreases in sucrose consumption (i.e., anhedonia) compared to male DR and male control rats. In the forced swim test (FST), male DIO rats exhibited increases in immobility and decreases in climbing behaviors in the pre-test sessions. Interestingly, male DR rats exhibited these same changes in both the pre-test and test sessions of the FST, suggesting that consumption of a HFD, even in the absence of the development of an obesity phenotype, has behavioral consequences. Female rats did not exhibit differences in sucrose preference, but female DIO rats exhibited increases in immobility exclusively in the test session of the FST, behavioral changes that were not affected by the stage of the estrous cycle. Collectively, these studies demonstrate that access to a HFD elicits different behavioral outcomes in male and female rats.
•Rats on a high-fat diet (HFD) segregate into resistant (DR) and obese (DIO) groups.•HFD induces different behavioral outcomes in male and female rats.•Male DIO rats exhibit anhedonia while male DR rats exhibit behavioral despair.•Female DIO rats exhibit behavioral despair but do not exhibit anhedonia.•Estrous cycle does not impact depressive-like behaviors in female DR and DIO rats.
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