Abstract
We present HST spectroscopy for 45 cataclysmic variables (CVs), observed with HST/COS and HST/STIS. For 36 CVs, the white dwarf is recognisable through its broad Ly α absorption profile and ...we measure the white dwarf effective temperatures (T
eff) by fitting the HST data assuming log g = 8.35, which corresponds to the average mass for CV white dwarfs (≃0.8 M⊙). Our results nearly double the number of CV white dwarfs with an accurate temperature measurement. We find that CVs above the period gap have, on average, higher temperatures (〈T
eff〉 ≃ 23 000 K) and exhibit much more scatter compared to those below the gap (〈T
eff〉 ≃ 15 000 K). While this behaviour broadly agrees with theoretical predictions, some discrepancies are present: (i) all our new measurements above the gap are characterized by lower temperatures (T
eff ≃ 16 000–26 000 K) than predicted by the present-day CV population models (T
eff ≃ 38 000–43 000 K); (ii) our results below the gap are not clustered in the predicted narrow track and exhibit in particular a relatively large spread near the period minimum, which may point to some shortcomings in the CV evolutionary models. Finally, in the standard model of CV evolution, reaching the minimum period, CVs are expected to evolve back towards longer periods with mean accretion rates
$\dot{M}\lesssim 2 \times 10^{-11}\,\mathrm{M}_{\odot }\,\mathrm{yr}^{-1}$
, corresponding to T
eff ≲ 11 500 K. We do not unambiguously identify any such system in our survey, suggesting that this major component of the predicted CV population still remains elusive to observations.
Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain ...the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.
To determine the predictive value of discharge destination as a surrogate for defining unfavorable outcome at 3- and 12-months poststroke.
Analysis of the prospectively collected data from a ...randomized, placebo-controlled trial in patients with ischemic stroke presenting within 3 hours of symptom onset.
Post hoc analysis of patients recruited in a clinical trial.
Patients (N=530) discharged alive from the hospital after ischemic stroke.
Not applicable.
Positive and negative predictive value and likelihood ratios of discharge destination for unfavorable outcome at 3- and 12-months poststroke defined by a Modified Rankin Scale (MRS) score of 2 to 6, 3 to 6, or 4 to 6. A likelihood ratio indicates how many times more (or less) likely a particular discharge destination is seen in patients with an unfavorable outcome compared with those without unfavorable outcome.
The positive predictive value of nursing home and rehabilitation facility discharges was highest for unfavorable outcome defined by an MRS score of 2 to 6 (95%) and rehabilitation facility (89%) at 3-months poststroke, respectively. The positive predictive value of rehabilitation facility/nursing home (90%) was also highest for unfavorable outcomes defined by an MRS score of 2 to 6 compared with those defined by MRS scores of 3 to 6 (79%) and 4 to 6 (57%). The positive likelihood ratio was highest for nursing home discharges (13; 95% confidence interval CI, 4.1-41) followed by rehabilitation facility discharges for unfavorable outcome defined by an MRS score of 2 to 6 at 3-months poststroke (5.3; 95% CI, 3.5-7.9). The negative likelihood ratio was the highest for home discharge for unfavorable outcome defined by an MRS score of 2 to 6 (4.5; 95% CI, 3.4-6.1). A similar pattern was observed with unfavorable outcome defined using various thresholds at 12 months.
Discharge destination can provide high predictive values and likelihood ratios for death and disability at 3-months poststroke, as defined by an MRS of score of 2 to 6.
The III–V semiconductor InGaAs is a key material for photonics because it provides optical emission and absorption in the 1.55 μm telecommunication wavelength window. However, InGaAs suffers from ...pronounced nonradiative effects associated with its surface states, which affect the performance of nanophotonic devices for optical interconnects, namely nanolasers and nanodetectors. This work reports the strong suppression of surface recombination of undoped InGaAs/InP nanostructured semiconductor pillars using a combination of ammonium sulfide, (NH4)2S, chemical treatment and silicon oxide, SiO x , coating. An 80-fold enhancement in the photoluminescence (PL) intensity of submicrometer pillars at a wavelength of 1550 nm is observed as compared with the unpassivated nanopillars. The PL decay time of ∼0.3 μm wide square nanopillars is dramatically increased from ∼100 ps to ∼25 ns after sulfur treatment and SiO x coating. The extremely long lifetimes reported here, to our knowledge the highest reported to date for undoped InGaAs nanostructures, are associated with a record-low surface recombination velocity of ∼260 cm/s. We also conclusively show that the SiO x capping layer plays an active role in the passivation. These results are crucial for the future development of high-performance nanoscale optoelectronic devices for applications in energy-efficient data optical links, single-photon sensing, and photovoltaics.
Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although ...immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described.
Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n=51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated.
Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 21%, 95% confidence interval (CI) 10% to 35% patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%,P<0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09–0.94;P = 0.04).
Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology with only two federally approved drug options. Given the complex molecular pathogenesis of IPF involving multiple cell ...types and multiple pathways, we explore the effects of a potential antifibrotic and antioxidant drug combination. Curcumin is a polyphenolic compound derived from turmeric with significant biological activity including a potential antifibrotic capacity. N-acetylcysteine (NAC) is a precursor to the antioxidant glutathione. To advance our understanding of these molecules, and to identify a clinical application, we present a small number of focused experiments that interrogates the effect of curcumin and NAC on pathways relevant to IPF in both fibroblasts and epithelial cells.
Primary epithelial cell and fibroblasts isolated from patients with IPF were challenged with a combination treatment of NAC and curcumin. Evaluation of the antifibrotic potential and effect on oxidative stress was performed through QPCR gene expression analysis and functional assays including scratch tests, viability assays, and measurement of induced reactive oxygen species.
We demonstrate that curcumin alone does have antifibrotic potential, but that effect is accompanied by proapoptotic increases in oxidative stress. Coupled with this, we find that NAC alone can reduce oxidative stress, but that epithelial cell viability is decreased through this treatment. However, co-administration of these two molecules decreases oxidative stress and maintains high cell viability in both cell types. In addition, this co-treatment maintains an antifibrotic potential.
These findings suggest a novel application for these molecules in IPF and encourage further exploration of this potential therapeutic approach.
NASA’s InSight mission to Mars will measure seismic signals to determine the planet’s interior structure. These highly sensitive seismometers are susceptible to corruption of their measurements by ...environmental changes. Magnetic fields, atmosphere pressure changes, and local winds can all induce apparent changes in the seismic records that are not due to propagating ground motions. Thus, InSight carries a set of sensors called the Auxiliary Payload Sensor Suite (APSS) which includes a magnetometer, an atmospheric pressure sensor, and a pair of wind and air temperature sensors. In the case of the magnetometer, knowledge of the amplitude of the fluctuating magnetic field at the InSight lander will allow the separation of seismic signals from potentially interfering magnetic signals of either natural or spacecraft origin. To acquire such data, a triaxial fluxgate magnetometer was installed on the deck of the lander to obtain magnetic records at the same cadence as the seismometer. Similarly, a highly sensitive pressure sensor is carried by InSight to enable the removal of local ground-surface tilts due to advecting pressure perturbations. Finally, the local winds (speed and direction) and air temperature are estimated using a hot-film wind sensor with heritage from REMS on the Curiosity rover. When winds are too high, seismic signals can be ignored or discounted. Herein we describe the APSS sensor suite, the test programs for its components, and the possible additional science investigations it enables.
Nanoscale light sources using metal cavities have been proposed to enable high integration density, efficient operation at low energy per bit and ultra-fast modulation, which would make them ...attractive for future low-power optical interconnects. For this application, such devices are required to be efficient, waveguide-coupled and integrated on a silicon substrate. We demonstrate a metal-cavity light-emitting diode coupled to a waveguide on silicon. The cavity consists of a metal-coated III-V semiconductor nanopillar which funnels a large fraction of spontaneous emission into the fundamental mode of an InP waveguide bonded to a silicon wafer showing full compatibility with membrane-on-Si photonic integration platforms. The device was characterized through a grating coupler and shows on-chip external quantum efficiency in the 10
-10
range at tens of microamp current injection levels, which greatly exceeds the performance of any waveguide-coupled nanoscale light source integrated on silicon in this current range. Furthermore, direct modulation experiments reveal sub-nanosecond electro-optical response with the potential for multi gigabit per second modulation speeds.
Noradrenaline can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. ...Here we identify Src as a key regulator of phosphoproteomic signalling networks activated in response to beta-adrenergic signalling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumour cell migration, invasion and growth. In human ovarian cancer samples, high tumoural noradrenaline levels were correlated with high pSrc(Y419) levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signalling in the tumour microenvironment.
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