Controlling a spillover pathway with the molecular cork effect

Spillover of reactants from one active site to another is important in heterogeneous catalysis and has recently been shown to enhance hydrogen storage in a variety of materials. The spillover of hydrogen is notoriously hard to detect or control. We report herein that the hydrogen spillover pathway on a Pd/Cu alloy can be controlled by reversible adsorption of a spectator molecule. Pd atoms in the Cu surface serve as hydrogen dissociation sites from which H atoms can spillover onto surrounding Cu regions. Selective adsorption of CO at these atomic Pd sites is shown to either prevent the uptake of hydrogen on, or inhibit its desorption from, the surface. In this way, the hydrogen coverage on the whole surface can be controlled by molecular adsorption at a minority site, which we term a ‘molecular cork’ effect. We show that the molecular cork effect is present during a surface catalysed hydrogenation reaction and illustrate how it can be used as a method for controlling uptake and release of hydrogen in a model storage system

hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor for immunotherapy of uterine serous papillary carcinoma

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immunoconjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. METHODS: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3\ufe levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h 51Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50\u2013100 IU ml 1). RESULTS: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; Po0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing\ub1s.d., 65.6\ub13.7%, range 57.5\u201377.0%, Po0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. CONCLUSION: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities

The UV-SCOPE mission: ultraviolet spectroscopic characterization of planets and their environments

UV-SCOPE is a mission concept to determine the causes of atmospheric mass loss in exoplanets, investigate the mechanisms driving aerosol formation in hot Jupiters, and study the influence of the stellar environment on atmospheric evolution and habitability. As part of these investigations, the mission will generate a broad-purpose legacy database of time-domain ultraviolet (UV) spectra for nearly 200 stars and planets. The observatory consists of a 60 cm, f/10 telescope paired to a long-slit spectrograph, yielding simultaneous, almost continuous coverage between 1203 Å and 4000 Å, with resolutions ranging from 6000 to 240. The efficient instrument provides throughputs < 4% (far-UV; FUV) and < 15% (near-UV; NUV), comparable to HST/COS and much better than HST/STIS, over the same spectral range. A key design feature is the LiF prism, which serves as a dispersive element and provides high throughput even after accounting for radiation degradation. The use of two delta-doped Electron-Multiplying CCD detectors with UV-optimized, single-layer anti-reflection coatings provides high quantum efficiency and low detector noise. From the Earth-Sun second Lagrangian point, UV-SCOPE will continuously observe planetary transits and stellar variability in the full FUV-to-NUV range, with negligible astrophysical background. All these features make UV-SCOPE the ideal instrument to study exoplanetary atmospheres and the impact of host stars on their planets. UV-SCOPE was proposed to NASA as a Medium Explorer (MidEx) mission for the 2021 Announcement of Opportunity. If approved, the observatory will be developed over a 5-year period. Its primary science mission takes 34 months to complete. The spacecraft carries enough fuel for 6 years of operations

Impact of glucocorticoid receptor density on ligand-independent dimerization, cooperative ligand-binding and basal priming of transactivation: a cell culture model

Glucocorticoid receptor (GR) levels vary between tissues and individuals and are altered by physiological and pharmacological effectors. However, the effects and implications of differences in GR concentration have not been fully elucidated. Using three statistically different GR concentrations in transiently transfected COS-1 cells, we demonstrate, using co-immunoprecipitation (CoIP) and fluorescent resonance energy transfer (FRET), that high levels of wild type GR (wtGR), but not of dimerization deficient GR (GRdim), display ligand-independent dimerization. Whole-cell saturation ligand-binding experiments furthermore establish that positive cooperative ligand-binding, with a concomitant increased ligand-binding affinity, is facilitated by ligand-independent dimerization at high concentrations of wtGR, but not GRdim. The down-stream consequences of ligand-independent dimerization at high concentrations of wtGR, but not GRdim, are shown to include basal priming of the system as witnessed by ligand-independent transactivation of both a GRE-containing promoter-reporter and the endogenous glucocorticoid (GC)-responsive gene, GILZ, as well as ligand-independent loading of GR onto the GILZ promoter. Pursuant to the basal priming of the system, addition of ligand results in a significantly greater modulation of transactivation potency than would be expected solely from the increase in ligand-binding affinity. Thus ligand-independent dimerization of the GR at high concentrations primes the system, through ligand-independent DNA loading and transactivation, which together with positive cooperative ligand-binding increases the potency of GR agonists and shifts the bio-character of partial GR agonists. Clearly GR-levels are a major factor in determining the sensitivity to GCs and a critical factor regulating transcriptional programs

Vulnerability of marine megafauna to global at-sea anthropogenic threats

Marine megafauna species are affected by a wide range of anthropogenic threats. To evaluate the risk of such threats, species' vulnerability to each threat must first be determined. We build on the existing threats classification scheme and ranking system of the International Union for Conservation of Nature (IUCN) Red List of Threatened Species by assessing the vulnerability of 256 marine megafauna species to 23 at-sea threats. The threats we considered included individual fishing gear types, climate-change-related subthreats not previously assessed, and threats associated with coastal impacts and maritime disturbances. Our ratings resulted in 70 species having high vulnerability (v > 0.778 out of 1) to at least 1 threat, primarily drifting longlines, temperature extremes, or fixed gear. These 3 threats were also considered to have the most severe effects (i.e., steepest population declines). Overall, temperature extremes and plastics and other solid waste were rated as affecting the largest proportion of populations. Penguins, pinnipeds, and polar bears had the highest vulnerability to temperature extremes. Bony fishes had the highest vulnerability to drifting longlines and plastics and other solid waste; pelagic cetaceans to 4 maritime disturbance threats; elasmobranchs to 5 fishing threats; and flying birds to drifting longlines and 2 maritime disturbance threats. Sirenians and turtles had the highest vulnerability to at least one threat from all 4 categories. Despite not necessarily having severe effects for most taxonomic groups, temperature extremes were rated among the top threats for all taxa except bony fishes. The vulnerability scores we provide are an important first step in estimating the risk of threats to marine megafauna. Importantly, they help differentiate scope from severity, which is key to identifying threats that should be prioritized for mitigation

Oral abstracts of the 21st International AIDS Conference 18-22 July 2016, Durban, South Africa

The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n=122) recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression.Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL) and CD4 T cell count) and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy). To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed.Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants.Expression of ‘exhaustion’ or ‘immune checkpoint’ markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches