We demonstrate the highly effective extraction of waveguided light from the active region of organic light-emitting devices using a non-diffractive dielectric grid layer placed between the ...transparent anode and the substrate. The sub-anode grid couples out all waveguide mode power into the substrate without changing the device electrical properties, resulting in an increase in both the external quantum efficiency and luminous efficacy for green phosphorescent organic light-emitting devices from 15 ± 1% and 36 ± 2 lm W-1 to 18 ± 1% and 43 ± 2 lm W-1 . These characteristics are further increased to 40 ± 2% and 95 ± 4 lm W-1 when all glass modes are also extracted. The use of a thick electron transport layer further reduces surface plasmon modes, resulting in an increase in the substrate and air modes by 50 ± 8% compared with devices lacking the grids. The sub-anode grid has minimal impact on organic light-emitting device emission wavelength and viewing angle, and is likely to prove beneficial for a broad range of display and lighting applications.
CD44 is a transmembrane glycoprotein that binds to hyaluronic acid, plays roles in a number of cellular processes and is expressed in a variety of cell types. It is up-regulated in stem cells and ...cancer. Anti-CD44 monoclonal antibodies affect cell motility and aggregation, and repress tumorigenesis and metastasis. Here we describe four new anti-CD44 monoclonal antibodies originating from B cells of a mouse injected with a plasmid expressing CD44 isoform 12. The four monoclonal antibodies bind to the terminal, extracellular, conserved domain of CD44 isoforms. Based on differences in western blot patterns of cancer cell lysates, the four anti-CD44 mAbs separated into three distinct categories that include P4G9, P3D2, and P3A7, and P3G4. Spot assay analysis with peptides generated in Escherichia coli support the conclusion that the monoclonal antibodies recognize unglycosylated sequences in the N-terminal conserved region between amino acid 21-220, and analyses with a peptide generated in human embryonic kidney 293 cells, demonstrate that these monoclonal antibodies bind to these peptides only after deglycosylation. Western blots with lysates from three cancer cell lines demonstrate that several CD44 isoforms are unglycosylated in the anti-CD44 target regions. The potential utility of the monoclonal antibodies in blocking tumorigenesis was tested by co-injection of cells of the breast cancer-derived tumorigenic cell line MDA-MB-231 with the anti-CD44 monoclonal antibody P3D2 into the mammary fat pads of mice. All five control mice injected with MDA-MB-231 cells plus anti-IgG formed palpable tumors, while only one of the six test mice injected with MDA-MB-231 cells plus P3D2 formed a tiny tumor, while the remaining five were tumor-free, indicating that the four anti-CD44 mAbs may be useful therapeutically.
Eumelanin is a ubiquitous biological pigment that rapidly and efficiently deactivates excited states created by UV or visible radiation. Paradoxically, photoirradiation of eumelanin also generates ...radicals and harmful reactive oxygen species, but the relationship between these pathways and excited‐state deactivation is uncertain. Here, greatly expanding the excitation tuning range (225–620 nm) and probing window (400–1500 nm) in femtosecond transient absorption spectroscopy of the synthetic eumelanin, DOPA melanin, enables the detection of photogenerated radials with ultrafast time resolution for the first time. Despite its heterogeneous nature, the transient absorption signals can be modeled by two spectral components assigned to solvated electrons and photogenerated radicals. Radical absorbance measured several nanoseconds after excitation increases exponentially with increasing photon energy, matching the trend in radical yields measured in electron paramagnetic resonance spectroscopy experiments. Spectral modeling of the transient signals reveals two radical generation mechanisms: (1) photoionization by UV light; and (2) photoinduced charge transfer among eumelanin chromophores by UVA and visible wavelengths capable of reaching the pigment in skin. Concurrent ultrafast relaxation and radical generation underlie the ability of eumelanin to be both photoprotective and photodamaging, and the branching between these pathways likely depends on the wavelength of the absorbed light.
Broadband femtosecond transient absorption measurements provide evidence that ultrafast excited‐state deactivation in eumelanin is due to recombining radicals.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial phenotypic and etiological heterogeneity. Although 10%–20% of ASD cases are attributable to copy number variation ...(CNV), causative genomic loci and constituent genes remain unclarified. We have developed SNATCNV, a tool that outperforms existing tools, to identify 47 recurrent ASD CNV regions from 19,663 cases and 6,479 controls documented in the AutDB database. Analysis of ASD CNV gene content using FANTOM5 shows that constituent coding genes and long non-coding RNAs have brain-enriched patterns of expression. Notably, such enrichment is not observed for regions identified by using other tools. We also find evidence of sexual dimorphism, one locus uniquely comprising a single lncRNA gene, and correlation of CNVs to distinct clinical and behavioral traits. Finally, we analyze a large dataset for schizophrenia to further demonstrate that SNATCNV is an effective, publicly available tool to define genomic loci and causative genes for multiple CNV-associated conditions.
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•We introduce SNATCNV as a tool to analyze CNV associations with genetic diseases•SNATCNV identifies 47 recurrently duplicated/deleted CNVs associated with autism•We show that CNV regions are associated with distinct sets of DECIPHER phenotypes•We provide an extensive list of brain-enriched coding and lncRNA genes
Alinejad-Rokny et al. develop a tool, SNATCNV, to analyze CNV associations in genetic diseases and disorders. By application of SNATCNV to an autism cohort, they generate a high-confidence map of autism-associated CNVs and provide full lists of brain-enriched coding and lncRNA genes.
Oxide/(oxy)hydroxide overlayers such as cobalt (oxy)hydroxide phosphate (CoPi) enhance the performance of BiVO4 water-spitting photoanodes, but the mechanism of this enhancement remains unclear. We ...show that if the BiVO4 layer is thin and incompletely covers an underlying conductive glass, the performance dramatically decreases as CoPi loading is increased. This is consistent with direct contact between the CoPi and conducting glass that leads to “shunt” recombination of photogenerated holes accumulated in the CoPi. For thicker BiVO4 layers that completely cover the conducting glass, these shunt pathways are blocked. We then use a nanoelectrode atomic force microscopy probe to measure, in operando, the electrochemical potential of CoPi on thick BiVO4 films under illumination. We find that CoPi is charged to a potential necessary to drive water oxidation at a rate consistent with the measured photocurrent. CoPi acts as a hole collector and is the principal driver of water oxidation on BiVO4.
Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin ...therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+
/CD11b
+
inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Four ultrahigh energy gap organosilicon compounds diphenyldi(o-tolyl)silane (UGH1), p-bis(triphenylsilyl)benzene (UGH2), m-bis(triphenylsilyl)benzene (UGH3), and 9,9‘-spirobisilaanthracene (UGH4) ...were employed as host materials in the emissive layer of electrophosphorescent organic light-emitting diodes (OLEDs). The high singlet (∼4.5 eV) and triplet (∼3.5 eV) energies associated with these materials effectively suppress both the electron and energy transfer quenching pathways between the emissive dopant and the host material, leading to deep blue phosphorescent devices with high (∼10%) external quantum efficiencies. Furthermore, by direct charge injection from the adjacent hole and electron transport layers onto the phosphor doped into the UGH matrix, exciton formation occurs directly on the dopant, thereby eliminating exchange energy losses characteristic of guest−host energy transfer. We discuss the material design, and present device data for OLEDs employing UGHs. Among the four host materials, UGH2 and UGH3 have higher quantum efficiencies than UGH1 when used in OLEDs. Rapid device degradation was observed for the UGH4-based device due to electro- and/or photooxidation of the diphenylmethane moiety in UGH4. In addition to showing that UGH materials can be used to fabricate efficient blue OLEDs, we demonstrate that very high device efficiencies can be achieved in structures where the dopant transports both charge and excitons.
1. Shifts in the spatial and temporal patterns of flowering could affect the resources available to pollinators, and such shifts might become more common as climate change progresses. 2. As ...mid-summer temperatures have warmed, we found that a montane meadow ecosystem in the southern Rocky Mountains of the United States exhibits a trend toward a bimodal distribution of flower abundance, characterized by a mid-season reduction in total flower number, instead of a broad, unimodal flowering peak lasting most of the summer season. 3. We examined the shapes of community-level flowering curves in this system and found that the typical unimodal peak results from a pattern of complementary peaks in flowering among three distinct meadow types (dry, mesic and wet) within the larger ecosystem. However, high mid-summer temperatures were associated with divergent shifts in the flowering curves of these individual meadow types. Specifically, warmer summers appeared to cause increasing bimodality in mesic habitats, and a longer interval between early and late flowering peaks in wet and dry habitats. 4. Together, these habitat-specific shifts produced a longer mid-season valley in floral abundance across the larger ecosystem in warmer years. Because of these warming-induced changes in flowering patterns, and the significant increase in summer temperatures in our study area, there has been a trend toward non-normality of flowering curves over the period 1974-2009. This trend reflects increasing bimodality in total community-wide flowering. 5. The resulting longer periods of low flowering abundance in the middle of the summer season could negatively affect pollinators that are active throughout the season, and shifts in flowering peaks within habitats might create mismatches between floral resources and demand by pollinators with limited foraging ranges. 6. Synthesis. Early-season climate conditions are getting warmer and drier in the high altitudes of the southern Rocky Mountains. We present evidence that this climate change is disrupting flowering phenology within and among different moisture habitats in a sub-alpine meadow ecosystem, causing a mid-season decline in floral resources that might negatively affect mutualists, especially pollinators. Our findings suggest that climate change can have complex effects on phenology at small spatial scales, depending on patch-level habitat differences.
Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer ...cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated
in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.
Doxorubicin (DOX) efflux from multi-drug resistance C6 glioma cells (C6-ADR) is overcome through conjugation to superparamagnetic iron oxide nanoparticles (NP-DOX), and corresponds to improved cell kill.
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Conventional wisdom holds that, owing to the dominance of features such as chromatin level control, the expression of a gene cannot be readily predicted from knowledge of promoter architecture. This ...is reflected, for example, in a weak or absent correlation between promoter divergence and expression divergence between paralogs. However, an inability to predict may reflect an inability to accurately measure or employment of the wrong parameters. Here we address this issue through integration of two exceptional resources: ENCODE data on transcription factor binding and the FANTOM5 high-resolution expression atlas.
Consistent with the notion that in eukaryotes most transcription factors are activating, the number of transcription factors binding a promoter is a strong predictor of expression breadth. In addition, evolutionarily young duplicates have fewer transcription factor binders and narrower expression. Nonetheless, we find several binders and cooperative sets that are disproportionately associated with broad expression, indicating that models more complex than simple correlations should hold more predictive power. Indeed, a machine learning approach improves fit to the data compared with a simple correlation. Machine learning could at best moderately predict tissue of expression of tissue specific genes.
We find robust evidence that some expression parameters and paralog expression divergence are strongly predictable with knowledge of transcription factor binding repertoire. While some cooperative complexes can be identified, consistent with the notion that most eukaryotic transcription factors are activating, a simple predictor, the number of binding transcription factors found on a promoter, is a robust predictor of expression breadth.
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