The recognition of the immune system as a key component of the tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets of patients, understanding the ...activities of immune cells in the TME is required. Eosinophils are an integral part of the TME especially in mucosal tumors. Nonetheless, their role in the TME and the environmental cues that direct their activities are largely unknown. We report that breast cancer lung metastases are characterized by resident and recruited eosinophils. Eosinophil recruitment to the metastatic sites in the lung was regulated by G protein-coupled receptor signaling but independent of CCR3. Functionally, eosinophils promoted lymphocyte-mediated antitumor immunity. Transcriptome and proteomic analyses identified the TME rather than intrinsic differences between eosinophil subsets as a key instructing factor directing antitumorigenic eosinophil activities. Specifically, TNFα/IFNγ-activated eosinophils facilitated CD4
and CD8
T-cell infiltration and promoted antitumor immunity. Collectively, we identify a mechanism by which the TME trains eosinophils to adopt antitumorigenic properties, which may lead to the development of eosinophil-targeted therapeutics. SIGNIFICANCE: These findings demonstrate antitumor activities of eosinophils in the metastatic tumor microenvironment, suggesting that harnessing eosinophil activity may be a viable clinical strategy in patients with cancer.
Abstract
Males exhibit shorter life span and more cognitive deficits, in the absence of dementia, in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major ...source of biologic sex difference, in part, because males show decreased expression of select X factors (XY). While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a, transcriptionally escape silencing in females—resulting in lower transcript levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevating Kdm6a could benefit the aged male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water-maze. We found that acutely increasing Kdm6a—in a form without demethylase function—selectively improved learning and memory, in the aging XY brain, without altering total activity or anxiety-like measures. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.
The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants.
To ...determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles.
We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33).
This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas.
Although butadiene is currently a byproduct of naphtha cracking, interest in producing butadiene from biobased ethanol has increased because of the lower environmental impact of the ethanol to ...butadiene reaction. This work explores a multifunctional catalyst system composed of silica-supported Ag and ZrO2 used for the cascade reaction of ethanol to butadiene at 573 K. The Ag and ZrO2 components were synthesized on separate support particles, enabling the characterization of each component without interference from the other. High selectivity to butadiene (65%) at high ethanol conversion (75%) was achieved with an appropriate ratio of Ag and ZrO2 in the reactor. Silver catalyzed the initial dehydrogenation of ethanol to acetaldehyde, while ZrO2 catalyzed the C–C coupling and subsequent dehydration reactions. The silica-supported ZrO2 exhibited superior selectivity relative to bulk ZrO2 in the Ag-promoted ethanol to butadiene reaction. Results from Zr K-edge X-ray absorption spectroscopy and UV–vis spectroscopy showed that ZrO2 was highly dispersed on the silica support over a range of loadings. Infrared spectroscopy of adsorbed pyridine, CO, and CO2, and kinetics of probe reactions 1-butene double bond isomerization, 2-propanol decomposition, and ethanol hydrogenation of acetone were used to compare the acid–base nature and chemical reactivity of silica-supported ZrO2 to bulk ZrO2.
Objective To evaluate the effectiveness of a hospital-wide initiative to improve patient safety by implementing high-reliability practices as part of a quality improvement (QI) program aimed at ...reducing all preventable harm. Study design A hospital wide quasi-experimental time series QI initiative using high-reliability concepts, microsystem-based multidisciplinary teams, and QI science tools to reduce hospital acquired harm was implemented. Extensive error prevention training was provided for all employees. Change concepts were enacted using the Institute for Healthcare Improvement's Model for Improvement. Compliance with change packages was measured. Results Between 2010 and 2012, the serious safety event rate decreased from 1.15 events to 0.19 event per 10 000 adjusted hospital-days, an 83.3% reduction ( P < .001). Preventable harm events decreased by 53%, from a quarterly peak of 150 in the first quarter of 2010 to 71 in the fourth quarter of 2012 ( P < .01). Observed hospital mortality decreased from 1.0% to 0.75% ( P < .001), although severity-adjusted expected mortality actually increased slightly, and estimated harm-related hospital costs decreased by 22.0%. Hospital-wide safety climate scores increased significantly. Conclusion Substantial reductions in serious safety event rate, preventable harm, hospital mortality, and cost were seen after implementation of our multifaceted approach. Measurable improvements in the safety culture were noted as well.
Silica nanoparticles have received great attention as versatile nanomaterials in many fields such as drug delivery, sensing, and imaging due to their physical and chemical flexibility. Specifically, ...the silanol groups at the surface of silica nanoparticles have enabled various surface modifications and functionalization to tailor the nanoparticles for each application. Chemical tailoring to switch from negative to positive surface charge has been one important strategy to enhance cell internalization and biodistribution of the nanoparticles. However, efficient surface charge modification that is sustained upon dispersion is difficult to achieve and has not been well characterized though it can be a critical requirement for successful nanoparticle performance. In this study, solid spherical silica nanoparticles and hollow spherical silica nanoparticles around 45 nm in diameter were synthesized, both possessing tunable positive ζ potentials in aqueous colloidal suspension, to investigate the relationship between time-dependent ζ potential changes and their morphologies. A set of three different particles showing varied ζ potentials of approximately 5, 20, and >30 mV in both morphologies were prepared, and their colloidal surface electric potential fluctuations were measured. These studies reveal that the hollow morphologies are much more effectively able to maintain positive ζ potentials for 7 days of aqueous incubation, whereas the magnitude of the ζ potential of the solid silica spheres decreases uncontrollably, largely due to hydrolysis of the interior siloxane bonds, resulting in adsorption of the released silicic acid onto the nanoparticle surface.
Surface plasmons excited by light in metal structures provide a means for manipulating optical energy at the nanoscale. Plasmons are associated with the collective oscillations of conduction ...electrons in metals and play a role intermediate between photonics and electronics. As such, plasmonic devices have been created that mimic photonic waveguides as well as electrical circuits operating at optical frequencies. We review the plasmon technologies and circuits proposed, modeled, and demonstrated over the past decade that have potential applications in optical computing and optical information processing.
Thermal desorption profiles were modelled based on SIMS measurements of implantation profiles and using the multi-trap diffusion code TMAP7 G.R. Longhurst, TMAP7: Tritium Migration Analysis Program, ...User Manual, Idaho National Laboratory, INEEL/EXT-04-02352 (2004). The thermal desorption profiles were the result of 500eV/D+ irradiations on single crystal tungsten at 300 and 500K to fluences of 1022–1024D+/m2. SIMS depth profiling was performed after irradiation to obtain the distribution of trapped D within the top 60nm of the surface. Thermal desorption spectroscopy (TDS) was performed subsequently to obtain desorption profiles and to extract the total trapped D inventory. The SIMS profiles were calibrated to give D concentrations. To account for the total trapped D inventory measured by TDS, SIMS depth distributions were used in the near-surface (surface to 30nm), NRA measurements V.Kh. Alimov, J. Roth, M. Mayer, J. Nucl. Mater. 337–339 (2005) 619 were used in the range 1–7μm, and a linear drop in the D distribution was assumed in the intermediate sub-surface region (∼30nm to 1μm). Traps were assumed to be saturated so that the D distribution also represented the trap distribution. Three trap energies, 1.07±0.03, 1.34±0.03 and 2.1±0.05eV were required to model the 520, 640 and 900K desorption peaks, respectively. The 1.34 and 1.07eV traps correspond to trapping of a first and second D atom at a vacancy, respectively, while the 2.1eV trap corresponds to atomic D trapping at a void. A fourth trap energy of 0.65eV was used to fit the 400K desorption peak observed by Quastel et al. A.D. Quastel, J.W. Davis, A.A. Haasz, R.G. Macaulay-Newcombe, J. Nucl. Mater. 359 (2006) 8.
Facing severe air pollution issues, China has implemented a series of clean air policies aimed to improve the country's air quality. These policies largely focused on reducing emissions of major air ...pollutants such as sulfur dioxide (SO2) and primary aerosols. However, changes in such pollution also affect radiative forcing. To understand the climate consequences of these clean air actions in China, we evaluate the near-equilibrium climate response to sustained changes in aerosol (and precursors) emission rates equivalent to those that occurred in China between 2006 and 2017. During this period, China's SO2 emissions declined by ∼70%, and black carbon emissions declined by ∼30%. Climate simulations that used a fully coupled ocean and atmosphere climate model indicate that China's reductions in aerosol emission rates from 2006 to 2017 may exert a net increase in global radiative forcing of 0.09 ± 0.03 W m−2 and a mean warming of 0.12 ± 0.01 °C in the Northern Hemisphere; and may also affect the precipitation rates in East Asia and in more distant regions. The success of Chinese policies to further reduce aerosol emissions may bring additional net warming, and this 'unmasked' warming would in turn compound the challenge and urgency of international climate mitigation efforts.
The Dark Side of Plasmonics Gómez, D. E; Teo, Z. Q; Altissimo, M ...
Nano letters,
08/2013, Letnik:
13, Številka:
8
Journal Article
Recenzirano
Plasmonic dark modes are pure near-field modes that can arise from the plasmon hybridization in a set of interacting nanoparticles. When compared to bright modes, dark modes have longer lifetimes due ...to their lack of a net dipole moment, making them attractive for a number of applications. We demonstrate the excitation and optical detection of a collective dark plasmonic mode from individual plasmonic trimers. The trimers consist of triangular arrangements of gold nanorods, and due to this symmetry, the lowest–energy dark plasmonic mode can interact with radially polarized light. The experimental data presented confirm the excitation of this mode, and its assignment is supported with an electrostatic approximation wherein these dark modes are described in terms of plasmon hybridization. The strong confinement of energy in these modes and their associated near fields hold great promise for achieving strong coupling to single photon emitters.
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