Flexoelectricity refers to electric polarization generated by heterogeneous mechanical strains, namely strain gradients, in materials of arbitrary crystal symmetries. Despite more than 50 years of ...work on this effect, an accurate identification of its coupling strength remains an experimental challenge for most materials, which impedes its wide recognition. Here, we show the presence of flexoelectricity in the recently discovered polar vortices in PbTiO3/SrTiO3 superlattices based on a combination of machine-learning analysis of the atomic-scale electron microscopy imaging data and phenomenological phase-field modeling. By scrutinizing the influence of flexocoupling on the global vortex structure, we match theory and experiment using computer vision methodologies to determine the flexoelectric coefficients for PbTiO3 and SrTiO3. Our findings highlight the inherent, nontrivial role of flexoelectricity in the generation of emergent complex polarization morphologies and demonstrate a viable approach to delineating this effect, conducive to the deeper exploration of both topics.
Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and ...their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO
)
/(SrTiO
)
suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses
. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.
Abstract
In this first paper in the SUPER GOODS series on powerfully star-forming galaxies in the two GOODS fields, we present a deep SCUBA-2 survey of the GOODS-N at both 850 and 450
μ
m (central ...rms noise of 0.28 mJy and 2.6 mJy, respectively). In the central region, the 850
μ
m observations cover the GOODS-N to near the confusion limit of ∼1.65 mJy, while over a wider 450 arcmin
2
region—well complemented by
Herschel
far-infrared imaging—they have a median
limit of 3.5 mJy. We present
catalogs of 186 850
μ
m and 31 450
μ
m selected sources. We use interferometric observations from the Submillimeter Array (SMA) and the Karl G. Jansky Very Large Array (VLA) to obtain precise positions for 114 SCUBA-2 sources (28 from the SMA, all of which are also VLA sources). We present new spectroscopic redshifts and include all existing spectroscopic or photometric redshifts. We also compare redshifts estimated using the 20 cm/850
μ
m and the 250 cm/850
μ
m flux ratios. We show that the redshift distribution increases with increasing flux, and we parameterize the dependence. We compute the star formation history and the star formation rate (SFR) density distribution functions in various redshift intervals, finding that they reach a peak at
before dropping to higher redshifts. We show that the number density per unit volume of
galaxies measured from the SCUBA-2 sample does not change much relative to that of lower SFR galaxies from UV selected samples over
, suggesting that, apart from changes in the normalization, the shape in the number density as a function of SFR is invariant over this redshift interval.
Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis ...factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.
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•TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation•Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization•CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination•Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy
Lim et al. show that inflammation increases PD-L1 expression in tumors through TNF-α-mediated activation of NF-κB, leading to transactivation of CSN5. CSN5 reduces PD-L1 ubiquitination and stabilizes it. Inhibition of CSN5 cooperates with anti-CTLA4 to enhance anti-tumor T cell function and reduce tumor growth.
Hypoxia plays a critical role during the evolution of malignant cells and tumour microenvironment (TME).Tumour-derived exosomes contain informative microRNAs involved in the interaction of cancer and ...stromal cells, thus contributing to tissue remodelling of tumour microenvironment. This study aims to clarify how hypoxia affects tumour angiogenesis through exosomes shed from lung cancer cells. Lung cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. miR-23a was significantly upregulated in exosomes from lung cancer under hypoxic conditions. Exosomal miR-23a directly suppressed its target prolyl hydroxylase 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1 α (HIF-1 α) in endothelial cells. Consequently, hypoxic lung cancer cells enhanced angiogenesis by exosomes derived from hypoxic cancer under both normoxic and hypoxic conditions. In addition, exosomal miR-23a also inhibits tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration. Inhibition of miR-23a by inhibitor administration decreased angiogenesis and tumour growth in a mouse model. Furthermore, elevated levels of circulating miR-23a are found in the sera of lung cancer patients, and miR-23a levels are positively correlated with proangiogenic activities. Taken together, our study reveals the clinical relevance and prognostic value of cancer-derived exosomal miR-23a under hypoxic conditions, and investigates a unique intercellular communication, mediated by cancer-derived exosomes, which modulates tumour vasculature.
Breast cancer affects approximately 1 in 8 women, and it is estimated that over 246,660 women in the USA will be diagnosed with breast cancer in 2016. Breast cancer mortality has decline over the ...last two decades due to early detection and improved treatment. Over the last few years, there is mounting evidence to demonstrate the prominent role of receptor tyrosine kinases (RTKs) in tumor initiation and progression, and targeted therapies against the RTKs have been developed, evaluated in clinical trials, and approved for many cancer types, including breast cancer. However, not all breast cancers are the same as evidenced by the multiple subtypes of the disease, with some more aggressive than others, showing differential treatment response to different types of drugs. Moreover, in addition to canonical signaling from the cell surface, many RTKs can be trafficked to various subcellular compartments, e.g., the multivesicular body and nucleus, where they carry out critical cellular functions, such as cell proliferation, DNA replication and repair, and therapeutic resistance. In this review, we provide a brief summary on the role of a selected number of RTKs in breast cancer and describe some mechanisms of resistance to targeted therapies.
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that ...epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.
We combine deep X-ray survey data from the Chandra
observatory and the wide-area/shallow XMM-XXL field to estimate the active galactic nuclei (AGN) X-ray luminosity function in the redshift range ...z = 3–5. The sample consists of nearly 340 sources with either photometric (212) or spectroscopic (128) redshift in the above range. The combination of deep and shallow survey fields also provides a luminosity baseline of three orders of magnitude, L
X(2–10 keV) ≈ 1043–1046 erg s− 1 at z > 3. We follow a Bayesian approach to determine the binned AGN space density and explore their evolution in a model-independent way. Our methodology properly accounts for Poisson errors in the determination of X-ray fluxes and uncertainties in photometric redshift estimates. We demonstrate that the latter is essential for unbiased measurement of space densities. We find that the AGN X-ray luminosity function evolves strongly between the redshift intervals z = 3–4 and z = 4–5. There is also suggestive evidence that the amplitude of this evolution is luminosity dependent. The space density of AGN with L
X(2–10 keV) < 1045 erg s− 1 drops by a factor of 5 between the redshift intervals above, while the evolution of brighter AGN appears to be milder. Comparison of our X-ray luminosity function with that of ultraviolet (UV)/optical selected quasi-stellar objects at similar redshifts shows broad agreement at bright luminosities, L
X(2–10 keV) > 1045 erg s− 1. At fainter luminosities X-ray surveys measure higher AGN space densities. The faint-end slope of UV/optical luminosity functions, however, is steeper than for X-ray selected AGN. This implies that the Type I AGN fraction increases with decreasing luminosity at z > 3, opposite to trends established at lower redshift. We also assess the significance of AGN in keeping the hydrogen ionized at high redshift. Our X-ray luminosity function yields ionizing photon rate densities that are insufficient to keep the Universe
ionized at redshift z > 4. A source of uncertainty in this calculation is the escape fraction of UV photons for X-ray selected AGN.
The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and ...immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1
TIM-3
T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3
cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T
cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T
cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.
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