The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid ...leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.
Inspired by P(c)(4380) and P(c)(4450) recently observed by LHCb, a QCD sum rule investigation is performed, by which they can be identified as exotic hidden-charm pentaquarks composed of an ...anticharmed meson and a charmed baryon. Our results suggest that P(c)(4380) and P(c)(4450) have quantum numbers J(P)=3/2(-) and 5/2(+), respectively. Furthermore, two extra hidden-charm pentaqurks with configurations D̅Σ(c)(*) and D̅(*)Σ(c)(*) are predicted, which have spin-parity quantum numbers J(P)=3/2(-) and J(P)=5/2(+), respectively. As an important extension, the mass predictions of hidden-bottom pentaquarks are also given. Searches for these partners of P(c)(4380) and P(c)(4450) are especially accessible at future experiments like LHCb and BelleII.
By combining angle-resolved photoemission spectroscopy and quantum oscillation measurements, we performed a comprehensive investigation on the electronic structure of LaSb, which exhibits ...near-quadratic extremely large magnetoresistance (XMR) without any sign of saturation at magnetic fields as high as 40 T. We clearly resolve one spherical and one intersecting-ellipsoidal hole Fermi surfaces (FSs) at the Brillouin zone (BZ) center Γ and one ellipsoidal electron FS at the BZ boundary X. The hole and electron carriers calculated from the enclosed FS volumes are perfectly compensated, and the carrier compensation is unaffected by temperature. We further reveal that LaSb is topologically trivial but shares many similarities with the Weyl semimetal TaAs family in the bulk electronic structure. Based on these results, we have examined the mechanisms that have been proposed so far to explain the near-quadratic XMR in semimetals.
Metasurfaces control light propagation at the nanoscale for applications in both free-space and surface-confined geometries. However, dynamically changing the properties of metasurfaces can be a ...major challenge. Here we demonstrate a reconfigurable hyperbolic metasurface comprised of a heterostructure of isotopically enriched hexagonal boron nitride (hBN) in direct contact with the phase-change material (PCM) single-crystal vanadium dioxide (VO
). Metallic and dielectric domains in VO
provide spatially localized changes in the local dielectric environment, enabling launching, reflection, and transmission of hyperbolic phonon polaritons (HPhPs) at the PCM domain boundaries, and tuning the wavelength of HPhPs propagating in hBN over these domains by a factor of 1.6. We show that this system supports in-plane HPhP refraction, thus providing a prototype for a class of planar refractive optics. This approach offers reconfigurable control of in-plane HPhP propagation and exemplifies a generalizable framework based on combining hyperbolic media and PCMs to design optical functionality.
Aims
CLARITY is a novel technique which enables three‐dimensional visualization of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. ...In this study, we aimed to compare methodological differences in the application of CLARITY between rodent and large human post mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualize Lewy pathology in a post mortem Parkinson's brain.
Methods
Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualizing under a confocal microscope.
Results
We found that tissue clearing speed using passive CLARITY differs according to species (human vs. rodents), brain region and degree of fixation (fresh vs. formalin‐fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualized Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue.
Conclusions
The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.
By refining the method for CLARITY studies in human brain tissue the authors pave the way for advancing the contribution of three‐dimensional microscopic analysis in the investigation of neurological disorders.
We identify stellar structures in the PHANGS sample of 74 nearby galaxies and construct morphological masks of sub-galactic environments based on
Spitzer
3.6
μ
m images. At the simplest level, we ...distinguish five environments: centres, bars, spiral arms, interarm regions, and discs without strong spirals. Slightly more sophisticated masks include rings and lenses, which are publicly released but not explicitly used in this paper. We examine trends with environment in the molecular gas content, star formation rate, and depletion time using PHANGS–ALMA CO(2–1) intensity maps and tracers of star formation. The interarm regions and discs without strong spirals clearly dominate in area, whereas molecular gas and star formation are quite evenly distributed among the five basic environments. We reproduce the molecular Kennicutt–Schmidt relation with a slope compatible with unity within the uncertainties and without significant slope differences among environments. In contrast to what has been suggested by early studies, we find that bars are not always deserts devoid of gas and star formation, but instead they show large diversity. Similarly, spiral arms do not account for most of the gas and star formation in disc galaxies, and they do not have shorter depletion times than the interarm regions. Spiral arms accumulate gas and star formation, without systematically boosting the star formation efficiency. Centres harbour remarkably high surface densities and on average shorter depletion times than other environments. Centres of barred galaxies show higher surface densities and wider distributions compared to the outer disc; yet, depletion times are similar to unbarred galaxies, suggesting highly intermittent periods of star formation when bars episodically drive gas inflow, without enhancing the central star formation efficiency permanently. In conclusion, we provide quantitative evidence that stellar structures in galaxies strongly affect the organisation of molecular gas and star formation, but their impact on star formation efficiency is more subtle.
An austenitic stainless steel 316L part was fabricated by cold metal transfer wire and arc additive manufacturing (CMT-WAAM), and its microstructure, microhardness and tensile properties were ...investigated. Results showed that the as-built 316L part exhibited a multilayered structure along the building direction. In the transverse direction (perpendicular to scanning direction) of each layer, there was also a multilayered structure of alternating overlapping zone (OA) and re-melting zone (RA). Compared with the OA, the RA had higher ferrite content, smaller austenite dendrite size, more dispersed orientation and lower residual stress. The overall multilayered structure and the intra-layer non-equilibrium microstructure exhibit a great influence on the mechanical properties of as-built 316L part. Along the building and transverse direction, the microhardness distribution in the OA was uniform, while the RA showed a trend of lower hardness in the middle and higher hardness on both sides of the RA layer. The effect of multilayered structure on tensile properties was stronger in the transverse direction than that in the building direction. The deformation feature was obviously inconsistent between the OA and RA. Local necking and fracture always occurred in the OA. Microvoids trended to initiate at silicate impurity particles, grow into large cracks, and finally lead to material failure during tension.
Aims.
The complexity of star formation at the physical scale of molecular clouds is not yet fully understood. We investigate the mechanisms regulating the formation of stars in different environments ...within nearby star-forming galaxies from the Physics at High Angular resolution in Nearby GalaxieS (PHANGS) sample.
Methods.
Integral field spectroscopic data and radio-interferometric observations of 18 galaxies were combined to explore the existence of the resolved star formation main sequence (Σ
stellar
versus Σ
SFR
), resolved Kennicutt–Schmidt relation (Σ
mol. gas
versus Σ
SFR
), and resolved molecular gas main sequence (Σ
stellar
versus Σ
mol. gas
), and we derived their slope and scatter at spatial resolutions from 100 pc to 1 kpc (under various assumptions).
Results.
All three relations were recovered at the highest spatial resolution (100 pc). Furthermore, significant variations in these scaling relations were observed across different galactic environments. The exclusion of non-detections has a systematic impact on the inferred slope as a function of the spatial scale. Finally, the scatter of the Σ
mol. gas + stellar
versus Σ
SFR
correlation is smaller than that of the resolved star formation main sequence, but higher than that found for the resolved Kennicutt–Schmidt relation.
Conclusions.
The resolved molecular gas main sequence has the tightest relation at a spatial scale of 100 pc (scatter of 0.34 dex), followed by the resolved Kennicutt–Schmidt relation (0.41 dex) and then the resolved star formation main sequence (0.51 dex). This is consistent with expectations from the timescales involved in the evolutionary cycle of molecular clouds. Surprisingly, the resolved Kennicutt–Schmidt relation shows the least variation across galaxies and environments, suggesting a tight link between molecular gas and subsequent star formation. The scatter of the three relations decreases at lower spatial resolutions, with the resolved Kennicutt–Schmidt relation being the tightest (0.27 dex) at a spatial scale of 1 kpc. Variation in the slope of the resolved star formation main sequence among galaxies is partially due to different detection fractions of Σ
SFR
with respect to Σ
stellar
.
Abstract Background A meta-analysis was conducted to investigate the much-debated relationship between the gene expression of programmed cell death-ligand 1 (PD-L1) and cancer patient prognosis. The ...prognostic value of measuring PD-L1 expression in non-small cell lung cancer (NSCLC) patients was analyzed. Methods We searched PubMed for studies about the relationship between PD-L1 expression and NSCLC patient prognosis. Only studies with patient survival data related to PD-L1 expression in NSCLC patients with different characteristics were included. The effect size (ES) for this analysis was the hazard ratio (HR) with 95% confidence intervals (CI) for overall survival (OS). Results Six studies with 1157 patients were included with the defined including and excluding criteria. There is no significant heterogeneity among the studies (I2 = 0%, p = 0.683). PD-L1 expression was significantly associated with the differentiation of tumor (poor vs. well: OR = 1.91, 95% CI: 1.33–2.75, p = 0.001). High PD-L1 expression was also correlated with poor prognosis in terms of the OS of patients with NSCLC (pooled HR = 1.75, 95% CI: 140–2.20, p < 0.001; heterogeneity test: I2 = 0%, p = 0.643). Conclusions NSCLC patients with positive PD-L1 expression exhibited poor OS. The PD-L1 expression was higher in tumors with poor differentiation.
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