Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two ...basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC.
The evolution of precipitates and the elevated-temperature mechanical and creep properties of Al–Cu 224 cast alloys with the microalloyed transition metals (TMs) of Zr, V, and Sc were investigated. ...The results showed that the addition of TMs can generally delay the transformation from θ″ to θ′ during T7 aging and can effectively increase the coarsening resistance of θ′ during prolonged thermal exposure (T7A), especially in the alloys with combined TM additions. Meanwhile, thermally stable L12-Al3M dispersoids were observed in alloys with Zr and Sc + Zr additions. With the increased thermal stability of the predominant strengthener θ′, both the yield strength and creep resistance at 300 °C were remarkably improved. Under the T7A condition, the alloy with the combined Zr + V addition achieved the highest yield strength at 300 °C with an increase of 37% relative to the base alloy. The alloy microalloyed with Sc + Zr exhibited the best creep resistance with a minimum creep rate of 5.5 × 10−9 s−1 compared with 2.0 × 10−7 s−1 for the base alloy, owing to the co-existence of thermally stable θ′ and Al3(Sc, Zr). The relationship between the evolution of the microstructure and the mechanical properties under the T7A condition was rationalized using the proposed strengthening mechanisms.
The flow stress behavior of 7150 aluminum alloys with different Zr (0–0.15wt%) and V (0.01–0.15wt%) additions was investigated using uniaxial compression tests conducted at various temperatures and ...strain rates. Using the revised Sellars’ constitutive analysis, the activation energy maps for hot deformation of 7150 alloys are proposed, which are considered as a function of deformation temperature, strain rate and micro-alloying elements. The results reveal that the activation energies of all 7150 alloys decrease with increasing deformation temperature and increasing strain rate. The activation energies for hot deformation of the alloy with 0.12–0.15% Zr are remarkably increased compared with those of the base alloy at most deformation conditions due to the pinning effect of Al3Zr dispersoids on dislocation and the restrained dynamic recovery. The 0.05% V addition significantly increases activation energies, preferentially at lower temperatures of 573–623K, correlated with the V solute drag effect. At higher V additions from 0.11% to 0.15%, the activation energy generally increases at the majority of deformation conditions due to the Al21V2 dispersoid pinning effect. However, remarkable decreases in activation energy are exhibited at low deformation temperatures of 573–700K and at low strain rates of 0.001–0.008s−1, attributed to the enhanced dynamical precipitation and severe depletion of solutes. Comparing the activation energy maps for the alloys studied, the effects of the micro-alloying of Zr and V on plastic deformation under specific deformation conditions can be better understood.
Bacterial poly(3-hydroxybutyrate) (P3HB) is a perfectly isotactic, crystalline material possessing properties suitable for substituting petroleum plastics, but high costs and low volumes of its ...production are impractical for commodity applications. The chemical synthesis of P3HB via ring-opening polymerization (ROP) of racemic β-butyrolactone has attracted intensive efforts since the 1960s, but not yet produced P3HB with high isotacticity and molecular weight. Here, we report a route utilizing racemic cyclic diolide (rac-DL) derived from bio-sourced succinate. With stereoselective racemic catalysts, the ROP of rac-DL under ambient conditions produces rapidly P3HB with perfect isotacticity (mm > 99%), high melting temperature (T
= 171 °C), and high molecular weight (M
= 1.54 × 10
g mol
, Đ = 1.01). With enantiomeric catalysts, kinetic resolution polymerizations of rac-DL automatically stops at 50% conversion and yields enantiopure (R,R)-DL and (S,S)-DL with >99% e.e. and the corresponding poly(S)-3HB and poly(R)-3HB with high T
= 175 °C.
MicroRNA-146a and Human Disease Li, L; Chen, X.-P; Li, Y.-J
Scandinavian journal of immunology,
April 2010, Letnik:
71, Številka:
4
Journal Article
Recenzirano
MicroRNAs (MiRNAs) belong to a class of small non-coding regulatory RNAs that act through repression of protein expression at post-transcriptional level and emerge to play important roles in many ...physiological and pathophysiological processes. MiR-146a is a miRNA supposed to regulate innate immune, inflammatory response and antiviral pathway negatively. In this review, we focus on the recent progress in functional role of miR-146a in innate immune, inflammatory response, virus infection and human diseases. Together, these findings indicate that manipulation of miR-146a expression may represent a potential new therapy for several human diseases. Potential use of miR-146a as a biomarker for disease diagnosis, prevention and treatment is also discussed.
Background
Diet and exercise during pregnancy have been used to prevent gestational diabetes mellitus (GDM) with some success.
Objective
To examine the effectiveness of lifestyle intervention on GDM ...prevention and to identify key effectiveness moderators to improve the prevention strategy.
Search strategy
Pubmed, Scopus, Cochrane, and cross‐references were searched.
Selection criteria
Randomised controlled trials (RCTs) evaluating lifestyle interventions during pregnancy for GDM prevention.
Data collection and analysis
Two independent reviewers extracted data. A random‐effects model was used to analyse the relative risk (RR) and 95% confidence interval (95% CI). Meta‐regressions and subgroup analyses were used to investigate important moderators of effectiveness.
Main results
Forty‐seven RCTs involving 15 745 participants showed that diet and exercise during pregnancy were preventive of GDM (RR 0.77, 95% CI 0.69–0.87). Four key aspects were identified to improve the preventive effect: targeting the high‐risk population; an early initiation of the intervention; the correct intensity and frequency of exercise; and gestational weight gain management. Although 24 RCTs targeted women who were overweight or obese, body mass index (BMI) failed to predict the effectiveness of an intervention. Instead, interventions are most effective in high‐incidence populations rather than simply in women who are overweight or obese. Furthermore, exercise of moderate intensity for 50–60 minutes twice a week could lead to an approximately 24% reduction in GDM.
Conclusion
The best strategy to prevent GDM is to target the high‐risk population predicted by risk evaluation models and to control the gestational weight gain of women through intensified diet and exercise modifications early in their pregnancy.
Tweetable
Four key effectiveness moderators of lifestyle interventions for GDM prevention.
Tweetable
Four key effectiveness moderators of lifestyle interventions for GDM prevention.
The hot deformation behavior of a homogenized AA7150 aluminum alloy was studied in compression tests conducted at various temperatures (573–723K) and strain rates (0.001–10s−1). The flow stress ...behavior and microstructural evolution were observed during the hot deformation process. A revised Sellars’ constitutive equation was proposed, which considered the effects of the deformation temperature and strain rate on the material variables and which provided an accurate estimate of the hot deformation behavior of the AA7150 aluminum alloy. The results revealed that the activation energy for the hot deformation of the AA7150 aluminum alloy is not a constant value but rather varies as a function of the deformation conditions. The activation energy for hot deformation decreased with increasing deformation temperature and strain rate. The peak flow stresses under various deformation conditions were predicted by a revised constitutive equation and correlated with the experimental data with excellent accuracy.
The corrosion and electrochemical behaviour of carefully prepared ultra-lightweight magnesium-lithium (Mg-Li) alloys were investigated and compared. The alloy compositions studied were selected to ...provide the ability to compare unique microstructures and crystal structures, which arise from specific alloying additions of Li. Mg-4%Li is hexagonal closed-packed (HCP) alloy with Li in solid solution of Mg (α-Mg); Mg-14%Li is a fully solid solution BCC (β-Li) alloy, whilst Mg-7.5%Li is a duplex (α-Mg + β-Li) alloy. Testing in 0.1 M NaCl revealed that the corrosion performance and electrochemical response of the Mg-Li system evolved with the composition and crystallographic structure. For Mg-4%Li alloy, filiform-like corrosion morphology can be observed on the corroded surface, whilst a mixture of filiform-like corrosion to the α-Mg and localised dissolution of β-Li existed on the corroded surface of Mg-7.5%Li alloy. In the case of the BCC structured Mg-14%Li alloy, minor pitting was observed, concomitant with a generally low corrosion rate (particularly low corrosion rate for typical Mg alloys) and an increasing corrosion resistance with exposure time were also revealed. A combination of exposure testing inclusive of hydrogen collection and mass loss, in addition to potentiodynamic polarisation and impedance spectroscopy elucidated and quantified the corrosion performance of three differently structured Mg-Li alloys. It revealed that in spite of being composed of reactive elements of Mg and Li, the formation of β-Li phases with BCC structure could facilitate the formation of a highly protective surface film which results in a predictable and consistently low corrosion rate of the Mg-14%Li alloy.
•Corrosion behaviour was dependent on the crystal structure of Mg-Li alloys.•Mg-4Li, Mg-7.5Li and Mg-14Li (wt.%) alloys were HCP, HCP + BCC and BCC structure, respectively.•Corrosion attack preferentially occurred in α-Mg phase of Mg-7.5Li alloy.•Mg-14Li alloy revealed a high corrosion resistance which increased with immersion time.•A highly protective surface film could form on Mg-14Li alloy with single β-Li phase.
The transition-metal-based kagome metals provide a versatile platform for correlated topological phases hosting various electronic instabilities. While superconductivity is rare in layered kagome ...compounds, its interplay with nontrivial topology could offer an engaging space to realize exotic excitations of quasiparticles. Here, we use scanning tunneling microscopy to study a newly discoveredZ2topological kagome metalCsV3Sb5with a superconducting ground state. We observe charge modulation associated with the opening of an energy gap near the Fermi level. When across single-unit-cell surface step edges, the intensity of this charge modulation exhibits aπ-phase shift, suggesting a three-dimensional2×2×2charge density wave ordering. Interestingly, while conventional Caroli–de Gennes–Matricon bound states are observed inside the superconducting vortex on the Sb surfaces, a robust zero-bias conductance peak emerges that does not split in a large distance when moving away from the vortex center on the Cs2×2surfaces, resembling the Majorana bound states arising from the superconducting Dirac surface states inBi2Te3/NbSe2heterostructures. Our findings establishCsV3Sb5as a promising candidate for realizing exotic excitations at the confluence of nontrivial lattice geometry, topology and multiple electronic orders.
Abstract Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, ...the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.
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