Highlights • Guanabenz extended the lifespan of SOD1 G93A mice. • Guanabenz delayed the disease onset of SOD1 G93A mice. • Guanabenz improved motor performance in SOD1 G93A mice. • Guanabenz ...attenuated motor neuron loss in SOD1 G93A mice. • Guanabenz attenuated ER stress and mitochondrial stress.
On monolithic Ni-Nb metallic glass films, we experimentally revealed 6.6% elastic strain limit by in-situ transmission electron microscopy observations. The origin of high elastic strain limit may ...link with high free volume in the film, causing the rearrangement of loosely bonded atomic clusters (or atoms) upon elastic deformation. This high elastic limit of metallic glass films will shed light on new application fields for metallic glasses, and also trigger more studies for deformation mechanism of amorphous materials in general.
Large-scale, highly integrated and low-power-consuming hardware is becoming progressively more important for realizing optical neural networks (ONNs) capable of advanced optical computing. ...Traditional experimental implementations need N
units such as Mach-Zehnder interferometers (MZIs) for an input dimension N to realize typical computing operations (convolutions and matrix multiplication), resulting in limited scalability and consuming excessive power. Here, we propose the integrated diffractive optical network for implementing parallel Fourier transforms, convolution operations and application-specific optical computing using two ultracompact diffractive cells (Fourier transform operation) and only N MZIs. The footprint and energy consumption scales linearly with the input data dimension, instead of the quadratic scaling in the traditional ONN framework. A ~10-fold reduction in both footprint and energy consumption, as well as equal high accuracy with previous MZI-based ONNs was experimentally achieved for computations performed on the MNIST and Fashion-MNIST datasets. The integrated diffractive optical network (IDNN) chip demonstrates a promising avenue towards scalable and low-power-consumption optical computational chips for optical-artificial-intelligence.
Complex-valued neural networks have many advantages over their real-valued counterparts. Conventional digital electronic computing platforms are incapable of executing truly complex-valued ...representations and operations. In contrast, optical computing platforms that encode information in both phase and magnitude can execute complex arithmetic by optical interference, offering significantly enhanced computational speed and energy efficiency. However, to date, most demonstrations of optical neural networks still only utilize conventional real-valued frameworks that are designed for digital computers, forfeiting many of the advantages of optical computing such as efficient complex-valued operations. In this article, we highlight an optical neural chip (ONC) that implements truly complex-valued neural networks. We benchmark the performance of our complex-valued ONC in four settings: simple Boolean tasks, species classification of an Iris dataset, classifying nonlinear datasets (Circle and Spiral), and handwriting recognition. Strong learning capabilities (i.e., high accuracy, fast convergence and the capability to construct nonlinear decision boundaries) are achieved by our complex-valued ONC compared to its real-valued counterpart.
Evasion of immune system is a hallmark of cancer, which enables cancer cells to escape the attack from immune cells. Cancer cells can express many immune inhibitory signalling proteins to cause ...immune cell dysfunction and apoptosis. One of these inhibitory molecules is programmed death-ligand-1 (PD-L1), which binds to programmed death-1 (PD-1) expressed on T-cells, B-cells, dendritic cells and natural killer T-cells to suppress anti-cancer immunity. Therefore, anti-PD-L1 and anti-PD-1 antibodies have been used for the treatment of cancer, showing promising outcomes. However, only a proportion of patients respond to the treatments. Further understanding of the regulation of PD-L1 expression could be helpful for the improvement of anti-PD-L1 and anti-PD-1 treatments. Studies have shown that PD-L1 expression is regulated by signalling pathways, transcriptional factors and epigenetic factors. In this review, we summarise the recent progress of the regulation of PD-L1 expression in cancer cells and propose a regulatory model for unified explanation. Both PI3K and MAPK pathways are involved in PD-L1 regulation but the downstream molecules that control PD-L1 and cell proliferation may differ. Transcriptional factors hypoxia-inducible factor-1α and signal transducer and activation of transcription-3 act on the promoter of PD-L1 to regulate its expression. In addition, microRNAs including miR-570, miR-513, miR-197, miR-34a and miR-200 negatively regulate PD-L1. Clinically, it could increase treatment efficacy of targeted therapy by choosing those molecules that control both PD-L1 expression and cell proliferation.
Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy ...(nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).
Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596).
A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28, with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).
NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.
•The CMISG1701 trial assessed the safety and efficacy of nCRT versus nCT followed by MIE for locally advanced bulky ESCC.•The nCRT followed by MIE strategy could not improve survival significantly compared with the nCT strategy.•The best strategy of neoadjuvant therapy for locally advanced bulky ESCC remains a pending issue.
The microstructure, mechanical and corrosion properties of a cost-effective face-center cubic (fcc)-structured Co-free Fe50Mn27Ni10Cr13 high entropy alloy (HEA), which is developed here, has been ...studied using a comprehensive approach of ex-situ tensile tests, in-situ SEM/EBSD tensile measurements, ex-situ TEM studies, Tafel polarization, and immersion tests. After thermo-mechanical treatments, this alloy exhibits a tensile strength of 463 MPa and elongation of over 40% which are comparable to other expensive HEAs. A miniature-designed dog-bone specimen for in-situ SEM/EBSD measurements was successfully employed to study the underlying deformation mechanisms of the alloy, exhibiting the double-fiber 111 and 001 texture typical of TWIP steels. Nano-, meso- and macro-scale studies revealed that the excellent combination of strength and ductility of this newly-developed cost-effective fcc-structured HEA is originated from the formation of stacking faults and nano-twins during tensile deformation. This newly-developed alloy also exhibits good corrosion resistance in the following solutions: NaCl > NaOH >H2SO4 > HCl. The corrosion resistance was mostly found to be dependent on the amount of Mn-oxide in the passive film formed on the surface of the alloy. This work, following the non-equiatomic HEA design strategy, develops a cost-effective HEA with a good combination of mechanical with corrosion properties, which will trigger more investigations.
•Novel Fe50Mn27Ni10Cr13 HEA exhibits a 111 and 001 double-fiber texture after deformation.•Successful in-situ EBSD/SEM tensile-test at higher strains.•Dislocation glide and mechanical twinning deformation mechanisms.•Good corrosion response as follows: NaCl > NaOH > H2SO4 > HCl.
•The phase selection experienced a crossover and fully amorphous structure was obtained at 300 W.•The competition between surface diffusion and deposition rate was responsible for the microstructure ...of thin films.•Excellent mechanical properties including higher H, σf, and so on were observed for higher deposition power films.
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Recently, medium-entropy alloys (MEAs) combining high hardness with excellent ductility have attracted numerous attentions. Here we synthesize a series of Co-Ni-V-Al MEA thin films by magnetron sputtering at room temperature with deposition power from 60 W to 300 W. The film microstructure, morphology, and mechanical properties depended remarkably on atomic fluence, proportional to deposition power. With increasing atomic fluence, the amorphous phase fraction experienced a process of first decreasing and then increasing, and fully amorphous structure was obtained at 300 W. Surface diffusion is dominated in low incident atomic energy range, while deposition rate effect is dominant over surface diffusion effect in high incident atomic energy range, resulting in the crossover in phase selection. The nanocolumn size increased with atomic fluence from 60 W-films to 150 W-films, accompanied by roughness rise, and remained constant with further increasing atomic fluence, along with roughness drop caused by fully amorphous structure. Excellent mechanical properties including higher hardness, tensile fracture strength, lateral Young’s modulus, better scratch-resistance, lower coefficient of friction, were observed for higher incident atomic energy films. In low atomic fluence range from 60 W-films to 150 W-films, the improved mechanical response mainly come from the reduced fraction of interfacial region between adjacent nanocolumns. Further increasing atomic fluence, it is the bombardment-induced dense nanocolumn boundaries, rather than enhanced adatom diffusion at high atomic fluence, that cause further improved mechanical response. Our current work could pave a way for a controlled synthesis of high-performance MEA thin films via tuning deposition power.
We have recently identified and characterized a novel oncogene, maelstrom (MAEL) from 1q24, in the pathogenesis of hepatocellular carcinoma. In this study, MAEL was investigated for its oncogenic ...role in urothelial carcinoma of the bladder (UCB) tumorigenesis/aggressiveness and underlying molecular mechanisms. Here, we report that overexpression of MAEL in UCB is important in the acquisition of an aggressive and/or poor prognostic phenotype. In UCB cell lines, knockdown of MAEL by short hairpin RNA is sufficient to inhibit cell growth, invasiveness/metastasis and suppressed epithelial-mesenchymal transition (EMT), whereas ectopic overexpression of MAEL promoted cell growth, invasive and/or metastatic capacity and enhanced EMT both in vitro and in vivo. We further demonstrate that MAEL could induce UCB cell EMT by downregulating a critical downstream target, the metastasis suppressor 1 (MTSS1) gene, ultimately leading to an increased invasiveness of cancer cells. Notably, overexpression of MAEL in UCB cells substantially enhanced the enrichment of DNA methyltrans-ferase (DNMT)3B and histone deacetylase (HDAC)1/2 on the promoter of the MTSS1, and thereby epigenetically suppressing the MTSS1 transcription. Downregulation of MTSS1 by MAEL in UCB cells is partially dependent on DNMT3B. Furthermore, we identify that beside the gene amplification of MAEL, miR-186 is a key negative regulator of MAEL and downregulation of miR-186 is another important mechanism for MAEL overexpression in UCBs. These data suggest that overexpression of MAEL, caused by gene amplification and/or decreased miR-186, has a critical oncogenic role in UCB pathogenesis by downregulation of MTSS1, and MAEL could be used as a novel prognostic marker and/or effective therapeutic target for human UCB.
Highlights • The Notch pathway was activated in in vitro and in vivo models of ALS. • Suppression of Notch activation reduced the neuronal apoptotic signaling. • Lithium and VPA suppressed Notch ...activation associated with SOD1 mutation. • Lithium–VPA co-treatment had a synergistic effect in the Notch pathway inhibition.
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