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Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+subset polarization in a paracrine mode, in which TGFβ and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.govas #NCT03764228.

A fundamental understanding of the oxidation mechanisms of aluminum (Al) alloys is of great importance for its applications in corrosion, catalysis, sensors, etc. In this work, we systematically investigated the first-stage oxidation behaviors of three low-index Al facets with O coverage up to two monolayers (ML) by using density-functional theory (DFT). The large negative adsorption energies indicated favorable oxidation on all three facets. However, distinctive structural and electronic changes induced by the adsorption of oxygen have led to different oxidation modes. More specifically, the oxidation process proceeded by “intercalating” into the subsurface region along the (111) plane out of the (110) facet with spontaneous O ingress into (110) far below one ML, as revealed by the electron density distribution, whereas the oxide ad-layer grew in a “layer-by-layer” mode on Al(111) and (001) facets. Moreover, various Al–O complexes with different atomic coordination numbers (CN), configurations, and sizes may be indicators of the tendency of an Al surface to be oxidized. Besides, the oxide phases formed on (111)/(001) and (110) assembled the Al–O bond distribution within α-Al2O3and γ-Al2O3, respectively.

Long-time discontinuous contact is easy to cause tool wear during milling. To decrease the impact of severe wear on workpiece quality and processing efficiency, cutting tools should be replaced timely. Therefore, tool wear prediction is an important aspect in improving process efficiency, ensuring machining precision and realizing intelligent manufacturing. To boost the precision of online prediction of tool wear, this paper suggests a novel approach to monitor tool wear by optimizing backpropagation (BP) neural network via firefly algorithm (FA). Specifically, the progressive semi-soft threshold function is applied to the process of cutting force signal noise reduction, which reduces redundant signals and noise interference in the signal. Time-domain analysis, frequency-domain analysis, and wavelet packet decomposition are utilized, cutting force features are extracted, and Pearson correlation coefficient is used to sift out signal features that are highly connected to tool wear. The FA is used to improve the BP neural network's weights and thresholds. Through learning nonlinear mapping, relationship between tool flank wear and signal features is realized. A prediction model of tool wear of FA-BP is constructed. Milling experiments validate the prediction model in the milling process. The experimental outcomes confirm the precision and reliability of the method. In comparison to BP neural network, genetic algorithm optimized BP neural network and particle swarm optimization algorithm optimized BP neural network prediction method, it has a greater prediction accuracy and a stronger training impact, and has superior performance. The research results can give a theoretical foundation and technological assistance for predicting tool wear, which is crucial for improving workpiece quality, processing efficiency, and promoting intelligent development.

This case demonstrated the possibility of using GATA3-positive circulating tumor cells (CTCs) to detect early-stage breast cancer (BrC).

Some antinuclear antibodies (ANAs) bind extracellular nucleic acids released into tumor environments and are pulled into the nuclei of live cancer cells through nucleoside salvage pathways, independent of tumor-specific surface antigens. Here we show that ANA nuclear penetration induces nuclear flux by the lysosomal protease cathepsin B and leverage this mechanism to design an antinuclear antibody–drug conjugate (ANADC) with cathepsin B-labile drug linker. The ANADC targets nucleic acid exhaust from necrotic tumors and crosses membrane barriers through nucleoside salvage as a DNA-seeking and tumor agnostic “antinuclear missile” cancer therapy.

Chemical derivatization is a widely employed strategy in metabolomics to enhance metabolite coverage by improving chromatographic behavior and increasing the ionization rates in mass spectroscopy (MS). However, derivatization might complicate MS data, posing challenges for data mining due to the lack of a corresponding benchmark database. To address this issue, we developed a triple-dimensional combinatorial derivatization strategy for nontargeted metabolomics. This strategy utilizes three structurally similar derivatization reagents and is supported by MS-TDF software for accelerated data processing. Notably, simultaneous derivatization of specific metabolite functional groups in biological samples produced compounds with stable but distinct chromatographic retention times and mass numbers, facilitating discrimination by MS-TDF, an in-house MS data processing software. In this study, carbonyl analogues in human plasma were derivatized using a combination of three hydrazide-based derivatization reagents: 2-hydrazinopyridine, 2-hydrazino-5-methylpyridine, and 2-hydrazino-5-cyanopyridine (6-hydrazinonicotinonitrile). This approach was applied to identify potential carbonyl biomarkers in lung cancer. Analysis and validation of human plasma samples demonstrated that our strategy improved the recognition accuracy of metabolites and reduced the risk of false positives, providing a useful method for nontargeted metabolomics studies. The MATLAB code for MS-TDF is available on GitHub at https://github.com/CaixiaYuan/MS-TDF.

Bispecific antibodies (BsAbs) are undergoing continued development for applications in oncology and autoimmune diseases. While increasing activity by having more than one targeting arm, most BsAb engineering employs single Fc engagement as monoclonal antibodies. Here, we designed a novel immunoglobulin gamma-1 (IgG1)-derived dual-Fc BsAb containing two Fc regions and two distinct asymmetric antigen binding arms comprising a Fab arm and another VHH domain. In conjunction with the knob-into-hole technology, dual-Fc BsAbs could be produced with a high yield and good stability. We explore how Fc engineering effects on dual-Fc constructs could boost the desired therapeutic efficacy. This new format enabled simultaneous bispecific binding to corresponding antigens. Furthermore, compared to the one-Fc control molecules, dual-Fc BsAbs were shown to increase the avidity-based binding to FcγRs to result in higher ADCC and ADCP activities by potent avidity via binding to two antigens and Fc receptors. Overall, this novel BsAb format with enhanced effector functionalities provides a new option for antibody-based immunotherapy.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n= 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n= 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P= 0.003), higher overall response rate (44.0% versus 13.0%, P= 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P= 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239.

ABSTRACTCrizotinib, a small-molecule tyrosine kinase inhibitor targeting ALK, MET and ROS1, is the first-line drug for ALK-positive metastatic non-small cell lung cancer and is associated with severe, sometimes fatal, cases of cardiac failure, which increases the risk of mortality. However, the underlying mechanism remains unclear, which causes the lack of therapeutic strategy. We established in vitro and in vivo models for crizotinib-induced cardiotoxicity and found that crizotinib caused left ventricular dysfunction, myocardial injury and pathological remodeling in mice and induced cardiomyocyte apoptosis and mitochondrial injury. In addition, we found that crizotinib prevented the degradation of MET protein by interrupting autophagosome-lysosome fusion and silence of MET or re-activating macroautophagy/autophagy flux rescued the cardiomyocytes death and mitochondrial injury caused by crizotinib, suggesting that impaired autophagy activity is the key reason for crizotinib-induced cardiotoxicity. We further confirmed that recovering the phosphorylation of PRKAA/AMPK (Ser485/491) by metformin re-activated autophagy flux in cardiomyocytes and metformin rescued crizotinib-induced cardiomyocyte injury and cardiac complications. In summary, we revealed a novel mechanism for crizotinib-induced cardiotoxicity, wherein the crizotinib-impaired autophagy process causes cardiomyocyte death and cardiac injury by inhibiting the degradation of MET protein, demonstrated a new function of impeded autophagosome-lysosome fusion in drugs-induced cardiotoxicity, pointed out the essential role of the phosphorylation of PRKAA (Ser485/491) in autophagosome-lysosome fusion and confirmed metformin as a potential therapeutic strategy for crizotinib-induced cardiotoxicity.Abbreviations and Acronyms:AAV: adeno-associated virus; ACAC/ACC: acetyl-Co A carboxylase; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; CHX: cycloheximide; CKMB: creatine kinase myocardial band; CQ: chloroquine; c-PARP: cleaved poly (ADP-ribose) polymerase; DAPI: 4ʹ6-diamidino-2-phenylindole; EF: ejection fraction; FOXO: forkhead box O; FS: fractional shortening; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HF: heart failure; HW: TL: ratio of heart weight to tibia length; IR: ischemia-reperfusion; KEGG: Kyoto encyclopedia of genes and genomes; LAMP2: lysosomal-associated membrane protein 2; LDH: lactate dehydrogenase; MCMs: mouse cardiomyocytes; MMP: mitochondrial membrane potential; mtDNA: mitochondrial DNA; MYH6: myosin, heavy peptide 6, cardiac muscle, alpha; MYH7: myosin, heavy peptide 7, cardiac muscle, beta; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; PI: propidium iodide; PI3K: phosphoinositide 3-kinase; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; qPCR: quantitative real-time PCR; SD: standard deviation; SRB: sulforhodamine B; TKI: tyrosine kinase inhibitor; WGA: wheat germ agglutinin

This article investigates the fault-tolerant coordinated tracking control problem for networked fixed-wing unmanned aerial vehicles (UAVs) against faults and communication delays. By supplementing the commonly used Gaussian functions in the fuzzy neural networks (FNNs) with sine–cosine functions and constructing two kinds of recurrent loops within the FNN architecture, double recurrent perturbation FNNs are cleverly designed to learn the unknown terms containing faults and uncertainties. Then, adaptive laws are designed for double recurrent perturbation FNNs. Moreover, by assimilating fractional-order calculus into the sliding-mode surfaces and the control signals, refined transient-state and steady-state adjustment performances can be obtained. It is shown by Lyapunov stability analysis that all fixed-wing UAVs can coordinately track their desired trajectories and the tracking errors are uniformly ultimately bounded. Comparative simulation results are provided to show the effectiveness of the proposed control strategy.

• In-situ bulk metallic glass composites (BMGCs) with excellent ductility and work hardening were successfully developed using a low vacuum high pressure die casting (LV-HPDC) technology along with industrial grade raw materials. • The LV-HPDC method shows a smaller volume fraction difference of the dendrite phase for BMGCs with the same composition, although the size of the β-phase is generally larger compared to the copper mold suction casting method. • The ductility of the BMGCs prepared by LV-HPDC can be maintained if two conditions are met: (1) the volume fraction of β phase stays below 62% ± 2%, and (2) the appearance of the dendritic phase satisfies a size uniformity. The glass-forming ability and mechanical properties of metallic glasses and their composites are well known to be sensitive to the preparation conditions and are highly deteriorated by industrial preparing conditions such as low-purity raw materials and low vacuum. Here, we showed that a series of in-situ bulk metallic glass composites (BMGCs) which exhibit excellent ductility and segmental work hardening were successfully developed utilizing a high vacuum high-pressure die casting (HV-HPDC) technology along with industrial-grade raw materials. The tensile properties of these BMGCs are systematically investigated and correlated with the alloy microstructure. As compared with the copper mold suction casting method, the volume fraction difference of the dendrite phase for the BMGCs with the same composition is not significant when fabricated by the HV-HPDC, whereas the size of the β-phase is generally larger. In-situ BMGCs with the composition of Ti 48 Zr 20 (V 12/17 Cu 5/17) 19 Be 13 obtained by the HV-HPDC process show ductility up to 11.3% under tension at room temperature and exhibit a certain amount of work hardening. Two conditions need to be met to enable the BMGCs, which are prepared by vacuum die-casting to retain favorable ductility: (1) The volume fraction of β phase stays below 62% ± 2%; (2) The equiaxed crystals with a more uniform size in the range of 5–10 μm. Meanwhile, the results of the present study provided guidance for developing BMGCs with good ductile properties under industrial conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

To overcome the problems of low recall and precision and high error rate of satisfaction evaluation in traditional evaluation methods, a user satisfaction evaluation method of MOOC teaching platform based on multidimensional association rules is proposed. We use Boolean matrix and weight to improve apriori algorithm, and multidimensional association rules mining algorithm based on improved apriori algorithm to mine MOOC teaching platform data. The evaluation index system is constructed according to the data mined, and the evaluation index weight is calculated in combination with the weight factor, so as to build a satisfaction evaluation model based on second-order hidden Markov. The evaluation index data is input into the model, and the user satisfaction results of MOOC teaching platform are obtained. The simulation results show that the average recall rate is 96.9%, the average accuracy rate is 96.2%, and the evaluation error rate is always below 2.2%.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n= 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n= 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%–58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%–33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%–39.6%; P= 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%–35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%–17.9%); P= 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3–4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948.

Scanning electrochemical cell microscopy (SECCM) allows for electrochemical imaging at the micro- or nanoscale by confining the electrochemical reaction cell in a small meniscus formed at the end of a micro- or nanopipette. This technique has gained popularity in electrochemical imaging due to its high-throughput nature. Although it shows considerable application potential in corrosion science, there are still formidable and exciting challenges to be faced, particularly relating to the high-throughput characterization and analysis of microelectrochemical big data. The objective of this perspective is to arouse attention and provide opinions on the challenges, recent progress, and future prospects of the SECCM technique to the electrochemical society, particularly from the viewpoint of corrosion scientists. Specifically, four main topics are systematically reviewed and discussed: (1) the development of SECCM; (2) the applications of SECCM for corrosion studies; (3) the challenges of SECCM in corrosion studies; and (4) the opportunities of SECCM for corrosion science.

The coronavirus disease 2019 (COVID-19) continues to spread worldwide. Integrated Chinese and Western medicine have had some successes in treating COVID-19.

Corrosion under insulation (CUI) is a crucial issue in the industry. Its importance has been increasingly acknowledged because of the high cost and potential danger of causing severe losses. This review gives essential knowledge of CUI and summarizes the research from several aspects, including lab experiments, field tests, CUI prediction methods and numerical simulation research in porous materials. Insulation material, coating, substrate metallic material of the equipment, operating temperature and surroundings are some critical factors that should be considered in the CUI problem. Experimental research methods of CUI and mass transfer in insulation materials were summarized, as well as the applications of data science in CUI prediction. This review also focuses on simulation researches on heat and moisture transfer in porous insulation materials since numerical simulations are helpful for establishing validated models for CUI by modeling to describe the specific processes and predict environmental conditions of CUI for further corrosion research. Combined experimental and simulation work of CUI would be a practical and effective method for CUI research.

The elongation of photosynthesis, or functional staygreen, represents a feasible strategy to propel metabolite flux towards cereal kernels. However, achieving this goal remains a challenge in food crops. Here we report the cloning of wheat CO2assimilation and kernel enhanced 2(cake2), the mechanism underlying the photosynthesis advantages and natural alleles amenable to breeding elite varieties. A premature stop mutation in the A-genome copy of the ASPARTIC PROTEASE 1(APP-A1) gene increased the photosynthesis rate and yield. APP1 bound and degraded PsbO, the protective extrinsic member of photosystem II critical for increasing photosynthesis and yield. Furthermore, a natural polymorphism of the APP-A1gene in common wheat reduced APP-A1’s activity and promoted photosynthesis and grain size and weight. This work demonstrates that the modification of APP1increases photosynthesis, grain size and yield potentials. The genetic resources could propel photosynthesis and high-yield potentials in elite varieties of tetraploid and hexaploid wheat.

The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer.

Older patients represent an inordinate proportion of intensive care unit (ICU) admissions and ICU mortality associated with coronavirus disease 2019 (COVID-19). In this retrospective cohort study, we examine 198 patients, aged 18 years or older, admitted to the ICU from March to June 2020. We aim to understand the relationships between age, number of comorbidities, and independent living prior to admission on outcomes of mortality, length of stay, renal failure, respiratory failure, and shock. In this cohort, we find that overall mortality was associated with respiratory failure severity (for every decrease of P:F by 50, odds ratio (OR) 2.98 (1.65–6.08)), acute renal failure (OR 4.61 (1.2–19.7)), and age 65 or greater (OR: 3.7 (1.86–7.36)). Surprisingly, increasing age was associated with less severe respiratory failure (R = 0.22, p < 0.01). When adjusting for pre-existing chronic kidney disease, age was not associated with development of acute kidney injury (OR: 1.01 (0.99–1.03)). While chronologic age is associated with mortality, it is not associated independently with severe end organ damage. This is consistent with growing evidence suggesting that a complex interplay between multimorbidity, immunosenescence, and physiologic age is primarily responsible for the vulnerability to COVID-19.

Introduction: Animal experiments have shown that anti-GBM antibodies play a pathogenic role in anti-GBM disease. However, the relationship between anti-GBM antibody levels and kidney outcomes in patients with anti-GBM disease is unclear. Methods: We performed a retrospective analysis of 110 patients diagnosed with anti-GBM disease. We compared their baseline characteristics stratifying on different anti-GBM antibody levels, and used Cox regression analysis to analyze the correlation between antibody levels and kidney survival. We further selected 69 patients to evaluate the modification of antibody titers over 14 days of treatment, then compared kidney survival of patients in the group with antibody level decrease &lt; 48% to those with antibody decrease ≥ 48%. Results: The 110 patients had a median follow-up of 27.1 (Q1–Q3: 7.9–80.1) months, and among them 90 (81.8%) developed kidney failure. Multivariate analysis suggested that anti-GBM antibody level was an independent risk factor for progression to kidney failure in patients with anti-GBM disease (HR 1.08, 95% CI 1.01–1.16). The patients who reduced the antibodies levels quickly had better kidney survival than those who did not, and multivariate analysis also indicated that antibody decrease rate was related to kidney outcomes. Conclusions: Anti-GBM antibody level is closely related to kidney outcomes in patients with anti-GBM disease, and short-term reduction of antibodies can be beneficial to improving kidney outcomes. Graphical abstract:

A novel oxyfluoride red phosphor of K3Nb2F11O:Mn4+(KNOF:Mn4+) was synthesized by the hydrothermal and the cation exchange methods. Detailed calculations of crystal field strength (Dq), Racah parameters (Band C) and nephelauxetic ratio (β1) were performed to assess the crystal field environment of Mn4+in K3Nb2F11O. The non-equivalent substitution of Nb5+ions by Mn4+ions produces a bright narrow red emission under blue light excitation. K3Nb2F11O:Mn4+red phosphor shows a narrow emission band in the 580–660 nm under excitation at 470 nm. At the Mn4+doping concentration of 7 mol%, the greatest luminescence of the sample was observed. In addition, doping Mo6+as the charge compensation ion has been shown to enhance the luminescence intensity of the red phosphor to 7 times. The resulting red phosphor (KNOF:Mn4+, Mo6+) exhibits exceptional water stability and thermal stability. After being immersed in water for 6 h, it maintained 91 % of its initial luminous intensity and 82 % of its initial luminous intensity at the test temperature of 423K. The prepared red phosphors KNOF:Mn4+and KNOF:Mn4+, Mo6+as red components can be combined with commercial yellow phosphor (YAG:Ce3+) and InGaN blue chip, as well as with commercial blue, green phosphors (BaMgAl10O17:Eu2+, (Ba, Sr)2SiO4:Eu2+) and UV chip to encapsulate warm white light emitting diodes (WLEDs), respectively. It is noteworthy that the correlated color temperature (CCT) and color rendering index (CRI) of the warm WLED devices prepared with KNOF:Mn4+, Mo6+as the red component have considerably improved. Finally, flexible KNOF:Mn4+, Mo6+-PDMS (Polydimethylsiloxane) film was prepared and encapsulated into red LED, which significantly enhanced the versatility of the phosphor.

A hydrothermal method was used to synthesize two highly stable Zn(II) metal–organic frameworks (MOFs), namely, [Zn2(L)2(HIPA)]n(1) and [Zn9(L)6(BTEC)3(H2O)4·6H2O]n(2) (HL= 3-amino-1H-1,2,4-triazole, H2HIPA= 5-hydroxyisophthalic acid, H4BTEC= benzene-1,2,4,5-tetracarboxylic acid). The physicochemical properties of 1and 2were characterized using a range of analytical techniques. The scanning electron microscopy images confirmed the stability of the MOFs under heating at 120 °C for 12 h. Following their preparation, the two MOFs were used as catalysts in the grafting of poly(ε-caprolactone) on wood nanofibers (WNFs) by means of a homogeneous ring-opening polymerization protocol in an ionic liquid. The grafting ratio achieved using catalyst 1was higher than that achieved for catalyst 2, wherein a maximum of 92.43% was obtained using the former. Under comparable reaction conditions, the grafting ratio of 1was found to be significantly higher than those achieved using 4-dimethylamino pyridine, Sn(Oct)2, and UiO-67 catalysts. In addition, fluorescence emission was detected from the residual catalysts present in the products. The calculated electrostatic potentials and average local ionization energies indicated that the grafting of ε-caprolactone on the WNFs follows a “coordination–insertion” mechanism. Overall, these two new and efficient MOF catalysts have the potential to replace highly toxic traditional catalysts in polymerization reactions. The grafted cellulose material with fluorescence emission may also be suitable for use in biomedical applications.

Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)—the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WTGBM. In line with these findings, BRD8is highly expressed with H2AZin proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WTGBM.

Students’ perceived values and costs of learning chemistry influence their performance and intentions of choosing chemistry-related majors or careers. Based on Situated Expectancy-Value Theory, this study adopted a mixed method approach to examine the conceptualization of values and costs among Chinese high school students and identify their relations with chemistry test performance across gender. Qualitative content analyses revealed that students’ perceived values for chemistry could be categorized into five broad categories: utility value, epistemic value, intrinsic value, aesthetic value, and social value. Chi-square tests and multidimensional scaling revealed that boys and girls perceived values and costs in different ways: relational utility value was more salient to boys while practical utility value and epistemic value were more salient to girls; Girls perceived greater distinctions among different types of values (i.e., epistemic- and emotional-related values) and costs (i.e., emotional and ego cost) than boys. Independent ttests showed that boys reported mostly higher values and lower costs than girls. Hierarchical multiple regression found that gender, intrinsic value, social value and cost significantly predicted students’ chemistry exam scores. In addition, the interaction between gender and social value was identified. This study highlights the complexity of perceived values and costs of learning chemistry and provide implications for developing activities or interventions that foster student engagement in chemistry learning.

Predicting and optimizing thermal conductivity of materials used in infrared thermal imaging sensors is an effective method to improve thermal isolation performance, which can substantially reduce the thermal crosstalk among pixels. This article reports an electrospun poly(vinylidene fluoride-trifluorethylene) (P(VDF-TrFE)) nanofiber film used as an adiabatic support structure in thermal sensor array and investigates its effect on imaging performance of thermal sensor. Based on solid heat transfer simulation, the thermal conductivities of electrospun P(VDF-TrFE) films with different packing ratios were theoretically calculated, showing a significant decrease compared with the spin-coated counterpart. The temperature increment of thermal sensor using nanofiber film with 43.71% packing ratio is calculated as 1.68 times higher than that using spin-coated film. An average temperature rise of 1.73 times was experimentally obtained, and the thermal response time was also reduced to half, compared with the sensor using spin-coated film. The method of improving thermal isolation performance using electrospun fibrous film could be of great advantage to high-sensitivity infrared imaging sensor.

The effect of cysteine on the corrosion characteristics of Cu5Zn5Al1Sn alloy in 3.5 wt% NaCl solution has been studied by electrochemical and surface characterization techniques in various immersion times. The results of electrochemical impedance spectroscopy (EIS) revealed that the degradation of Cu5Zn5Al1Sn alloy occurred in 3.5 wt% NaCl and was aggravated with increasing immersion time. The results of inhibition efficiency calculated from EIS data showed that cysteine can act as an effective anti-corrosion substance, which was also proved by the less eroded morphology of the alloy surface observed on scanning electron microscopy (SEM). Furthermore, the elemental analysis of alloy surfaces was investigated by Raman, electron dispersion spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS), which confirmed the presence of S and N species. An adequate adsorption isotherm and inhibition mechanism was also suggested based on EIS results.

Investigating urban expansion patterns aids in the management of urbanization and in ameliorating the socioeconomic and environmental issues associated with economic transformation and sustainable development. Applying Harmonized Defense Meteorological Satellite Program-Operational Line-scan System (DMSP-OLS) and the Suomi National Polar-Orbiting Partnership-Visible Infrared Imagery Radiometer Suite (NPP-VIIRS) Nighttime Light (NTL) data, this paper investigated the characteristics of urban landscape in West Africa. Using the harmonized NTL data, spatial comparison and empirical threshold methods were employed to detect urban changes from 1993 to 2018. We examined the rate of urban change and calculated the direction of the urban expansion of West Africa using the center-of-gravity method for urban areas. In addition, we used the landscape expansion index method to assess the processes and stages of urban growth in West Africa. The accuracy of urban area extraction based on NTL data were R2= 0.8314 in 2000, R2= 0.8809 in 2006, R2= 0.9051 in 2012 for the DMSP-OLS and the simulated NPP-VIIRS was R2= 0.8426 in 2018, by using Google Earth images as validation. The results indicated that there was a high rate and acceleration of urban landscapes in West Africa, with rates of 0.016 0, 0.017 3, 0.018 9, and 0.068 6, and accelerations of 0.31, 0.42, 0.54, and 0.90 for the periods of 1998–2003, 2003–2008, 2008–2013, and 2013–2018, respectively. The expansion direction of urban agglomeration in West Africa during 1993–2018 was mainly from the coast to inland. However, cities located in the Sahel Region of Africa and in the middle zone expanded from north to south. Finally, the results showed that the urban landscape of West Africa was mainly in a scattered and disordered ‘diffusion’ process, whereas only a few cities located in coastal areas experiencing the process of ‘coalescence’ according to urban growth phase theory. This study provides urban planners with relevant insights for the urban expansion characteristics of West Africa.

Background: Genetic variations of the human adiponectin gene are associated with metabolic phenotypes, including obesity, insulin sensitivity, and diabetes. However, these associations have not been examined in an elderly population. Objective: The objective of the study was to investigate whether the genetic variants of adiponectin are associated with any metabolic phenotype in the elderly. Design: In a population-based, case-control genetic association study, a total of 1438 subjects >65 y old were recruited from the community. The phenotypes of the metabolic syndrome (MetS) were measured. Four single-nucleotide polymorphisms (SNP) were genotyped by mass spectrometry. Results: The G allele of SNP276 in intron 2 was associated with a reduced risk of obesity, MetS, and diabetes mellitus. The GT genotype relative to the GG genotype had an age- and sex-adjusted odds ratio of 1.32 for obesity [body mass index (BMI; in kg/[m.sup.2]) [greater than or equal to] 25; P = 0.014] and of 1.33 (P = 0.01l) and 1.47 (P = 0.001) for MetS according to modified National Cholesterol Education Program and International Diabetes Federation criteria, respectively. The age-, sex-, and BMI-adjusted odds ratio of diabetes mellitus for the GTand TT genotypes relative to the GG genotype were 1.28 (P = 0.042) and 1.72 (P = 0.013), respectively, and there was an obvious dosage effect (P for trend = 0.004). In linear regression after adjustment for age, sex, and BMI, the GT and TT genotypes were associated with fasting plasma glucose concentrations 5.2 and 11.1 mg/dL higher, respectively, than those of the GG genotype. Conclusions: Genetic variation of the adiponectin gene is associated with obesity, MetS, and diabetes mellitus in the elderly. The genetic effect on diabetes mellitus is partially independent of BMI. Am J Clin Nutr 2007;86:509-13. KEY WORDS Adiponectin, genetics, metabolic syndrome, obesity, diabetes, elderly

Almost 185,000 Gossypium EST sequences comprising > 94,800,000 nucleotides were amassed from 30 cDNA libraries constructed from a variety of tissues and organs under a range of conditions. The assembly and information collected provided a framework for future investigation of cotton functional and evolutionary genomics.

The main objective of the study was to evaluate the bioequivalence of two rosuvastatin calcium tablets in healthy Chinese subjects under fasted and fed conditions. The study was carried out using a randomized, open‐label, two‐formulation, two‐sequence, two‐period, single‐dose crossover design, with a washout period of 7 days. Both the fasted study and fed study enrolled 28 subjects. In each study period, the subjects were administrated a single oral dose of the test product or reference product of rosuvastatin 10 mg. Blood samples were collected from pre‐dose to 72 hours after administration with 16 time points in total. Bioequivalence evaluation was performed using ln‐transformed pharmacokinetic parameters of rosuvastatin, including Cmax, AUC0–t, and AUC0–∞. In the present study, 95% confidence intervals (CIs) of test/reference geometric mean ratios (GMRs) of Cmax, AUC0–t, and AUC0–∞under the fasted and fed conditions were all within the acceptance range of 80%–125%. Additionally, only one subject experienced one adverse event (AE). High‐fat meals reduced the Cmax, AUC0–t, and AUC0–∞, but had no significant effects on the λz, t1/2, or Tmaxof rosuvastatin. In the current study, the test product was bioequivalent to the reference product, and a single dose of rosuvastatin (10 mg) was well‐tolerated. Food decreased the systemic exposure of rosuvastatin without the effects on the Tmaxor elimination rate.

In urban building design, introducing openings in the webs of structural members allows the flexible installation of ductwork and piping. This study investigated the effects of the shape, location, and spacing of web openings on the buckling behavior of cold-formed steel hat purlins. Eigenvalue analysis shows that the existence of web openings reduced the buckling moment of a section by up to 24%. The shape and location of the web openings also affected the buckling behavior. In particular, the buckling moment decrease when the web opening was located at mid-span. It was found that, the buckling moment increase when the web opening spacing increases. The section with diamond web openings shows the highest buckling moment and the section with elongated circle openings shows the smallest buckling moment compared to other web opening shapes. The results of this study should provide guidance on hat purlins with openings design to meet structural performance requirements.

Scale is the range or measurement unit of the characteristics of natural or human ontology in the temporal or spatial dimension and is widely used in daily life and the study of various disciplines. Scale effect pertains to certain laws and characteristics that can only be reflected on a specific scale, so choosing the appropriate scale remains the basic premise of scientific research. The concept of the urban spatial system is complex and has the characteristics of scale dependence, and the selection of an appropriate spatial scale is important for the accurate estimation and description of urban issues. In this paper, we discuss spatial scale in urban research using cases that primarily come from the Chinese experience, provide some examples that demonstrate the importance of appropriate scale in urban research, including urban shrinkage, and highlight problems in spatial research. Ultimately, we suggest that scale consciousness should be the basic consciousness required in empirical research.

IMPORTANCE: The psychological symptoms associated with having a family member admitted to the intensive care unit (ICU) during the COVID-19 pandemic are not well defined. OBJECTIVE: To examine the prevalence of symptoms of stress-related disorders, primarily posttraumatic stress disorder (PTSD), in family members of patients admitted to the ICU with COVID-19 approximately 90 days after admission. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multisite, mixed-methods observational cohort study assessed 330 family members of patients admitted to the ICU (except in New York City, which had a random sample of 25% of all admitted patients per month) between February 1 and July 31, 2020, at 8 academic-affiliated and 4 community-based hospitals in 5 US states. EXPOSURE: Having a family member in the ICU with COVID-19. MAIN OUTCOMES AND MEASURES: Symptoms of PTSD at 3 months, as defined by a score of 10 or higher on the Impact of Events Scale 6 (IES-6). RESULTS: A total of 330 participants (mean [SD] age, 51.2 [15.1] years; 228 [69.1%] women; 150 [52.8%] White; 92 [29.8%] Hispanic) were surveyed at the 3-month time point. Most individuals were the patients’ child (129 [40.6%]) or spouse or partner (81 [25.5%]). The mean (SD) IES-6 score at 3 months was 11.9 (6.1), with 201 of 316 respondents (63.6%) having scores of 10 or higher, indicating significant symptoms of PTSD. Female participants had an adjusted mean IES-6 score of 2.6 points higher (95% CI, 1.4-3.8; P &lt; .001) than male participants, whereas Hispanic participants scored a mean of 2.7 points higher compared with non-Hispanic participants (95% CI, 1.0-4.3; P = .002). Those with graduate school experience had an adjusted mean score of 3.3 points lower (95% CI, 1.5-5.1; P &lt; .001) compared with those with up to a high school degree or equivalent. Qualitative analyses found no substantive differences in the emotional or communication-related experiences between those with high vs low PTSD scores, but those with higher scores exhibited more distrust of practitioners. CONCLUSIONS AND RELEVANCE: In this cohort study, symptoms of PTSD among family members of ICU patients with COVID-19 were high. Hispanic ethnicity and female gender were associated with higher symptoms. Those with higher scores reported more distrust of practitioners.

ABSTRACTExcessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific Atg7−/+heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of Ccn2through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction in vivo, suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of Hmgb1(high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.

This article investigates the distributed fault-tolerant time-varying formation control problem for multiple unmanned airships (UAs) against limited communication ranges and input saturation to achieve the safe observation of a smart city. To address the strongly nonlinear functions caused by the time-varying formation flight with limited communication ranges and bias faults, intelligent adaptive learning mechanisms are proposed by incorporating fuzzy neural networks. Moreover, Nussbaum functions are introduced to handle the input saturation and loss-of-effectiveness faults. The distinct features of the proposed control scheme are that time-varying formation flight, actuator faults including bias and loss-of-effectiveness faults, limited communication ranges, and input saturation are simultaneously considered. It is proven by Lyapunov stability analysis that all UAs can achieve a safe formation flight for the smart city observation even in the presence of actuator faults. Hardware-in-the-loop experiments with open-source Pixhawk autopilots are conducted to show the effectiveness of the proposed control scheme. [ABSTRACT FROM AUTHOR]