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The asymmetric functionalization of unstrained C(sp3)–C(sp3) bonds could be a powerful strategy to stereoselectively reconstruct the backbone of an organic compound, but such reactions are rare. Although allylic substitutions have been used frequently to construct C–C bonds by the cleavage of more reactive C–X bonds (X is usually an O atom of an ester) by transition metals, the reverse process that involves the replacement of a C–C bond with a C–heteroatom bond is rare and generally considered thermodynamically unfavorable. We show that an unstrained, inert allylic C–C σ bond can be converted to a C–N bond stereoselectively via a designed solubility-control strategy, which makes the thermodynamically unfavorable process possible. The C–C bond amination occurs with a range of amine nucleophiles and cleaves multiple classes of alkyl C–C bonds in good yields with high enantioselectivity. A novel resolution strategy is also reported that transforms racemic allylic amines to the corresponding optically active allylic amine by the sequential conversion of a C–N bond to a C–C bond and back to a C–N bond. Mechanistic studies show that formation of the C–N bond is the rate-limiting step and is driven by the low solubility of the salt formed from the cleaved alkyl group in a nonpolar solvent.

Light-to-electricity conversion is crucial for energy harvesting and photodetection, requiring efficient electron–hole pair separation to prevent recombination. Traditional junction-based mechanisms using built-in electric fields fail in nonbarrier regions. Homogeneous material harvesting under a photovoltaic effect is appealing but is only realized in noncentrosymmetric systems via a bulk photovoltaic effect. Here we report the realization of a photovoltaic effect by employing surface acoustic waves (SAWs) to generate zero-bias photocurrent in the conventional layered semiconductor MoSe2. SAWs induce periodic modulation to electronic bands and drag the photoexcited pairs toward the traveling direction. The photocurrent is extracted from a local barrier. The separation of generation and extraction processes suppresses recombination and yields a large nonlocal photoresponse. We distinguish the acousto-electric drag and electron–hole pair separation effect by fabricating devices of different configurations. The acousto-drag photovoltaic effect, enabled by piezoelectric integration, offers an efficient light-to-electricity conversion method, independent of semiconductor crystal symmetry.

In order to ameliorate microstructure and optimize properties of Inconel 718 alloy, a novel heat treatment method combining high-temperature ultra-short annealing at 980 °C for 1 min with subsequent double aging was proposed. The results showed that ultra-short annealing generated partially recrystallized microstructure and recrystallized nuclei were formed even in deformed grains, which was confirmed by KAM maps. Therefore, high-temperature ultra-short annealing overcame recrystallization barrier, and the subsequent recrystallization process could be completed during aging treatment with relatively low temperature, resulting in the uniformly refined microstructure (∼3.59 µm). The 980-1min-aged sample exhibited outstanding tensile properties. The room temperature ultimate strength and total elongation were 1600 MPa and 19%, respectively. The corresponding values of high- temperature (650 °C) tensile tests were ∼1350 MPa and ∼26%. Consequently, ultra-short annealing can be a promising route to enhance the properties of Inconel 718 alloy.

Acid phosphatase (ACP) is a ubiquitous phosphatase in living organisms. The abnormal variation of ACP is related to various diseases. Herein, we propose a colorimetric method based on CeO2-modified gold core shell nanoparticles (Au@CeO2NPs) to analyze ACP activity with high sensitivity and specificity. In this design, 2-phospho-L-ascorbic acid trisodium salt (AAP) is dephosphorylated by ACP and produces reductive ascorbic acid (AA), which makes the CeO2shell decomposition. A remarkable blue shift of localized surface plasmon resonance peak (LSPR, from yellow to green) along with the scattering intensity ratio changes from individual Au@CeO2NPs are observed. ACP activity can be quantified by calculating the ratio changes of individual Au@CeO2NPs. This assay reveals limit of detection (LOD) of 0.044 mU/mL and the linear range of 0.05–5.0 mU/mL, which are much lower than most of spectroscopic measurements in bulk solution. Furthermore, the recovery measurements in real samples are satisfactory and the capacity for practical application is demonstrated. As a consequence, Au@CeO2NPs used in this assay will find new applications for the ultrasensitive detection of enzyme activity.

Thirteen new sativene sesquiterpenoids (1and 3–14), one new natural product (2), and 16 known compounds (15–30) were isolated from the endophytic fungus Bipolaris victoriaeS27. Their structures were elucidated by extensive spectroscopic analysis, NMR and ECD calculations, and X-ray crystal diffractions. Compound 1represented the first example of sativene sesquiterpenoids with a 6/5/3/5-caged tetracyclic ring system. All obtained compounds were evaluated for their plant-growth regulatory activity. The results showed that 1, 3, 4, 6, 8, 11, 12, 17, 19, 26, and 27could suppress the growth of Arabidopsis thaliana, while 2, 5, 13, 15, 18, and 25showed promoting effects. Among them, compound 3showed the most potent plant-growth inhibitory activity, which is obviously superior to that of the marked herbicide glyphosate.

We present the development and implementation of relativistic coupled cluster linear response theory (CC-LR), which allows the determination of molecular properties arising from time-dependent or time-independent electric, magnetic, or mixed electric-magnetic perturbations (within a common gauge origin for the magnetic properties) as well as taking into account the finite lifetime of excited states in the framework of damped response theory. We showcase our implementation, which is capable to offload the computationally intensive tensor contractions characteristic of coupled cluster theory onto graphical processing units, in the calculation of (a) frequency-(in)dependent dipole–dipole polarizabilities of IIB atoms and selected diatomic molecules, with a particular emphasis on the calculation of valence absorption cross sections for the I2molecule; (b) indirect spin–spin coupling constants for benchmark systems such as the hydrogen halides (HX, X = F–I) as well the H2Se–H2O dimer as a prototypical system containing hydrogen bonds; and (c) optical rotations at the sodium D line for hydrogen peroxide analogues (H2Y2, Y = O, S, Se, Te). Thanks to this implementation, we are able to show the similarities in performance, but often the significant discrepancies, between CC-LR and approximate methods such as density functional theory. Comparing standard CC response theory with the flavor based upon the equation of motion formalism, we find that for valence properties such as polarizabilities, the two frameworks yield very similar results across the periodic table as found elsewhere in the literature; for properties that probe the core region, such as spin–spin couplings, on the other hand, we show a progressive differentiation between the two as relativistic effects become more important. Our results also suggest that as one goes down the periodic table, it may become increasingly difficult to measure pure optical rotation at the sodium D line due to the appearance of absorbing states.

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A–D (1–4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhizaBunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both invitroand invivoexperiments, (±)-13edemonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

The rhodium-catalyzed hydroacylation of terminal alkynes provides an efficient strategy for the construction of unsaturated ketones. Density functional theory calculations were carried out to study the mechanisms and understand the origins of the ligand-controlled regioselectivity. The results demonstrate that the reaction follows the classical Chalk–Harrod-type mechanism. Distortion/interaction analyses show that the branched selectivity with L1ligand stems from the electronic and steric effects, while the linear selectivity with L2ligand arises from the repulsive interaction between the ligand and substrate. These findings offer crucial insights into the origin of ligand-controlled regioselectivity and furnish valuable guidance for further refining reactions of this nature.

Fine-grained remote sensing object detection aims at precisely locating objects and determining the fine-level categories. This task is exceptionally challenging due to the substantial interclass similarity, presenting difficulties in capturing discriminative features. We attribute this to the absence of essential information that can serve as supervision for the learning. This involves comprehensive visual patterns of objects and intrinsic relationships of multigranular features. In this article, we propose a novel scheme dubbed as digging into the multigranular archetype (DIMA) for fine-grained remote sensing object detection. In detail, we first design a simple yet effective frequency-aware representation supplement (FARS) mechanism learning from original images and their auxiliary frequency counterparts simultaneously. The FARS introduces high- and low-frequency representations to reinforce a range of visual cues, such as particular regions associated with the former and contours of objects related to the latter. Then, we further devise a module named hierarchical classification paradigm (HCP), which constructs the interhierarchy relationships between coarse and fine-level representations and then exploits them to guide fine-grained feature enhancement. HCP eventually selects and boosts samples that are hard to discriminate by keeping consistency in multilevels. Our method can be easily integrated into prevailing oriented object detectors and brings consistent performance improvements across these detectors. Notably, our method combined with oriented RCNN (ORCNN) achieves 44.44% (+3.62%) on the FAIR1M and 91.0% (+6.9%) on the MAR20. Moreover, thoughtful discussions about qualitative results and rich visualizations are provided to intuitively underscore the superiority of our approach. The source code is available at https://github.com/chengjc2019/DIMA.

A novel Al-alloyed press-hardening steel (PHS) was developed, which exhibits excellent tensile, bending and antioxidation properties. Al is a ferrite-forming element that can hinder the formation of cementite and enhance the stability of austenite. The incorporation of Al not only induces the formation of ferrite within martensitic matrix but also enhances the stability of retained austenite (RA). The microstructure of novel steel consists of martensite, ferrite, and RA after press hardening. Investigations into the role of Al in RA development were supported by thermo-kinetic calculations. The simultaneous introduction of ferrite and RA into the martensitic matrix via tailored chemical compositions significantly enhances the elongation and bending toughness of the novel PHS. Additionally, Al can form a dense Al oxide at the bottom of oxide layer, resulting in the improved antioxidant properties. Compared to 22MnB5 steel, it is an exciting discovery as there is a significant improvement in total elongation and bending toughness of novel PHS without compromising strength. The novel PHS, with its exceptional balance of strength and ductility, will play a crucial role in reducing weight when it replaces the existing class 22MnB5 PHS in different structural components of vehicle bodies.

Therapeutic options for large or locally advanced hepatocellular carcinoma (HCC) have limited efficacy. This study investigated the efficacy and safety of drug-eluting beads trans-arterial chemo-embolization (dTACE), portal vein embolization (PVE), tyrosine kinase inhibitor (TKI), and immune checkpoint inhibitors (ICI) compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) for large or locally advanced HCC.

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.

Despite the usefulness of white light endoscopy (WLE) and non-magnified narrow-band imaging (NBI) for screening for superficial oesophageal squamous cell carcinoma and precancerous lesions, these lesions might be missed due to their subtle features and interpretation variations among endoscopists. Our team has developed an artificial intelligence (AI) system to detect superficial oesophageal squamous cell carcinoma and precancerous lesions using WLE and non-magnified NBI. We aimed to evaluate the auxiliary diagnostic performance of the AI system in a real clinical setting.

We present the implementation of quadratic response theory based upon the relativistic equation-of-motion coupled cluster method. We showcase our implementation, whose generality allows us to consider both time-dependent and time-independent electric and magnetic perturbations, by considering the static and frequency-dependent hyperpolarizability of hydrogen halides (HX, X = F–At), providing comprehensive insights into their electronic response characteristics. Additionally, we evaluated the Verdet constant for noble gases Xe and Rn and discussed the relative importance of relativistic and electron correlation effects for these magneto-optical properties. Finally, we calculate the two-photon absorption cross sections of transition [ns1S0→ (n+ 1)s1S0] of Ga+and In+, which are suggested as candidates for new ion clocks. As our implementation allows for the use of nonrelativistic Hamiltonians as well, we have compared our EOM-QRCC results to the QR-CC implementation in the DALTON code and show that the differences between CC and EOMCC response are in general smaller than 5% for the properties considered. Collectively, the results underscore the versatility of our implementation and its potential as a benchmark tool for other approximated models, such as density functional theory for higher-order properties.

With the rise of deep convolutional neural networks, object detection has achieved prominent advances in past years. However, such prosperity could not camouflage the unsatisfactory situation of Small Object Detection (SOD), one of the notoriously challenging tasks in computer vision, owing to the poor visual appearance and noisy representation caused by the intrinsic structure of small targets. In addition, large-scale dataset for benchmarking small object detection methods remains a bottleneck. In this paper, we first conduct a thorough review of small object detection. Then, to catalyze the development of SOD, we construct two large-scale Small Object Detection dAtasets (SODA), SODA-D and SODA-A, which focus on the Driving and Aerial scenarios respectively. SODA-D includes 24828 high-quality traffic images and 278433 instances of nine categories. For SODA-A, we harvest 2513 high resolution aerial images and annotate 872069 instances over nine classes. The proposed datasets, as we know, are the first-ever attempt to large-scale benchmarks with a vast collection of exhaustively annotated instances tailored for multi-category SOD. Finally, we evaluate the performance of mainstream methods on SODA. We expect the released benchmarks could facilitate the development of SOD and spawn more breakthroughs in this field.

Modern deep neural networks can easily overfit to biased training data containing corrupted labels or class imbalance. Sample re-weighting methods are popularly used to alleviate this data bias issue. Most current methods, however, require to manually pre-specify the weighting schemes relying on the characteristics of the investigated problem and training data. This makes them fairly hard to be generally applied in practical scenarios, due to their significant complexities and inter-class variations of data bias. To address this issue, we propose a meta-model capable of adaptively learning an explicit weighting scheme directly from data. Specifically, by seeing each training class as a separate learning task, our method aims to extract an explicit weighting function with sample loss and task/class feature as input, and sample weight as output, expecting to impose adaptively varying weighting schemes to different sample classes based on their own intrinsic bias characteristics. Extensive experiments substantiate the capability of our method on achieving proper weighting schemes in various data bias cases, like class imbalance, feature-independent and dependent label noises, and more complicated bias scenarios beyond conventional cases. Besides, the task-transferability of the learned weighting scheme is also substantiated, by readily deploying the weighting function learned on relatively smaller-scale CIFAR-10 dataset on much larger-scale full WebVision dataset. The general availability of our method for multiple robust deep learning issues, including partial-label learning, semi-supervised learning and selective classification, has also been validated. Code for reproducing our experiments is available at https://github.com/xjtushujun/CMW-Net.

Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specific ciRNA-Fmn1and report that changes in ciRNA-Fmn1expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury. ciRNA-Fmn1was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production of ciRNA-Fmn1by binding to DNA-tandem repeats. Blocking ciRNA-Fmn1downregulation reversed nerve-injury-induced reductions in both the binding of ciRNA-Fmn1to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation of ciRNA-Fmn1in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus, ciRNA-Fmn1downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.

Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.

Cancer stem cells (CSCs) are a minority population of cancer cells with stemness and multiple differentiation potentials, leading to cancer progression and therapeutic resistance. However, the concrete mechanism of CSCs in hepatocellular carcinoma (HCC) remains obscure. We found that in advanced HCC tissues, collagen I was upregulated, which is consistent with the expression of its receptor DDR1. Accordingly, high collagen I levels accompanied by high DDR1 expression are associated with poor prognoses in patients with HCC. Collagen I-induced DDR1 activation enhanced HCC cell stemness in vitro and in vivo. Mechanistically, DDR1 interacts with CD44, which acts as a co-receptor that amplifies collagen I-induced DDR1 signaling, and collagen I-DDR1 signaling antagonized Hippo signaling by facilitating the recruitment of PP2AA to MST1, leading to exaggerated YAP activation. The combined inhibition of DDR1 and YAP synergistically abrogated HCC cell stemness in vitro and tumorigenesis in vivo. A radiomic model based on T2 weighted images can noninvasively predict collagen I expression. These findings reveal the molecular basis of collagen I-DDR1 signaling inhibiting Hippo signaling and highlight the role of CD44/DDR1/YAP axis in promoting cancer cell stemness, suggesting that DDR1 and YAP may serve as novel prognostic biomarkers and therapeutic targets in HCC.

Lycium barbarumpolysaccharide (LBP) is a substance with various biological activities extracted from Lycium barbarum. LbGPs are peptidoglycans with a short peptide backbone and a complex, branched glycan moiety, which is further extracted and isolated from LBPs. Previous studies have shown that LbGP can inhibit cancer cell growth, but its specific mechanism is not completely clear. In this study, we found that LbGP could inhibit the proliferation of glioma cells and promote the expression of period 2 (PER2) through the PKA-CREB pathway. In addition, LbGP could inhibit the de novo synthesis of lipids by downregulating SREBP1c and its target genes, which depended on the expression of PER2. Moreover, PER2 negatively regulated the expression of SREBP1c via suppressing PI3K/AKT/mTOR pathway. In summary, LbGP may upregulate the expression of PER2 to reduce the expression of SREBP1c, inhibit lipid synthesis in glioblastoma, and inhibit glioblastoma cell proliferation. This study provides an alternative drug for the treatment of glioma and elucidates its potential mechanism.

In the last decade, deep neural networks (DNNs) have become dominant tools for various of supervised learning tasks, especially classification. However, it is demonstrated that they can easily overfit to training set biases, such as label noise and class imbalance. Example reweighting algorithms are simple and effective solutions against this issue, but most of them require manually specifying the weighting functions as well as additional hyperparameters. Recently, a meta-learning-based method Meta-Weight-Net (MW-Net) has been proposed to automatically learn the weighting function parameterized by an MLP via additional unbiased metadata, which significantly improves the robustness of prior arts. The method, however, is proposed in a deterministic manner, and short of intrinsic statistical support. In this work, we propose a probabilistic formulation for MW-Net, probabilistic MW-Net (PMW-Net) in short, which treats the weighting function in a probabilistic way, and can include the original MW-Net as a special case. By this probabilistic formulation, additional randomness is introduced while the flexibility of the weighting function can be further controlled during learning. Our experimental results on both synthetic and real datasets show that the proposed method improves the performance of the original MW-Net. Besides, the proposed PMW-Net can also be further extended to fully Bayesian models, to improve their robustness.

Three highly oxidized hybrid flavonoids neosophoflavonoids A–C (1, 2a, and 2b) were isolated from the roots of Sophora flavescens. Neosophoflavonoid A possesses a unique highly oxidized heptacyclic 6/6/6/6/6/6/5 system. Neosophoflavonoids B and C are isomers and share the same highly oxidized hexacyclic 6/6/6/6/6/6 systems. Their planar structures were elucidated from 1D/2D nuclear magnetic resonance (NMR), ultraviolet spectroscopy (UV), infrared spectroscopy (IR), and high resolution electrospray ionization mass spectroscopy (HRESIMS) data. Their absolute configurations were determined by thorough GIAO 13C NMR (DP4+) calculation protocol and electronic circular dichroism (ECD) calculation method. The plausible biosynthetic routes for the compounds were also proposed. All compounds exhibited significant protein tyrosine phosphatase-1B (PTP1B) inhibitory activity with half maximal inhibitory concentration (IC50) values 3.94 ± 0.01, 0.38 ± 0.13, and 0.70 ± 0.01 μmol/L, respectively. In addition, compared to a positive control fenofibrate (Feno) at 20 μmol/L, compounds 2aand 2bexhibited stronger inhibitory effects on lipid accumulation in the oleic acid (OA)-induced cell model at 5 and 10 μmol/L.

A mechanistic investigation of α-alkynylation and α-allenylation of aldehydes under the synergistic catalysis of AuCl/amine was performed using density functional theory (DFT) calculations. For such a reaction that delivers two products, this study reveals that the reaction undergoes such a mechanistic mode: reactants → alkynyl product → allenyl product, implying that the allenyl product cannot be obtained directly from reactants. The product ratio obtained experimentally was rationalized based on the computed results that both products can reversibly interconvert with AuCl as the catalyst and with N-containing Lewis bases as additives such as 4,5-diazafluorenone. For the relative stability of alkynyl versus allenyl compounds, unsaturated substituents are found to favor the allenyl compounds.

Density functional theory (DFT) calculations have been conducted to study the mechanisms, substituent effects, and the role of bases in Au- and Cu-catalyzed hydroacylation of terminal alkyne with glyoxal derivatives. The two reactions, despite being catalyzed by the same group of transition metals, follow distinctive reaction mechanisms. Through the detailed DFT calculations, insights into the mechanisms are obtained, and the substituent effects and the role of the bases are understood.

A novel processing route involving twin-roll casting and two-stage cold rolling was proposed to manufacture Inconel 718 alloy. Due to the sub-rapid solidification rate (412.5 °C/s) of as-cast strip, the element segregation can be alleviated and the growth of Laves phase was effectively suppressed. It was also observed that the dissolution of Laves phases during subsequent homogenization was significantly accelerated because of their refined size. The corresponding homogenization time can be shortened from dozens of hours to 1 h. Additionally, the non-uniform microstructure of cold-rolled and annealed samples caused by coarse grains from homogenization treatment can be eliminated by two-stage cold rolling method. Furthermore, a large amount of granular δ phases precipitated during intermediate annealing. After double aging treatment, the final products exhibited an excellent combination of strength and elongation. The ultimate tensile strength when deformed at room temperature and at 650 °C were about 1475 and 1120 MPa, and the corresponding total elongation were ∼ 15% and ∼ 22%. These results indicated that the twin-roll casting was a promising route to produce Inconel 718 alloy.

Graphical abstract:

The strength of traditional commercially pure titanium (CP-Ti) alloys often fails to meet the demand of structural materials. In order to enhance their mechanical properties, the cold-rolled CP-Ti alloys were annealed at different temperatures, and the recrystallization behavior and texture evolution were investigated. It was found that the bimodal microstructure (equiaxed and elongated grains) was formed after partial recrystallization, and the corresponding sample exhibited an excellent combination of ultimate tensile strength (702 MPa) and total elongation (36.4%). The recrystallization nucleation of CP-Ti sheets occurred preferentially in the high strain and the high-angle grain boundaries (HAGBs) regions. Meanwhile, the internal misorientations of the deformed heterogeneous grains increased and transformed into HAGBs, which further promoted the recrystallization nucleation. The main recrystallization texture was basal TD-split texture transformed from cold-rolled basal RD-split texture, and the oriented nucleation played a dominated role during recrystallization.

The first synthesis of flavanostilbenes with a 2-cyclohepten-1-one core was carried out by applying an effective strategy in three steps from abundant polymerized flavanol resources. A key regio- and stereoselective Cu-mediated [5 + 2] cycloaddition/decarboxylation cascade was explored and applied without the use of protecting groups, and water as an environmentally friendly solvent contributed to the cascade. The intramolecular [5 + 2] cycloaddition mechanism, involving oxidation and dearomatization of the flavanol unit as a diene, was proposed and supported by the synthesis of the intermediate. The regioselectivity of the cyclization was found to be dependent on the substitution effects of the stilbene units by the exploration of substrate scope.

Cell-based ex vivogene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines ex vivolarge-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.

Recently, a ternary-layered material BiOCl has elicited intense interest in photocatalysis, environmental remediation, and ultraviolet light detection because of its unique band gap of around 3.6 eV, low toxicity, and earth abundance. In particular, Gibson et al. reported a measurement of the in-plane thermal conductivity of BiOCl experimentally using a four-point-probe method [Science, 373,1017–1022 (2021)], which is only 1.25 W/m K at 300 K. Motivated by the work, we studied the thermoelectric property of monolayer BiOCl using first-principles calculations combined with the Boltzmann transport equation. The calculated phonon thermal conductivity of monolayer BiOCl is 3 W/m K at 300 K, which is far below that of other promising 2D thermoelectric materials like graphyne and MoS2. A comprehensive analysis of phonon modes is conducted to reveal the low thermal conductivity. Moreover, the maximal ZTvalue is as high as 1.8 at 300 K and 5.7 at 800 K for the p-type doping with the 2 × 1015cm–2concentration. More importantly, we found that the thermoelectric efficiency of such 2D materials is significantly enhanced to 8 at 800 K by applying 1.5% tensile strain, which clearly outperforms that of the reported 2D thermoelectric material SnSe. The results shed light on the promising application in medium-temperature (600–900 K) thermoelectric devices.

Hyperactive signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in human triple-negative breast cancer (TNBC) and gastric cancer, leading to uncontrolled tumor growth, resistance to chemotherapy, and poor prognosis. Thus, inhibition of STAT3 signaling is a promising therapeutic approach for both TNBC and gastric cancer, which have high incidences and mortality and limited effective therapeutic approaches. Here, we report a small molecule, WZ-2-033, capable of inhibiting STAT3 activation and dimerization and STAT3-related malignant transformation. We present in vitro evidence from surface plasmon resonance analysis that WZ-2-033 interacts with the STAT3 protein and from confocal imaging that WZ-2-033 disrupts HA-STAT3 and Flag-STAT3 dimerization in intact cells. WZ-2-033 suppresses STAT3-DNA-binding activity but has no effect on STAT5-DNA binding. WZ-2-033 inhibits the phosphorylation and nuclear accumulation of pY705-STAT3 and consequently suppresses STAT3-dependent transcriptional activity and the expression of STAT3 downstream genes. Moreover, WZ-2-033 significantly inhibited the proliferation, colony survival, migration, and invasion of TNBC cells and gastric cancer cells with aberrant STAT3 activation. Furthermore, administration of WZ-2-033 in vivo induced a significant antitumor response in mouse models of TNBC and gastric cancer that correlated with the inhibition of constitutively active STAT3 and the suppression of known STAT3 downstream genes. Thus, our study provides a novel STAT3 inhibitor with significant antitumor activity in human TNBC and gastric cancer harboring persistently active STAT3.

Objectives: To delineate the disease-causing mutations of the Stargardt disease-related genes in Chinese patients diagnosed with Stargardt disease or retinitis pigmentosa (RP) by whole exome sequencing analysis. Methods: A total of 123 sporadic RP or Stargardt disease patients and 2 Stargardt disease families were recruited. All sporadic patients and the probands of the families were subjected to whole exome sequencing analysis. The candidate mutations were verified by direct sequencing based on the cosegregation pattern and in 200 control subjects and by the bioinformatics analyses. Results: A total of three reported ABCA4mutations were identified in the probands of the two Stargardt disease families. The probands and the affected family members with either homozygous or compound heterozygous mutations showed typical Stargardt disease features, which was absent in their unaffected family members. The cosegregation pattern confirmed the mode of recessive inheritance. Moreover, two sporadic Stargardt disease patients were identified to carry two novel ABCA4and one PROM1mutations. In addition, 13 novel variants were found in 119 sporadic RP patients in 7 Stargardt disease-related genes, and 8 novel missense variants were conserved across different species and predicted to be damaging to the protein. All 15 novel variants were absent in our 200 control subjects. Conclusions: This study revealed 22.4% study subjects carrying Stargardt disease-related gene mutations with total 15 novel variants in seven Stargardt disease-related genes, assuring that targeted next-generation sequencing analysis is a high throughput strategy to facilitate the clinical diagnosis from suspicious patients and recommended as a routine examination for inherited retinal dystrophies.

Dear Editor, This letter aims to establish a privacy-preserving distributed optimization algorithm by combining the consensus iteration by subgradients, which not only enables the privacy preservation of optimization but also guarantees the optimality of solutions with some bias bounds.

Selective hydroarylation of internal alkynes catalyzed by a dimeric manganese complex provides a powerful strategy for the construction of multisubstituted alkenes. In this work, density functional theory (DFT) calculations and experimental studies were carried out to explore the mechanism and origin of regiodivergent hydroarylation of internal alkynes reported by our group. The results demonstrate that this reaction first proceeds via a bimetallic mechanism to generate the active catalyst that subsequently undergoes a monometallic mechanism to run the three-stage catalytic cycle: alkyne migratory insertion, protonation, and active catalyst regeneration. Alkyne migratory insertion is considered as the regioselectivity-determining step. Energy decomposition analyses on insertion transition states suggest that the interaction between the substrate and catalyst is mainly responsible for the observed exclusive γ-selectivity of 1a, while the deformation of these two sections induced by the sterically hindered phenyl group and aryl group accounts for the complete β-position arylation of 1e. The decrease of γ-selectivity with the regulation of a tertiary alcohol motif in 1aoriginates from the reduced noncovalent interaction. The computational results provide important insights into the origin of regiodivergent selectivities and useful information for further designing and adjusting the strategy in Mn-catalyzed alkyne hydroarylation.

Background: Intrapapillary capillary loop (IPCL) is an important factor for predicting invasion depth of esophageal squamous cell carcinoma (ESCC). The invasion depth is closely related to the selection of treatment strategy. However, diagnosis of IPCLs is complicated and subject to interobserver variability. This study aimed to develop an artificial intelligence (AI) system to predict IPCLs subtypes of precancerous lesions and superficial ESCC. Methods: Images of magnifying endoscopy with narrow band imaging from three hospitals were collected retrospectively. IPCLs subtypes were annotated on images by expert endoscopists according to Japanese Endoscopic Society classification. The performance of the AI system was evaluated using internal and external validation datasets (IVD and EVD) and compared with that of the 11 endoscopists. Results: A total of 7094 images from 685 patients were used to train and validate the AI system. The combined accuracy of the AI system for diagnosing IPCLs subtypes in IVD and EVD was 91.3% and 89.8%, respectively. The AI system achieved better performance than endoscopists in predicting IPCLs subtypes and invasion depth. The ability of junior endoscopists to diagnose IPCLs subtypes (combined accuracy: 84.7% vs 78.2%, P< 0.0001) and invasion depth (combined accuracy: 74.4% vs 67.9%, P< 0.0001) were significantly improved with AI system assistance. Although there was no significant differences, the performance of senior endoscopists was slightly elevated. Conclusions: The proposed AI system could improve the diagnostic ability of endoscopists to predict IPCLs classification of precancerous lesions and superficial ESCC.

YABBYgenes are plant-specific transcription factors (TFs) that function in plant growth and development. We investigated the functions of the YABBYgenes in plants' stress tolerance by analyzing the YABBYgenes in foxtail millet (Setaria italica) and studying their functions on plant growth and responses to different stresses. Eight YABBYgenes were identified on five chromosomes, which showed strong relationships with YABBYgenes in other monocot species. Phylogenetical SiYABs were classified into four clades: FIL/YAB3, YAB2, INO, and CRC. No monocot YABBY member was classified into the YAB5 clade. Four conserved motifs were identified, and motif 1 constituted the YABBY domain, whereas motifs 2 and 3 formed the C2-C2 region. SiYABgenes were highly expressed in reproductive tissues. SiDL, one of the SiYABs, was selected to be overexpressed in Arabidopsis thalianato check the functions of the YABBYgenes. Overexpression of SiDLin A. thalianacaused delayed flowering, leaf curling, and reduced seed size. In addition, SiDLacted as a negative regulator in plant response to salt stress. Our study provides information to assist in studying the YABBYgene functions in S. italica.

Landau band crossings typically stem from the intra-band evolution of electronic states in magnetic fields and enhance the interaction effect in their vicinity. Here in the extreme quantum limit of topological insulator HfTe5, we report the observation of a topological Lifshitz transition from inter-band Landau level crossings using magneto-infrared spectroscopy. By tracking the Landau level transitions, we demonstrate that band inversion drives the zeroth Landau bands to cross with each other after 4.5 T and forms a one-dimensional Weyl mode with the fundamental gap persistently closed. The unusual reduction of the zeroth Landau level transition activity suggests a topological Lifshitz transition at 21 T, which shifts the Weyl mode close to the Fermi level. As a result, a broad and asymmetric absorption feature emerges due to the Pauli blocking effect in one dimension, along with a distinctive negative magneto-resistivity. Our results provide a strategy for realizing one-dimensional Weyl quasiparticles in bulk crystals.

Background: The ability of endoscopists to identify gastric lesions is uneven. Even experienced endoscopists may miss or misdiagnose lesions due to heavy workload or fatigue or subtle changes in lesions under white-light endoscopy (WLE). This study aimed to develop an artificial intelligence (AI) system that could diagnose six common gastric lesions under WLEand to explore its role in assisting endoscopists in diagnosis. Methods: Images of early gastric cancer, advanced gastric cancer, submucosal tumor, polyp, peptic ulcer, erosion, and lesion-free gastric mucosa were retrospectively collected to train and test the system. The performance of the system was compared with that of 12 endoscopists. The performance of endoscopists with or without referring to the system was also evaluated. Results: A total of 29,809 images from 8947 patients and 1579 images from 496 patients were used to train and test the system, respectively. For per-lesion analysis, the overall accuracy of the system was 85.7%, which was comparable to that of senior endoscopists (85.1%, P= 0.729) and significantly higher than that of junior endoscopists (78.8%, P< 0.001). With system assistance, the overall accuracies of senior and junior endoscopists increased to 89.3% (4.2%, P< 0.001) and 86.2% (7.4%, P< 0.001), respectively. Senior and junior endoscopists achieved varying degrees of improvement in the diagnostic performance of other types of lesions except for polyp. The diagnostic times of senior (3.8 vs 3.2 s per image, P= 0.500) and junior endoscopists (6.2 vs 4.6 s per image, P= 0.144) assisted by the system were both slightly shortened, despite no significant differences. Conclusions: The proposed AI system could be applied as an auxiliary tool to reduce the workload of endoscopists and improve the diagnostic accuracy of gastric lesions.

Three matrine-derived alkaloids, alopecuroidine A (1), alopecuroidine B (2a) and alopecuroidine C (2b) were isolated from the seeds of Sophora alopecuroides. Their structures were elucidated by extensive spectroscopic analyses and X-ray diffraction. Three compounds possess an unprecedented rearranged fused 7/6/5/6 tetracyclic skeleton with a diazacycloheptane structure. Their plausible biosynthetic pathway was also proposed. The anti-proliferative activities of compounds 1and 2awere examined by the MTT assay. Compound 1inhibited the viability of human lung cancer A549 cells, having a half maximal inhibitory concentration (IC50) of 7.58 ± 2.47 µmol/L at 72 h. The flow cytometric analysis suggested that 1inhibited A549 cell growth by inducing apoptosis and cell-cycle arrest. Additionally, 1induced the loss of mitochondrial membrane potential, elevated intracellular reactive oxygen species, increased the Bax/Bcl-2 ratio, stimulated cleaved-caspase-3 and P53 protein levels, and suppressed the pro-caspase-3 level. Thus, 1appeared to induce A549 cells apoptosis through a mitochondria-mediated apoptotic pathway.

Arnebinones B, E, and D (1–3) have been found to be sensitive to light, generating complex and diverse proton transfer products when triggered by light. A unique two-step irreversible intramolecular proton transfer of 1produced five scalemic mixtures, of which four possessed intriguing dual planar chirality. The unprecedented orientation epimerization equilibrium of the intra-annular double bond was first observed and researched in the homologous meroterpenoids by HPLC monitoring and DFT calculations. A “p-benzoquinone-CH2/CH-π” moiety in the structure was the common key feature for the occurrence of this type of photoenolization reaction. The product transformation processes and universality of this photoinduced irreversible proton transfer reaction were analyzed together with the cytotoxic activities of arnebinones B, D, and E, and their photoreaction products.

A computational study is conducted to understand the mechanisms and exclusive chemo- and regioselectivity in di- and mononuclear manganese-catalyzed hydroarylation of unsymmetrical 1,3-diyne alcohols reported by the Xie group [Yan, Z., Angew. Chem., Int. Ed.20185712906−12910]. The results find that the main difference in di- and mononuclear manganese-catalyzed hydroarylation reactions lies in the initial generation of active Mn(I) species and the rate-determining step. In the dinuclear Mn2(CO)8Br2-catalyzed hydroarylation process, the active Mn(I) species is generated by the reaction of the precatalyst Mn2(CO)8Br2with NaOAc and 2avia ligand substitution. The diyne migratory insertion step is identified as the rate- and selectivity-determining step. However, in the mononuclear Mn(CO)5Br-catalyzed hydroarylation reaction, the generation of the active Mn(I) species undergoes the ligand substitution of Mn(CO)5Br with NaOAc and the decarbonylation process, which is the rate-determining step in this catalytic process. The bromine anion is found to play a significantly important stabilization role in this decarbonylation process. After the generation of the active Mn(I) catalyst, the catalytic hydroarylation reaction follows a four-stage mechanism: transmetalation, alkyne insertion, protonation, and active catalyst regeneration. The 2,1-migratory insertion of the C1≡C2unit in diyne into the Mn–C(aryl) species is the energetically most favorable pathway compared with other insertions (1,2-, 3,4-, and 4,3-insertions). The calculated selectivity is in good agreement with the experimental selective functionalization of diynes. Energy decomposition analysis (EDA) on the diyne insertion transition state suggests that the deformation of the diyne section is mainly responsible for the observed exclusive selectivity, combined with the OH···π interaction between the hydroxyl group of diyne and the aryl phenyl ring. However, for monoalkyne, EDA demonstrates the interaction between monoalkyne and Mn section accounts for the experimentally obtained reactive selectivity. This study provides deeper insights into the mechanisms and the origins of the exclusive selectivity of the title reaction and guides the design of efficient Mn-based catalysts for the hydroarylation reaction.

Adrenaline (AD) is an important hormone in central nervous system of mammals, and also works as a medium to transmit signal. The abnormal level of AD in nerve tissues and biological fluids can cause a variety of diseases. In this work, we developed a simple and sensitive dark-field microscopy (DFM)-based single-particle detection (SPD) method for quantitative detection of AD in aqueous solution. MnO2layer of GNP@MnO2core-shell nanoparticles could be readily etched due to the reducibility of AD. Since the localized surface plasmon resonance (LSPR) of GNPs was sensitive to the dielectric change of local environment, the etching process resulted in an evident color change of the probe and could be easily observed in real time under dark-field microscope. The AD was thus sensitively detected in a wide linear concentration range (0.02–5 μmol/L) with a limit of detection (LOD) of 7.17 nmol/L. Moreover, this method was used for the analysis of AD content in commercial injection and satisfactory recoveries were acquired. As a consequence, the sensing assay demonstrated herein based on GNP@MnO2NPs showed great application prospects in molecular recognition and drug quality assay.

Liver cell therapy presents a promising alternative to liver transplantation for patients with liver failure and hereditary liver diseases. However, its clinical implementation is limited largely due to the scarcity of human hepatocytes. Here, we review strategies to generate functional human hepatocytes with a mature phenotype and liver repopulation capability and highlight their potential clinical applications in hepatocyte transplantation and bioartificial liver transplantation. We summarize new delivery methods to improve hepatocyte engraftment, such as patch grafting and ectopic transplantation, and discuss potential future directions.

An approach for distinguishing two types of positional isomers of dimeric shikonin and its analogs was explored with 4JC,Hlong-range correlation by prolonging the acquisition time at 2,3JC,Hvalues of 2.0 and 8.0 Hz. Furthermore, the 1H (proton) nuclear magnetic resonance (NMR) pattern of phenolic hydroxyl protons was developed as a “diagnosis signal” to ascertain the relative location of each side chain in DMSO‑d6at sample concentrations of 0.022–0.034 mol/L. The chemical shift differences of 0.6 ppm between OH-5′ and OH-1 and between OH-8′ and OH-4 are assigned to Type A and Type B, respectively. All reported ambiguous structures were corrected by this pattern. Additionally, the steric structures of isolated compounds were elucidated by quantum chemical calculations of electronic circular dichroism (ECD) spectra.

Alginate-encapsulated hepatocyte transplantation is a promising strategy to treat liver failure. However, its clinical application was impeded by the lack of primary human hepatocytes and difficulty in controlling their quality. We previously reported proliferating human hepatocytes (ProliHHs). Here, quality-controlled ProliHHs were produced in mass and engineered as liver organoids to improve their maturity. Encapsulated ProliHHs liver organoids (eLO) were intraperitoneally transplanted to treat liver failure animals. Notably, eLO treatment increased the survival of mice with post-hepatectomy liver failure (PHLF) and ameliorated hyperammonemia and hypoglycemia by providing liver functions. Additionally, eLO treatment protected the gut from PHLF-augmented permeability and normalized the increased serum endotoxin and inflammatory response, which facilitated liver regeneration. The therapeutic effect of eLO was additionally proved in acetaminophen-induced liver failure. Furthermore, we performed assessments of toxicity and biodistribution, demonstrating that eLO had no adverse effects on animals and remained non-tumorigenic.

EuCd2As2was theoretically predicted to be a minimal model of Weyl semimetals with a single pair of Weyl points in the ferromagnet state. However, the heavily p-doped EuCd2As2crystals in previous experiments prevent direct identification of the semimetal hypothesis. Here, we present a comprehensive magneto-transport study of high-quality EuCd2As2crystals with ultralow bulk carrier density (1013cm−3). In contrast to the general expectation of a Weyl semimetal phase, EuCd2As2shows insulating behavior in both antiferromagnetic and ferromagnetic states as well as surface-dominated conduction from band bending. Moreover, the application of a dcbias current can dramatically modulate the resistance by over one order of magnitude, and induce a periodic resistance oscillation due to the geometric resonance. Such nonlinear transport results from the high nonequilibrium state induced by an electrical field near the band edge. Our results suggest an insulating phase in EuCd2As2and put a strong constraint on the underlying mechanism of anomalous transport properties in this system.

Wilson’s disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.

•Poly lactic-co-glycolic acid (PLGA)-coated ropivacaine is continuously released in vitro for at least 6 days.•PLGA-coated ropivacaine abolishes postoperative pain.•PLGA-coated ropivacaine leads to a long-lasting analgesia in neuropathic pain.•PLGA-coated ropivacaine does not produce marked toxicity and inflammation.