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Abstract Asymmetric catalysis for enantioselective intramolecular hydroamination of alkenes is a critical method in the construction of enantioenriched nitrogen-containing rings, often prevalent in biologically active compounds and natural products. Herein, we demonstrate a facile enantioselective intramolecular hydroamination of alkenes for the synthesis of chiral pyrrolidine, piperidine, and indoline moieties, using a manganese (II) chiral aprotic cyclic urea catalyst. The cyclic ligand hinders the inversion of the N atom of the urea and effectively discriminate between the enantiomers of substrates. High-resolution mass spectrometry, deuterium labeling experiments, and molecular orbital energy analysis clearly reveal the intermediates and mechanism of the transformation. As a key step, oxygen coordination by chiral aprotic urea presents a robust control over the asymmetric intra-HA reaction through the involvement of a convergent assembly of two vital intermediates (Mn-N and C-Mn-Br), providing access to chiral cyclic amine systems in high yields with excellent enantioselectivity.

Grid-connected converters (GCCs) exhibit diverse stability characteristics at different operating points. However, traditional stability analysis methods usually study the stability of GCC at a specific operating point. To analyze the stability under time-varying operation conditions, this paper proposes an area-based stability analysis method. Firstly, operating point variables are introduced by the coordinate transformation relationship in phase-locked loop (PLL). Secondly, the small-signal model of GCC considering the coupling between PLL and current control is built. Based on the built model, the stable operation domain can be obtained. The stability of the system can be quickly determined by the relative position of the operating point to the stable boundary. Then, the mechanisms of impedance parameters and control parameters on the stable domain are analyzed to improve the stability of GCC. Finally, the effectiveness and correctness of the proposed area-based stability analysis method are verified by simulation and experiment.

Objective Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies.Methods We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines.Results Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON, L1CAM, KMT2D, and ASPM. Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses.Conclusion GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.

Due to the fatigue and continuous energy input during high-speed dynamic friction polishing (DFP), the diamond crystal beneath the polished surface (roughness 50 nm) and even preferential crystal cleavage with the non-diamond phase (distributing at the position in micrometers range).

Abstract Background Over the past two decades, dengue fever (DF) has emerged as a significant arboviral disease in Yunnan province, China, particularly in the China-Myanmar border area. Aedes aegypti, an invasive mosquito species, plays a crucial role in transmitting the dengue virus to the local population. Insecticide-based vector control has been the primary tool employed to combat DF, but the current susceptibility status of Ae. aegypti to commonly used insecticides is unknown. Assessment of Ae. aegypti resistance to pyrethroid insecticides and an understanding of the underlying mechanisms of this resistance in the China-Myanmar border region is of significant strategic importance for effectively controlling the DF epidemic in the area. Methods Aedes aegypti larvae collected from Ruili and Gengma counties in Yunnan Province were reared to adults in the laboratory and tested for susceptibility to three pyrethroid insecticides (3.20% permethrin, 0.08% lambda-cyhalothrin and 0.20% deltamethrin) by the standard WHO susceptibility bioassay. Genotyping of mutations in the knockdown gene (kdr), namely S989P, V1016G and F1534C, that are responsible for resistance to pyrethroid insecticides was performed using allele-specific PCR methods. A possible association between the observed resistant phenotype and mutations in the voltage-gated sodium channel gene (VGSC) was also studied. Results Aedes aegypti mosquitoes collected from the two counties and reared in the laboratory were resistant to all of the pyrethroids tested, with the exception of Ae. aegypti from Gengma County, which showed sensitivity to 0.20% deltamethrin. The mortality rate of Ae. aegypti from Ruili county exposed to 3.20% permethrin did not differ significantly from that of Ae. aegypti from Gengma County (χ 2 = 0.311, P = 0.577). By contrast, the mortality rate of Ae. aegypti from Ruili County exposed to 0.08% lambda-cyhalothrin and 0.20% deltamethrin, respectively, was significantly different from that of Ae. aegypti from Gengma. There was no significant difference in the observed KDT50 of Ae. aegypti from the two counties to various insecticides. Four mutation types and 12 genotypes were detected at three kdr mutation sites. Based on results from all tested Ae. aegypti, the V1016G mutation was the most prevalent kdr mutation (100% prevalence), followed by the S989P mutation (81.6%) and the F1534C mutation (78.9%). The constituent ratio of VGSC gene mutation types was significantly different in Ae. aegypti mosquitoes from Ruili and those Gengma. The triple mutant S989P + V1016G + F1534C was observed in 274 Ae. aegypti mosquitoes (60.8%), with the most common genotype being SP + GG + FC (31.4%). The prevalence of the F1534C mutation was significantly higher in resistant Ae. aegypti from Ruili (odds ratio [OR] 7.43; 95% confidence interval [CI] 1.71–32.29; P = 0.01) and Gengma (OR 9.29; 95% CI 3.38–25.50; P = 0.00) counties than in susceptible Ae. aegypti when exposed to 3.20% permethrin and 0.08% lambda-cyhalothrin, respectively. No significant association was observed in the triple mutation genotypes with the Ae. aegypti population exposed to 3.20% permethrin and 0.20% deltamethrin resistance (P > 0.05), except for Ae. aegypti from Gengma County when exposed to 0.08% lambda-cyhalothrin (OR 2.86; 95% CI 1.20–6.81; P = 0.02). Conclusions Aedes aegypti from Ruili and Gengma counties have developed resistance to various pyrethroid insecticides. The occurrence of multiple mutant sites in VGSC strongly correlated with the high levels of resistance to pyrethroids in the Ae. aegypti populations, highlighting the need for alternative strategies to manage the spread of resistance. A region-specific control strategy for dengue vectors needs to be implemented in the future based on the status of insecticide resistance and kdr mutations. Graphical Abstract

Abstract Background The prognostic significance of the CRAFITY score (CRP and AFP in ImmunoTherapY) has been demonstrated in hepatocellular carcinoma (HCC) patients receiving immunotherapy. The purpose of this study was to investigate the utility and the predictive value of CRAFITY score in HCC after transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) and immunotherapy. Materials and methods Data from patients with advanced HCC treated with TACE plus TKIs and PD-1 inhibitor from January 2019 to June 2022 were collected and analyzed retrospectively. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. Patients were divided into three groups according to their CRAFITY score (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). The differences in overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared among the three groups. Tumor response was evaluated at 3, 6 and 12 months after the first combination treatment. Risk factors for OS and PFS were assessed. Results A total of 70 patients were included. The patients were assigned CRAFITY scores of 0 points (CRAFITY-low, n = 25 [35.71%]), 1 point (CRAFITY-intermediate, n = 29 [41.42%]), and 2 points (CRAFITY-high, n = 16 [22.81%]). Multivariate analysis showed that lower CRAFITY score was an independent factor for the improved OS (P =.045) and PFS (P

Abstract Two novel koninginin derivatives, koningipyridines A and B (1 and 2), along with four known compounds (3˗6) were isolated from the EtOAc extract of the endophytic fungus Trichoderma koningiopsis SC-5. Among them, koningipyridine A featured an unprecedented pentacyclic ketal skeleton with the formation of a fascinating 6/6/5/6/5 fused ring system and shared a characteristic pyridine core, which represents the first example of nitrogen-containing koninginin-type natural product. Moreover, koningipyridine B was the first member in the koninginin family sharing a unique 6/6/5 dihydropyridine skeleton, and it was suggested to be the critical biosynthetic precursor of koningipyridine A. The structures of 1 and 2 were elucidated by the interpretation of 1D and 2D NMR spectroscopy, HRESIMS data, as well as theoretical calculations of 13C NMR and electronic circular dichroism (ECD). Moreover, all isolates were screened for antimicrobial activities against Staphylococcus aureus, MRSA, and Escherichia coli as well as the cytotoxic effects against three cancer cell lines (A549, Hela, and HepG2). Graphical Abstract

Designing adhesive hydrogels with optimal properties for the treatment of injured tissues is challenging due to the tradeoff between material stiffness and toughness while maintaining adherence to wet tissue surfaces. In most cases, bioadhesives with improved mechanical strength often lack an appropriate elastic compliance, hindering their application for sealing soft, elastic, and dynamic tissues. Here, we present a novel strategy for engineering tissue adhesives in which molecular building blocks are manipulated to allow for precise control and optimization of the various aforementioned properties without any tradeoffs. To introduce tunable mechanical properties and robust tissue adhesion, the hydrogel network presents different modes of covalent and noncovalent interactions using N-hydroxysuccinimide ester (NHS) conjugated alginate (Alg-NHS), poly (ethylene glycol) diacrylate (PEGDA), tannic acid (TA), and Fe3+ ions. Through combining and tuning different molecular interactions and a variety of crosslinking mechanisms, we were able to design an extremely elastic (924%) and tough (4697 kJ/m3) multifunctional hydrogel that could quickly adhere to wet tissue surfaces within 5 s of gentle pressing and deform to support physiological tissue function over time under wet conditions. While Alg-NHS provides covalent bonding with the tissue surfaces, the catechol moieties of TA molecules synergistically adopt a mussel-inspired adhesive mechanism to establish robust adherence to the wet tissue. The strong adhesion of the engineered bioadhesive patch is showcased by its application to rabbit conjunctiva and porcine cornea. Meanwhile, the engineered bioadhesive demonstrated painless detachable characteristics and in vitro biocompatibility. Additionally, due to the molecular interactions between TA and Fe3+, antioxidant and antibacterial properties required to support the wound healing pathways were also highlighted. Overall, by tuning various molecular interactions, we were able to develop a single-hydrogel platform with an “all-in-one” multifunctionality that can address current challenges of engineering hydrogel-based bioadhesives for tissue repair and sealing.

Abstract The automatic reclosing strategy is an effective measure to improve the reliability of a distribution network. It can quickly clear instantaneous faults in the grid. The traditional transformer has proven to be reliable and robust during the reclosing process. However, the influence of the reclosing process on the operational characteristics and reliability of solid-state transformers (SST) is still unclear. The reclosing action may generate a huge inrush current, resulting in shutdown and even damage of the SST. To address this problem, this paper proposes an inrush current suppression strategy. First, the operational performance of the SST under a reclosing process is discussed, and the inrush current generation mechanism is analyzed in detail. Then, considering the controllability of distributed generation (DG), a novel DG-supported inrush current suppression strategy is proposed. The suppression ability of the DG on inrush current in different initial conditions is analyzed. Finally, the effectiveness of the proposed strategy is verified by simulation and experiment. These show that the proposed strategy can help to enhance the FRT capability of the SST, as well as support the SST to maintain continuous power supply and physical integrity during grid faults.

Bacterial resistance to antibiotics can lead to long-lasting, hard-to-cure infections that pose significant threats to human health. One key mechanism of antimicrobial resistance (AMR) is to reduce the antibiotic permeation of cellular membranes. For instance, the lack of outer membrane porins (OMPs) can lead to elevated AMR levels. However, knowledge on whether mutations of OMPs can also influence antibiotic susceptibility is limited. This work aims to address this question and identified an A226D mutation in OmpC, a trimeric OMP, in Escherichia coli. Surveillance studies found that this mutation is present in 50 E. coli strains for which whole genomic sequences are available. Measurement of minimum inhibition concentrations (MICs) found that this mutation leads to a 2-fold decrease in MICs for β-lactams ampicillin and piperacillin. Further survival assays confirmed the role this mutation plays in β-lactam susceptibility. With molecular dynamics, we found that the A226D mutation led to increased overall flexibility of the protein, thus facilitating antibiotic uptake, and that binding with piperacillin was weakened, leading to easier antibiotic penetration. This work reports a novel mutation that plays a role in antibiotic susceptibility, along with mechanistic studies, and further confirms the role of OMPs in bacterial tolerance to antibiotics.

Currently, the high-purity single crystal diamond preparation is still a challenging task, which restricts the application of diamond in electronics. In this paper, the chemical vapor deposition (CVD) IIa type single crystal diamond was prepared on the IIa type high pressure high temperature (HPHT) substrate by combining the chamber design with the plasma purifying technology, and the performance of diamond detectors using both IIa type single crystal diamonds were compared based on the defect analysis. The dislocations in diamonds were directly observed by synchrotron radiation X-ray white-beam topography. The CVD diamond shows the comparatively low dislocation density resulting from the high-quality HPHT diamond substrate. No observable NV impurity could be found in photoluminescence (PL) spectrum. The trace impurity of substitutional nitrogen (Ns) was characterized by electron paramagnetic resonance (EPR). It shows the very low concentration in the CVD diamond (2.1 ppb) compared with the several tens ppb in HPHT diamond. This value is comparable with the electronic-grade diamond reported by Element Six. Furthermore, both of the HPHT and CVD single crystal diamonds were packaged as the α-particle radiation detectors with the typical sandwich structure and used Ni/Al (50 nm/500 nm) as metal electrodes. The energy resolution of HPHT and CVD diamond detectors were 2.04% and 0.86%, respectively. Based on Schottky contact and defect regulation, at 0 voltage, the CVD diamond detector achieved response of α-particle radiation and the charge collection efficiency (CCE) was 10.76%. Under positive voltage, the CCE of HPHT and CVD diamond detectors were 38.11% and 86.65%, respectively. The deep level trapping effect of Ns impurities on charge carriers resulted in low CCE of HPHT diamond detector. The spatial polarization effect caused by defects leaded to the formation of an internal electric field, which was the main reason affecting the transport of charge carriers in CVD diamond.

【Objective】On the occasion of the implementation of the policy of returning farmland to forest for 20 years, the dynamic changes of soil aggregates and soil organic carbon (SOC) after returning farmland to forest in upper reaches of the Minjiang River were quantitatively studied, which provided scientific data support for ecological governance and ecological agriculture development in arid valleys.【Method】Taking the native forest as the control and the ecological forests (eco-forests) and orchards (cherry, crisp plum, apple) as research objects, the particle size composition, stability and SOC distribution of soil water-stable aggregates of various land types were analyzed, and the mixed effect was applied to determine the contribution of forest land type, soil depth, altitude gradient, gravel content (GC) and other factors to soil aggregate stability and organic carbon dynamics.【Result】The content of macro-aggregates (> 0.25 mm) in orchards was significantly lower than that in eco-forests, and that in both was significantly lower than that in native forests. The contents of soil agglomerates of various sizes in the native and eco-forests showed as: 5-10 mm > 2-5 mm > 0.25-2 mm > 0.053-0.25 mm > 0-0.053 mm, those in the orchards ranked as: 0.25-2 mm > 2-5 mm > 5-10 mm > 0.053-0.25 mm > 0-0.053 mm. In the 5-15 cm soil layer, the contents of 5-10 mm and 2-5 mm agglomerates in cherry orchards were significantly greater than those in crisp plum orchards and apple orchards. Soil aggregate stability indexes(MWD and GMD) showed as: native forests > eco-forests > cherry orchards > crisp plum orchards and apple orchards, and there were no significant differences between crisp plum orchards and apple orchards. The SOC content(SOCC) in the 0-5 cm soil layer showed as native forests > eco-forests > cherry orchards > crisp plum orchards and apple orchards, and the difference showed a decreasing trend with the increase of soil depth. SOC(SOCS) stocks at a depth of 0-30 cm were highest in eco-forests (63.1 t/hm2), followed by cherry orchards (56.1 t/hm2), apple orchards (52.5 t/hm2), and crisp plum orchards (51.3 t/hm2), while the SOCS in native forests were the lowest (47.3 t/hm2). At a dep th of 30-60 cm, cherry orchards had the highest SOCS (40.3 t/hm2), followed by crisp plum orchards (32.9 t/hm2), and apple orchards (2 9.3 t/hm2), and eco-forests had the l owest SOCS (24.7 t/hm2). SOC distribution was characterized as 'high content and low stock' in native forests, 'high content and high stock' in eco-forests, and 'low content and high stock' in orchards. The dominant factor of soil aggregates stability and organic carbon content was forest type, and the dominant factor of SOCS was soil depth.【Conclusion】The mountain agriculture of 'eco-forests on the higher valley and orchards on the lower valley, fruit trees and cattle on the gentle slopes and terraced fields' is an ideal model for the agriculture development in arid valleys, and the improvement of SOC accumulation in the topsoil should be the priority for the management of orchards in the future.

In order to build a low-cost and high-efficiency 5G low-frequency network, it is necessary to study the best plan of plowing low-frequency 3G and 4G networks into 5G in advance.Under the condition of no ideal low frequency 5G test environment due to no re-farming, the coverage capacity after re-farming was estimated through theoretical analysis and was indirectly verified based on the current network test data.The key setting of link budget and model selection were discussed, the rationality of the estimation results was indirectly verified by the actual test data.The conclusion had been actually applied to the planning scheme of a major operator for the national 900 MHz network, which has essential reference significance to guide the network refarming.

During the landing and taxiing process of aircraft, the frame-type landing gear (FTLG) usually generates large pitch vibrations under external excitation. Excessive vibration increases localized loads on the landing gear, which may lead to localized failure of the structure. To minimize this undesirable vibration, a passive oil–pneumatic pitch-stabilizing buffer (PSB) is designed in this paper to provide pitch damping. This paper applies the basic principles of dynamics to establish a dynamic model of FTLG considering the influence of PSB. And based on the design of experiments (DOE) method, by changing the filling parameters and structural parameters of PSB, the results of the changes of the frame vibration angle, angular velocity, and landing gear load are obtained, so as to analyze the effects of different parameters on the dynamic performance of the landing gear in the landing and taxiing process. The results demonstrate that increasing the oil damping coefficient of PSB and decreasing the installation angle of PSB on the main strut during the landing period resulted in less frame vibration and lower wheelset load ratios, but increased the landing overloads of landing gears. In the taxiing phase, increasing the PSB air spring stiffness can effectively reduce the frame vibration caused by the uneven road surface. The PSB structural parameters have little effect on the dynamic performance of FTLG.

IntroductionOrganic agriculture is highly regarded by people for its commitment to health, ecology, care, and fairness. The soil microbial community responds quickly to environmental changes and is a good indicator for evaluating soil microecology. Therefore, from the perspective of soil microbial communities, elucidating the impact of organic management on soil microecology in tea plantations has great significance for improving local tea plantation systems.MethodsThe study collected bulk soil from organic management (OM) and conventional management (CM) tea plantations in Pu'er City, a major tea-producing area in China, and analyzed their species diversity, structural composition, and co-occurrence networks using metagenomics technology.ResultsCompared with CM, the diversity index (Shannon) and evenness index (Heip) of soil fungi increased by 7.38% and 84.2% in OM tea plantations, respectively. The relative abundance of microorganisms related to the nitrogen cycle increased. Specifically, there was a significant increase in Rhodobiales, a 2-fold increase in Nitrospirae, and approximately 1.95 and 2.03 times increases in unclassified genera within Betaproteobacteria and Deltaproteobacteria, respectively. The relative abundance of plant residue degradation species, Gemmatimonadetes, Ascomycota, and Basidiomycota, increased by 2.8, 1, and 1.4 times, respectively. The OM was conducive to the establishment of collaborative relationships among bacterial species and increased the diversity and complexity of species relationships in fungal communities. The network stability of soil ecosystems was promoted. The organic tea plantations' keystone taxa contained mycorrhizal fungi (Pezoloma_ericae, Rhizophagus_irregularis, Rhizophagus_clarus), as well as species involved in soil nitrogen metabolism (Acidobacteria_bacterium, Acidobacteriia_bacterium_AA117, Sphingomonas_sp._URHD0007, Enhydrobacter_aerosaccus), pathogen (Erysiphe_pulchra), and parasites (Paramycosporidium saccamoeba). The partial least squares method (PLS-SEM) indicated that OM affected N-NH4+ negatively, increasing the abundance of fungi, and thereby positively affecting the Shannon index.ConclusionIn brief, reasonable organic management can improve the diversity of soil microorganisms, increase the relative abundance of beneficial bacteria in tea plantation soil, and promote the stability of the soil microbial ecological network.

Microorganisms promoted corrosion has caused significant loss to marine engineering and the antibacterial coatings have served as a solution that has gained attention. In this study, the chemical vapour deposition technique has been employed to grow three different types of diamond coatings, namely, ultrananocrystalline diamond (UNCD), nanocrystalline diamond (NCD), and microcrystalline diamond (MCD) coatings. The evolution of associated surface morphology and the surface functional groups of the grown coatings have demonstrated antibacterial activity in seawater environments. It is found that different ratio of sp3/sp2 carbon bonds on the diamond coatings influences their surface property (hydrophobic/hydrophilic), which changes the anti-adhesion behaviour of diamond coatings against bacteria. This plays a critical role in determining the antibacterial property of the developed coatings. The results show that the diamond coatings arising from the deposition process kill the bacteria via a combination of the mechanical effects and the functional groups on the surface of UNCD, NCD, and MCD coatings, respectively. These antibacterial coatings are effective to both Gram-negative bacteria (E. coli) and Gram-positive bacteria (B. subtilis) for 1–6 h of incubation time. When the contact duration is prolonged to 6 h or over, the MCD coatings begin to reduce the bacteria colonies drastically and enhance the bacteriostatic rate for both E. coli and B. subtilis.

Electrically-excited flux-switching machines are advantageous in simple and reliable structure, good speed control performance, low cost, etc., so they have arouse wide concerns from new energy field. However, they have much lower torque density/thrust density compared with the same type PM machines. To overcome this challenge, electromagnetic-thermal coupled analysis is carried out with respect to water-cooled electrically-excited flux-switching linear machines (EEFSLM). The simulation results indicate that the conventional fixed copper loss method (FCLM) is no longer suitable for high thrust density design, since it is unable to consider the strong coupling between the electromagnetic and thermal performance. Hence, a multi-step electromagnetic-thermal joint optimisation method is proposed, which first ensures the consistency between the electromagnetic and thermal modelling and then considers the effect of different field/armature coil sizes. By using the proposed joint optimisation method, it is found that the combination of relatively large size of field coil and relatively low field copper loss is favourable for achieving high thrust force for the current EEFSLM design. Moreover, the thrust force is raised by 13-15% compared with using the FCLM. The electromagnetic and thermal performance of the EEFSLM is validated by the prototype test.

ObjectivesTo explore the value of radiomics based on Dual-energy CT (DECT) for discriminating preinvasive or MIA from IA appearing as GGNs before surgery.MethodsThe retrospective study included 92 patients with lung adenocarcinoma comprising 30 IA and 62 preinvasive-MIA, which were further divided into a training (n=64) and a test set (n=28). Clinical and radiographic features along with quantitative parameters were recorded. Radiomics features were derived from virtual monoenergetic images (VMI), including 50kev and 150kev images. Intraclass correlation coefficients (ICCs), Pearson’s correlation analysis and least absolute shrinkage and selection operator (LASSO) penalized logistic regression were conducted to eliminate unstable and redundant features. The performance of the models was evaluated by area under the curve (AUC) and the clinical utility was assessed using decision curve analysis (DCA).ResultsThe DECT-based radiomics model performed well with an AUC of 0.957 and 0.865 in the training and test set. The clinical-DECT model, comprising sex, age, tumor size, density, smoking, alcohol, effective atomic number, and normalized iodine concentration, had an AUC of 0.929 in the training and 0.719 in the test set. In addition, the radiomics model revealed a higher AUC value and a greater net benefit to patients than the clinical-DECT model.ConclusionDECT-based radiomics features were valuable in predicting the invasiveness of GGNs, yielding a better predictive performance than the clinical-DECT model.

BackgroundObservational studies about the association between serum total bilirubin and cholelithiasis are inconsistent. Hence, it is essential to reevaluate the association between serum total bilirubin and cholelithiasis and to verify whether such association is causal or not.MethodsWe selected single-nucleotide polymorphisms (SNPs) that are strongly associated with exposure as instrumental variable and conducted a bidirectional two-sample Mendelian randomization (MR) study to explore the causal association between serum total bilirubin and cholelithiasis. We implemented the inverse-variance weighted approach as a primary analysis to combine the Wald ratio estimates. Four additional analyses, namely, MR-Egger regression, weighted median, weighted mode, and MR–pleiotropy residual sum and outlier (PRESSO), were utilized to investigate the causal association and the influence of potential pleiotropy.ResultsA total of 116 SNPs were selected as valid instrumental variables to estimate the causal association of serum total bilirubin on cholelithiasis, and causal association between genetically determined serum total bilirubin and cholelithiasis was demonstrated [beta = 0.10; 95% confident interval (CI), 0.07 to 0.14; p < 0.001]. Likewise, the other methods, namely, the weighted median (beta = 0.12; 95% CI, 0.08 to 0.15; p < 0.001), MR-Egger (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), weighted mode (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), and MR-PRESSO approaches, further confirmed that this result (p = 0.054) indicates similar results. In addition, seven SNPs were selected as instrumental variable to estimate causal association of cholelithiasis on serum total bilirubin, and the result supported the causal effect of cholelithiasis to serum total bilirubin (beta = 0.12; 95% CI, 0.09 to 0.15; p < 0.001). At the same time, the other methods, namely, the weighted median (beta = 0.10; 95% CI, 0.06 to 0.13; p < 0.001), MR-Egger (beta = 0.12; 95% CI, 0.07 to 0.18; p = 0.007), weighted mode (beta = 0.09; 95% CI, 0.03 to 0.14, p = 0.019), and MR-PRESSO methods, further confirmed this result (p < 0.001).ConclusionOur MR study revealed that the serum total bilirubin was causally associated with the risk of cholelithiasis, and the genetic predisposition to cholelithiasis was causally associated with the increased serum total bilirubin levels.

Mitochondrial supercomplexes are observed in mammalian tissues with high energy demand and may influence metabolism and redox signaling. Nevertheless, the mechanisms that regulate supercomplex abundance remain unclear. In this study, we examined the composition of supercomplexes derived from murine cardiac mitochondria and determined how their abundance changes with substrate provision or by genetically induced changes to the cardiac glucose-fatty acid cycle. Protein complexes from digitonin-solubilized cardiac mitochondria were resolved by blue-native polyacrylamide gel electrophoresis and were identified by mass spectrometry and immunoblotting to contain constituents of Complexes I, III, IV, and V as well as accessory proteins involved in supercomplex assembly and stability, cristae architecture, carbohydrate and fat oxidation, and oxidant detoxification. Respiratory analysis of high molecular mass supercomplexes confirmed the presence of intact respirasomes, capable of transferring electrons from NADH to O2. Provision of respiratory substrates to isolated mitochondria augmented supercomplex abundance, with fatty acyl substrate (octanoylcarnitine) promoting higher supercomplex abundance than carbohydrate-derived substrate (pyruvate). Mitochondria isolated from transgenic hearts that express kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (GlycoLo), which decreases glucose utilization and increases reliance on fatty acid oxidation for energy, had higher mitochondrial supercomplex abundance and activity compared with mitochondria from wild-type or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-expressing hearts (GlycoHi), the latter of which encourages reliance on glucose catabolism for energy. These findings indicate that high energetic reliance on fatty acid catabolism bolsters levels of mitochondrial supercomplexes, supporting the idea that the energetic state of the heart is regulatory factor in supercomplex assembly or stability.

Purpose: In recent years, a rising number of multiple primary lung cancers have been detected with the advancement of imaging technology. No detailed study has assessed the prognosis of multiple primary lung adenocarcinomas based on computed tomography characteristics. The present study aimed to analyze outcomes and determine valuable factors for predicting the prognosis of multiple primary lung adenocarcinoma. Methods: This single-center retrospective study was performed from January 2013 to October 2021. All patients were divided into 3 groups based on tumor density as follows: multi-pure ground-glass nodules, at least one part-solid nodule without solid nodules, and at least one solid nodule. Clinicopathologic features, computed tomography signs, and survival outcomes were compared between these groups. The Kaplan-Meier method was used for survival analysis. The multivariable Cox proportional hazards regression model was used to identify independent predictors for recurrence-free survival and overall survival. Results: The sample included 283 patients with 623 lesions who met the inclusion criteria for multiple primary lung adenocarcinoma. Of these patients, 71 (25.1%) presented with multi-pure ground-glass nodules, 100 (35.3%) with at least one part-solid nodule without solid nodule, and 112 (39.6%) with at least one solid nodule. The 3 groups had distinguished clinicopathologic and radiological features of age, adjuvant therapy, types of tumor resection, TNM stage, pathological subtypes, pleural indentation, spicule, and vacuole (all P

A new bergamotane sesquiterpenoid, named xylariterpenoid H (1), along with fourteen known compounds (2–15), were isolated from the crude extract of Aspergillus fumigatus, an endophytic fungus isolated from Delphinium grandiflorum L. Their structures were elucidated mainly by extensive analyses of NMR and MS spectroscopic data. In addition, the screening results of antibacterial and cytotoxic activities of compounds 1–15 showed that compound 4 displayed antibacterial activities against Staphylococcus aureus and MRSA (methicillin-resistant S. aureus) with an MIC value of 3.12 µg/mL.

Abstract We evaluated pulmonary sequelae in COVID-19 survivors by quantitative inspiratory–expiratory chest CT (QCT) and explored abnormal pulmonary diffusion risk factors at the 6-month follow-up. This retrospective study enrolled 205 COVID-19 survivors with baseline CT data and QCT scans at 6-month follow-up. Patients without follow-up pulmonary function tests were excluded. All subjects were divided into group 1 (carbon monoxide diffusion capacity [DLCO] 75%). Data was analyzed by two-sample t-test, Spearman test, etc. 29% survivors showed air trapping by follow-up QCT. Semiquantitative CT score and QCT parameter of air trapping in group 1 were significantly greater than group 2 (p

Koninginins X-Z (1–3), three novel polyketides, were isolated from the solid fermentation of the endophytic fungus Trichoderma koningiopsis SC-5. Their structures, including the absolute configurations, were comprehensively characterized by a combination of NMR spectroscopic methods, HRESIMS, 13C NMR, DFT GIAO 13C NMR, and electronic circular dichroism calculations as well as single crystal X-ray diffraction. In addition, all the compounds were evaluated for antifungal activity against Candida albicans.

The orthogonal experiment of laser planarization of CVD polycrystalline diamond film was carried out, and the morphology was analyzed by using scanning electron microscope (SEM). The surface roughness Ra, the surface roughness Sa and the taper of kerf were measured by confocal laser scanning microscope. The influence of laser parameters on cutting quality was analyzed. The results show that the factors affecting kerf taper are pulse width, pulse frequency, feed speed and laser current in turn, and the factors affecting line roughness are feed speed, laser current, pulse frequency and pulse width in turn. After optimization by orthogonal test, the best groove surface morphology can be obtained with laser current of 64 A, pulse width of 400 μs, pulse frequency of 275 Hz and feed speed of 100 mm/min. Using the optimized parameters, the surface roughness Sa was measured to be 11.7 μm. When the incident angle increased to 75°, the surface roughness Sa decreased to 1.9 μm, and the actual removal efficiency reached 1.1 mm3/min.

The burgeoning multi-field applications of diamond concurrently bring up a foremost consideration associated with nitrogen. Ubiquitous nitrogen in both natural and artificial diamond in most cases as disruptive impurity is undesirable for diamond material properties, eg deterioration in electrical performance. However, the feat of this most common element-nitrogen, can change diamond growth evolution, endow diamond fancy colors and even give quantum technology a solid boost. This perspective reviews the understanding and progress of nitrogen in diamond including natural occurring gemstones and their synthetic counterparts formed by high temperature high pressure (HPHT) and chemical vapor deposition (CVD) methods. The review paper covers a variety of topics ranging from the basis of physical state of nitrogen and its related defects as well as the resulting effects in diamond (including nitrogen termination on diamond surface), to precise control of nitrogen incorporation associated with selective post-treatments and finally to the practical utilization. Among the multitudinous potential nitrogen related centers, the nitrogen-vacancy (NV) defects in diamond have attracted particular interest and are still ceaselessly drawing extensive attentions for quantum frontiers advance.

D-mannose is a natural and biologically active monosaccharide. It is the C-2 epimer of glucose and a component of a variety of polysaccharides in plants. In addition, D-mannose also naturally exists in some cells of the human body and participates in the immune regulation of cells as a prebiotic. Its good physiological benefits to human health and wide application in the food and pharmaceutical industries have attracted widespread attention. Therefore, in-depth research on preparation methods of D-mannose has been widely developed. This article summarizes the main production methods of D-mannose in recent years, especially the in-depth excavation from biomass raw materials such as coffee grounds, konjac flour, acai berry, etc., to provide new ideas for the green manufacture of D-mannose.

Colon cancer is a highly malignant cancer with poor prognosis. Astragalus membranaceus (Fisch.) Bunge (Huang Qi in Chinese, HQ), a well-known Chinese herbal medicine and a popular food additive, possesses various biological functions and has been frequently used for clinical treatment of colon cancer. However, the underlying mechanism is not fully understood. Isoflavonoids, including formononetin (FMNT) and calycosin (CS), are the main bioactive ingredients isolated from HQ. Thus, this study aimed to explore the inhibitory effects and mechanism of HQ, FMNT and CS against colon cancer by using network pharmacology coupled with experimental validation and molecular docking. The network pharmacology analysis revealed that FMNT and CS exerted their anticarcinogenic actions against colon cancer by regulating multiple signaling molecules and pathways, including MAPK and PI3K-Akt signaling pathways. The experimental validation data showed that HQ, FMNT and CS significantly suppressed the viability and proliferation, and promoted the apoptosis in colon cancer Caco2 and HT-29 cells. HQ, FMNT and CS also markedly inhibited the migration of Caco2 and HT-29 cells, accompanied by a marked increase in E-cadherin expression, and a notable decrease in N-cadherin and Vimentin expression. In addition, HQ, FMNT and CS strikingly decreased the expression of ERK1/2 phosphorylation (p-ERK1/2) without marked change in total ERK1/2 expression. They also slightly downregulated the p-Akt expression without significant alteration in total Akt expression. Pearson correlation analysis showed a significant positive correlation between the inactivation of ERK1/2 signaling pathway and the HQ, FMNT and CS-induced suppression of colon cancer. The molecular docking results indicated that FMNT and CS had a strong binding affinity for the key molecules of ERK1/2 signaling pathway. Conclusively, HQ, FMNT and CS exerted good therapeutic effects against colon cancer by mainly inhibiting the ERK1/2 signaling pathway, suggesting that HQ, FMNT and CS could be useful supplements that may enhance chemotherapeutic outcomes and benefit colon cancer patients.

Alginate lyase is essential for the production of alginate oligosaccharides (AOSs), which exhibit diverse bioactivities and have numerous applications in the food and pharmaceutical industries. The creation of recombinant alginate lyase by genetic engineering lays a crucial foundation for the commercialization of alginate lyase. This study cloned and expressed the polysaccharide lyase family 6 (PL6) alginate lyase gene alyrm1 from Rubrivirga marina.The optimum temperature and pH for recombinant AlyRm1 are 30 °C and 10.0, respectively. AlyRm1 shows good alkaline stability, for it remained over 80% of the enzyme activity after being incubated at pH 10.0 for 24 h AlyRm1 preferentially degrades PolyM into AOSs with degrees of polymerization (DP) 2–5 and monosaccharides as an endolytic bifunctional lyase. In addition, the analysis of degradation products toward oligosaccharides revealed that the minimal substrate of AlyRm1 is trisaccharide and clarified the degradation patterns.

Worldwide, cancer is a growing epidemic that results in large social and economic burdens. Despite advances in current diagnosis and treatment, most of the prognosis in cancer patients remains poor. It is urgent to find alternative therapies with effective cancer prevention and treatment. Chinese herbal medicines (CHMs) have been increasingly used worldwide for cancer prevention and treatment due to their privileged properties. CHMs are useful in the suppression of various types of cancers through different mechanisms of action. Non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs and circular RNAs, are closely involved in the cancer progression and development. Regulation of ncRNAs in tumor cells may be a useful pharmacological strategy for the cancer prevention and treatment. Substantial evidence exists that various phytochemicals from CHMs exert potent anticarcinogenic effects by regulating ncRNAs-related targets and signaling pathways. Herein, the purpose of this paper is to conclude the current understanding of phytochemicals from CHMs in ncRNAs-mediated cancer suppression and the molecular mechanisms. This review will help to provide beneficial clues related to the clinical use of CHMs in the cancer prevention and treatment and further promote new drug discovery against cancer.

BackgroundChronic kidney disease patients have increased risk of cardiovascular abnormalities. This study investigated the relationship between cardiovascular abnormalities and the severity of chronic kidney disease using cardiac magnetic resonance imaging.MethodsWe enrolled 84 participants with various stages of chronic kidney disease (group I: stages 1–3, n = 23; group II: stages 4–5, n = 20; group III: hemodialysis patients, n = 41) and 32 healthy subjects. The demographics and biochemical parameters of the study subjects were evaluated. All subjects underwent non-contrast cardiac magnetic resonance scans. Myocardial strain, native T1, and T2 values were calculated from the scanning results. Analysis of covariance was used to compare the imaging parameters between group I-III and the controls.ResultsThe left ventricular ejection fraction (49 vs. 56%, p = 0.021), global radial strain (29 vs. 37, p = 0.019) and global circumferential strain (-17.4 vs. −20.6, p < 0.001) were significantly worse in group III patients compared with the controls. Furthermore, the global longitudinal strain had a significant decline in group II and III patients compared with the controls (-13.7 and −12.9 vs. −16.2, p < 0.05). Compared with the controls, the native T1 values were significantly higher in group II and III patients (1,041 ± 7 and 1,053 ± 6 vs. 1,009 ± 6, p < 0.05), and T2 values were obviously higher in group I-III patients (49.9 ± 0.6 and 53.2 ± 0.7 and 50.1 ± 0.5 vs. 46.6 ± 0.5, p < 0.001). The advanced chronic kidney disease stage showed significant positive correlation with global radial strain (r = 0.436, p < 0.001), global circumferential strain (r = 0.386, p < 0.001), native T1 (r = 0.5, p < 0.001) and T2 (r = 0.467, p < 0.001) values. In comparison with the group II patients, hemodialysis patients showed significantly lower T2 values (53.2 ± 0.7 vs. 50.1 ± 0.5, p = 0.002), but no significant difference in T1 values (1,041 ± 7 vs. 1,053 ± 6).ConclusionsOur study showed that myocardial strain, native T1, and T2 values progressively got worse with advancing chronic kidney disease stage. The increased T1 values and decreased T2 values of hemodialysis patients might be due to increasing myocardial fibrosis but with reduction in oedema following effective fluid management.Trial registration numberChiCTR2100053561 (http://www.chictr.org.cn/edit.aspx?pid=139737&htm=4).

Two previously undescribed lactones, phomolides A and B (1 and 2), and three new sesquiterpenoids, phomenes A–C (3–5), together with one known compound, colletotricholide A (6), were isolated from the endophytic fungus Phomopsis sp. SZSJ-7B. Their chemical structures, including the absolute configurations, were comprehensively established by extensive analyses of NMR, high-resolution electrospray ionization mass spectrometry, electronic circular dichroism powered by theoretical calculations, and X-ray diffractions. Moreover, the cytotoxic and antibacterial activities of compounds 1–6 were also evaluated, and the results demonstrated that compound 2 showed significant antibacterial effects towards methicillin-resistant Staphylococcus aureus and S. aureus strains with minimum inhibitory concentration as low as 6.25 μg/ml, which was comparable to that of the clinical drug vancomycin. Moreover, all compounds showed no cytotoxic activity.

Backgrounds/AimsA history of upper abdominal surgery has been identified as a relative contraindication for laparoscopy. This study aimed to compare the clinical efficacy and safety of laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) in patients with and without previous upper abdominal surgery.MethodsIn total, 131 patients with previous upper abdominal surgery and 64 without upper abdominal surgery underwent LC or LCBDE between September 2017 and September 2021 at the Shengjing Hospital of China Medical University. Patients with previous upper abdominal surgery were divided into four groups: group A included patients with previous right upper abdominal surgery who underwent LC (n = 17), group B included patients with previous other upper abdominal surgery who underwent LC (n = 66), group C included patients with previous right upper abdominal surgery who underwent LCBDE (n = 30), and group D included patients with previous other upper abdominal surgery who underwent LCBDE (n = 18). Patient demographics and perioperative outcomes were retrospectively analyzed.ResultsThe preoperative liver function indexes showed no significant difference between the observation and control groups. For patients who underwent LC, groups A and B had more abdominal adhesions than the control group. One case was converted to open surgery in each of groups A and B. There was no statistical difference in operation time, estimated blood loss, postoperative hospital stay, and drainage volume. For patients who underwent LCBDE, groups C and D had more estimated blood loss than the control group (group C, 41.33 ± 50.84 vs. 18.97 ± 13.12 ml, p = 0.026; group D, 66.11 ± 87.46 vs. 18.97 ± 13.12 ml, p = 0.036). Compared with the control group, group C exhibited longer operative time (173.87 ± 60.91 vs. 138.38 ± 57.38 min, p = 0.025), higher drainage volume (296.83 ± 282.97 vs. 150.83 ± 127.04 ml, p = 0.015), and longer postoperative hospital stay (7.97 ± 3.68 vs. 6.17 ± 1.63 days, p = 0.021). There was no mortality in all groups.ConclusionsLC or LCBDE is a safe and feasible procedure for experienced laparoscopic surgeons to perform on patients with previous upper abdominal surgery.

With its high incidence and mortality rates, cancer is one of the largest health problems worldwide. Investigating various cancer treatment options has been the focus of many domestic and international researchers, and significant progress has been made in the study of the anticancer effects of traditional Chinese medicines. Osthole, a coumarin compound extracted from Cnidium monnieri (L.) Cuss., has become a new research hotspot. There have been many reports on its anticancer effects, and recent studies have elucidated that its underlying mechanism of action mainly involves inhibiting cancer cell proliferation, inducing cancer cell apoptosis, inhibiting invasion and migration of cancer cells, inhibiting cancer angiogenesis, increasing sensitivity to chemotherapy drugs, and reversing multidrug resistance of cancer cells. This mini-review summarizes the research progress on the anticancer effects of osthole in recent years.

Four examples of N,N-bis(aryl)butane-2,3-diimine–nickel(II) bromide complexes, [ArN=C(Me)-C(Me)=NAr]NiBr2 (where Ar = 2-(C5H9)-4,6-(CHPh2)2C6H2 (Ni1), Ar = 2-(C6H11)-4,6-(CHPh2)2C6H2 (Ni2), 2-(C8H15)-4,6-(CHPh2)2C6H2 (Ni3) and 2-(C12H23)-4,6-(CHPh2)2C6H2 (Ni4)), disparate in the ring size of the ortho-cycloalkyl substituents, were prepared using a straightforward one-pot synthetic method. The molecular structures of Ni2 and Ni4 highlight the variation in the steric hindrance of the ortho-cyclohexyl and -cyclododecyl rings exerted on the nickel center, respectively. By employing EtAlCl2, Et2AlCl or MAO as activators, Ni1–Ni4 displayed moderate to high activity as catalysts for ethylene polymerization, with levels falling in the order Ni2 (cyclohexyl) > Ni1 (cyclopentyl) > Ni4 (cyclododecyl) > Ni3 (cyclooctyl). Notably, cyclohexyl-containing Ni2/MAO reached a peak level of 13.2 × 106 g(PE) of (mol of Ni)−1 h−1 at 40 °C, yielding high-molecular-weight (ca. 1 million g mol−1) and highly branched polyethylene elastomers with generally narrow dispersity. The analysis of polyethylenes with 13C NMR spectroscopy revealed branching density between 73 and 104 per 1000 carbon atoms, with the run temperature and the nature of the aluminum activator being influential; selectivity for short-chain methyl branches (81.8% (EtAlCl2); 81.1% (Et2AlCl); 82.9% (MAO)) was a notable feature. The mechanical properties of these polyethylene samples measured at either 30 °C or 60 °C were also evaluated and confirmed that crystallinity (Xc) and molecular weight (Mw) were the main factors affecting tensile strength and strain at break (εb = 353–861%). In addition, the stress–strain recovery tests indicated that these polyethylenes possessed good elastic recovery (47.4–71.2%), properties that align with thermoplastic elastomers (TPEs).

Abstract Ketone bodies (KB) serve as the food for mitochondrial biogenetics. Interestingly, probiotics are known to promote KB formation in the gut (especially those that belong to the Lactobacillus genus). Furthermore, Lactobacillus helps produce folate that lowers the levels of homocysteine (Hcy); a hallmark non‐proteinogenic amino acid that defines the importance of epigenetics, and its landscape. In this study, we decided to test whether hydrogen sulfide (H2S), another Hcy lowering agent regulates the epigenetic gene writer DNA methyltransferase (DNMT), eraser FTO and TET2, and thus mitigates the skeletal muscle remodeling. We treated hyperhomocysteinemic (HHcy, cystathionine beta‐synthase heterozygote knockout; CBS+/−) mice with NaHS (the H2S donor). The results suggested multi‐organ damage by HHcy in the CBS+/−mouse strain compared with WT control mice (CBS+/+). H2S treatment abrogated most of the HHcy‐induced damage. The levels of gene writer (DNMT2) and H3K9 (methylation) were higher in the CBS+/− mice, and the H2S treatment normalized their levels. More importantly, the levels of eraser FTO, TET, and associated GADD45, and MMP‐13 were decreased in the CBS+/− mice; however, H2S treatment mitigated their respective decrease. These events were associated with mitochondrial fission, i.e., an increase in DRP1, and mitophagy. Although the MMP‐2 level was lower in CBS+/− compared to WT but H2S could further lower it in the CBS+/− mice. The MMPs levels were associated with an increase in interstitial fibrosis in the CBS+/− skeletal muscle. Due to fibrosis, the femoral artery blood flow was reduced in the CBS+/− mice, and that was normalized by H2S. The bone and muscle strengths were found to be decreased in the CBS+/− mice but the H2S treatment normalized skeletal muscle strength in the CBS+/− mice. Our findings suggest that H2S mitigates the mitophagy‐led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function.

Plateau pikas (Ochotona curzoniae) are high-altitude model animals and famous “ecosystem engineers” on the Qinghai-Tibet Plateau. Pika activities may accelerate the degradation of alpine meadows. Nevertheless, little is known about the responses of bacterial, fungal, and archaeal communities, and ecosystem multifunctionality to pika perturbations. To address this question, we studied the impacts of only pika disturbance and combined disturbance (pika disturbance and grazing) on ecological networks of soil microbial communities and ecosystem multifunctionality. Our results demonstrated that Proteobacteria, Ascomycota, and Crenarchaeota were dominant in bacteria, fungi, and archaea, respectively. Bacteria, fungi, and archaea were all influenced by the combined disturbance of grazing and pika. Most fungal communities became convergent, while bacterial and archaeal communities became differentiated during the succession of surface types. In particular, the bacterial and fungal networks were less stable than archaeal networks. In response to the interference, cross-domain cooperation between bacterial and fungal communities increased, while competitive interactions between bacterial and archaeal communities increased. Pika disturbance at high intensity significantly reduced the ecosystem multifunctionality. However, the mixed effects of grazing and pika weakened such influences. This study revealed how pika activities affected microbial networks and ecosystem multifunctionality. These results provide insights to designing reasonable ecological management strategies for alpine grassland ecosystems.

BackgroundCurrently, no second-line systemic treatment regimen has been recommended in advanced biliary tract cancer (BTC). Cumulative clinical evidence showed that systemic treatment with tyrosine kinase inhibitors (TKIs) in combination with immunotherapy may shed light on the dim clinical outcome in advanced BTC.ObjectiveThe aim of this study is to evaluate the anticancer efficacy of lenvatinib plus programmed cell death protein-1 (PD-1) antibody in patients with BTC who progressed after first-line cisplatin/gemcitabine (CisGem) chemotherapy.MethodsPatients with advanced BTCs who progressed after CisGem were recruited. A combination regimen of lenvatinib (8/12 mg daily) plus PD-1 antibody (200/240 mg injection every 3 weeks) was prescribed. Clinicopathological information and therapeutic outcome, including tumor subtypes, biomarkers, treatment duration, adverse events (AE), progression-free survival (PFS), and overall survival (OS), were recorded and estimated.ResultsA total of 351 patients with BTCs were reviewed and 74 were recruited eventually: 35 had intrahepatic cholangiocarcinoma (47.3%), 4 had extrahepatic cholangiocarcinoma (5.4%), and 35 had gallbladder cancer (47.3%). The median administered cycles of PD-1 antibody were 6.43 (95% CI: 5.83–7.04) cycles, and the median duration of lenvatinib medication was 21.0 weeks (95% CI: 18.04–23.93). Twenty-eight patients (37.83%) experienced detectable objective response per RECIST1.1 within a median follow-up duration of 15.0 months. The objective response rate (ORR) was 20.27% (95% CI: 10.89%–29.65%), and the disease control rate (DCR) was 71.62% (95% CI: 61.11%–82.14%). The median PFS and OS were 4.0 months (95% CI: 3.5–5.0) and 9.50 months (95% CI: 9.0–11.0), respectively. Seventy-three patients (98.64%) reported AEs and 39 (52.70%) experienced ≥grade 3 AEs. In subgroup analyses, tumoral PD-L1 expression ≥50% and tumor mutation burden (TMB) ≥2.5 Muts/Mb were associated with prolonged PFS.ConclusionLenvatinib plus PD-1 antibody treatment shows an active trend towards improving survival in patients with advanced BTCs after failure with CisGem chemotherapy. The treatment-related AEs are worthy of attention and are manageable.

ObjectivesSpread through air spaces (STAS), a new invasive pattern in lung adenocarcinoma (LUAD), is a risk factor for poor outcome in early-stage LUAD. This study aimed to develop and validate a CT-based radiomics model for predicting STAS in stage IA LUAD.MethodsA total of 395 patients (169 STAS positive and 226 STAS negative cases, including 316 and 79 patients in the training and test sets, respectively) with stage IA LUAD before surgery were retrospectively included. On all CT images, tumor size, types of nodules (solid, mix ground-glass opacities [mGGO] and pure GGO [pGGO]), and GGO percentage were recorded. Region of interest (ROI) segmentation was performed semi-automatically, and 1,037 radiomics features were extracted from every segmented lesion. Intraclass correlation coefficients (ICCs), Pearson’s correlation analysis and least absolute shrinkage and selection operator (LASSO) penalized logistic regression were used to filter unstable (ICC < 0.75) and redundant features (r > 0.8). A temporary model was established by multivariable logistic regression (LR) analysis based on selected radiomics features. Then, seven radiomics features contributing the most were selected for establishing the radiomics model. We then built two predictive models (clinical-CT model and MixModel) based on clinical and CT features only, and the combination of clinical-CT and Rad-score, respectively. The performances of these three models were assessed.ResultsThe radiomics model achieved good performance with an area under of curve (AUC) of 0.812 in the training set, versus 0.850 in the test set. Furthermore, compared with the clinical-CT model, both radiomics model and MixModel showed higher AUC and better net benefit to patients in the training and test cohorts.ConclusionThe CT-based radiomics model showed satisfying diagnostic performance in early-stage LUAD for preoperatively predicting STAS, with superiority over the clinical-CT model.

Abstract Background Distal 8p duplication is rare but clinically significant. Duplication syndrome results in variable phenotypes, such as developmental delay, intellectual disability, and malformation of the heart. We aimed to provide a better understanding of the phenotypes by studying duplication and its effects in a single family. Methods In a family with a previously induced labor (second fetus) at 12 weeks gestation due to increased nuchal translucency (3.5 mm), copy number variation sequencing (CNV-seq) revealed a 16.22 Mb deletion of 8p23.3p22. For their subsequent pregnancy, the family requested a prenatal diagnosis as well as CNV-seq, karyotyping and FISH testing of all family members. Results The first and third children were found to have a 16.22 Mb duplication of 8p23.3p22, containing the 8p23.1 duplication syndrome region. The duplication was inherited from their father, a carrier with a translocation of 8p22 and 22q13. We confirmed that the duplication site was located on chromosome 22q13 by combining the results of CNV-seq, karyotype and FISH. The first child is a 7.5-year-old boy. At one month old, he was diagnosed with a ventricular septal defect and treated surgically at age four. His growth and intelligence developed well, and he performed well in school. His primary issue is an inability to distinguish between the blade alveolars and retroflexes in speech. The third fetus had a normal ultrasound index from beginning until birth. The family elected to continue the pregnancy, and the baby was born healthy, providing us the opportunity to evaluate the effects of 8p23.3p22 duplication by comparison with the brother. Conclusion Our study makes a significant contribution to the literature because this relatively rare condition can have significant phenotypical consequences, and an understanding of the inheritance and variability of phenotypes caused by this mutation is essential to an increased understanding of the condition.

Objectives: To compare the clinical characteristics and chest CT findings of patients infected with Omicron and Delta variants and the original strain of COVID-19. Methods: A total of 503 patients infected with the original strain (245 cases), Delta variant (90 cases), and Omicron variant (168 cases) were retrospectively analyzed. The differences in clinical severity and chest CT findings were analyzed. We also compared the infection severity of patients with different vaccination statuses and quantified pneumonia by a deep-learning approach. Results: The rate of severe disease decreased significantly from the original strain to the Delta variant and Omicron variant (27% vs. 10% vs. 4.8%, p < 0.001). In the Omicron group, 44% (73/168) of CT scans were categorized as abnormal compared with 81% (73/90) in the Delta group and 96% (235/245, p < 0.05) in the original group. Trends of a gradual decrease in total CT score, lesion volume, and lesion CT value of AI evaluation were observed across the groups (p < 0.001 for all). Omicron patients who received the booster vaccine had less clinical severity (p = 0.015) and lower lung involvement rate than those without the booster vaccine (36% vs. 57%, p = 0.009). Conclusions: Compared with the original strain and Delta variant, the Omicron variant had less clinical severity and less lung injury on CT scans.

Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder and is characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. Although the maternal chromosomal region 15q11.2‐q13 deletion is the most common mechanism of AS, ~10% of individuals with AS are caused by the intragenic variants in the maternally inherited UBE3A, which encodes an E3 ubiquitin ligase. Methods Clinical diagnoses were based on detailed clinical findings. Trio‐based exome sequencing was performed on the proband and her parents to identify the underlying genetic variants. The candidate variants were confirmed by Sanger sequencing following PCR amplification. In silico analyses were conducted to predict the effect of the identified variant on the function of UBE3A protein. Results We identified a novel variant c.2029G>C (p. Gly677Arg) in UBE3A as the most promising candidate. In silico analyses showed that p.Gly677Arg in the UBE3A affects a highly conserved residue. Her mother had the variant at this locus. Sanger sequencing results showed that II‐2, II‐5, II‐7, IV‐1, III‐5, III‐7, III‐8, and III‐9 have the variant c.2029G>C, and all patients inherited maternally variant in UBE3A, while the offsprings of the male carrier were unaffected. Conclusions We identified a novel variant (c.2029G>C) in the UBE3A in a Chinese family with multigenerational intellectual disability and developmental delay. Our findings expanded the genotypic spectrum of AS and provided important information for genetic counseling.

The ability to alter surface chemistry on a variety of materials makes polydopamine (PDA) and excellent surface coating material, but weak wear resistance and high surface roughness limits its application. Here, the authors demonstrate a laser annealing process to improve the mechanical properties of PDA coatings.

Doubly-fed flux reversal permanent magnet (DF-FRPM) machine with two independent armature windings accommodating in stator and rotor slots separately exhibits larger torque density than conventional FRPM due to higher utilization rate of rotor space. In this paper, the investigation is focused on the airgap field modulation and torque contribution of dominating harmonics in DF-FRPM machine. Besides the open-circuit airgap flux density, both stator and rotor armature reaction are qualitatively analyzed by magneto-motive force (MMF)-permeance model considering stator and rotor saliency since the two independently supplied armature windings both make contributions to the torque production. The pole pairs and rotating speed of field harmonics are addressed. Dominating field harmonics that contribute to electromagnetic torque are identified and validated by finite element (FE) analysis.

Science and technology innovation are crucial components underpinning agriculture. We constructed an evaluation framework including 4 pillars and 21 indicators, taking 31 provinces in China as examples to examine the level of agriculture science and technology development from a regional perspective. We found that there is an obvious gap between east and west nationwide, and that only about half of the provinces have reached the high and medium levels. It was worth noting that the innovation conditions in Shanghai and Beijing presented huge advantages, of vital importance to a first-class talent team, a complete innovation system, a stable and prosperous market, and active exchanges and cooperation. In addition, to maximize the transformation of agricultural science and technology achievements into real productivity, local government should also strengthen the construction of agricultural research and innovation platforms, technology transfer, and transformation of results. The findings advance understanding of the strengths and weaknesses of the evaluation subjects’ agricultural science and technology development from a regional perspective and are expected to provide some basis for the government and stakeholders to make relevant decisions.

Cancer remains a major public health threat. The mitigation of the associated morbidity and mortality remains a major research focus. From a molecular biological perspective, cancer is defined as uncontrolled cell division and abnormal cell growth caused by various gene mutations. Therefore, there remains an urgent need to develop safe and effective antitumor drugs. The antitumor effect of plant extracts, which are characterized by relatively low toxicity and adverse effect, has attracted significant attention. For example, increasing attention has been paid to the antitumor effects of tetramethylpyrazine (TMP), the active component of the Chinese medicine Chuanqiong, which can affect tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis, as well as reverse chemotherapeutic resistance in neoplasms, thereby triggering antitumor effects. Moreover, TMP can be used in combination with chemotherapeutic agents to enhance their effects and reduce the side effect associated with chemotherapy. Herein, we review the antitumor effects of TMP to provide a theoretical basis and foundation for the further exploration of its underlying antitumor mechanisms and promoting its clinical application.

Natural antioxidants derived from agricultural by-products have great promise and ecological advantages in the treatment of oxidative stress-related diseases. The eggshell membrane (ESM) from hatched eggs, i.e., the hatched ESM, is a globally abundant agricultural byproduct, and its high-value utilization has been rarely studied compared to the well-studied ESM from fresh eggs. In this research, we systematically characterized the hatched ESM as a novel source of antioxidant hydrolysates and explored their potential role in H2O2-induced human chondrocytes. The results showed that the hatched ESM is a protein-rich fibrous mesh material with a significantly different structure and composition from those of fresh ESM. Enzymatic hydrolysis of hatched ESM can produce antioxidant hydrolysates rich in low molecular weight (MW) peptides, which mainly derived from the Lysyl oxidase homolog by Nano-LC-MS/MS analysis. The peptide fraction with MW < 3 kDa (HEMH-I) exhibited the highest DPPH radical scavenging, Fe2+-chelating, and Fe3+-reducing abilities. In H2O2-induced human SW1353 chondrocytes, HEMH-I treatment significantly increased the cell viability and ameliorated oxidative stress, inflammatory response, and cartilage matrix degradation by reducing the level of ROS, matrix metalloprotease 3 (MMP3), MMP13, and IL-6, and by promoting the expression of SOD and type II collagen, potentially through activating the cellular Keap1/Nrf2/HO-1 pathway. This study provides a theoretical basis for the value-added application of hatched ESM waste to produce antioxidant hydrolysates and indicates their potential as functional food and pharmaceuticals.

During acute heart failure (HF), remote ischemic conditioning (RIC) has proven to be beneficial; however, it is currently unclear whether it also extends benefits from chronic congestive, cardiopulmonary heart failure (CHF). Previous studies from our laboratory have shown three phases describing CHF viz. (1) HF with preserved ejection fraction (HFpEF), (2) HF with reduced EF (HFrEF), and (3) HF with reversed EF. Although reciprocal organ interaction, ablation of sympathetic, and calcium signaling genes are associated with HFpEF to HFrEF, the mechanism is unclear. The HFrEF ensues, in part, due to reduced angiogenesis, coronary reserve, and leakage of endocardial endothelial (EE) and finally breakdown of the blood-heart barrier (BHB) integrity. In fact, our hypothesis states that a change in phenotype from compensatory HFpEF to decompensatory HFrEF is determined by a potential decrease in regenerative, proangiogenic factors along with a concomitant increase in epigenetic memory, inflammation that combinedly causes oxidative, and proteolytic stress response. To test this hypothesis, we created CHF by aorta-vena-cava (AV) fistula in a group of mice that were subsequently treated with that of hind-limb RIC. HFpEF vs. HFrEF transition was determined by serial/longitudinal echo measurements. Results revealed an increase in skeletal muscle musclin contents, bone-marrow (CD71), and sympathetic activation (β2-AR) by RIC. We also observed a decrease in vascular density and attenuation of EE-BHB function due to a corresponding increase in the activity of MMP-2, vascular endothelial growth factor (VEGF), caspase, and calpain. This decrease was successfully mitigated by RIC-released skeletal muscle exosomes that contain musclin, the myokine along with bone marrow, and sympathetic activation. In short, based on proteome (omics) analysis, ∼20 proteins that appear to be involved in signaling pathways responsible for the synthesis, contraction, and relaxation of cardiac muscle were found to be the dominant features. Thus, our results support that the CHF phenotype causes dysfunction of cardiac metabolism, its contraction, and relaxation. Interestingly, RIC was able to mitigate many of the deleterious changes, as revealed by our multi-omics findings.

Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.

Lytic polysaccharide monooxygenase (LPMO) is a newly discovered and widely studied enzyme in recent years. These enzymes play a key role in the depolymerization of sugar-based biopolymers (including cellulose, hemicellulose, chitin and starch), and have a positive significance for biomass conversion. LPMO is a copper-dependent enzyme that can oxidize and cleave glycosidic bonds in cellulose and other polysaccharides. Their mechanism of action depends on the correct coordination of copper ions in the active site. There are still difficulties in the analysis of LPMO activity, which often requires multiple methods to be used in concert. In this review, we discussed various LPMO activity analysis methods reported so far, including mature mass spectrometry, chromatography, labeling, and indirect measurements, and summarized the advantages, disadvantages and applicability of different methods.