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Abstract Background DNA methylation contributes to the epigenetic regulation of nuclear gene expression, and is associated with plant growth, development, and stress responses. Compelling evidence has emerged that long non-coding RNA (lncRNA) regulates DNA methylation. Previous genetic and physiological evidence indicates that lncRNA-CRIR1 plays a positive role in the responses of cassava plants to cold stress. However, it is unclear whether global DNA methylation changes with CRIR1-promoted cold tolerance. Results In this study, a comprehensive comparative analysis of DNA methylation and transcriptome profiles was performed to reveal the gene expression and epigenetic dynamics after CRIR1 overexpression. Compared with the wild-type plants, CRIR1-overexpressing plants present gained DNA methylation in over 37,000 genomic regions and lost DNA methylation in about 16,000 genomic regions, indicating a global decrease in DNA methylation after CRIR1 overexpression. Declining DNA methylation is not correlated with decreased/increased expression of the DNA methylase/demethylase genes, but is associated with increased transcripts of a few transcription factors, chlorophyll metabolism and photosynthesis-related genes, which could contribute to the CRIR1-promoted cold tolerance. Conclusions In summary, a first set of transcriptome and epigenome data was integrated in this study to reveal the gene expression and epigenetic dynamics after CRIR1 overexpression, with the identification of several TFs, chlorophyll metabolism and photosynthesis-related genes that may be involved in CRIR1-promoted cold tolerance. Therefore, our study has provided valuable data for the systematic study of molecular insights for plant cold stress response.

Abstract Background IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease. Methods To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes. Results In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15–2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09–2.91]; GALSS: HR = 1.66[1.09–2.54]; UCSF: HR = 1.33[1.00–1.77]; UPENN HR = 1.29[1.04–1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust

A two-dimensional porous silica nanomesh (VMT-SiO2) was used as a carrier to prepare MgO-CuO-based catalysts and tested for one-step ethanol conversion to 1,3-butadiene. The effects of catalyst composition and different calcination temperatures on the reaction performances of the catalysts were mainly investigated. Combining various characterization techniques, such as HRTEM, XRD, FT-IR, and TPD, it was found that the dispersion state of MgO and CuO on the catalyst surface was related to the calcination temperature, which further induced changes in the acid–base properties. A small number of acidic centers and a proper proportion of medium–strong alkaline centers maintained a subtle balance, affecting catalytic performance. A lower total acid/base ratio is more conducive to ethanol conversion and 1,3-butadiene formation. At the same time, the synergistic effect of CuO and MgO promotes the transformation of the intermediate acetaldehyde product, which is the key to ensuring the subsequent aldol condensation and then 1,3-butadiene formation. Among the investigated samples, the CuO/MgO-VMT-SiO2 catalyst calcined at 500 °C exhibited the best catalytic performance, with an impressive ethanol conversion of 47.8% and 1,3-butadiene formation (42.6% selectivity and a space-time yield of 182.0 gC4H6·kgcat−1·h−1).

The branch impact failure mechanism has gradually received attention from scholars, along with the application of impact cutting methods in plantation forest pruning. In this paper, the impact cutting failure mechanism of Populus tomentosa branches was mainly studied. The impact cutting process of branches was simulated by using Finite Element Method (FEM)-based explicit dynamics. The stress change and deformation characteristics in the branch failure process were studied. A theoretical model of branch impact cutting mechanism with branch diameter, cutting clearance, and branch angle as the main factors was proposed. The model describes the branch cutting damage process and the changing characteristics of cutting force. A branch failure state equation was proposed to describe the branch impact cutting failure patterns. The forest experiment was conducted to validate the branch impact cutting mechanism and the branch failure state equation. This work fills a vacancy of relevant theory and provides a theoretical basis for the future development of forestry and agricultural equipment using impact cutting.

Abstract Background The identification of essential proteins can help in understanding the minimum requirements for cell survival and development to discover drug targets and prevent disease. Nowadays, node ranking methods are a common way to identify essential proteins, but the poor data quality of the underlying PIN has somewhat hindered the identification accuracy of essential proteins for these methods in the PIN. Therefore, researchers constructed refinement networks by considering certain biological properties of interacting protein pairs to improve the performance of node ranking methods in the PIN. Studies show that proteins in a complex are more likely to be essential than proteins not present in the complex. However, the modularity is usually ignored for the refinement methods of the PINs. Methods Based on this, we proposed a network refinement method based on module discovery and biological information. The idea is, first, to extract the maximal connected subgraph in the PIN, and to divide it into different modules by using Fast-unfolding algorithm; then, to detect critical modules according to the orthologous information, subcellular localization information and topology information within each module; finally, to construct a more refined network (CM-PIN) by using the identified critical modules. Results To evaluate the effectiveness of the proposed method, we used 12 typical node ranking methods (LAC, DC, DMNC, NC, TP, LID, CC, BC, PR, LR, PeC, WDC) to compare the overall performance of the CM-PIN with those on the S-PIN, D-PIN and RD-PIN. The experimental results showed that the CM-PIN was optimal in terms of the identification number of essential proteins, precision-recall curve, Jackknifing method and other criteria, and can help to identify essential proteins more accurately.

Abstract This study aims to investigate the effects of different mapping unit scales and study area scales on the uncertainty rules of landslide susceptibility prediction (LSP). To illustrate various study area scales, Ganzhou City in China, its eastern region (Ganzhou East), and Ruijin County in Ganzhou East were chosen. Different mapping unit scales are represented by grid units with spatial resolution of 30 and 60 m, as well as slope units that were extracted by multi-scale segmentation method. The 3855 landslide locations and 21 typical environmental factors in Ganzhou City are first determined to create spatial datasets with input-outputs. Then, landslide susceptibility maps (LSMs) of Ganzhou City, Ganzhou East and Ruijin County are produced using a support vector machine (SVM) and random forest (RF), respectively. The LSMs of the above three regions are then extracted by mask from the LSM of Ganzhou City, along with the LSMs of Ruijin County from Ganzhou East. Additionally, LSMs of Ruijin at various mapping unit scales are generated in accordance. Accuracy and landslide susceptibility indexes (LSIs) distribution are used to express LSP uncertainties. The LSP uncertainties under grid units significantly decrease as study area scales decrease from Ganzhou City, Ganzhou East to Ruijin County, whereas those under slope units are less affected by study area scales. Of course, attentions should also be paid to the broader representativeness of large study areas. The LSP accuracy of slope units increases by about 6%–10% compared with those under grid units with 30 m and 60 m resolution in the same study area's scale. The significance of environmental factors exhibits an averaging trend as study area scale increases from small to large. The importance of environmental factors varies greatly with the 60 m grid unit, but it tends to be consistent to some extent in the 30 m grid unit and the slope unit. Graphic abstract

PCrNi3MoV steel is a medium-carbon, low-alloy quenched and tempered steel that finds its applications in military gun barrels due to the high wear resistance and ablation resistance. To study the penetration and failure modes of PCrNi3MoV plates impacted by tungsten spheres, tungsten spheres of various diameters (5 mm, 8 mm, and 10 mm) were used to impact PCrNi3MoV steel plates with thicknesses of 6 mm, 9 mm, and 14 mm. The penetration performance of the spheres was analyzed for different velocities, and the ultimate penetration velocity of the plate was obtained. It was found that the primary failure modes of the PCrNi3MoV plate were compression pitting failure and shear failure. Using the dimensional analysis method, a relationship between the bulge height of the steel plate and the fragment velocity, an equation for the ultimate penetration velocity, and a relationship between the target penetration energy and the fragment velocity were obtained. Then, a projectile–target action index was proposed to describe the process of tungsten spheres with different velocities impacting target plates. The results suggested that under the same thickness of the target plate, a larger-diameter fragment required more kinetic energy to obtain the same ultimate penetration effect as a smaller-diameter fragment. The equations obtained through dimensional analysis predicted values that agreed well with experimental values, indicating that these equations can be applied to engineering applications.

This paper proposes a type of double-layer charge liner fabricated using chemical vapor deposition (CVD) that has tungsten as its inner liner. The feasibility of this design was evaluated through penetration tests. Double-layer charge liners were fabricated by using CVD to deposit tungsten layers on the inner surfaces of pure T2 copper liners. The microstructures of the tungsten layers were analyzed using a scanning electron microscope (SEM). The feasibility analysis was carried out by pulsed X-rays, slug-retrieval test and static penetration tests. The shaped charge jet forming and penetration law of inner tungsten-coated double-layer liner were studied by numerical simulation method. The results showed that the double-layer liners could form well-shaped jets. The errors between the X-ray test results and the numerical results were within 11.07%. A slug-retrieval test was found that the retrieved slug was similar to a numerically simulated slug. Compared with the traditional pure copper shaped charge jet, the penetration depth of the double-layer shaped charge liner increased by 11.4% and >10.8% respectively. In summary, the test results are good, and the numerical simulation is in good agreement with the test, which verified the feasibility of using the CVD method to fabricate double-layer charge liners with a high-density and high-strength refractory metal as the inner liner.

[Objective] Excavation of foundation pit will cause deformation of surrounding strata and buildings , which affects construction progress and even causes engineering accidents in some degree. In order to ensure the stability and safety of deep large foundation pit in urban rail transit stations, it is necessary to study the stress and deformation characteristics of the soil layer and the enclosure structure during the foundation pit excavation. [Method] With the deep foundation pit excavation for a metro station in Qingdao as the project background and in view of the characteristics of soil rock composite stratum, numerical simulation method is used to analyze the deformation and internal force of the deep foundation pit. Based on the on-site data, the deformation law of ground settlement, retaining pile displacement and supporting axial force during excavation of deep foundation pit under soil rock composite stratum is studied. [Result & Conclusion] The numerical simulation shows that when biaxial high-pressure rotary jet grouting pile is not under construction, the lateral displacement occurs in the east, west and south walls of the end shaft, all towards the internal of the foundation pit, and the maximum lateral displacement of 2.19 mm occurs in the middle of the south wall. During the construction, the deformation of the side wall of the end shaft reaches peak in the process of reinforcement of the rotary jet grouting pile at the end shaft of the foundation pit, and the maximum deformation is 2.21 mm. When the biaxial high-pressure rotary jet grouting pile is not under construction, the peak value of the internal force of the diaphragm wall appears at its waist, and the maximum value is 101 kN. During construction, the internal force of the diaphragm wall structure at the stratum side strengthened by the end shaft jet grouting pile changes obviously, and the peak value of the internal force appears at the waist of the diaphragm wall, and the maximum value is 96 kN. It can be seen that the biaxial high-pressure rotary jet pile has certain effect on reducing the internal force of the diaphragm wall under different construction conditions, but has little effect on the deformation of foundation pit.

Abstract Amyloid beta (Abeta) synergistically enhances excitotoxicity of glutamate load by impairing glutamate transporter 1 (GLT1) expression and function, which exacerbates the development of Alzheimer’s disease (AD). Our previous studies suggested that sulbactam can upregulate the expression levels and capacity of GLT1. Therefore, this study aims to investigate whether sulbactam improves neuronal tolerance against neurotoxicity of Abeta and glutamate load by up-regulating GLT1 in primary neuron-astrocyte co-cultures. Early postnatal P0–P1 Wistar rat pups’ cortices were collected for primary neuron–astrocyte cultures. Hoechst–propidium iodide (HO–PI) stain and lactate dehydrogenase (LDH) assays were used to analyze neuronal death. Cell counting kit 8 (CCK8) was applied to determine cell viability. Immunofluorescence staining and western blotting were used to assess protein expressions including GLT1, B-cell lymphoma 2 (BCL2), BCL2 associated X (BAX), and cleaved caspase 3 (CCP3). Under the double effect of Abeta and glutamate load, more neurons were lost than that induced by Abeta or glutamate alone, shown as decreased cell viability, increased LDH concentration in the cultural medium, HO–PI positive stains, high CCP3 expression, and high BAX/BCL2 ratio resulting from increased BAX and decreased BCL2 expressions. Notably, pre-incubation with sulbactam significantly attenuated the neuronal loss and activation of apoptosis induced by both Abeta and glutamate in a dose-dependent manner. Simultaneously, both astrocytic and neuronal GLT1 expressions were upregulated after sulbactam incubation. Taken together, it could be concluded that sulbactam protected neurons against double neurotoxicity of Abeta and glutamate load by upregulating GLT1 expression. The conclusion provides evidence for potential intervention using sulbactam in AD research.

In this work, a Cu–10Ta alloy with a copper to tantalum mass ratio of 9:1 is prepared using powder metallurgy technology. Physical properties of the alloy, including density, microstructure, melting point, and constant-volume specific heat, are tested. Via the split Hopkinson pressure bar (SHPB) and flyer-plate impact experiments, the relationship between equivalent stress and equivalent plastic strain of the material is studied at temperatures of 298–823 K and under strain rates of 1 × 10−3–5.2 × 103 s−1, and the Hugoniot relationship at impact pressures of 1.46–17.25 GPa and impact velocities of 108–942 m/s is obtained. Evolution of the Cu–10Ta microstructure that occurs during high-strain-rate impact is analyzed. Results indicate that the Cu–10Ta alloy possesses good thermal stability, and at ambient temperatures of up to 50% its melting point, stress softening of less than 15% of the initial strength is observed. A modified J-C constitutive model is employed to accurately predict the variation of yield strength with strain rate. Under strong impact, the copper phase is identified as the primary source of plastic deformation in the Cu–10Ta alloy, while significant deformation of the high-strength tantalum particles is less pronounced. Furthermore, the longitudinal wave speed D is found to correlate linearly with the particle velocity u upon strong impact. Analysis reveals that the sound speed and spallation strength of the alloy increase with increasing impact pressure.

ObjectivesThis study aimed to investigate the epidemiological and drug resistance (DR) characteristics of extrapulmonary tuberculosis (EPTB) in South-Central China.MethodsEPTB inpatients who were culture-positive for Mycobacterium tuberculosis were retrospectively included in a study at a provincial TB hospital in Hunan, a province in South-Central China, from January 2013 to December 2021. Demographic, clinical, and drug susceptibility data were retrieved from TB treatment records. Descriptive statistical methods and a Chi-squared test were used to analyze the epidemiological and DR characteristics of EPTB patients. A logistic regression model was used to explore the risk factors of rifampicin-resistant/multidrug-resistant (RR/MDR)-EPTB.ResultsA total of 1,324 cases were included. The majority of EPTB patients were in the age range of 20–29 years, were predominantly men (male-to-female ratio: 2.03), and were farmers (65.63%). Most EPTB cases were found in 2013 and 2017 from 2013 to 2021. The most prevalent subtypes of EPTB were lymphatic TB (29.83%, 395/1,324), multiple EPTB (20.85%, 276/1,324), and musculoskeletal TB (14.65%, 194/1,324). Musculoskeletal TB and genitourinary TB predominantly presented as exclusive EPTB forms, while lymphatic TB and pharyngeal/laryngeal TB often co-occurred with pulmonary TB (PTB). Drug susceptibility testing results showed that total DR rates (resistance to any of RFP, isoniazid [INH], streptomycin [STR], and/or ethambutol [EMB]) and RR/MDR rates in EPTB were 25.23% and 12.39%, respectively. Musculoskeletal TB exhibited the highest rates of total DR (31.40%), INH resistance (28.90%), STR resistance (20.10%), EMB resistance (6.20%), MDR (13.90%), and poly-DR (6.70%). The multivariable logistic regression model showed that patients aged from 20 to 59 years (compared to those aged 10 years), workers (compared to retirees), and EPTB patients from the south and west of Hunan (compared to those from the east of Hunan) were at an increased risk of developing RR/MDR EPTB (all OR values > 1).ConclusionOur study provided a detailed account of the epidemiological and DR characteristics of EPTB in Hunan province, China. The significant DR rates, particularly in musculoskeletal TB cases, highlight the need for timely diagnosis, effective drug susceptibility testing, and the development of more effective treatment regimens for EPTB, especially targeting musculoskeletal TB treatments.

ObjectivesTo investigate the clinical epidemiological and drug resistance (DR) characteristics of lymph node tuberculosis (LNTB) in Hunan Province which locates in South-central China, and to provide scientific clues for effective prevention and treatment of LNTB.MethodsWe retrospectively collected LNTB patients with Mycobacterium tuberculosis culture positive at Hunan Chest Hospital, the biggest TB reference hospital in South-central China, from January 2013 to December 2021. The multiple demographic, clinical and drug susceptibility data of patients were collected from the hospital’s electronic patient records. Descriptive statistical methods, Chi-square test and logistic regression analysis were employed as statistical methods.ResultsOf the 577 LNTB cases, 373 (64.64%) were males, 352 (61.01%) were farmers; majority (161, 33.10%) aged at 20–29 years old; 147 (25.48%) had simple LNTB, 350 (60.66%) had LNTB combined with pulmonary TB (PTB) (defined as LNTB-PTB), and 80 (13.86%) had LNTB combined with other extrapulmonary TB (EPTB) (defined as LNTB-EPTB). A total of 345 (59.79%, 345/577) LNTB patients had cervical node infection, and the simple LNTB patients (81.63%, 120/147) had higher proportion of this infection than LNTB-PTB (51.71%, 181/350) and LNTB-EPTB (55.00%, 44/80) (both p values

Ligustrum lucidum W.T. Aiton is an outstanding herb with the homology of medicine and food. Its ripe fruits are traditionally used as an important tonic for kidneys and liver in China. Ligustrum lucidum W.T. Aiton is rich in nutritional components and a variety of bioactive ingredients. A total of 206 compounds have been isolated and identified, they mainly include flavonoids, phenylpropanoids, iridoid glycosides, and triterpenoids. These compounds exert anti-osteoporosis, anti-tumor, liver protective, antioxidant, anti-inflammatory, and immunomodulatory effects. Ligustrum lucidum W.T. Aiton has been traditionally used to treat many complex diseases, including osteoporotic bone pain, rheumatic bone, cancer, related aging symptoms, and so on. In the 2020 Edition of Chinese Pharmacopoeia, there are more than 100 prescriptions containing L. lucidum W.T. Aiton. Among them, some classical preparations including Er Zhi Wan and Zhenqi fuzheng formula, are used in the treatment of various cancers with good therapeutic effects. Additionally, L. lucidum W.T. Aiton has also many excellent applications for functional food, ornamental plants, bioindicator of air pollution, algicidal agents, and feed additives. Ligustrum lucidum W.T. Aiton has rich plant resources. However, the application potential of it has not been fully exploited. We hope that this paper provides a theoretical basis for the high-value and high-connotation development of L. lucidum W.T. Aiton in the future.

Abstract Rolling bearings working in oscillating applications often suffer from false brinelling and fretting corrosion that limit their service life. At present, the study of oscillation-induced failures is primarily dominated by a large number of sliding and bench tests. However, most of the previous work are not able to fully describe the two closely related but different failure mechanisms. In this study, the origin and evolution of the two failures are thoroughly investigated under strictly controlled oscillating rolling conditions. The results show that failure evolves from false brinelling to fretting corrosion under dry friction conditions regardless of the oscillation amplitude. This process is accompanied by a large area peeling and serious oxidation, and the oxygen content increases from 2.50 wt% to 21.22 wt%. Oxidation is a crucial factor in the evolution of false brinelling into fretting corrosion. However, the distribution of microwear and oxygen content depend on the oscillation amplitude. Under lubrication conditions, the friction coefficient (COF) is smaller in the initial stage and led to local slip or transient instability of rolling elements. Therefore, the size of the wear marks and COF increased and appeared to be larger than those under a dry friction condition. However, grease can separate the contact surfaces, only surface deformation owing to false brinelling and slight damage at the roughness level occurred. The evolution of false brinelling and fretting corrosion is also closely related to residual stress. False brinelling often occurrs with residual stress accomulation, meanwhile, the residual stress increases from 120 to 300 MPa. When peeling occurs, residual stress is released. The failure pattern transformed from false brinelling to fretting corrosion and is accompanied by oxidation. So far, none of investigation is able to show satisfactory evolution of oscillating-induced failures, this study may contribute to more scientific understanding of rolling bearings against long-run reciprocating oscillating wear.

Abstract Background The development of deep learning (DL) algorithms for use in dentistry is an emerging trend. Periodontitis is one of the most prevalent oral diseases, which has a notable impact on the life quality of patients. Therefore, it is crucial to classify periodontitis accurately and efficiently. This systematic review aimed to identify the application of DL for the classification of periodontitis and assess the accuracy of this approach. Methods A literature search up to November 2023 was implemented through EMBASE, PubMed, Web of Science, Scopus, and Google Scholar databases. Inclusion and exclusion criteria were used to screen eligible studies, and the quality of the studies was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. Random-effects inverse-variance model was used to perform the meta-analysis of a diagnostic test, with which pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR) were calculated, and a summary receiver operating characteristic (SROC) plot was constructed. Results Thirteen studies were included in the meta-analysis. After excluding an outlier, the pooled sensitivity, specificity, positive LR, negative LR and DOR were 0.88 (95%CI 0.82–0.92), 0.82 (95%CI 0.72–0.89), 4.9 (95%CI 3.2–7.5), 0.15 (95%CI 0.10–0.22) and 33 (95%CI 19–59), respectively. The area under the SROC was 0.92 (95%CI 0.89–0.94). Conclusions The accuracy of DL-based classification of periodontitis is high, and this approach could be employed in the future to reduce the workload of dental professionals and enhance the consistency of classification.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood–brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Abstract Inspired by structures of natural metalloenzymes, a biomimetic synthetic strategy is developed for scalable synthesis of porous Fe-N3 single atom nanozymes (pFeSAN) using hemoglobin as Fe-source and template. pFeSAN delivers 3.3- and 8791-fold higher oxidase-like activity than Fe-N4 and Fe3O4 nanozymes. The high catalytic performance is attributed to (1) the suppressed aggregation of atomically dispersed Fe; (2) facilitated mass transfer and maximized exposure of active sites for the created mesopores by thermal removal of hemoglobin (2 ~ 3 nm); and (3) unique electronic configuration of Fe-N3 for the oxygen-to-water oxidation pathway (analogy with natural cytochrome c oxidase). The pFeSAN is successfully demonstrated for the rapid colorimetric detection of glutathione with a low limit of detection (2.4 nM) and wide range (50 nM–1 mM), and further developed as a real-time, facile, rapid (~6 min) and precise visualization analysis methodology of tumors via glutathione level, showing its potentials for diagnostic and clinic applications.

Abstract Background Glioblastoma (GBM), the most common primary malignant brain tumor, has a poor prognosis, with a median survival of only 14.6 months. The Warburg effect is an abnormal energy metabolism, which is the main cause of the acidic tumor microenvironment. This study explored the role of the Warburg effect in the prognosis and immune microenvironment of GBM. Methods A prognostic risk score model of Warburg effect‐related genes (Warburg effect signature) was constructed using GBM cohort data from The Cancer Genome Atlas. Cox analysis was performed to identify independent prognostic factors. Next, the nomogram was built to predict the prognosis for GBM patients. Finally, the drug sensitivity analysis was utilized to find the drugs that specifically target Warburg effect‐related genes. Results Age, radiotherapy, chemotherapy, and WRGs score were confirmed as independent prognostic factors for GBM by Cox analyses. The C‐index (0.633 for the training set and 0.696 for the validation set) and area under curve (>0.7) indicated that the nomogram exhibited excellent performance. The calibration curve also indicates excellent consistency of the nomogram between predictions and actual observations. In addition, immune microenvironment analysis revealed that patients with high WRGs scores had high immunosuppressive scores, a high abundance of immunosuppressive cells, and a low response to immunotherapy. The Cell Counting Kit‐8 assays showed that the drugs targeting Warburg effect‐related genes could inhibit the GBM cells growth in vitro. Conclusion Our research showed that the Warburg effect is connected with the prognosis and immune microenvironment of GBM. Therefore, targeting Warburg effect‐related genes may provide novel therapeutic options.

Background: Rising clarithromycin resistance undermines Helicobacter pylori (H. pylori) treatment efficacy. We aimed to determine clarithromycin's minimum inhibitory concentration (MIC) levels and identify specific mutation sites in the 23S ribosomal subunit (23S rRNA) that predict treatment outcomes in a 14-day regimen of clarithromycin bismuth quadruple therapy (amoxicillin 1g, clarithromycin 500 mg, rabeprazole 10 mg, and colloidal bismuth pectin 200 mg). Materials and methods: We included adult H. pylori patients who hadn't previously undergone clarithromycin-based treatment, either as initial or rescue therapy. Exclusions were made for penicillin allergy, recent use of related medications, severe illnesses, or inability to cooperate. Patients underwent a 14-day clarithromycin bismuth quadruple therapy. Gastric mucosa specimens were obtained during endoscopy before eradication. MIC against amoxicillin and clarithromycin was determined using the E-test method. The receiver operating characteristic (ROC) curve helped to find the optimal clarithromycin resistance MIC breakpoint. Genetic sequences of H. pylori 23S rRNA were identified through Sanger Sequencing. (ChiCTR2200061476) Results: Out of 196 patients recruited, 92 met the inclusion criteria for the per-protocol (PP) population. The overall intention-to-treat (ITT) eradication rate was 80.00 % (84/105), while the modified intention-to-treat (MITT) and PP eradication rates were 90.32 % (84/93) and 91.30 % (84/92) respectively. No amoxicillin resistance was observed, but clarithromycin resistance rates were 36.19 % (38/105), 35.48 % (33/93), and 34.78 % (33/92) in the ITT, MITT, and PP populations respectively. Compared with the traditional clarithromycin resistance breakpoint of 0.25 μg/mL, a MIC threshold of 12 μg/mL predicted better eradication. Among 173 mutations on 152 sites in the 23S rRNA gene, only the 2143A > G mutation could predict eradication outcomes (p G mutation has limited specificity in predicting eradication outcomes, necessitating further investigation into additional mutation sites associated with clarithromycin resistance.

In this study, different proportions of Le were used to amend purple, yellow, and yellow–brown soils of karst areas to investigate the effect of litter extract (Le) from Ficus virens on Cd(II) and Pb(II) adsorption in karst soils. The basic physicochemical properties of Le-amended karst soils were determined, and the microscopic morphology of Le-amended karst soils was detected. The batch method was used to study the isothermal adsorption characteristics of Cd(II) and Pb(II) adsorption on different Le-amended karst soils. Physicochemical properties and microscopic morphology results showed that Le was amended on the karst soil surface and changed the surface properties of the karst soil. The maximum adsorption capacity range of Cd(II) and Pb(II) by Le-amended karst soils was 92.10–241.61 and 108.91–262.12 mmol/kg, respectively, and the peak value was reached when the karst soils were amended with 20 % of Le. Increasing the pH and temperature were beneficial to Cd(II) and Pb(II) adsorption in each Le-amended karst soil. The adsorption amount of Cd(II) and Pb(II) initially increased and then decreased with the increase in ionic strength. Cd(II) and Pb(II) adsorption was a spontaneous, endothermic, and entropy-increasing process, and electrostatic attraction, precipitation, complexation, and ion exchange were the main adsorption mechanisms. The adsorption amount of Cd(II) and Pb(II) by Le-amended yellow–brown soil maintained approximately 85 % of original sample after three rounds of regeneration.

IntroductionGlioblastoma (GBM) presents significant challenges due to its malignancy and limited treatment options. Precision treatment requires subtyping patients based on prognosis. Disulfidptosis, a novel cell death mechanism, is linked to aberrant glucose metabolism and disulfide stress, particularly in tumors expressing high levels of SLC7A11. The exploration of disulfidptosis may provide a new perspective for precise diagnosis and treatment of glioblastoma.MethodsTranscriptome sequencing was conducted on samples from GBM patients treated at Tiantan Hospital (January 2022 - December 2023). Data from CGGA and TCGA databases were collected. Consensus clustering based on disulfidptosis features categorized GBM patients into two subtypes (DRGclusters). Tumor immune microenvironment, response to immunotherapy, and drug sensitivity were analyzed. An 8-gene disulfidptosis-based subtype predictor was developed using LASSO machine learning algorithm and validated on CGGA dataset.ResultsPatients in DRGcluster A exhibited improved overall survival (OS) compared to DRGcluster B. DRGcluster subtypes showed differences in tumor immune microenvironment and response to immunotherapy. The predictor effectively stratified patients into high and low-risk groups. Significant differences in IC50 values for chemotherapy and targeted therapy were observed between risk groups.DiscussionDisulfidptosis-based classification offers promise as a prognostic predictor for GBM. It provides insights into tumor immune microenvironment and response to therapy. The predictor aids in patient stratification and personalized treatment selection, potentially improving outcomes for GBM patients.

Backgrounds: The validity of heart rate variability (HRV) has been substantiated in mental workload assessments. However, cognitive tasks often coincide with physical exertion in practical mental work, but their synergic effects on HRV remains insufficiently established. The study aims were to investigate the combined effects of cognitive and physical load on autonomic nerve functions.Methods: Thirty-five healthy male subjects (aged 23.5 ± 3.3 years) were eligible and enrolled in the study. The subjects engaged in n-back cognitive tasks (1-back, 2-back, and 3-back) under three distinct physical conditions, involving isotonic contraction of the left upper limb with loads of 0 kg, 3 kg, and 5 kg. Electrocardiogram signals and cognitive task performance were recorded throughout the tasks, and post-task assessment of subjective experiences were conducted using the NASA-TLX scale.Results: The execution of n-back tasks resulted in enhanced perceptions of task-load feelings and increased reaction times among subjects, accompanied by a decline in the accuracy rate (p < 0.05). These effects were synchronously intensified by the imposition of physical load. Comparative analysis with a no-physical-load scenario revealed significant alterations in the HRV of the subjects during the cognitive task under moderate and high physical conditions. The main features were a decreased power of the high frequency component (p < 0.05) and an increased low frequency component (p < 0.05), signifying an elevation in sympathetic activity. This physiological response manifested similarly at both moderate and high physical levels. In addition, a discernible linear correlation was observed between HRV and task-load feelings, as well as task performance under the influence of physical load (p < 0.05).Conclusion: HRV can serve as a viable indicator for assessing mental workload in the context of physical activities, making it suitable for real-world mental work scenarios.

IntroductionThe methylation status of oxygen 6-methylguanine-DNA methyltransferase (MGMT) is closely related to the treatment and prognosis of glioblastoma. However, there are currently some challenges in detecting the methylation status of MGMT promoters. The hematoxylin and eosin (H&E)-stained histopathological slides have always been the gold standard for tumor diagnosis.MethodsIn this study, based on the TCGA database and H&E-stained Whole slide images (WSI) of Beijing Tiantan Hospital, we constructed a weakly supervised prediction model of MGMT promoter methylation status in glioblastoma by using two Transformer structure models.ResultsThe accuracy scores of this model in the TCGA dataset and our independent dataset were 0.79 (AUC = 0.86) and 0.76 (AUC = 0.83), respectively.ConclusionThe model demonstrates effective prediction of MGMT promoter methylation status in glioblastoma and exhibits some degree of generalization capability. At the same time, our study also shows that adding Patches automatic screening module to the computational pathology research framework of glioma can significantly improve the model effect.

Kaixinsan (KXS) is a noteworthy classical prescription, which consists of four Chinese medicinal herbs, namely Polygalae Radix, Ginseng Radix et Rhizoma, Poria, and Acori Tatarinowii Rhizoma. KXS was initially documented in the Chinese ancient book Beiji Qianjin Yaofang written by Sun Simiao of the Tang Dynasty in 652 A.D. As a traditional Chinese medicine (TCM) prescription, it functions to nourish the heart and replenish Qi, calm the heart tranquilize the mind, and excrete dampness. Originally used to treat amnesia, it is now also effective in memory decline and applied to depression. Although there remains an abundance of literature investigating KXS from multiple aspects, few reviews summarize the features and research, which impedes better exploration and exploitation of KXS. This article intends to comprehensively analyze and summarize up-to-date information concerning the chemical constituents, pharmacology, pharmacokinetics, clinical applications, and safety of KXS based on the scientific literature, as well as to examine possible scientific gaps in current research and tackle issues in the next step. The chemical constituents of KXS primarily consist of saponins, xanthones, oligosaccharide esters, triterpenoids, volatile oils, and flavonoids. Of these, saponins are the predominant active ingredients, and increasing evidence has indicated that they exert therapeutic properties against mental disease. Pharmacokinetic research has illustrated that the crucial exposed substances in rat plasma after KXS administration are ginsenoside Re (GRe), ginsenoside Rb1 (GRb1), and polygalaxanthone III (POL). This article provides additional descriptions of the safety. In this review, current issues are highlighted to guide further comprehensive research of KXS and other classical prescriptions.

The randomly distributed fracture network in coal body is the main flow channel of coalbed methane, and the key to study the flow characteristics of coalbed methane is to accurately simulate the complex fracture network in coal body. Based on the pixel probability decomposition theory, a new discrete fracture network modeling method is introduced. Compared with the traditional method, which assumes that the fracture is a smooth fracture, this method can fully consider the rough characteristics of the fracture. Combined with numerical simulation, the influence of different fracture characteristic parameters on the permeability of the coal seam is analyzed. The results show that the porosity (0.1-0.25), fractal dimension (1.55-1.85), maximum fracture length (0.011-0.026 m) and proportion coefficient (0.006~0.08) have a good power-law growth relationship with the outlet velocity of the fracture network, while the tortuosity fractal dimension (1.0-1.02), fracture dip angle (10°-85°) and the outlet velocity of the fracture network have a power-law decrease relationship; among them, the proportion coefficient, fracture dip angle and maximum fracture length have the most significant effects on the outlet velocity of fracture network.

Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency (HRD). HRD is found in a subgroup of cancer patients for several tumor types, and it has a clinical relevance to cancer prevention and therapies. Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose) polymerase inhibitors and platinum-based chemotherapies. Nevertheless, the biology of HRD is complex, and its applications and the benefits of different HRD biomarker assays are controversial. This is primarily due to inconsistencies in HRD assessments and definitions (gene-level tests, genomic scars, mutational signatures, or a combination of these methods) and difficulties in assessing the contribution of each genomic event. Therefore, we aim to review the biological rationale and clinical evidence of HRD as a biomarker. This review provides a blueprint for the standardization and harmonization of HRD assessments.

Abstract Background The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC. Methods We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance. Results We observed a robust positive correlation between PD1/TIM3 expression in GBC (R = 0.614, P

Drought stress impairs plant growth and other physiological functions. MeHDZ14, a homeodomain-leucine zipper I transcription factor, is strongly induced by drought stress in various cassava cultivars. However, the role of MeHDZ14 in cassava growth regulation has remained unclear. Here we report that MeHDZ14 affected plant height, such that a dwarf phenotype and altered internode elongation were observed in transgenic cassava lines. MeHDZ14 was found to negatively regulate the biosynthesis of lignin. Its overexpression resulted in abaxially rolled leaves. The morphogenesis of leaf epidermal cells was inhibited by overexpression of MeHDZ14, with decreased auxin and gibberellin and increased cytokinin contents. MeHDZ14 was found to regulate many drought-responsive genes, including genes involved in cell wall synthesis and expansion. MeHDZ14 bound to the promoter of caffeic acid 3-O-methyltransferase 1 (MeCOMT1), acting as a transcriptional repressor of genes involved in cell wall development. MeHDZ14 appears to act as a negative regulator of internode elongation and epidermal cell morphogenesis during cassava leaf development.

The union of Edge Computing (EC) and Artificial Intelligence (AI) has brought forward the Edge AI concept to provide intelligent solutions close to the end-user environment, for privacy preservation, low latency to real-time performance, and resource optimization. Machine Learning (ML), as the most advanced branch of AI in the past few years, has shown encouraging results and applications in the edge environment. Nevertheless, edge-powered ML solutions are more complex to realize due to the joint constraints from both edge computing and AI domains, and the corresponding solutions are expected to be efficient and adapted in technologies such as data processing, model compression, distributed inference, and advanced learning paradigms for Edge ML requirements. Despite the fact that a great deal of the attention garnered by Edge ML is gained in both the academic and industrial communities, we noticed the lack of a complete survey on existing Edge ML technologies to provide a common understanding of this concept. To tackle this, this paper aims at providing a comprehensive taxonomy and a systematic review of Edge ML techniques, focusing on the soft computing aspects of existing paradigms and techniques. We start by identifying the Edge ML requirements driven by the joint constraints. We then extensively survey more than twenty paradigms and techniques along with their representative work, covering two main parts: edge inference, and edge learning. In particular, we analyze how each technique fits into Edge ML by meeting a subset of the identified requirements. We also summarize Edge ML frameworks and open issues to shed light on future directions for Edge ML.

Abstract Small extracellular–vesicule-associated microRNA (sEV-miRNA) is an important biomarker for cancer diagnosis. However, rapid and sensitive detection of low-abundance sEV-miRNA in clinical samples is challenging. Herein, a simple electrochemical biosensor that uses a DNA nanowire to localize catalytic hairpin assembly (CHA), also called domino-type localized catalytic hairpin assembly (DT-LCHA), has been proposed for sEV-miRNA1246 detection. The DT-LCHA offers triple amplification, (i). CHA system was localized in DNA nanowire, which shorten the distance between hairpin substrate, inducing the high collision efficiency of H1 and H2 and domino effect. Then, larger numbers of CHAs were triggered, capture probe bind DT-LCHA by exposed c sites. (ii) The DNA nanowire can load large number of electroactive substance RuHex as amplified electrochemical signal tags. (iii) multiple DT-LCHA was carried by the DNA nanowire, only one CHA was triggered, the DNA nanowire was trapped by the capture probe, which greatly improve the detection sensitivity, especially when the target concentration is extremely low. Owing to the triple signal amplification in this strategy, sEV-miRNA at a concentration of as low as 24.55 aM can be detected in 20 min with good specificity. The accuracy of the measurements was also confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, the platform showed good performance in discriminating healthy donors from patients with early gastric cancer (area under the curve [AUC]: 0.96) and was equally able to discriminate between benign gastric tumors and early cancers (AUC: 0.77). Thus, the platform has substantial potential in biosensing and clinical diagnosis. Graphical Abstract

In order to comprehensively evaluate the temperature and humidity detection performance of the ground microwave radiometer (referred to as radiometer, the same below) and improve the accuracy of temperature and relative humidity profiles, by using the ground microwave radiometer data, radiosonde data, and ERA5 reanalysis data of Beijing from March to August 2021, this paper analyzes the temperature and humidity detection performance of the radiometer under sunny, cloudy and rainy days. In the meanwhile, this paper uses radiosonde data and corrected ERA5 data to verify temperature and humidity profiles of radiometer and correct temperature and humidity data of radiometer based on the linear deviation correction method. The results show that: (1) The temperature of microwave radiometer has good consistency with radiosonde temperature under sunny and cloudy days, but it is higher than the radiosonde temperature in rainy days. The relative humidity of microwave radiometer is higher than that of radiosonde in sunny days and lower in cloudy and rainy days. The linear deviation correction effect of radiosonde on ground-based microwave radiometers in rainy days is better than that in sunny and cloudy days. (2) Above 4 km, ERA5 relative humidity data has obvious deviation with radiosonde data, while the temperature correlation between ERA5 and radiosonde is higher than relative humidity correlation. (3) The ERA5 data after radiosonde correction can improve the temperature and humidity profile accuracy of the Microwave radiometer, and the effect is better in rainy days than in sunny days. In vertical direction, with the increase of height, the correction effect of radiometer temperature and humidity data is more obvious. (4) The two true values of radiosonde data and corrected ERA5 data were used to analyze the temperature and humidity data of the ground-based microwave radiometer corrected by ERA5, and the results showed that the vertical distribution characteristics of the error (mean error BIAS and root mean square error RMSE) profiles of radiometer and radiosonde, radiometer and corrected ERA5 data were similar under sunny and cloud conditions. Under rainy conditions, there were obvious differences between the two in the middle and upper height (7-10 km), among which the temperature RMSE differed by 4 K and the relative humidity RMSE differed by 20%.

Differentiation matrices are an important tool in the implementation of the spectral collocation method to solve various types of problems involving differential operators. Fractional differentiation of Jacobi orthogonal polynomials can be expressed explicitly through Jacobi–Jacobi transformations between two indexes. In the current paper, an algorithm is presented to construct a fractional differentiation matrix with a matrix representation for Riemann–Liouville, Caputo and Riesz derivatives, which makes the computation stable and efficient. Applications of the fractional differentiation matrix with the spectral collocation method to various problems, including fractional eigenvalue problems and fractional ordinary and partial differential equations, are presented to show the effectiveness of the presented method.

Objective: This study aims to analyze a severe adverse reaction of pulmonary fibrosis induced by dronedarone hydrochloride tablets, and to provide a reference for clinical rational medication through drug precautions. Methods: A case of pulmonary fibrosis induced by dronedarone hydrochloride tablets, along with related literature was retrospectively analyzed. Results: Patients over 65 years old with a history of exposure to amiodarone may increase the incidence of pulmonary toxicity induced by dronedarone, and dronedarone should not be selected as a substitute treatment drug for patients with amiodarone-induced pulmonary toxicity. Conclusions: It is recommended that clinicians monitor the diffusion capacity of carbon monoxide and lung ventilation function of patients before and after using dronedarone for treatment. For patients with a history of amiodarone exposure, intermittent monitoring of chest X-rays and lung function is necessary. If lung function decreases, dronedarone should be immediately discontinued.

Abstract Monitoring tumor biomarkers in a non‐invasive manner for tumor diagnosis has attracted increasing attention. Liquid biopsy mainly includes three types of biomarkers: circulating tumor cells, extracellular vesicles, and circulating nucleic acids. These biomarkers released by tumor cells can travel to other parts of the circulation system. The analysis of circulating tumor markers in the circulation enables early tumor diagnosis, progression evolution, and treatment monitoring, which are important for individualized clinical decisions. In this study, we summarize different DNA nanotechnology strategies that can be used to capture, amplify, and measure circulating biomarkers and discuss the current challenges and outlook.

Recent studies have shown that B cells and the associated tertiary lymphoid structures (TLS) correlate with the response of patients to immune checkpoint inhibitors (ICIs) and predict overall survival (OS) in cancer patients. We screened 145 B cell marker genes (BCMG) by a comprehensive analysis of single-cell RNA-sequencing (scRNA-seq) data of head and neck squamous cell carcinoma (HNSC) from the Gene Expression Omnibus (GEO) database. The BCMG signature (BCMGS) was established using The Cancer Genome Atlas (TCGA) dataset of HNSC and verified in four independent datasets. The multivariate Cox regression analysis identified the signature as an independent prognostic factor. A prognostic nomogram was constructed with independent prognostic factors using the TCGA dataset. GO and KEGG analysis revealed the underlying signaling pathways related to this signature. Study of immune profiles showed that patients in the low-risk group presented discriminative immune-cell infiltrations. Furthermore, the low-risk group was featured by higher TCR and BCR diversity, which suggested that low-risk patients may be more sensitive to ICIs. Immunohistochemistry was performed, and we found that high expression of FTH1 was significantly correlated with poor OS (P = 0.025). The expression of TIM-3, LAG-3 and PD-1 was positively correlated and associated with better OS in HNSC. However, there was no statistically significant difference between PD-L1, PD-L2, CTLA-4, TIGIT and prognosis. The BCMGS was a promising prognostic biomarker in HNSC, which may help to interpret the responses to immunotherapy and provide a new perspective for future research on the treatment in HNSC.

Abstract Self‐assembling of peptides is essential for a variety of biological and medical applications. However, it is challenging to investigate the self‐assembling properties of peptides within the complete sequence space due to the enormous sequence quantities. Here, it is demonstrated that a transformer‐based deep learning model is effective in predicting the aggregation propensity (AP) of peptide systems, even for decapeptide and mixed‐pentapeptide systems with over 10 trillion sequence quantities. Based on the predicted AP values, not only the aggregation laws for designing self‐assembling peptides are derived, but the transferability relation among the APs of pentapeptides, decapeptides, and mixed pentapeptides is also revealed, leading to discoveries of self‐assembling peptides by concatenating or mixing, as consolidated by experiments. This deep learning approach enables speedy, accurate, and thorough search and design of self‐assembling peptides within the complete sequence space of oligopeptides, advancing peptide science by inspiring new biological and medical applications.

To determine the fates of the persistent pollutants cadmium (Cd) and micro-plastics in agricultural soils, an in-depth understanding of the interactions between Cd and mulching film is required. In the present work, pot experiments are conducted under natural conditions to study the influence of various Cd concentrations on the aging process of polyethylene mulching film in soil collected from Changzhi, Shanxi Province. The results indicate that during 150 days, the aging degree of the mulch film increases gradually as the increased Cd concentration in the soil. Further, the results of attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrometry and X-ray photoelectron spectroscopy (XPS) demonstrate that the average vinyl index (VI) of the aging mulch film increases from 1.29 to 1.82, while the oxygen-to-carbon (O/C) ratio of the mulch film decreases significantly from 0.344 to 0.045, as the Cd concentration is increased from 0 to 10 mg kg–1. When the aging time exceeds 90 days, the oxygen-containing functional groups (C–O and CO) generated consumed by the adsorbed Cd. In addition, electron paramagnetic resonance (EPR) measurements indicate that Cd both enhances the formation of hydroxyl radical (·OH) on the surface of the mulch film and prevents the combination of ·OH and electrons, thereby accelerating the aging of the mulch. Hence, the present study indicates that the presence of Cd will hasten the decomposition of mulch, which will inevitably result in the faster release of micro-plastics from the mulch into the soil environment.

Abstract Background Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. Methods This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. Results Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug–related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. Conclusions FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. Trial registration ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

Abstract Background Postoperative cognitive dysfunction (POCD) is a common postoperative disorder that is frequently observed after general anesthesia, which seriously threatens the quality of patients’ life. Existing studies have demonstrated that S-ketamine plays an important role in improving neuroinflammation. This trial aimed to explore the effects of S-ketamine on quality of recovery and cognitive function in patients following modified radical mastectomy (MRM). Methods Ninety patients aged 45 to 70 years with ASA grades of I or II, who underwent MRM, were selected. Patients were randomly assigned to the S-ketamine or control group. In the S-ketamine group, patients were induced with S-ketamine instead of sufentanil and maintained with S-ketamine and remifentanil. In the control group, patients were induced with sufentanil and maintained with remifentanil. The primary outcome was the Mini-Mental State Examination (MMSE) and Quality of Recovery-15 (QoR-15) score. Secondary outcomes including visual analog scale (VAS) score, cumulative propofol and opioids consumption, post anesthesia care unit (PACU) recovery time, occurrence of remedial analgesia, postoperative nausea and vomiting (PONV), other adverse events, as well as patient satisfaction. Results The global QoR-15 scores at postoperative day 1 (POD1) were significantly higher in the S-ketamine group than in the control group (124 [119.5–128.0] vs. 119 [114.0–123.5], P = 0.002), with a median difference of 5 points (95% confidence interval [CI] [-8 to -2]). Similarly, the global QoR-15 scores at postoperative day 2 (POD2) in the S-ketamine group were significantly higher than in the control group (140.0 [133.0–145.0] vs. 132.0 [126.5–141.5], P = 0.004). In addition, among the five subcomponents of the 15-item scale, S-ketamine group had a higher score in terms of physical comfort, pain, and emotional state both at POD1 and POD2. In terms of MMSE score, S-ketamine could promote the recovery of postoperative cognitive function at POD1, but not at POD2. Furthermore, the consumption of opioids, VAS score, and remedial analgesia in the S-ketamine group decreased significantly. Conclusions Collectively, our findings support that general anesthesia with S-ketamine as a potential strategy showed high safety and could not only improve the quality of recovery mainly through improving pain, physical comfort, and emotional state but also promote the recovery of cognitive function on POD1 in patients undergoing MRM. Trial registration The study was registered in the Chinese Clinical Trial Registry (registration No:ChiCTR2200057226, Date of registration: 04/03/2022).

Abstract The amino acid sequences of peptides determine their self-assembling properties. Accurate prediction of peptidic hydrogel formation, however, remains a challenging task. This work describes an interactive approach involving the mutual information exchange between experiment and machine learning for robust prediction and design of (tetra)peptide hydrogels. We chemically synthesize more than 160 natural tetrapeptides and evaluate their hydrogel-forming ability, and then employ machine learning-experiment iterative loops to improve the accuracy of the gelation prediction. We construct a score function coupling the aggregation propensity, hydrophobicity, and gelation corrector C g , and generate an 8,000-sequence library, within which the success rate of predicting hydrogel formation reaches 87.1%. Notably, the de novo-designed peptide hydrogel selected from this work boosts the immune response of the receptor binding domain of SARS-CoV-2 in the mice model. Our approach taps into the potential of machine learning for predicting peptide hydrogelator and significantly expands the scope of natural peptide hydrogels.

Objective: This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid (CGA) in patients with recurrent high-grade glioma after standard of care treatments, through a first-in-human, open-label, dose-escalation phase I trial. Methods: A total of 26 eligible patients were enrolled, received intramuscular CGA injections at 5 dose levels, and were followed up for 5 years. CGA was well tolerated, and the maximum tolerated dose was 5.5 mg/kg. Results: The most common treatment-related adverse events occurred at the sites of injection. No grade 3 or 4 adverse events (e.g., drug allergy) were reported for these patients except for induration at the injection sites. A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma, with a t1/2 of 0.95–1.27 h on day 1 and 1.19–1.39 h on day 30, and no detectable CGA was observed on days 9, 11, 13, 23, 25, 27, and 29 before CGA administration. After the first treatment cycle, 52.2% of patients (12 of 23) achieved stable disease. Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients. Of the 18 patients with grade 3 glioma, the median overall survival was 9.5 months. Two patients remained alive at the cutoff day. Conclusions: This phase I study demonstrated that CGA has a favorable safety profile (with no severe toxicity), and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies, thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.

Abstract The effect of curvature on the band alignment of one-dimensional (1D) van der Waals (vdW) transition metal dichalcogenide (TMDC) heterostructures is studied by comprehensive first-principles calculations. We find that, as the diameter of a TMDC nanotube decreases, the combined effect of curvature-induced flexoelectricity and circumferential tensile strain causes a rapid lowering of the conduction band minimum, whereas the valence band maximum exhibits an initial lowering before rising. As individual TMDC nanotubes form coaxial heterostructures, the concerted effect of diameter-dependent band-edge levels and intertube coupling via flexovoltage can result in a transition of intertube band alignment from Type II to Type I in multiple heterostructural systems, including large-diameter MoSe2@WS2, MoTe2@MoSe2, and MoTe2@WS2 heterostructures. These results lay down a foundation for the rational design of 1D vdW heterostructures.

Abstract With the power conversion efficiency of binary polymer solar cells dramatically improved, the thermal stability of the small-molecule acceptors raised the main concerns on the device operating stability. Here, to address this issue, thiophene-dicarboxylate spacer tethered small-molecule acceptors are designed, and their molecular geometries are further regulated via the thiophene-core isomerism engineering, affording dimeric TDY-α with a 2, 5-substitution and TDY-β with 3, 4-substitution on the core. It shows that TDY-α processes a higher glass transition temperature, better crystallinity relative to its individual small-molecule acceptor segment and isomeric counterpart of TDY-β, and a more stable morphology with the polymer donor. As a result, the TDY-α based device delivers a higher device efficiency of 18.1%, and most important, achieves an extrapolated lifetime of about 35000 hours that retaining 80% of their initial efficiency. Our result suggests that with proper geometry design, the tethered small-molecule acceptors can achieve both high device efficiency and operating stability.

Soybean [Glycine max (L.) Merr.], an essential staple food and oil crop worldwide, boasts abundant vegetable proteins and fats beneficial for both human and animal consumption. However, the soybean pod borer (Leguminivora glycinivorella) (SPB) stands as the most destructive soybean insect pest in northeast China and other northeastern Asian regions, leading to significant annual losses in soybean yield and economic burden. Therefore, this study aims to investigate the introduction of a previously tested codon-optimized cry1c gene, cry1c*, into the soybean genome and assess its effect on the SPB infestation by generating and characterizing stable transgenic soybeans overexpressing cry1c*. The transgenic soybean lines that constitutively overexpressed cry1c* exhibited a significant reduction in the percentage of damaged seeds, reaching as low as 5% in plants under field conditions. Additionally, feeding transgenic leaves to the larvae of S. exigua, S. litura, and M. separta resulted in inhibited larval growth, decreased larval body weight, and lower survival rates compared to larvae fed on wild-type leaves. These findings showed that the transgenic lines maintained their resistance to SPB and other lepidopteran pests, especially the transgenic line KC1. Southern blotting and genome-wide resequencing analysis revealed that T-DNA integration occurred as a single copy between loci 50,868,122 and 50,868,123 of chromosome 10 in the transgenic line KC1. Therefore, the transgenic line KC1, overexpressing high levels of cry1c* in leaves and seeds, holds strong potential for commercial use in the integrated management of SPB and other lepidopteran pests.

Abstract Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase III clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

Abstract Background Individuals experiencing multimorbidity have more complex healthcare needs, use more healthcare services, and access multiple service providers across the healthcare continuum. They also experience higher rates of functional decline. Rehabilitation therapists are well positioned to address these functional needs; however, little is known about the influence of rehabilitation therapy on patient outcomes, and subsequent unplanned healthcare utilization for people with multimorbidity. The aims of this study were to: 1) describe and compare the characteristics of people with multimorbidity receiving: home care rehabilitation therapy alone, other home care services without rehabilitation therapy, and the combination of home care rehabilitation therapy and other home care services, and 2) determine the association between home care rehabilitation therapy and subsequent healthcare utilization among those recently discharged from an acute care unit. Methods This retrospective cohort study used linked health administrative data housed within ICES, Ontario, Canada. The cohort included long-stay home care clients experiencing multimorbidity who were discharged from acute care settings between 2007–2015 (N = 43,145). Descriptive statistics, ANOVA’s, t-tests, and chi-square analyses were used to describe and compare cohort characteristics. Multivariable logistic regression was used to understand the association between receipt of rehabilitation therapy and healthcare utilization. Results Of those with multimorbidity receiving long-stay home care services, 45.5% had five or more chronic conditions and 46.3% required some assistance with ADLs. Compared to people receiving other home care services, those receiving home care rehabilitation therapy only were less likely to be readmitted to the hospital (OR = 0.78; 95% CI: 0.73–0.83) and use emergency department services (OR = 0.73; 95% CI: 0.69–0.78) within the first 3-months following hospital discharge. Conclusions Receipt of rehabilitation therapy was associated with less unplanned healthcare service use when transitioning from hospital to home among persons with multimorbidity. These findings suggest rehabilitation therapy may help to reduce the healthcare burden for individuals and health systems. Future research should evaluate the potential cost savings and health outcomes associated with providing rehabilitation therapy services for people with multimorbidity.

Abstract Background The differential diagnosis of mucoepidermoid carcinoma (MEC) from neoplasm undergoing mucinous features brings more pitfalls to pathologists. Combining specific MAML2 gene rearrangement and histological characteristics may be the solution. Methods Twenty‐five tumors with mucinous components were selected for differential diagnosis of MEC. All the cases were detected for MAML2 gene rearrangement. The cases diagnosed as MEC were classified into four variants: classic, oncocytic, Warthin‐like, and nonclassified, and they were graded using the Brandwein system. The histological characteristics of non‐MECs were summarized for differential diagnosis. Univariate survival analysis was performed on MECs. Results There were 16 MECs; 62.5% were MAML2 rearranged. For the low‐, intermediate‐, and high‐grade MECs, the rate of rearrangement was 83.3%, 100%, and 28.6%, respectively. Both the oncocytic and Warthin‐like MECs were MAML2 rearranged. For the classic and nonclassified MECs without MAML2 rearrangement, non‐keratinized squamoid cells and distinctive mucinous cells were essential diagnostic criteria. On survival analysis, all the disease progression occurred in high‐grade MECs (p = 0.038). Nine cases were diagnosed as non‐MECs: pleomorphic adenoma with mucinous metaplasia showed no ex‐capsular involvement; metaplastic Warthin tumor appeared with overt keratinization and residual oncocytic bilayered epithelium; mix squamous cell and glandular papilloma showed an endobronchial papillary growing pattern; adenosquamous carcinoma was accompanied by squamous carcinoma in situ of the overlying mucosa. All the non‐MECs were negative for MAML2 rearrangement. Conclusion The application of combining MAML2 rearrangement and histological characteristics is helpful in the differential diagnosis between MEC and other tumors with mucinous components.