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Abstract Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

Abstract Multiplexed imaging technologies have made it possible to interrogate complex tissue microenvironments at sub-cellular resolution within their native spatial context. However, proper quantification of this complexity requires the ability to easily and accurately segment cells into their sub-cellular compartments. Within the supervised learning paradigm, deep learning-based segmentation methods demonstrating human level performance have emerged. However, limited work has been done in developing such generalist methods within the unsupervised context. Here we present an easy-to-use unsupervised segmentation (UNSEG) method that achieves deep learning level performance without requiring any training data via leveraging a Bayesian-like framework, and nucleus and cell membrane markers. We show that UNSEG is internally consistent and better at generalizing to the complexity of tissue morphology than current deep learning methods, allowing it to unambiguously identify the cytoplasmic compartment of a cell, and localize molecules to their correct sub-cellular compartment. We also introduce a perturbed watershed algorithm for stably and automatically segmenting a cluster of cell nuclei into individual nuclei that increases the accuracy of classical watershed. Finally, we demonstrate the efficacy of UNSEG on a high-quality annotated gastrointestinal tissue dataset we have generated, on publicly available datasets, and in a range of practical scenarios.

Abstract Full-Heusler alloys with earth-abundant elements exhibit high mechanical strength and favorable electrical transport behavior, but their high intrinsic lattice thermal conductivity limits potential thermoelectric application. Here, the thermoelectric transport properties of Fe-based Full-Heusler Fe2MAl (M = V, Nb, Ta) alloys are comprehensively investigated utilizing density functional theory. The results suggest that Fe2NbAl exhibits exceptionally low lattice thermal conductivity due to low phonon velocities and weakly bound Nb atoms. In Fe2NbAl, the underbonding of the Nb atoms leads large Grüneisen parameters and high anharmonic scattering rates of low-frequency acoustic phonon. Meanwhile, the high band degeneracy and large electrical conductivity lead to a maximum p-type power factor of 255.6 μW·K−2·cm−1 at 900 K. The combination of low lattice thermal conductivity and favorable electrical transport properties leads a maximum p-type dimensionless figure of merit of 1.7. Our work indicates Fe2NbAl, as a low-cost, environmentally friendly, is a potential high-performance p-type thermoelectric material.

Abstract The effect of circumference and displacement of the third fracture fragment on fracture healing after intramedullary nailing of femoral shaft fractures with a third fracture fragment was investigated. A retrospective cohort study was conducted to analyze the data of 142 patients who suffered femoral shaft fractures with a third fracture fragment and were admitted to the First People’s Hospital of Lianyungang from February 2016 to December 2021. According to the circumference of the third fracture fragments, these were divided into three types of type 1: 71 cases; type 2: 52 cases; and type 3: 19 cases. On the basis of the diaphyseal diameter, the degree of displacement of the third fracture fragment was classified into three degrees of degree I: 95 cases; degree II: 31 cases; and degree III: 16 cases. Postoperative follow-up was performed to compare the fracture healing rate, healing time, and the modified Radiographic Union Scale for Tibia (mRUST) at 9th month after surgery in each group. All 142 patients were followed up after operation, with an average of (14.7 ± 4.1) months, and the overall healing rate was 73.4%. When the third fracture fragments were displaced in degree II and III, the mRUST score at 9th month in the type 1 group was higher than that in the type 2 and 3 groups (P = 0.017). Logistic regression analysis showed that greater displacement of third fracture fragments and greater circumference were associated with lower fracture healing rates (P

Ground losses due to tunneling would induce settlement of nearby raft foundations. To study the change in behavior of the raft foundations over time due to tunnel excavation in soft clay, a series of centrifuge model tests were conducted. The results reveal that the raft stiffness has a significant influence on the development of the gap between the raft and the ground. The width of the gap beneath the flexible foundation would increase over time, leading to a further increase in tensile strain after excavation, whereas the gap for raft foundations with a large stiffness would reduce with time, causing a gradual decrease in tensile strain. The modification factor (MF) design approach is also evaluated with the test results and demonstrates that the MF design approach would underestimate the tensile strain of the flexible raft and provide a relatively conservative prediction for larger stiffnesses.

Abstract Because of its distinct function and geographic conditions, the impact of climate change on the operation, safety, and income of airports in coastal areas is becoming increasingly significant. The measurement of climate resilience can help identify priority needs and measures to adapt to climate change, which is a crucial step in developing an aviation adaptation plan. At present, the concept of climate resilience is relatively complex and lacks a clear uniformity of composition, which has made it challenging to effectively support the development of adaptation strategies. Based on the definition of climate resilience, our first step was to construct an evaluation system for coastal airports to visually represent the level of climate resilience. Next, in this study, we introduced a coupling coordination and obstacle degree model to analyze the coordinated development and key drivers of climate resilience, which could be used to develop a targeted improvement strategy based on the calculation results. In the future, additional measures can be combined from the natural environment, socioeconomics, governance capacity, and climate change risk to enhance the capacity development of the aviation industry to address climate change and foster the establishment of a sustainable development model between the industry and the environment.

Abstract Objective We aimed to compare the clinical efficacy of inverted triangular cannulated compression screws combined with Gotfried positive or negative buttress reduction in the healing of femoral neck fractures. Methods Between October 2017 and March 2021, 55 patients with femoral neck fractures underwent treatment using inverted triangular cannulated compression screws combined with Gotfried positive or negative buttress reduction. Among these patients, 29 received inverted triangular cannulated compression screws combined with Gotfried positive buttress reduction treatment. This group consisted of 16 males and 13 females, with an average age of 43.45 ± 8.23 years. Additionally, 26 patients received inverted triangular cannulated compression nails combined with Gotfried negative buttress reduction treatment. This group included 14 males and 12 females, with an average age of 41.96 ± 8.69 years. Postsurgery, various measurements were taken, including the degree of shortening of the femoral neck, degree of bone nonunion, degree of fixation failure, degree of ischemic necrosis of the femoral head, and Harris score of the hip joint. Results All patients were followed up for a minimum of 18 months. The group that underwent treatment with an inverted triangular cannulated compression screw combined with Gotfried positive buttress reduction did not experience any cases of bone nonunion, fixation failure, or ischemic necrosis of the femoral head. In the group that received treatment with inverted triangle cannulated compression screws combined with Gotfried negative buttress reduction, there was one case of bone nonunion, three cases of early fixation failure, and one case of ischemic necrosis. Ultimately, five patients (19.23% of the total) underwent joint replacement surgery. The average shortening lengths in the vertical plane were 4.07 ± 1.98 mm and 8.08 ± 3.54 mm, respectively. In the horizontal plane, the average shortening lengths were 3.90 ± 1.57 mm and 7.77 ± 3.31 mm, respectively. At the last follow-up, the group that received Gotfried positive buttress reduction had a greater Harris hip joint score. Conclusion The success rate of combining inverted triangular cannulated compression screws with Gotfried positive buttress reduction surgery is relatively high. This surgical approach effectively prevents femoral neck shortening and improves hip joint function. Moreover, it is crucial to avoid negative buttress reduction when managing femoral neck fractures.

Abstract Background APRI and FIB-4 scores are used to exclude clinically significant fibrosis (defined as stage ≥ F2) in patients with chronic viral hepatitis. However, the cut-offs for these scores (generated by Youden indices) vary between different patient cohorts. This study aimed to evaluate whether serum dithiothreitol-oxidizing capacity (DOC), i.e., a surrogate test of quiescin sulfhydryl oxidase-1, which is a matrix remodeling enzyme, could be used to non-invasively identify significant fibrosis in patients with various chronic liver diseases (CLDs). Methods Diagnostic performance of DOC was compared with APRI and FIB-4 for identifying significant fibrosis. ROC curve analyses were undertaken in: a) two chronic hepatitis B (CHB) cohorts, independently established from hospitals in Wenzhou (n = 208) and Hefei (n = 120); b) a MASLD cohort from Wenzhou hospital (n = 122); and c) a cohort with multiple CLD etiologies (except CHB and MASLD; n = 102), which was identified from patients in both hospitals. Cut-offs were calculated using the Youden index. All CLD patients (n = 552) were then stratified by age for ROC curve analyses and cut-off calculations. Results Stratified by CLD etiology or age, ROC curve analyses consistently showed that the DOC test was superior to APRI and FIB-4 for discriminating between clinically significant fibrosis and no fibrosis, when APRI and FIB-4 showed poor/modest diagnostic performance (P 0.05 in 11 cohort comparisons). DOC had a significant advantage over APRI or FIB-4 scores for establishing a uniform cut-off independently of age and CLD etiology (coefficients of variation of DOC, APRI and FIB-4 cut-offs were 1.7%, 22.9% and 47.6% in cohorts stratified by CLD etiology, 2.0%, 26.7% and 29.5% in cohorts stratified by age, respectively). The uniform cut-off was 2.13, yielded from all patients examined. Surprisingly, the uniform cut-off was the same as the DOC upper limit of normal with a specificity of 99%, estimated from 275 healthy control individuals. Hence, the uniform cut-off should possess a high negative predictive value for excluding significant fibrosis in primary care settings. A high DOC cut-off with 97.5% specificity could be used for detecting significant fibrosis (≥ F2) with an acceptable positive predictive value (87.1%). Conclusions This proof-of-concept study suggests that the DOC test may efficiently rule out and rule in significant liver fibrosis, thereby reducing the numbers of unnecessary liver biopsies. Moreover, the DOC test may be helpful for clinicians to exclude significant liver fibrosis in the general population.

Abstract Background The intrusion of maxillary anterior teeth is often required and there are various intrusion modes with mini-implants in clear aligner treatment. The objective of this study was to evaluate the effectiveness of maxillary anterior teeth intrusion with different intrusion modes, aiming to provide references for precise and safe intrusion movements in clinical practice. Methods Cone-beam computed tomography and intraoral optical scanning data of a patient were collected. Finite element models of the maxilla, maxillary dentition, periodontal ligaments (PDLs), clear aligner (CA), attachments, and mini-implants were established. Different intrusion modes of the maxillary anterior teeth were simulated by changing the mini-implant site (between central incisors, between central and lateral incisor, between lateral incisor and canine), loading site (between central incisors, on central incisor, between central and lateral incisor, between lateral incisor and canine), and loading mode (labial loading and labiolingual loading). Ten conditions were generated and intrusive forces of 100 g were applied totally. Then displacement tendency of the maxillary anterior teeth and CA, and stress of the PDLs were analyzed. Results For the central incisor under condition L14 and for the canine under conditions L11, L13, L23, and L33, the intrusion amount was negative. Under other conditions, the intrusion amount was positive. The labiolingual angulation of maxillary anterior teeth exhibited positive changes under all conditions, with greater changes under linguoincisal loading. The mesiodistal angulation of canine exhibited positive changes under labial loading, while negative changes under linguoincisal loading except for condition L14. Conclusions The intrusion amount, labiolingual and mesiodistal angulations of the maxillary anterior teeth were affected by the mini-implant site, loading site, and loading mode. Labial and linguoincisal loading may have opposite effects on the intrusion amount of maxillary anterior teeth and the mesiodistal angulation of canine. The labiolingual angulation of the maxillary incisors would increase under all intrusion modes, with greater increases under linguoincisal loading.

Abstract Background Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to various discomforts such as inflammation of the ocular surface and visual issues. However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease. Methods Entered the keywords “Dry eye”, “Microbiota”, “Bacteria” through PUBMED, summarised the articles that meet the inclusion criteria and then filtered them while the publication time range of the literature was defined in the past 5 years, with a deadline of 2023.A total of 13 clinical and 1 animal-related research articles were screened out and included in the summary. Results Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects. Fecal microbiota transplantation or probiotic intervention can alleviate signs of inflammation on the ocular surface of dry eye animal models. Conclusions By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. Analyzing the correlation between the intestinal tract and the eyes from the perspective of microbiota can provide a theoretical basis and a new idea for relieving dry eyes in multiple ways in the future.

Abstract Background Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in Chinese type 1 diabetes mellitus (T1DM) patients. So there are still significant knowledge gaps regarding clinical and patient-reported outcomes in China. Aims This study aims to compare the glycated hemoglobin (HbA1C), insulin therapy related quality of life (ITR-QOL), fear of hypoglycemia (FOH) of adult T1DM patients treated with MDI and CSII based on propensity score matching in real-world conditions in China. Methods Four hundred twenty adult T1DM patients who were treated with MDI or CSII continuously for more than 12 months in a national metabolic center from June 2021 to June 2023 were selected as the study subjects. Their QOL and FOH were evaluated with Insulin Therapy Related Quality of Life Measure Questionnaire-Chinese version (ITR-QOL-CV) and the Chinese Version Hypoglycemia Fear Survey-Worry Scale (CHFSII-WS), and their HbA1C were collected at the same time. Potential confounding variables between the two groups were matched using propensity score matching. Results Of the 420 patients included in the study, 315 were in MDI group and 105 were in CSII group. 102 pairs were successfully matched. After matching, the total score of ITR-QOL-CV scale in CSII group was significantly higher than that in MDI group (87.08 ± 13.53 vs. 80.66 ± 19.25, P = 0.006). Among them, the dimensions of daily life, social life, and psychological state were all statistically different (P

Thermochemical conversions are pathways for biomass utilization to produce various value-added energy and chemical products. For the development of novel thermochemical conversion technologies, an accurate understanding of the reaction performance and kinetics is essential. Given the diversity of the thermal analysis techniques, it is necessary to understand the features and limitations of the reactors, ensuring that the selected thermal analysis reactor meets the specific need for reaction characterization. This paper provides a critical overview of the thermal analysis reactors based on the following perspectives: 1) gas flow conditions in the reactor, 2) particle's external and internal heat and mass transfer limitations, 3) heating rate, 4) temperature distribution, 5) nascent char production and reaction, 6) liquid feeding and atomization, 7) simultaneous sampling and analyzing of bed materials, and 8) reacting atmosphere change. Finally, prospects and future research directions in the development of analysis techniques are proposed.

BackgroundHypobaric hypoxic conditions encountered at high altitudes can significantly impact the physiological functions of human body. Therefore, accurate and real-time monitoring of physiological characteristics is crucial for the prevention of brain injuries in individuals with acute and chronic high-altitude exposure.MethodsIn this study, a wireless wearable cerebral oximeter (WORTH band) was used for the continuous, real-time monitoring of physiological parameters, including regional cerebral oxygen saturation (rSO2) and heart rate (HR), among subjects with high-altitude exposure.ResultsDuring the high-altitude (from 46 m to 4300 m) expedition task, there was a significant decrease in rSO2 accompanied by a corresponding increase in heart rate as the altitude increased. Additionally, during the long-term (52 days) high-altitude (from 356 m to 4658 m) cycling task, the altitudes were significantly correlated with the rSO2 and SpO2 in the elderly subjects.ConclusionThe current findings indicate that the WORTH band oximeter can serve as a promising instrument for measuring rSO2 at high altitudes. We hope that the insights derived from this study could contribute to the management of cerebral oxygenation for individuals with high-altitude exposure and further expand the existing understanding of brain functional detection at high altitudes.

Abstract Background Droplet digital PCR (ddPCR) is widely applied to monitor measurable residual disease (MRD). However, there are limited studies on the feasibility of ddPCR-MRD monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially targeting multiple molecular markers simultaneously. Methods Our study collected samples from patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in complete remission after allo-HSCT between January 2018 and August 2021 to evaluate whether posttransplant ddPCR-MRD monitoring can identify patients at high risk of relapse. Results Of 152 patients, 58 (38.2%) were MRD positive by ddPCR within 4 months posttransplant, with a median variant allele frequency of 0.198%. The detectable DTA mutations (DNMT3A, TET2, and ASXL1 mutations) after allo-HSCT were not associated with an increased risk of relapse. After excluding DTA mutations, patients with ddPCR-MRD positivity had a significantly higher cumulative incidence of relapse (CIR, 38.7% vs. 9.7%, P

Abstract Background The prognostic significance of myelofibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains elusive. Methods We retrospectively analyzed data from 153 patients with MDS who underwent allo-HSCT and divided the patients into the MF-0/1 (N = 119) and MF-2/3 (N = 34) cohorts to explore the impact of MF on outcomes of allo-HSCT. Results The 2-year rates of relapse, non-relapse mortality (NRM), overall survival (OS), and progression-free survival (PFS) were 10.9% (95% confidence interval [CI] 5.9%–17.7%), 16.3% (95% CI 10.2%–23.6%), 76.6% (95% CI 69.0%–85.1%), and 72.8% (95% CI 65.0%–81.5%) in the MF-0/1 cohort, and 16.9% (95% CI 5.8%–32.9%), 14.7% (95% CI 5.3%–28.7%), 71.8% (95% CI 57.6%–89.6%), and 68.4% (95% CI 53.6%–87.2%) in the MF-2/3 cohort, respectively. No significant difference in the outcomes of allo-HSCT was observed between the two cohorts. Both univariate and multivariate analyses confirmed that MF-2/3 in patients with MDS had no effect on the prognosis of transplantation. In addition, major/bidirectional ABO blood type between donors and recipients was an independent risk factor for OS (hazard ratio [HR], 2.55; 95% CI 1.25–5.21; P = 0.010) and PFS (HR, 2.21; 95% CI 1.10–4.42; P = 0.025) in the multivariate analysis. In the subgroup of patients diagnosed with MDS with increased blasts (MDS-IB), it was consistently demonstrated that the clinical outcomes of the MF-2/3 cohort were comparable with those of the MF-0/1 cohort. The risk factors for OS and PFS in patients with MDS-IB were non-complete remission at transplantation and major/bidirectional ABO blood type. Conclusions In conclusion, MF grade had no significant effect on prognosis of allo-HSCT in patients diagnosed with MDS. Major/bidirectional ABO blood type should be carefully considered in the context of more than one available donor.

Abstract Background Acute myeloid leukemia (AML) with biallelic (CEBPA bi) as well as single mutations located in the bZIP region is associated with a favorable prognosis, but the underlying mechanisms are still unclear. Here, we propose that two isoforms of C/EBPα regulate DNA damage-inducible transcript 3 (DDIT3) transcription in AML cells corporately, leading to altered susceptibility to endoplasmic reticulum (ER) stress and related drugs. Methods Human AML cell lines and murine myeloid precursor cell line 32Dcl3 cells were infected with recombinant lentiviruses to knock down CEBPA expression or over-express the two isoforms of C/EBPα. Quantitative real-time PCR and western immunoblotting were employed to determine gene expression levels. Cell apoptosis rates were assessed by flow cytometry. CFU assays were utilized to evaluate the differentiation potential of 32Dcl3 cells. Luciferase reporter analysis, ChIP-seq and ChIP-qPCR were used to validate the transcriptional regulatory ability and affinity of each C/EBPα isoform to specific sites at DDIT3 promoter. Finally, an AML xenograft model was generated to evaluate the in vivo therapeutic effect of agents. Results We found a negative correlation between CEBPA expression and DDIT3 levels in AML cells. After knockdown of CEBPA, DDIT3 expression was upregulated, resulting in increased apoptotic rate of AML cells induced by ER stress. Cebpa knockdown in mouse 32Dcl3 cells also led to impaired cell viability due to upregulation of Ddit3, thereby preventing leukemogenesis since their differentiation was blocked. Then we discovered that the two isoforms of C/EBPα regulate DDIT3 transcription in the opposite way. C/EBPα-p30 upregulated DDIT3 transcription when C/EBPα-p42 downregulated it instead. Both isoforms directly bound to the promoter region of DDIT3. However, C/EBPα-p30 has a unique binding site with stronger affinity than C/EBPα-p42. These findings indicated that balance of two isoforms of C/EBPα maintains protein homeostasis and surveil leukemia, and at least partially explained why AML cells with disrupted C/EBPα-p42 and/or overexpressed C/EBPα-p30 exhibit better response to chemotherapy stress. Additionally, we found that a low C/EBPα p42/p30 ratio induces resistance in AML cells to the BCL2 inhibitor venetoclax since BCL2 is a major target of DDIT3. This resistance can be overcome by combining ER stress inducers, such as tunicamycin and sorafenib in vitro and in vivo. Conclusion Our results indicate that AML patients with a low C/EBPα p42/p30 ratio (e.g., CEBPA bi) may not benefit from monotherapy with BCL2 inhibitors. However, this issue can be resolved by combining ER stress inducers.

Abstract Background Early childhood caries (ECC) causes severe, widespread oral health issues in children. Dental undergraduates and residents are expected to have a solid understanding of ECC for children’s oral health promotion. This study aimed to evaluate the knowledge, attitude, and clinical practice on ECC among dental undergraduates and residents in China. Methods A 23-item electronic questionnaire was distributed to 598 dental undergraduates (4th- and 5th-year undergraduates) and residents (1st-, 2nd-, and 3rd-year residents) at the School of Stomatology, Wuhan University, China (in April–May 2023). SPSS Statistics was used to analyze the data using the Chi-square test at a significance level of 0.05. Results A total of 422 questionnaires were completed by participants (recovery rate: 70.6%) from various academic levels. Around 77.3% of participants had heard of ECC (mainly from textbooks), and only 27.5% considered themselves familiar with it. Residents (79.8%) had higher risk awareness of ECC on children’s overall health than undergraduates (58.3%) (p

Pythium species are distributed globally, with certain members playing significant roles as plant and animal pathogens. Pythium cedri Chen 4 has been identified as a pathogenic isolate responsible for causing root rot on Cedrus deodara. Here, a comprehensive genome-wide sequence of P. cedri strain Chen 4 utilizing the Illumina NovaSeq sequencing platform and a Pacific Biosciences Sequel sequencing platform is presented. The genome of P. cedri strain Chen 4 was assembled into 150 contigs containing a combined size of 41.25 Mb, N50 value of 1,717,859 bp and N90 value of 431,829 bp. Genome annotation revealed 14,077 protein-encoding genes and 364 of the 1016 predicted proteins were putative effectors. The present work enriches the genetic resources of P. cedri for studying its evolution and can contribute to a better understanding of P. cedri–host interaction.

Background The detection of foetal DNA and extravillus trophoblasts (EVTs) in early pregnancy in cervical and uterine samples offers a potential pathway for non-invasive prenatal diagnostics. However, the challenge lies in effectively quantifying these samples. This study introduces a novel approach using the Ras association domain family 1 A (RASSF1A), which exhibits hypermethylation in foetal cells and hypomethylation in maternal cells. The differential methylation pattern of RASSF1A provides a unique biomarker for quantifying foetal cells in cervical and intrauterine samples.Methods This study was conducted between September 2022 and May 2023. In total, 23 samples (12 cervical cell samples and 11 intrauterine samples) were collected from women in the Sichuan Jinxin Women & Children Hospital, Jingxiu District, Chengdu, China. The cervical cell samples were collected via lavage and brush techniques, and the intrauterine cell samples were obtained via uterine lavage. These samples were collected as part of a broader effort to advance our understanding of foetal cell dynamics during early pregnancy. The sampling methods were chosen for their minimally invasive nature and their potential in capturing a representative cell population from the respective sites. After digestion of the cell samples using a methylation-sensitive restriction enzyme cocktail, a critical step to differentiate between maternal and foetal DNA, the quantitative polymerase chain reaction (qPCR) of RASSF1A and β-actin (ACTB) were employed to measure foetal DNA and cell concentrations. Immunofluorescence techniques targeting histocompatibility complex, class I G (HLA-G) and GATA binding protein 3 (GATA-3) were employed to detect EVTs in the cell samples and in decidual tissue, with the latter providing an additional layer of confirmation for the presence of foetal cells.Results The results showed no hypermethylated RASSF1A was detected in any of the cervical samples, irrespective of whether the samples were obtained by brush or lavage. However, an average of 17,236 ± 7490 foetal cells per sample were detected in the uterine lavage samples. Foetal cells accounted for approximately 0.14% ± 0.10% of the total cell population in these samples. The presence of EVTs in these samples was confirmed by their expression of both HLA-G and GATA-3.Conclusion The detection of foetal cells in uterine cavity samples based on hypermethylation of RASSF1A and quantification of foetal cells can be used to prenatal screening. GATA-3 can be used to label EVTs.

BackgroundChimeric antigen receptor T-cell (CAR-T) therapy, a rapidly emerging treatment for cancer that has gained momentum since its approval by the FDA in 2017, involves the genetic engineering of patients’ T cells to target tumors. Although significant therapeutic benefits have been observed, life-threatening adverse pulmonary events have been reported.MethodsUsing SAS 9.4 with MedDRA 26.1, we retrospectively analyzed data from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database, covering the period from 2017 to 2023. The analysis included the Reporting Odds Ratio Proportional Reporting Ratio Information Component and Empirical Bayes Geometric Mean to assess the association between CAR-T cell therapy and adverse pulmonary events (PAEs).ResultsThe FAERS database recorded 9,400 adverse events (AEs) pertaining to CAR-T therapies, of which 940 (10%) were PAEs. Among these CAR-T cell-related AEs, hypoxia was the most frequently reported (344 cases), followed by respiratory failure (127 cases). Notably, different CAR-T cell treatments demonstrated varying degrees of association with PAEs. Specifically, Tisa-cel was associated with severe events including respiratory failure and hypoxia, whereas Axi-cel was strongly correlated with both hypoxia and tachypnea. Additionally, other CAR-T therapies, namely, Brexu-cel, Liso-cel, Ide-cel, and Cilta-cel, have also been linked to distinct PAEs. Notably, the majority of these PAEs occurred within the first 30 days post-treatment. The fatality rates varied among the different CAR-T therapies, with Tisa-cel exhibiting the highest fatality rate (43.6%), followed by Ide-cel (18.8%).ConclusionThis study comprehensively analyzed the PAEs reported in the FAERS database among recipients of CAR-T cell therapy, revealing conditions such as hypoxia, respiratory failure, pleural effusion, and atelectasis. These CAR-T cell therapy-associated events are clinically significant and merit the attention of clinicians and researchers.

Pomegranate seeds (PS) are the dried seeds derived from pomegranate fruit, accounting for approximately 20% of the fruit’s total weight, and are a by-product of pomegranate juice extraction. These seeds hold significance in traditional medicine among Uyghurs and Tibetan cultures, featuring diverse clinical applications within traditional Chinese medicine. These applications include management of gastric coldness and acidity, abdominal distension, liver and gallbladder fever, and pediatric enteritis. PS demonstrates properties such as stomach tonicity, qi regulation, analgesia, and anti-inflammatory effects. Extensive research underscores the richness of PS in various phytochemical compounds and metabolites, notably unsaturated fatty acids (particularly linolenic acid and linoleic acid), phenolic compounds tocopherols, proteins, and volatile oils. Notably, among these bioactive compounds, punicic acid (PA), found within PS, demonstrates potential in the prevention and treatment of cancers, diabetes, obesity, and other ailments. Despite extensive literature on pomegranate as a botanical entity, a comprehensive review focusing specifically on the chemical composition and pharmacological effects of PS remains elusive. Therefore, this review aimed to consolidate knowledge regarding the medicinal properties of PS, summarizing its chemical composition, traditional uses, and pharmacological effects in treating various diseases, thereby laying a foundation for the advancement and application of PS in the field of pharmacology.

IntroductionThis study was conducted to evaluate the effects of dietary galacto-oligosaccharides (GOS) and hyocholic acids (HCA) during late gestation and lactation on reproductive performance, colostrum quality, antioxidant capacity and gut microbiota in multiparous sows.MethodsA total of 60 healthy multiparous cross-bred sows (Landrace × Yorkshire) were randomly fed 4 groups diets as follows: the basal diets (CTRL group), or the basal diets containing only 600 mg/kg GOS (GOS group), 600 mg/kg GOS + 100 mg/kg HCA (GOS + Low HCA group), and 600 mg/kg + 200 mg/kg HCA (GOS + High HCA group) from d 85 of gestation to weaning. Multiple parameters of sows were determined.ResultsThere was a trend of shortening the labor process of sows (p = 0.07) in the GOS group and GOS + Low/High HCA group. Compared with the CTRL group, the GOS + Low/High HCA group increased the average piglets weight at birth (p

BackgroundAccompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported that metaplasticity is involved in this process. However, the mechanisms still remain unclear. This study investigated the role of Ih current in the metaplastic changes and learning and memory impairment induced by ECS in depressive rats.MethodsDepressive rats received ECS after modelling using chronic unpredictable. ZD7288, a type of Ih current inhibitor was used to verify the effect of Ih current. The sucrose preference test and Morris water maze were used for behavior testing. Changes in metaplasticity was assessed with the LTD/LTP threshold by stimulation at different frequencies. Spontaneous and evoked action potentials (APs) were measured to confirm difference of neuronal excitability. Additionally, the amplitude of Ih current was analyzed.ResultsECS exerts antidepressant effect, but also induce spatial learning and memory dysfunction. ECS up-regulates the LTD/LTP threshold. In rats treated with ECS, the frequency of spontaneous and evoked APs is significantly reduced. In addition, ECS induces changes in the intrinsic properties of AP, including a decrease of AP-half width and peak amplitude, and an increase in AP time to peak and post-hyperpolarization potential amplitude. In particular, ECS increases both instantaneous and steady-state Ih currents. However, Inhibition of Ih current with ZD7288 results in a relief of learning and memory impairment and a decrease in threshold, as well as a significant reversal of whole-cell electrophysiological changes.ConclusionECS-induced learning and memory impairment is caused by neuronal hypoexcitability mediated metaplasticity, and upregulation of LTD/LTP threshold by an increase in Ih current.

Transparent conductive oxide (TCO) films, known for their role as carrier transport layers in solar cells, can be adversely affected by hydrolysis products from encapsulants. In this study, we explored the morphology, optical-electrical properties, and deterioration mechanisms of In2O3-based TCO films under acetic acid stress. A reduction in film thickness and carrier concentration due to acid-induced corrosion was observed. X-ray photoelectron spectroscopy and inductively coupled plasma emission spectrometry analyses revealed that TCOs doped with less-reactive metals exhibited enhanced corrosion resistance. The efficiency of silicon heterojunction (SHJ) solar cells with tin-doped indium oxide, titanium-doped indium oxide, and zinc-doped indium oxide films decreased by 10%, 26%, and 100%, respectively, after 200 ​h of corrosion. We also found that tungsten-doped indium oxide could effectively safeguard SHJ solar cells against acetic acid corrosion, which offers a potential option for achieving long-term stability and lower levelized cost of solar cell systems. This research provides essential insights into selecting TCO films for solar cells and highlights the implications of ethylene-vinyl acetate hydrolysis for photovoltaic modules.

Exploring novel therapeutic targets of Diffuse large B cell lymphoma (DLBCL) to overcome its resistance to Bruton's Tyrosine Kinase (BTK) inhibitors is a key topic. Lipid metabolism, crucial in the resistance landscape of various cancers, may unlock new aspects of BTK inhibitor resistance in DLBCL. Despite the known importance of lipid metabolism in oncological resistance patterns, its intricate role in DLBCL and its resistance to BTK inhibitor therapies remains largely uncharted. This review will explore the complex relationship between lipid metabolism and BTK inhibitor resistance, giving new insights for improving the effectiveness of BTK inhibitors and developing innovative combination treatment methods for DLBCL. This review holds the potential for guiding future research directions, optimizing existing therapeutic processes, and inspiring the development of innovative combinatorial therapeutic strategies that improve outcomes in patients with DLBCL.

Abstract Background: Precocious puberty (PP) involves early activation of the hypothalamic gonadotropin-releasing hormone (GnRH) generator. The RFamide-related peptide/G protein-coupled receptor 147 (RFRP3/GPR147) signaling pathway is vital in inhibiting GnRH and delaying puberty onset. The nourishing Yin-removing fire (NYRF) herbal mixture has shown promising results in treating PP. Objective: This study aimed to assess the impact of the NYRF herbal mixture on the RFRP3/GPR147 signaling pathway in the hypothalamus and its potential in alleviating PP in female rats. Materials and Methods: In a controlled experiment, 24 female Sprague-Dawley rats (11.20 ± 0.69 gr, postnatal day [PD5]) were divided into normal, model, normal saline, and NYRF groups (n = 6/each). PP was induced in the model, normal saline, and NYRF groups by subcutaneous injection of danazol at PD5. The NYRF herbal mixture or normal saline was administered from PD15. Serum sex hormone levels and hypothalamic samples were collected for mRNA and protein expression at PD30. Results: In the model group, hypothalamic GnRH and kisspeptin levels increased, while RFRP3 and GPR147 levels decreased, luteinizing hormone levels elevated, reproductive organ coefficients increased, and the vagina opened earlier compared to the normal group. Conversely, the NYRF group exhibited lower GnRH and kisspeptin levels but higher RFRP3 levels in the hypothalamus. Serum luteinizing hormone levels were reduced, reproductive organ coefficients were reduced, and the vaginal opening was delayed compared to the model and normal saline groups. Conclusion: The NYRF herbal mixture delayed sexual development in rats with PP by hypothalamic upregulating RFRP3 and downregulating GnRH and kisspeptin.

Abstract Objectives To develop and validate a magnetic resonance imaging-based (MRI) deep multiple instance learning (D-MIL) model and combine it with clinical parameters for preoperative prediction of lymph node metastasis (LNM) in operable cervical cancer. Methods A total of 392 patients with cervical cancer were retrospectively enrolled. Clinical parameters were analysed by logistical regression to construct a clinical model (M1). A ResNet50 structure is applied to extract features at the instance level without using manual annotations about the tumour region and then construct a D-MIL model (M2). A hybrid model (M3) was constructed by M1 and M2 scores. The diagnostic performance of each model was evaluated by the area under the receiver operating characteristic curve (AUC) and compared using the Delong method. Disease-free survival (DFS) was evaluated by the Kaplan‒Meier method. Results SCC-Ag, maximum lymph node short diameter (LNmax), and tumour volume were found to be independent predictors of M1 model. For the diagnosis of LNM, the AUC of the training/internal/external cohort of M1 was 0.736/0.690/0.732, the AUC of the training/internal/external cohort of M2 was 0.757/0.714/0.765, and the AUC of the training/internal/external cohort of M3 was 0.838/0.764/0.835. M3 showed better performance than M1 and M2. Through the survival analysis, patients with higher hybrid model scores had a shorter time to reach DFS. Conclusion The proposed hybrid model could be used as a personalised non-invasive tool, which is helpful for predicting LNM in operable cervical cancer. The score of the hybrid model could also reflect the DFS of operable cervical cancer. Critical relevance statement Lymph node metastasis is an important factor affecting the prognosis of cervical cancer. Preoperative prediction of lymph node status is helpful to make treatment decisions, improve prognosis, and prolong survival time. Key points • The MRI-based deep-learning model can predict the LNM in operable cervical cancer. • The hybrid model has the highest diagnostic efficiency for the LNM prediction. • The score of the hybrid model can reflect the DFS of operable cervical cancer. Graphical Abstract

Abstract Purpose Lower back pain (LBP), mainly caused by intervertebral disk (IVD) degeneration (IDD), is widely prevalent worldwide and is a serious socioeconomic burden. Numerous factors may trigger this degenerative process, and microbial dysbiosis has recently been implicated as one of the likely causes. However, the exact relationship between IDD and the microbiome remains obscure. In this study, we investigated the gut microbiota composition and fecal metabolic phenotype and discussed the possible influences of microbiome dysbiosis on IDD. Methods Fecal DNA was extracted from 16 fecal samples (eight rabbit models with IDD and eight sex- and age-matched healthy controls) and analyzed by high-throughput 16S rDNA sequencing. The fecal samples were also analyzed by liquid chromatography–mass spectrometry-based metabolomics. Multivariate analyses were conducted for the relationship between the omics data and IDD, linear discriminant analysis effect size was employed for biomarker discovery. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to annotate the differential metabolites. The potential correlation between differential gut microbiota and metabolites was then assessed. Results The 16S rDNA sequencing results showed that the β-diversity of the gut microbiota was significantly different between the IDD and control groups, with distinct abundance levels of dominant genera. Moreover, 59 metabolites were significantly upregulated and 91 were downregulated in IDD rabbits versus the controls. The KEGG enrichment analysis revealed that the top pathways remarkably impacted by IDD were tyrosine metabolism, amino sugar and nucleotide sugar metabolism, benzoate degradation, ABC transporters, ascorbate and aldarate metabolism, pantothenate and CoA biosynthesis, and pyrimidine metabolism. The correlation analysis revealed that DL-tyrosine and N-acetylmuramic acid were associated with multiple differential bacterial genera, including Helicobacter and Vibrio, which may play important roles in the process of IVD degeneration. Conclusion Our findings revealed that IDD altered gut microbiota and fecal metabolites in a rabbit model. The correlation analysis of microbiota and metabolome provides a deeper understanding of IDD and its possible etiopathogenesis. These results also provide a direction and theoretical basis for the clinical application of fecal transplantation, probiotics, and other methods to regulate gut microbiota in the treatment of LBP caused by IDD.

In recent eras, the complexity and fluctuations of the global crude oil prices have affected the economic progress of society. It is therefore, the oil price prediction has hauled the attention of scholars and policymakers. Driven by this critical concern for forecasting of crude oil prices, we introduces a novel hybrid model keeping in mind the primary objective of enhancing prediction accuracy while considering the specific characteristics as inherent in the data. To achieve this achievement, the trend is eliminated, allowing the scrutiny of whether the residual component validates the assurance of a series ran by stochastic trends. Following the removal of the trend, the residual component undergoes rigorous evaluation through autoregressive model following the decomposition model. Then we got support from the support vector machine, autoregressive integrated moving average and long-short term memory. The predictions accuracy can be evaluated by using the various performance metrics. The proposed hybrid model’s robustness and forecasting performance are rigorously evaluated through Diebold-Mariano test in comparison to competing models. Furthermore, the forecasting ability is evaluated via directional forecast. Ultimately, the empirical findings explicitly determine the superior predictive capabilities of the proposed hybrid model over alternative approaches.

This article introduces a research method aimed at achieving optimal control timing for the zero-voltage quasi-square wave switch (ZVS-QSW) in a silicon carbide buck converter across a wide range. The method establishes the correlation function between optimal control timing parameters and load current through composite segmented curve fitting to the plane of the ZVS-QSW state over the entire operating range. It also compensates for the charge change on the filter capacitor to determine the load current at the corresponding operating point. By collecting the input/output voltages and load currents and substituting them into the correlation function, the optimal timing parameters for achieving ZVS-QSW can be determined online. The proposed method is validated on a silicon carbide buck converter prototype with an input voltage of 400 V. ZVS-QSW can be achieved in the conversion ratio range of 0.1-0.9. Consequently, the proposed method not only reduces the difficulty of inductance current measurement but also simplifies and visualizes the timing control of the converter.

The application of multisampling technology in voltage-source inverters (VSIs) systems can significantly reduce the control delay and break the bandwidth limitations of traditional synchronous sampling schemes. However, when sampling the capacitor voltage, the high-frequency ripple is introduced into the control loop, leading to the local vertical crossing (VC) phenomenon. Previous studies have demonstrated that a moving average filter (MAF) or improved repetitive filter (IRF) can effectively remove the high-frequency ripple. However, they introduce additional phase lag, which undermines the advantages of multisampling technology in terms of phase boost. The approach of spectrum analysis can be used to study the impact of voltage ripple. The results indicate that after modulation, the output signal contains low-frequency harmonics, and the superposition of the ripple makes the modulation process more susceptible to saturation. Therefore, a 20k ripple notch filter (RNF) is proposed to attenuate the ripple signal while introducing a more minor phase lag. Additionally, a 90° phase shift filter is proposed to suppress the aliasing signals generated in the system. Finally, the effectiveness of the proposed methods is verified through the experimental test of a 10kW single-phase VSI system.

Motor control is a complex process of coordination and information interaction among neural, motor, and sensory functions. Investigating the correlation between motor-physiological information helps to understand the human motor control mechanisms and is important for the assessment of motor function status. In this manuscript, we investigated the differences in the neuromotor coupling analysis between healthy controls and stroke patients in different movements. We applied the corticokinematic coherence (CKC) function between the electroencephalogram (EEG) and acceleration (ACC) data. First, we collected the EEG and ACC data from 10 healthy controls and 10 stroke patients under the task of movement execution (ear touch and knee touch) and movement maintenance (ear touch and knee touch). After the preprocessing of raw data, we used frequency domain coherence method to analyze the full-frequency EEG and ACC data, which could be concluded that the CKC intensity in the movement execution was higher than that in the movement maintenance. However, there was no significant difference between healthy subjects and stroke patients. Secondly, the coherence results in local frequency bands showed that low-frequency bands could better reflect the difference between movement execution and maintenance. The intensity of coherence in healthy subjects was significantly higher than that in other bands, but not in stroke patients. Further comparison of coherence results in local frequency bands showed that the intensity of theta band in healthy controls was significantly higher than other rhythms, especially in the knee touch phase. Therefore, we infer that neurodynamic coupling analysis based on EEG and ACC data can show the differences between healthy subjects and stroke patients. Such researches could add to the understanding of neuro-motor control mechanisms and provide new quantitative indicators on the motor function assessment.

Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive functions to protect human health. Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement. Here, we identified the complete pathway to stereoselectively synthesize antiviral (−)-lariciresinol glucosides in Isatis indigotica roots, which consists of three-step sequential stereoselective enzymes DIR1/2, PLR, and UGT71B2. DIR1 was further identified as the key gene in respoJanuary 2024nse to stresses and was able to trigger stress defenses by mediating the elevation in lignan content. Mechanistically, the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1. These systematic results suggest that DIR1 as the first common step of the lignan pathway cooperates with PLR and UGT71B2 to stereoselectively synthesize (−)-lariciresinol derived antiviral lignans in I. indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses. In conclusion, the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.

ObjectiveWelding is a common method for connecting ship structures, but it obviously affects their acoustic and vibration characteristics. Thus, it is necessary to study the influence of welding process parameters on the acoustic and vibration characteristics of structures. MethodIn this paper, the thermo-elastoplastic finite element method and acoustic-structure coupling finite element method are combined to study the influence of welding parameters on the acoustic and vibration characteristics of typical ship stiffened plate structures. ResultsThe results show that welding residual stress is significantly affected by welding input power and speed. Higher welding input power and lower welding speeds both result in a larger welding residual stress distribution range which causes changes to the natural frequency, vibration response and radiated sound pressure of typical stiffened plate structures. ConclusionWelding residual stress should be analyzed to determine the acoustic and vibration response of low-damping welded structures, thereby providing guidance for the formulation of low-noise welding processes.

Abstract Background The European LeukemiaNet (ELN) risk classification system for acute myeloid leukemia (AML) patients has been used worldwide. In 2022, the ELN risk classification system modified risk genes including CEBPA mutation status, myelodysplasia‐related (MR) gene mutations and internal tandem duplications of FLT3 (FLT3‐ITD). Methods We include newly diagnosed de novo AML patients at our center from January 2017 to December 2021, regardless of the further treatment received. Clinical data and date of survival were included. Survival analysis were performed using the Kaplan–Meier method, and the log‐rank test was used to compare survival between different risk groups. Results We include 363 newly diagnosed de novo AML patients from 2017 to 2021 to assess the accuracy of the ELN risk classification system. Their survival results show that the ELN‐2022 risk classification system is not superior to the ELN‐2017 version; for patients with FLT3‐ITD mutations but without FLT3 inhibitor treatment, their survival is similar to the ELN‐2022 adverse risk group. The ELN‐2022 risk classification system cannot accurately clarify ECOG performance status (PS) 2–4 patients, especially in the ELN‐2022 favorable risk group. Conclusion The ELN‐2022 risk stratification system may not be appropriate for patients unable to receive intensive therapy or FLT3 inhibitor; more real‐world data is needed to straify patients with worse ECOG PS and inferior intensive therapy.

This paper presents a three-channel reconfigurable step attenuator based on radio frequency (RF) microelectromechanical system (MEMS) switches, in response to the current issues of high insertion loss and low attenuation accuracy of attenuators. The coplanar waveguide (CPW), cross-shaped power dividers, RF MEMS switches, and π-type attenuation resistor networks are designed as a basic unit of the attenuator. The attenuator implemented attenuation of 0~30 dB at 5 dB intervals in the frequency range of 1~25 GHz through two basic units. The results show that the insertion loss is less than 1.41 dB, the attenuation accuracy is better than 2.48 dB, and the geometric size is 2.4 mm × 4.0 mm × 0.7 mm. The attenuator can be applied to numerous fields such as radar, satellites, aerospace, electronic communication, and so on.

Myocardial infarction (MI), a severe outcome of cardiovascular disease, poses a serious threat to human health. Uncontrolled inflammation and excessive cardiomyocyte death, following an infarction event, significantly contribute to both the mortality rate and complications associated with MI. The protein IL-4-induced gene 1 (IL4I1 or FIG1) serves as a natural inhibitor of innate and adaptive immunity, playing a crucial role in CD4+ T cell differentiation, macrophage polarization, and ferroptosis inhibition. Previous studies have linked IL4I1 to acute MI. This review summarizes evidence from both basic and clinical research, highlighting IL4I1 as a critical immunoregulatory enzyme that not only regulates inflammatory responses, but also potentially mitigates MI-induced damage.

In the present experiment, two types of water-reducing agents, naphthalene (FDN) and polycarboxylic acid (PCE), were selected, and their effects on the mechanical properties of foamed phosphogypsum were evaluated. It was shown that when the water-reducing agent contents were increased, the strength of the foamed phosphogypsum first increased and then gradually decreased, and that the dry density of the foamed phosphogypsum first decreased and then gradually increased. The FDN samples had better mechanical properties and a lower dry density than the PCE samples. The effect of the water-reducing agent dose on the apparent viscosity and shear stress of the phosphogypsum slurries was in the order of 0% > 0.4% > 0.3% > 0.5% > 0.2% > 0.1%. The apparent viscosity and shear stress of the gypsum slurry mixed with 0.4% FDN or PCE were the highest. FDN and PCE both enlarged the pore size distribution range, increased the size and proportion of large pores, and decreased the total pore content of foamed phosphogypsum; however, the effect of PCE was more significant. The foamed phosphogypsum slurry mixed with 0.4% FDN had the highest total pore content. Among the samples, the total pore content of foamed phosphogypsum A was able to reach 91% and the total pore content of foamed phosphogypsum B reached 77%; the lowest proportion of large pores for foamed phosphogypsum A and B separately reached 17% and 7%, respectively. The water-reducing agents mainly reduced the water consumption of the phosphogypsum slurries; improved the viscosity and shear stress of the slurries; affected the stability of the foam in the gypsum slurries; influenced the pore size and distribution in the foamed phosphogypsum samples; and caused a difference in the strength and dry density of the foamed phosphogypsum samples. The viscosity of the gypsum slurry doped with 0.4% FDN better matched that of the foam; therefore, it had the highest macro-strength and the lowest dry density.

A knowledge and data-synergized intelligent computation architecture for materials was proposed within the data science paradigm. As a vital operation, two digital ensemble descriptors implying chemical composition and structural trend for crystals were created using the features contained in the Periodic Table of elements without a priori assumption, which affords causal emergence and regulation principles for the mechanical response of covalent and ionic solids. In addition to a linear correlation among structural state/mechanical response parameters, causal analytic relations in an exponential form between structural and thermodynamic state/mechanical response parameters and a digital ensemble descriptor were unveiled through least squares regression, in which the coefficients are classified in accordance with symmetry principles on the atom and lattice. Thereafter, the underlying physicochemical mechanisms of chemical pressure and chemical bonding are found responsible for the mechanical responses of bulk modulus and hardness of solids. At last, a physical prediction model was established for crystalline solids and demonstrated the feasibility of the predictive design of novel superhard materials. It is believed that by constructing suitable digital ensemble descriptors, this intelligent computation architecture and consequent physical prediction models on the basis of causal analytic relations are able to generalize by depicting crystalline solids with covalent and ionic bonds in other crystallographic structures.

Abstract CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co‐expressing CD47 and CDC7 (cell division cycle 7, a negative senescence‐related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual‐targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy‐resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.

In this paper, we introduce a new structure of multioptical bottles formed by the chirped circular Bessel Gaussian beams carrying annular spiral-zone power-exponent-phase (ASP). The ASP is a general term for complex phases composed of the radial phase, equiphase, and power spiral phase. By combining the influence of autofocusing properties, chirp factor, and ASP mode, the propagation dynamics of the proposed multioptical bottles beam such as the sizes, lengths, number and locations can be flexibly manipulated. Intriguingly, the effect of the power order of ASP mode on the beam propagation dynamics is firstly introduced and examined. The proposed beams can enable diversification the optical tweezers system in multiparticle manipulation, which is verified by the radiation force analysis on a Rayleigh particle.

Summary: Background: Cholesteryl ester (CE) accumulation in intracellular lipid droplets (LDs) is an essential signature of clear cell renal cell carcinoma (ccRCC), but its molecular mechanism and pathological significance remain elusive. Methods: Enabled by the label-free Raman spectromicroscopy, which integrated stimulated Raman scattering microscopy with confocal Raman spectroscopy on the same platform, we quantitatively analyzed LD distribution and composition at the single cell level in intact ccRCC cell and tissue specimens in situ without any processing or exogenous labeling. Since we found that commonly used ccRCC cell lines actually did not show the CE-rich signature, primary cancer cells were isolated from human tissues to retain the lipid signature of ccRCC with CE level as high as the original tissue, which offers a preferable cell model for the study of cholesterol metabolism in ccRCC. Moreover, we established a patient-derived xenograft (PDX) mouse model that retained the CE-rich phenotype of human ccRCC. Findings: Surprisingly, our results revealed that CE accumulation was induced by tumor suppressor VHL mutation, the most common mutation of ccRCC. Moreover, VHL mutation was found to promote CE accumulation by upregulating HIFα and subsequent PI3K/AKT/mTOR/SREBPs pathway. Inspiringly, inhibition of cholesterol esterification remarkably suppressed ccRCC aggressiveness in vitro and in vivo with negligible toxicity, through the reduced membrane cholesterol-mediated downregulations of integrin and MAPK signaling pathways. Interpretation: Collectively, our study improves current understanding of the role of CE accumulation in ccRCC and opens up new opportunities for treatment. Funding: This work was supported by National Natural Science Foundation of China (No. U23B2046 and No. 62027824), National Key R&D Program of China (No. 2023YFC2415500), Fundamental Research Funds for the Central Universities (No. YWF-22-L-547), PKU-Baidu Fund (No. 2020BD033), Peking University First Hospital Scientific and Technological Achievement Transformation Incubation Guidance Fund (No. 2022CX02), and Beijing Municipal Health Commission (No. 2020-2Z-40713).

Understanding the spatial patterns and interaction of trees is crucial for exploring forest dynamics. However, limited research has explored the spatial pattern and interactions between adult trees and their offspring population in arid mountain forest ecosystems. We investigated the spatial distribution and interaction of recruitment, survival, and mortality at different size classes in the Populus davidiana forest in the Luoshan Mountains (Ningxia, China), to gain insights into its stand dynamics. (1) This demonstrated the characteristic shift from an aggregated to random distribution as seedlings grew and developed into adult trees. (2) The adult trees exhibited strong positive and weak negative spatial associations with seedlings and saplings, respectively, with an increasing spatial scale, yet both stages underwent stark transitions from negative (1–15 m scales) to positive (> 20 m scale) associations. (3) Generally, the closer the individual trees were to each other, the greater the negative impact of neighboring trees on the size of an individual tree. (4) Additionally, adult trees strongly increased the risk of seedling mortality across the spatial scale of 0–50 m. (5) Live seedlings were less than the dead ones around dead seedlings. There was a stronger aggregation of dead seedlings than live seedlings. Moreover, the density-dependent mortality in our study rejected the random mortality hypothesis. In summary, these results suggest that spatial separation occurs between dead and live seedlings of P. davidiana. Under adult trees, negative dependence plays an important role in the arid mountain forest recruitment. Our findings will contribute to the restoration and conservation of arid mountain forests and provide theoretical support for forest management.

Anti-cancer response of cell lines to drugs is in urgent need for individualized precision medical decision-making in the era of precision medicine. Measurements with wet-experiments is time-consuming and expensive and it is almost impossible for wide ranges of application. The design of computational models that can precisely predict the responses between drugs and cell lines could provide a credible reference for further research. Existing methods of response prediction based on matrix factorization or neural networks have revealed that both linear or nonlinear latent characteristics are applicable and effective for the precise prediction of drug responses. However, the majority of them consider only linear or nonlinear relationships for drug response prediction. Herein, we propose a Dual Branch Deep Neural Matrix Factorization (DBDNMF) method to address the above-mentioned issues. DBDNMF learns the latent representation of drugs and cell lines through flexible inputs and reconstructs the partially observed matrix through a series of hidden neural network layers. Experimental results on the datasets of Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) show that the accuracy of drug prediction exceeds state-of-the-art drug response prediction algorithms, demonstrating its reliability and stability. The hierarchical clustering results show that drugs with similar response levels tend to target similar signaling pathway, and cell lines coming from the same tissue subtype tend to share the same pattern of response, which are consistent with previously published studies.

Summary: Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Abstract Hepatitis B protein x (HBx) has been reported to promote tumorigenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the mechanism awaits further investigation. In this study, we found that cFAM210A (a circular RNA derived from the third exon of transcript NM_001098801 of the FAM210A gene; CircBase ID: hsa_circ_0003979) can be silenced by HBx. cFAM210A expression was downregulated and negatively correlated with tumorigenesis in patients with HBV-related HCC. Furthermore, cFAM210A reduced the proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, HBx increased the N6-methyladenosine (m6A) level of cFAM210A by promoting the expression of RBM15 (an m6A methyltransferase), thus inducing the degradation of cFAM210A via the YTHDF2-HRSP12-RNase P/MRP pathway. cFAM210A bound to YBX1 and inhibited its phosphorylation, suppressing its transactivation function toward MET. These findings suggest the important role of circular RNAs in HBx-induced hepatocarcinogenesis and identify cFAM210A a potential target in the prevention and treatment of HBV-related HCC.

Abstract Industrial processing of kelp generates large amounts of kelp-soaking wastewater (KSW), which contains a large amount of nutrient-containing substances. The plant growth-promoting effect might be further improved by combined application of growth-promoting bacteria and the nutrient-containing KSW. Here, a greenhouse experiment was conducted to determine the effect of the mixture of KSW and Bacillus methylotrophicus M4-1 (MS) vs. KSW alone (SE) on wheat seedlings, soil properties and the microbial community structure in wheat rhizosphere soil. The available potassium, available nitrogen, organic matter content and urease activity of MS soil as well as the available potassium of the SE soil were significantly different (p