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BackgroundCD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs).MethodsFive suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 “mAb-trap” platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems.ResultsUsing hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a “mAb-trap” platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605–26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605–12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605–12C10 efficiently eradicated all established tumors in all mice.ConclusionA panel of BsAbs targeting CD38 and CD47 developed based on the “mAb-tarp” platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.

Abstract Background Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. Methods From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. Results Age, creatinine, neutrophil-to-lymphocyte ratio, and Child–Turcotte–Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P

Abstract Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106–4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

Abstract KMT2A-rearranged acute myeloid leukemia (KMT2Ar-AML) is an aggressive subtype of AML with poor response and prognosis. KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Herein, we investigated the effect and mechanism of VEN plus MEN1i in KMT2Ar-AML. Our results showed that VEN and MEN1i exhibited a striking synergistic effect in KMT2Ar-AML cell lines (in vitro), primary KMT2Ar-AML cells (ex vivo), and MOLM13 xenotransplantation model (in vivo). Furthermore, we found that VEN plus MEN1i significantly enhanced apoptotic induction in KMT2Ar-AML cell lines. VEN or MEN1i monotherapy disrupted balance of BCL-2/BCL-XL or down-regulated HOXA9/MEIS1, respectively, but these mechanisms were not further strengthened by their combination. RNA-Sequencing identified that HDAC9 was specifically repressed by VEN plus MEN1i rather than monotherapy. We demonstrated that HDAC9 was indispensable for KMT2Ar-AML proliferation and its repression contributed to proliferation inhibition of VEN plus MEN1i. Moreover, we found that hypoxia induced HDAC9 expression in KMT2Ar-AML, and VEN plus MEN1i inhibited hypoxia pathway, especially HIF-1A, and its target HDAC9. As our results indicated, VEN plus MEN1i-mediated HDAC9 down-regulation was partially dependent on HIF-1A repression in KMT2Ar-AML. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.

Abstract Background Accurate identification of extrahepatic cholangiocarcinoma (ECC) from an image is challenging because of the small size and complex background structure. Therefore, considering the limitation of manual delineation, it’s necessary to develop automated identification and segmentation methods for ECC. The aim of this study was to develop a deep learning approach for automatic identification and segmentation of ECC using MRI. Methods We recruited 137 ECC patients from our hospital as the main dataset (C1) and an additional 40 patients from other hospitals as the external validation set (C2). All patients underwent axial T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI). Manual delineations were performed and served as the ground truth. Next, we used 3D VB-Net to establish single-mode automatic identification and segmentation models based on T1WI (model 1), T2WI (model 2), and DWI (model 3) in the training cohort (80% of C1), and compared them with the combined model (model 4). Subsequently, the generalization capability of the best models was evaluated using the testing set (20% of C1) and the external validation set (C2). Finally, the performance of the developed models was further evaluated. Results Model 3 showed the best identification performance in the training, testing, and external validation cohorts with success rates of 0.980, 0.786, and 0.725, respectively. Furthermore, model 3 yielded an average Dice similarity coefficient (DSC) of 0.922, 0.495, and 0.466 to segment ECC automatically in the training, testing, and external validation cohorts, respectively. Conclusion The DWI-based model performed better in automatically identifying and segmenting ECC compared to T1WI and T2WI, which may guide clinical decisions and help determine prognosis.

To reduce defects in wood laser processing, this study establishes a multi-field coupling model that reflects the coupling relationship between laser energy, auxiliary gas, and slit quality. It reveals the temperature field distribution and heat transfer during this process at a macroscopic level. Using the COMSOL Multiphysics 5.6 software to simulate laser processing with or without helium gas assistance, we show that helium-assisted laser processing positively affects the quality of wood processing. We further researched the influence of different laser powers and spot radii on ablation damage volume and gasification volume, and the results indicate that the adopted model effectively simulates the influence of laser power and auxiliary gas on laser cutting ability, accurately reflecting the impact of different process parameters on cutting depth and kerf width. The accuracy and effectiveness of this model were validated through comparison with experimental data. This research enhances process reliability and economic benefits through numerical simulation and prediction, expands theoretical research and engineering applications in the laser processing field, and optimizes and innovates wood processing technology. It provides a promising method for enhancing the added value of wood products and efficiently using wood resources.

In the hot press process of high-performance bamboo-based fiber composites, there is a highly nonlinear relationship between the production parameters of hot press and the quality parameters of the finished boards. Consequently, it is challenging to accurately predict the quality of the boards based on the given production parameters, and it is equally difficult to preset the production parameters to achieve the desired board quality. The current approach relies on manual experience, which may result in subpar board quality and material waste. To address these issues, this paper proposes a bi-directional prediction model based on cHGWO-SCA-SVR, using the collaboration-based hybrid GWO-SCA optimizer to optimize the relevant parameters of the SVR, and then accurately predicting the production parameters and the quality of the finished boards in both directions. Finally the cHGWO-SCA-SVR prediction model achieves an average R2 of 0.9591 for the forward prediction model and lower MAE and MSE values compared to other models; for the reverse prediction model, it attains an average R2 of 0.9553 and lower MAE and MSE values compared to other models. The results demonstrate the superiority of the cHGWO-SCA-SVR prediction model in comparison with other existing models, proving its significance in guiding the production of high-performance bamboo-based fiber composites by hot compression.

Due to their outstanding properties, bamboo-based fiber composites are gaining significant traction in the fields of construction and decoration. Among the crucial process steps in their production, hot pressing stands out as a pivotal one. Temperature, being a key parameter in hot pressing, and its stability of control exert a profound impact on the finished mechanical properties and associated indices of bamboo-based fiber composites. In this investigation, we introduce an active disturbance rejection control (ADRC) methodology specifically tailored for the hot-pressing temperature of bamboo-based fiber composites. A mathematical model encompassing the motor, steam regulating valve, and, ultimately, the hot-pressing temperature is formulated, with the transfer functions at each level being precisely determined through parameter identification techniques. The simulation outcomes reveal that in the absence of signal interference, sinusoidal signal interference, or random signal interference, the ADRC method outperforms the traditional PID algorithm in the realm of hot-pressing temperature control for bamboo-based fiber composites. This approach effectively reduces the temperature fluctuations of the PID algorithm, thereby averting issues such as premature curing or board bursting. In summary, this study holds significant implications for enhancing the mechanical properties of bamboo-based fiber composites.

ObjectiveNational health is essential for economic and social development. The aim of this article is to examine the relationship, heterogeneity effects and influential mechanisms between National Forest Cities and the residents' health.MethodsThe article matches the China Family Panel Studies data in 2018 (CFPS2018) with the 2016–2018 National Forest Cities Construction List, resulting in a final sample of 20,041. Oprobit, Ologit, Instrumental Variable technique (2SLS) and interaction term analysis were used as the main research methods in this article.ResultsThe findings indicate that: (1) The construction of National Forest Cities significantly improves the residents' health in terms of both physical and mental health, and this conclusion is still valid after a series of robustness tests. (2) On the one hand, National Forest Cities promote residents' health by reducing air pollutants such as SO2 and soot to reduce residents' health risk exposure; On the other hand, it promotes residents' health by positively guiding them to engage in healthy behaviors. (3) National Forest Cities have a greater effect on the health of urban residents, older adult and lower-income group, suggesting that National Forest Cities are a public benefit.ConclusionsThe construction of National Forest Cities is a public welfare that promotes residents' health, and it is an important revelation for accelerating the realization of the Healthy China Strategy. The article provides new empirical evidence for understanding the welfare effects of forest cities and offers new practical paths for improving residents' health.

The two-dimensional thermodynamically consistent phase field model, which consists of the anisotropic Allen-Cahn type equation and the heat equation, is used to study the morphological pattern of the particle in the initial stage of crystal growth. The results reveal the locally reversible growth of the particle in the initial stage of crystal growth. Specifically, some parts of the particle interface first grow inward, while others grow outward from the interface of critical nucleation, until the growth speed of the interface becomes zero. After this, the inward growth parts start to grow outward with other parts. The locally reversible growth of the particle leads to the development of a petal-like shape. The particle radius size dependence of the temperatures along the parts of the particle interface in different crystallographic directions at different time points is studied. By a series of results, the correlations between the morphological pattern selection of the particle and the model parameters, including undercooling and anisotropic strength, are analyzed. These results contribute to understanding the fundamental mechanism of the particle evolution during crystal growth.

Tumor cell extravasation across endothelial barrier has been recognized as a pivotal event in orchestrating metastasis formation. This event is initiated by the interactions of extravasating tumor cells with endothelial cells (ECs). Therefore, targeting the crosstalk between tumor cells and ECs might be a promising therapeutic strategy to prevent metastasis. In this study, we demonstrated that Rh1, one of the main ingredients of ginseng, hindered the invasion of breast cancer (BC) cells as well as diminished the permeability of ECs both in vitro and in vivo, which was responsible for the attenuated tumor cell extravasation across endothelium. Noteworthily, we showed that ECs were capable of inducing the epithelial-mesenchymal transition (EMT) and invadopodia of BC cells that are essential for tumor cell migration and invasion through limiting the nuclear translocation of hematopoietically expressed homeobox (HHEX). The decreased nuclear HHEX paved the way for initiating the CCL20/CCR6 signaling axis, which in turn contributed to damaged endothelial junctions, uncovering a new crosstalk mode between tumor cells and ECs. Intriguingly, Rh1 inhibited the kinase activity of casein kinase II subunit alpha (CK2α) and further promoted the nuclear translocation of HHEX in the BC cells, which resulted in the disrupted crosstalk between chemokine (C-C motif) ligand 20 (CCL20) in the BC cells and chemokine (C-C motif) receptor 6 (CCR6) in the ECs. The prohibited CCL20-CCR6 axis by Rh1 enhanced vascular integrity and diminished tumor cell motility. Taken together, our data suggest that Rh1 serves as an effective natural CK2α inhibitor that can be further optimized to be a therapeutic agent for reducing tumor cell extravasation.

Conventional electrothermal floors suffer from low heating efficiency, uneven temperature distribution across the floor surface, local overheating, and severe heat accumulation. In order to improve the heating performance, an electrothermal composite floor with graphene as the heating layer was fabricated. The relationship between time and temperature rise, the relationship between power density and temperature rise, running stability, and surface temperature distribution were investigated and analyzed after heating, and the surface temperature profiles were simulated in two and three dimensions. The results were compared with the carbon fiber electrothermal composite floor and the resistance wire electrothermal composite floor. The results indicated that the temperature of the graphene electrothermal composite floor rose to 27.1 °C, the electrothermal conversion efficiency reached 90.1% after 40 min of electrification, and the temperature distribution unevenness was 4.4 °C, which were better than the carbon fiber electrothermal composite floor and the resistance wire electrothermal composite floor. The graphene electrothermal composite floor exhibited high heating performance, thus aiding the development and manufacture of such composite flooring.

To improve the processing quality of wood products, the effects of different wood microstructure on the cutting quality of cherry wood were studied in the experimental process of gas-assisted laser processing. Based on the absorption ability of wood relative to laser wavelength, the composite processing of CO2 laser and inert gas was carried out. Kerf width and surface roughness were used as evaluation indexes, with analysis by factor experiments. The results showed that under the same parameter conditions, due to the difference in internal structure of wood, the cavity structure in the tracheid was more conducive to the diffusion and absorption of laser energy during perpendicular cutting. In addition, the kerf width and surface roughness of parallel cutting were smaller than that of perpendicular cutting. The microscopic morphology and surface carbon content of the kerf surface showed that during perpendicular cutting, due to the plugging effect of small holes, heat accumulation was not conducive to the flow of flue gas and carbide; thus carbon particles remained in the tracheid, and the carbon content of kerf surface was higher.

Abstract Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278–16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

BackgroundA significant level of CD70 can be detected in various types of tumor tissues and CD27 is expressed on Treg cells, but CD70 expression is low in normal tissues. The interaction between CD70 and CD27 can stimulate the proliferation and survival of cancer cells and increase the level of soluble CD27, which is associated with poor prognosis in patients with lymphoma and certain solid tumors. Thus, it is a promising therapeutic target for the treatment of many major CD70+ cancer indications, including CD70+ lymphoma, RCC, NSCLC, HNSCC and OC.MethodsIMM40H was obtained through hybridoma screening and antibody humanization techniques. IMM40H was evaluated for its binding, blocking, Fc-dependent effector functions and antitumor activity characteristics in various in vitro and in vivo systems. The safety and tolerability profile of IMM40H were evaluated through single and repeated administration in cynomolgus monkeys.ResultsIn vitro cell-based assays demonstrated that IMM40H had considerably stronger CD70-binding affinity than competitor anti-CD70 antibodies, including cusatuzumab, which enabled it to block the interaction of between CD70 and CD27 more effectively. IMM40H also exhibited potent Fc-dependent effector functions (ADCC/CDC/ADCP), and could make a strong immune attack on tumor cells and enhance therapeutic efficacy. Preclinical findings showed that IMM40H had potent antitumor activity in multiple myeloma U266B1 xenograft model, and could eradicate subcutaneously established tumors at a low dose of 0.3 mg/kg. IMM40H (0.3 mg/kg) showed therapeutic effects faster than cusatuzumab (1 mg/kg). A strong synergistic effect between IMM01 (SIRPα-Fc fusion protein) and IMM40H was recorded in Burkitt’s lymphoma Raji and renal carcinoma cell A498 tumor models. In cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) for repeat-dose toxicity was up to 30 mg/kg, while the maximum tolerated dose (MTD) for single-dose toxicity was up to 100 mg/kg, confirming that IMM40H had a good safety and tolerability profile.ConclusionIMM40H is a high-affinity humanized IgG1 specifically targeting the CD70 monoclonal antibody with enhanced Fc-dependent activities. IMM40H has a dual mechanism of action: inducing cytotoxicity against CD70+ tumor cells via various effector functions (ADCC, ADCP and CDC) and obstructs the proliferation and activation of Tregs by inhibiting CD70/CD27 signaling.

Herein, four chitooligosaccharide derivatives (COS-RA, COS-FA, COS-VA, COS-GA) were prepared by laccase-catalyzed chitooligosaccharide modification with rosmarinic acid (RA), ferulic acid (FA), gallic acid (GA), and vanillic acid (VA), and structures were characterized. RA and FA resulted in higher amino-substitution in the chitooligosaccharides than GA and VA. COS-RA and COS-FA had greater DPPH scavenging rates than COS-GA and COS-VA. Compared with COS treatment, spraying 250 mg L−1 COS-RA or COS-VA 6 times (once per 7 days) increased soluble sugar and anthocyanin content by 18.6%–23.2% and 41.7%–46.7%, respectively, from the fruit expansion to harvest stage. COS-RA and COS-VA also enhanced gene expression related to anthocyanin synthesis (PAL, F3H, F3′5′H, DFR, and UFGT) and monomeric anthocyanin accumulation (Mal-3-O-glu, Petu-3-O-ace-glu, Del-3-O-glu). Therefore, chitooligosaccharide derivatives may improve grape fruit anthocyanin accumulation by regulating antioxidant systems, improving the photosynthetic rate and inducing gene expression related to anthocyanin synthesis.

A new type of graphene electric heating solid wood composite floor and its heat transfer model were designed to enable users to have a higher-quality and safe living experience. A heat transfer mathematical model was developed. The structural entity of the composite graphene heating floor was drawn using Solidworks software. The floor structure was abstracted as a two-dimensional model using MATLAB software to obtain the temperature rise curves and corresponding time of each group. Then, six groups of the best data were selected from the experimental data to simulate the heat storage capacity of graphene floors. The optimal group of the model was verified via experiments. According to the simulation, the comprehensive performance was optimal when the overall thickness of the floor was 18 mm, the thickness of the floor surface was 4 mm, and the thickness of the heat-accumulating layer was 2 mm. The experimental results showed a maximum difference between the measured and calculated data of only 3.2%, which shows the scientific validity, accuracy, and advancement of the model. The composite graphene electric heating energy storage floor designed in this study can be regarded as safe, reliable, environmentally friendly, and healthy.

Abstract Bone morphogenetic protein 9 (BMP9), also named as growth differentiation factor 2 (GDF-2), is the strongest cytokine that promotes osteogenic differentiation in the BMP family, and has broad clinical application value. Nevertheless, the mechanism of BMP9 promotes osteogenic differentiation remain unclear. TAZ, a transcriptional co-activator, has great effects on cell proliferation, differentiation, and stem cell self-renewal. In this research, we investigated the effects of TAZ in BMP9-induced osteogenic differentiation of mesenchymal stem cell line C3H10T1/2 (MSCs) and murine multi-lineage cell lines C2C12 and MEFs (MMCs) and explored its possible mechanisms. This study has found that BMP9 induces the expression of TAZ and promotes its nuclear translocation. Meanwhile, our study found that Ad-TAZ and TM-25659, a TAZ agonist, can enhance the osteogenic differentiation of MSCs and MMCs induced by BMP9. Conversely, Ad-si-TAZ and verteporfin, an inhibitor of TAZ, have the contradictory effect. Likewise, the promotion of TAZ to the BMP9-induced ectopic bone formation in vivo was confirmed by the subcutaneous transplantation of MSCs in nude mice. Furthermore, we have detected that TAZ might increase the levels of the phosphorylation of Smad1/5/8, p38, ERK1/2, and JNK induced by BMP9. Additionally, we also found that TAZ increased the total protein level of β-catenin induced by BMP9. In summary, our results strongly indicated that TAZ will promote the osteogenic differentiation in MSCs and MMCs induced by BMP9 through multiple signal pathways.

In this paper, a microheater that can absorb thermal stress and has a large heating area is demonstrated by optimizing the structure and process of the microheater. Four symmetrically distributed elongated support beam structures were machined around the microheater via deep silicon etching. This design efficiently mitigates the deformation of the heated region caused by thermal expansion and enhances the structural stability of the microheater. The updated microheater no longer converts the work area into a thin film; instead, it creates a stable heating platform that can uniformly heat a work area measuring 10 × 10 mm2. The microheater is verified to have high temperature uniformity and structural stability in finite element simulation. Finally, thorough investigations of electrical–thermal–structural characterization were conducted. The test findings show that the new microheater can achieve 350 °C with a power consumption of 6 W and a thermal reaction time of 22 s. A scan of its whole plane reveals that the surface of the working area of the new microheater is flat and does not distort in response to variations in temperature, offering good structural stability.

ABSTRACT Objective We investigated the characteristics and factors influencing eye emotion recognition in self‐limited epilepsy patients with centrotemporal spikes (SeLECTS) complicated with electrical status epilepticus during sleep (ESES). Methods We selected SeLECTS (n = 160) patients treated in the outpatient and inpatient departments of Anhui Children's Hospital from September 2020 to January 2022. According to the video electroencephalogram monitoring slow‐wave index (SWI), SeLECTS patients with SWI

BackgroundDiffuse large B-cell lymphoma (DLBCL) is a kind of highly heterogeneous non-Hodgkin lymphoma, both in clinical and genetic terms. DLBCL is admittedly categorized into six subtypes by genetics, which contain MCD, BN2, EZB, N1, ST2, and A53. Dyslipidemia is relevant to a multitude of solid tumors and has recently been reported to be associated with hematologic malignancies. We aim to present a retrospective study investigating dyslipidemia in DLBCL based on the molecular subtypes.ResultsThis study concluded that 259 patients with newly diagnosed DLBCL and their biopsy specimens were available for molecular typing. Results show that the incidence of dyslipidemia (87.0%, p

Abstract A novel recombinant SIRPα-Fc fusion protein, IMM01, was constructed and produced using an in-house developed CHO-K1 cell expression system, and the anti-tumor mechanism of IMM01 targeting the CD47-SIRPα pathway was explored. The phagocytosis and in vitro anti-tumor activity of IMM01 were evaluated by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) assays. In vivo mouse tumor model studies were used to explore therapeutic efficacy as well as the mechanism of action. An in vitro binding assay revealed that IMM01 has a strong binding affinity to CD47 with an EC50 of 0.4967 nM. IMM01 can induce strong ADCP and moderate ADCC, but not CDC. IMM01-induced strong phagocytosis against tumor cells was attributed to dual activities of blocking the "don’t eat me" signal and activating the "eat me" signal, and IMM01 exhibits strong and robust in vivo anti-tumor activities either as monotherapy on hematological malignancies, or in combination therapy with PD-L1 monoclonal antibody (mAb), PD-1 mAb, and HER-2 mAb on solid tumors. Finally, IMM01 demonstrated a favorable safety profile with no human RBC binding activity or hemagglutination induction. IMM01 inhibits the growth of tumor cells by the following three possible mechanisms: (1) directly activating macrophages to phagocytize tumor cells; (2) activated macrophages degrade phagocytized tumor cells and present tumor antigens to T cells through MHC molecules to activate T cells; (3) activated macrophages can convert "cold tumors" into "hot tumors" and increase the infiltration of immune cells through chemotaxis by secreting some cytokines and chemokines.

Pancreatitis is one of the most common inflammatory diseases of the pancreas caused by autodigestion induced by excessive premature protease activation. However, recognition of novel pathophysiological mechanisms remains a still challenge. Both genetic and environmental factors contribute to the pathogenesis of pancreatitis, and the gut microbiota is a potential source of an environmental effect. In recent years, several new frontiers in gut microbiota and genetic risk assessment research have emerged and improved the understanding of the disease. These investigations showed that the disease progression of pancreatitis could be regulated by the gut microbiome, either through a translocation influence or in a host immune response manner. Meanwhile, the onset of the disease is also associated with the heritage of a pathogenic mutation, and the disease progression could be modified by genetic risk factors. In this review, we focused on the recent advances in the role of gut microbiota in the pathogenesis of pancreatitis, and the genetic susceptibility in pancreatitis.

Abstract The combination of rituximab, lenalidomide, and Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib, followed by chemotherapy, has shown high efficacy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) in Smart Start trial. We aimed to evaluate the efficacy, safety of SMART (rituximab + lenalidomide + BTKi) regimen and SMART–START regimen as a first-line treatment in elderly or unfit DLBCL patients. 31 patients were included, 17 used SMART regimen, with median age 82 years, 14 unfit patients received SMART–START regimen. 14/16 (87.5%) patients in SMART group achieved overall response (OR), with 10/16 (62.5%) achieved complete response (CR). 12/13 (92.3%) patients in SMART–START group achieved OR, with 8/13 (61.5%) achieved CR. With a median follow-up of 15.4 (3–29.1) months, median progression-free survival (PFS) and overall survival (OS) have not been reached, 1-year PFS was 81% in SMART group and 84% in SMART–START group. Common grade 3–4 adverse events (AEs) during SMART regimen were neutropenia (8 [25.8%]), infection (6 [19.4%]) and skin rash (3 [9.7%]). Our study shows that SMART regimen is an effective and safe therapy for elderly DLBCL patients, and SMART–START regimen can be used in unfit patients who could not tolerate intensive chemotherapy in the onset.

Abstract Background Mesenchymal stem cell (MSC) therapy has been shown to be a promising option for liver fibrosis treatment. However, critical factors affecting the efficacy of MSC therapy for liver fibrosis remain unknown. Follistatin-like 1 (FSTL1), a TGF-β-induced matricellular protein, is documented as an intrinsic regulator of proliferation and differentiation in MSCs. In the present study, we characterized the potential role of FSTL1 in MSC-based anti-fibrotic therapy and further elucidated the mechanisms underlying its action. Methods Human umbilical cord-derived MSCs were characterized by flow cytometry. FSTL1low MSCs were achieved by FSTL1 siRNA. Migration capacity was evaluated by wound-healing and transwell assay. A murine liver fibrotic model was created by carbon tetrachloride (CCl4) injection, while control MSCs or FSTL1low MSC were transplanted via intravenous injection 12 weeks post CCl4 injection. Histopathology, liver function, fibrosis degree, and inflammation were analysed thereafter. Inflammatory cell infiltration was evaluated by flow cytometry after hepatic nonparenchymal cell isolation. An MSC-macrophage co-culture system was constructed to further confirm the role of FSTL1 in the immunosuppressive capacity of MSCs. RNA sequencing was used to screen target genes of FSTL1. Results FSTL1low MSCs had comparable gene expression for surface markers to wildtype but limited differentiation and migration capacity. FSTL1low MSCs failed to alleviate CCl4-induced hepatic fibrosis in a mouse model. Our data indicated that FSTL1 is essential for the immunosuppressive action of MSCs on inflammatory macrophages during liver fibrotic therapy. FSTL1 silencing attenuated this capacity by inhibiting the downstream JAK/STAT1/IDO pathway. Conclusions Our data suggest that FSTL1 facilitates the immunosuppression of MSCs on macrophages and that guarantee the anti-fibrotic effect of MSCs in liver fibrosis.

Abstract In order to promote the development of environmental protection, and the usage rate of green energy utilization, a progressive, innovative laser process method employing helium assisted is proposed, which optimizes the joint cutting process under the same energy consumption. This method provides a new idea for the wood process industry. The uniqueness of this paper establishes a mathematical model to address the diffusion of helium injection and the heat transfer of the laser beam on the processed surface. From the results, it can be exhibited that the oxygen concentration reduces when the helium is injected on the processed surface. The helium could destroy the combustion-supporting conditions and decrease the combustion zone of the processed joint cutting. Thus, the carbonized area of the processed surface is reduced, which could effectively enhance the processing quality of joint cutting. Notably, the helium with injection speed forms a sweeping effect on the processed surface, which could remove parts of the carbonized particles and residues on the processed surface, as well as improve the processing quality. Comparing the traditional laser process and helium-assisted laser process, the gas-assisted laser process owns higher process quality than that of traditional laser processing and cutting. In detail, it features the advantages of smaller joint cutting width, lower surface roughness and smoother surface. Eventually, a mathematical model based on the response surface method with the evaluation criteria of the kerf width, kerf depth, and surface roughness is established to analyze the interaction of laser power, cutting speed and inert gas pressure on the response factors. Comparing the error between the predicted and experimental measurement value, and the optimized process parameters could be acquired. In this paper, the helium-assisted laser process method proposed is meaningful and encouraging, which not only obtains better processing quality, but also provides a guide for developing green industry.

Abstract Human peripheral blood mononuclear cells (PBMCs) originate from hematopoietic stem cells in the bone marrow, which mainly includes lymphocytes (T cells, B cells, and natural killer cells) and monocytes. Cryopreserved PBMCs providing biobank resources are crucial for clinical application or scientific research. Here, we used flow cytometry to explore the influence of long-term cryopreservation on the quality of PBMCs with the aim of providing important evidence for the effective utilization of biobank resources. The PBMCs were isolated from the peripheral blood, which was collected from volunteers in the hospital. After long-term cryopreservation in liquid nitrogen, we analyzed the changes in cell numbers, viability, and multiple subtypes of PBMCs and studied the apoptosis, proliferation, activation, function, and status of T cells in comparison with freshly isolated PBMCs by flow cytometry, and then further tracked the effects of long-term cryopreservation on the same sample. Although the different cell types in the PBMCs dynamically changed compared with those in the freshly isolated samples, PBMC recovery and viability remained stable after long-term cryopreservation, and the number of most innate immune cells (e.g., monocytes and B cells) was significantly reduced compared to that of the freshly isolated PBMCs or long-term cryopreserved PBMCs; more importantly, the proportion of T cell subtypes, apoptosis, proliferation, and functional T cells, except for Tregs, were not affected by long-term cryopreservation. However, the proportions of activated T, naïve T, central memory T, effector T, and effector memory T cells dynamically changed after long-term cryopreservation. This article provides important evidence for the effective utilization of biobank resources. Long-term cryopreserved PBMCs can be partly used as biological resources for clinical research or basic studies, but the effect of cryopreservation on PBMCs should be considered when selecting cell samples, especially in research relating to activating or inhibiting function.

Ornamental breeding has traditionally focused on improving novelty, yield, quality, and resistance to biotic or abiotic stress. However, achieving these goals has often required laborious crossbreeding, while precise breeding techniques have been underutilized. Fortunately, recent advancements in plant genome sequencing and editing technology have opened up exciting new frontiers for revolutionizing ornamental breeding. In this review, we provide an overview of the current state of ornamental transgenic breeding and propose four promising breeding strategies that have already proven successful in crop breeding and could be adapted for ornamental breeding with the help of genome editing. These strategies include recombination manipulation, haploid inducer creation, clonal seed production, and reverse breeding. We also discuss in detail the research progress, application status, and feasibility of each of these tactics.

IntroductionThe study aimed to explore the association of serum 25(OH)D3 and hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients and to determine whether the effect of vitamin D (VD) is mediated by activation of the peroxisome proliferator-activated receptor α (PPARα) pathway.MethodsThe study contained a case-control study, in vivo and in vitro experiments. A case-control study was conducted to compare serum parameters between NAFLD patients and controls and to evaluate the association of 25(OH)D3 and NAFLD. In vivo study, male Wistar rats were randomly divided into control and model groups, fed a standard chow diet and a high-fat diet (HFD), respectively, for 7 weeks to generate an NAFLD model. Then, the rats were treated with VD and a PPARα antagonist (MK886) for 7 weeks. Tissue and serum were collected and assessed by biochemical assays, morphological analysis, histological analysis, and western blot analysis. In vitro, HepG2 cells were incubated with oleic acid (OA) to induce steatosis, which was evaluated by staining. HepG2 cells were pretreated with MK886 followed by calcitriol treatment, and differences in lipid metabolism-related proteins were detected by western blot.ResultsNAFLD patients were characterized by impaired liver function, dyslipidemia, and insulin resistance. Serum 25(OH)D3 was negatively associated with alanine aminotransferase (ALT) in NAFLD. VD deficiency was a risk factor for patients with no advanced fibrosis. Adequate VD status (25(OH)D3 >20 ng/mL) had a protective effect in patients after adjustment for confounding variables. NAFLD rats showed hyperlipidemia with severe hepatic steatosis, systematic inflammation, and lower serum 25(OH)D3. VD treatment ameliorated hepatic steatosis both in NAFLD rats and OA-induced HepG2 cells. Further, MK886 inhibited the anti-steatosis effect of VD.ConclusionThe study revealed that an adequate VD level may act as a protective factor in NAFLD and that VD may alleviate hepatic steatosis via the PPARα signaling pathway.

IntroductionSelenium (Se) is an essential trace element required for proper human and animal health.MethodsIn this paper, we investigated the uptake and distribution characteristics of a new Se fertilizer, which comprises algal polysaccharides–selenium nanoparticles (APS-SeNPs), in rice plants in both hydroponic and pot experiments.ResultsThe results from the hydroponic experiments revealed that the rice root uptake of APS-SeNPs fitted the Michaelis–Menten equation, with a Vmax of 13.54 μg g−1 root dry weight (DW) per hour, which was 7.69 and 2.23 times those of selenite and selenate treatments, respectively. The root uptake of APS-SeNPs was inhibited by AgNO3 (64.81%–79.09%) and carbonyl cyanide 3-chlorophenylhydrazone (CCCP; 19.83%–29.03%), indicating that the uptake of APS-SeNPs by rice roots is mainly via aquaporins and is also affected by metabolic activity. Moreover, sulfur deficiency caused rice roots to absorb more APS-SeNPs, but treatment with APS-SeNPs increased the expression of the sulfate transporter OsSULTR1;2 in the roots, suggesting that OsSULTR1;2 is probably involved in the uptake of APS-SeNPs. The application of APS-SeNPs significantly increased the Se content in rice plants and the apparent Se uptake efficiency compared with selenate and selenite treatments. Most of the Se in the roots of rice plants was distributed in the cell wall, while it was primarily located in the cytosol in the shoots when treated with APS-SeNPs. The results from the pot experiments indicated that the application of Se enhanced the Se content of each rice tissue. It is worth noting that the Se content in brown rice under APS-SeNP treatment was higher than that under selenite or selenate treatment and was mainly concentrated in the embryo end, with the Se in organic form.DiscussionOur findings provide important insights into the uptake mechanism and the distribution of APS-SeNPs in rice plants.

Bamboo-based fiber composite panel is a new type of composite material with excellent performance. When processing bamboo-based fiber composite panels, the dynamic stability of the circular saw blade affects the surface quality of the product and the life of the machinery and equipment. Sawing heat and vibration characteristics can significantly affect the dynamic stability of circular saw blades. Circular saw blade temperature and vibration characteristics are affected by the processing parameters, and the circular saw blade temperature and vibration characteristics are analyzed by changing the processing parameters. Adopting the thermoset coupling model can be used to analyze the change rule of circular saw blade temperature when sawing bamboo-based fiber composite boards, and at the same time to analyze the change rule of circular saw blade temperature, vibration speed, and vibration acceleration through the use of by CCD experiments. The regression equations for circular saw blade temperature, vibration velocity, and vibration acceleration were derived through the use of ANOVA and significance analysis. The thermoset coupling model predictions agree with the experimental results, and the density of the isotherms is progressively thinner as the temperature is conducted from the serrated region to the body of the saw. Finally, the accuracy of the regression equations for circular saw blade temperature, vibration velocity, and vibration acceleration was checked via error analysis. The temperature change regression equation has the highest fitting accuracy, with an average error of only 1.37%; the vibration velocity and vibration acceleration regression equations have poorer fitting accuracy, with an average error of 9.5% and 11.45%, respectively, but all of them have sufficient accuracy to predict the dynamic stability of circular saw blades. The results of the study can provide some guidance for the innovative design of circular saw blades.

Bamboo-based fiber composites, known as recombinant bamboo, have emerged as a new material in the construction and decoration industry. With its excellent mechanical and ornamental properties, recombinant bamboo is gaining popularity. However, its high hardness and abrasion resistance pose challenges in the milling process. To address this, we conducted an experimental study to investigate the milling machinability of recombinant bamboo. We studied the impact of various factors—fiber angle, feed rate, and spindle speed—on the tangential and normal roughness of milled surfaces. Our findings indicated that increasing the spindle speed within an acceptable range can effectively mitigate issues such as carbonization and endface cracking on a milled surface. Additionally, we developed a prediction model to assess the probability of end splitting in recombinant bamboo. This research aimed to enhance the milling quality of recombinant bamboo, improve control over surface roughness, reduce the likelihood of end splitting, and, ultimately, expand application possibilities.

This study presents a newly developed piezoelectric drive mechanism for the purpose of designing, analyzing, and testing a micro-positioning platform driven by piezoelectric actuators. The platform incorporates a piezoelectric ceramic actuator and a flexible hinge drive and features a symmetrical two-stage lever (STSL) amplification mechanism and a parallelogram output structure. The implementation of this design has led to notable enhancements in the dynamic properties of the platform, thereby eliminating the undesired parasitic displacement of the mechanism. An analytical model describing the fully elastic deformation of the platform is established, which is further verified by finite element simulation. Finally, the static and dynamic performances of the platform are comprehensively evaluated through experiments. A closed-loop control strategy is adopted to eliminate the nonlinear hysteresis phenomenon of the piezoceramic actuator (PEA). The experimental results show that the piezoelectric micro-actuator platform has a motion range of 97.84 μm × 98.03 μm; the output coupling displacement error is less than 1%; the resolutions of the two axes are 8.1 nm and 8 nm, respectively; and the x-axis and y-axis trajectory tracking errors are both 0.6%. The piezoelectric micromotion platform has good dynamic properties, precision, and stability. The design has a wide application potential in the field of micro-positioning.

Abstract Waterjet-Guided Laser (WJGL) machining is an advanced technique providing efficiency and precision for wood machining. The present study investigates the practical demonstration and analysis of laminated object manufacturing (LOM) WJGL for thin wood machining. A theoretical process of wood laser cutting was established, expressing relations between the cut kerf width and the influencing parameters. WJG Nd: YAG laser system was utilized for machining Korean pine and Northeast China ash specimen of 3 mm thickness, each with 7.21 and 7.13% of water content, respectively, under different machining conditions. The effects of process parameters and influences on woodcut surface geometry were analyzed via analysis of variance (ANOVA) and scanning electron microscopy (SEM). The investigated parameters include the laser cutting speed, power, kerf width, heat-affected zone (HAZ), and cut surface roughness. The study shows that the kerf width and surface were significantly influenced by WJGL power, followed by the cutting speed. For both wood specimens, at a fixed laser cutting speed of 2.36 mm/s, the kerf width increases significantly with laser power, affecting the cut surface quality accordingly. At 6 W and 8 W, the cut kerf geometry and surface quality were excellent for the Pinus Koraiensis, with kerf widths of 0.79 and 0.852 mm, respectively. At a fixed laser power of 8 W, the kerf width decreases with the cutting speed, affecting the cut surface quality. At a cutting speed of 4.33 mm/s, an excellent cut surface of Fraxinus mandshurica was observed with 0.808 mm of kerf width. Depending on the machining conditions, the kerf width variations of Korean pine were more significant than the Northeast China ash. LOM-WJGL is an efficient and eco-friendly technique for thin wood processing. Graphical abstract Article Highlights Practical modeling demonstration of waterjet guided laser (WJGL) wood machining. Experimental investigation of different wood specimens under influenced process parameters and machining conditions. Characterization and identification of suitable wood types for efficient and eco-friendly applications.

Although there are many therapeutic strategies such as surgery and chemotherapy, the prognosis of osteosarcoma (OS) is still far from being satisfactory. It is urgent to develop more effective, tolerable and safe drugs for the treatment of OS. In the present study, we investigated the anti-OS activity of Alantolactone (ALT), a natural eucalyptone sesquiterpene lactone mainly exists in Inula helenium, and probed the possible mechanism involved. We demonstrated that ALT significantly inhibited cell proliferation of various human OS cell lines while had relative lower cytotoxicity against normal cells. Then, we validated that ALT reduced migration, decreased invasion possibly through reversing epithelial mesenchymal transition (EMT) process and suppressing Matrix metalloproteinases (MMPs). Moreover, we confirmed that ALT promoted apoptosis and arrested cell cycle at G2/M phase of human OS cells in vitro. In addition, we confirmed that ALT restrained tumor growth and metastasis of OS 143 cells in a xenograft model in vivo. Mechanistically, ALT inhibited the activity of Wnt/β-catenin and p38, ERK1/2 and JNK Mitogen Activated Protein Kinases (MAPKs) signal pathway. Notably, the combination of ALT and Wnt/β-catenin inhibitor, as well as the combination of ALT and MAPKs inhibitors resulted in a synergistically effect on inhibiting the proliferation, migration and invasion of OS cells. Collectively, our results validate the ALT may inhibit proliferation, metastasis and promotes apoptosis of human OS cells possibly through suppressing Wnt/β-Catenin and MAPKs signaling pathways.

Immune checkpoint genes (ICGs) have recently been proven to perform instrumental functions in the maintenance of immune homeostasis and represent a promising therapeutic strategy; however, their expression patterns and prognostic values are not fully elucidated in hepatocellular carcinoma (HCC). In this investigation, we focused on establishing and validating a prognostic gene signature to facilitate decision-making in clinical practice. Clinical information, as well as transcriptome data, was obtained from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox method were employed to build a multi-gene signature in the TCGA database, while the ICGC database was used for validation. Subsequently, utilizing the six-gene signature, we were able to categorize patients into high- and low-risk groups. In two cohorts, survival analysis findings revealed a dismal outlook for the high-risk group. The receiver operating characteristic curves were utilized to estimate the gene signature's prediction ability. Moreover, correlation analysis showed high-risk group was linked to advanced pathological stage, infiltration of immune cells and therapeutic response. In summary, this unique gene profile might serve not only as a useful prognostic indicator but also as a marker of therapy responsiveness in HCC.

Alginate oligosaccharides (AOS) are functional substances in seaweed extracts that regulate crop quality and stress tolerance. In this paper, the effects of AOS spray application on the antioxidant system, photosynthesis and fruit sugar accumulation in citrus was investigated through a two-year field experiment. The results showed that 8-10 spray cycles of 300-500 mg L-1 AOS (once per 15 days) increased soluble sugar and soluble solid contents by 7.74-15.79% and 9.98-15.35%, respectively, from citrus fruit expansion to harvesting. Compared with the control, the antioxidant enzyme activity and the expression of some related genes in citrus leaves started to increase significantly after the 1st AOS spray application, while the net photosynthetic rate of leaves increased obviously only after the 3rd AOS spray cycle, and the soluble sugar content of AOS-treated leaves increased by 8.43-12.96% at harvest. This suggests that AOS may enhance photosynthesis and sugar accumulation in leaves by antioxidant system regulation. Moreover, analysis of fruit sugar metabolism showed that during the 3rd to 8th AOS spray cycles, AOS treatment increased the activity of enzymes related to sucrose synthesis (SPS, SSs), upregulated the expression of sucrose metabolism (CitSPS1, CitSPS2, SUS) and transport (SUC3, SUC4) genes, and promoted the accumulation of sucrose, glucose and fructose in fruits. Notably, the concentration of soluble sugars in citrus fruits was significantly reduced at all treatments with 40% reduction in leaves of the same branch, but the loss of soluble sugars in AOS-treated fruits (18.18%) was higher than that in the control treatment (14.10%). It showed that there was a positive effect of AOS application on leaf assimilation product transport and fruit sugar accumulation. In summary, AOS application may improve fruit sugar accumulation and quality by regulating the leaf antioxidant system, increasing the photosynthetic rate and assimilate product accumulation, and promoting sugar transfer from leaves to fruits. This study shows the potential application of AOS in the production of citrus fruits for sugar enhancement.

The surface roughness of wood has a great influence on its performance and is a very important indicator in processing and manufacturing. In this paper, we use the central composite design experiment (CCD experiment) and artificial neural network (ANN) model to study the changing pattern of surface roughness during the high-speed milling process of pine wood. In the CCD experiments, the spindle speed, feed speed, and depth of cut are used as the influencing factors, and the surface roughness is used as the index to analyze the variation law and fit the surface roughness parameter equation. By measuring the chip size in each group in the CCD experiment, the ANN model is used to predict the surface roughness under this machining parameter by measuring the chip size in each test group. The experimental results showed that the mean error of the surface roughness prediction values in the CCD experiment (12.2%) was larger than that of the ANN model (7.8%), and the mean squared error (MSE) of the ANN model was 0.025, the mean absolute percentage error(MAPE) was 0.01, and the coefficient of determination R2 was 0.95. Compared with the CCD experiment, the ANN model had a higher prediction accuracy. The results of this paper can provide some guidance for the prediction of surface roughness during wood processing.

Background: Natural killer (NK) cells play an indispensable role in anti-tumor immunity. TGF-β1 is the main accomplice of tumor immune escape, inhibiting tumor immunity mediated by NK cells. It is reported that Salvia miltiorrhiza can promote the immune killing effect of NK cells. In this study, Tanshinol, a water-soluble active component of Salvia miltiorrhiza, was used to investigate its effect on the inhibition of NK cell functions mediated by TGF-β1 in breast cancer. Methods: We constructed a mouse model of breast cancer by tail vein injection, H&E staining and ELISA were used to verify the role of TGF-β1 and the effects of Tanshinol on breast cancer and NK cells. In vitro, we used CCK8 and cytotoxicity assays to preliminarily evaluate the effect of Tanshinol on the anti-tumor effect of NK cells intervention by TGF-β1. We explored the killing activity of NK cells and related signal pathways by immunofluorescence imaging technology, RT-PCR, ELISA and flow cytometry. Also, Western blot, RT-PCR and immunofluorescence experiments were applied to investigate the expression level of the natural killer group 2 member D (NKG2D)-NKG2D ligands (NKG2DL) signal axis, and combined with immunoprecipitation, to detect the formation of NKG2D-DNAX-activating protein of 10 kD (DAP10) complex. Results: TGF-β1 played a role in promoting lung metastasis of breast cancer and inhibiting the secretion of cytotoxic mediators from NK cells, but Tanshinol could reverse it. High-dose Tanshinol also significantly optimized the survival rate of tumor-bearing mice. TGF-β1 could destroy the NKG2D-NKG2DL axis, down-regulate the expression and nuclear accumulation of p-smad2/3. Moreover, TGF-β1 inhibited the activation of PI3K-ERK1/2-PLCγ2 signaling pathway that is related to the degranulation of NK cells, and diminished the expression of degranulation marker CD107a and the release of anti-tumor cytotoxic killing medium of NK cells. However, Tanshinol was able to interfere with the negative regulation of TGF-β1 on the functions of NK cells, mainly through promoting the expression of NKG2D and its molecular chaperone DAP10, thereby propelling the formation of NKG2D-DAP10 complex. Conclusions: Collectively, Tanshinol enables NK cells to activate and release multiple killing mediators to carry out immune attacks on tumor cells.

Immunotherapy has been recognized as an effective and important therapeutic modality for multiple types of cancer. Nevertheless, it has been increasing recognized that clinical benefits of immunotherapy are less than expected as evidenced by the fact that only a small population of cancer patients respond favorably to immunotherapy. The structurally and functionally abnormal tumor vasculature is a hallmark of most solid tumors and contributes to an immunosuppressive microenvironment, which poses a major challenge to immunotherapy. In turn, multiple immune cell subsets have profound consequences on promoting neovascularization. Vascular normalization, a promising anti-angiogenic strategy, can enhance vascular perfusion and promote the infiltration of immune effector cells into tumors via correcting aberrant tumor blood vessels, resulting in the potentiation of immunotherapy. More interestingly, immunotherapies are prone to boost the efficacy of various anti-angiogenic therapies and/or promote the morphological and functional alterations in tumor vasculature. Therefore, immune reprograming and vascular normalization appear to be reciprocally regulated. In this review, we mainly summarize how tumor vasculature propels an immunosuppressive phenotype and how innate and adaptive immune cells modulate angiogenesis during tumor progression. We further highlight recent advances of anti-angiogenic immunotherapies in preclinical and clinical settings to solidify the concept that targeting both tumor blood vessels and immune suppressive cells provides an efficacious approach for the treatment of cancer.

Carbon storage services play an important role in maintaining ecosystem stability. Land use/cover change (LUCC) is the dominant factor generating changes in the ecosystem carbon storage. Demonstrating the impact of LUCC on regional carbon storage changes and predicting future carbon storage under different land use scenarios is of great significance for promoting regional carbon peak and carbon neutrality goals. Taking the main urban area of Chongqing as an example, this study analyzes carbon storage changes from 2000 to 2020 and the response to LUCC. The Markov-FLUS model is employed to predict the land use pattern of the main urban area in 2035 under four scenarios, and the InVEST model is used to assess carbon storage in 2035 under different scenarios. The results can be summarized as follows: 1) In the past 20 years, the area of cultivated land in the main urban areas of Chongqing decreased by 743.29 km2, and the area of construction land increased by 773.48 km2. About 18.8 % of the main urban area of Chongqing was transferred, the conversion of cultivated land to construction land being the most important type of transfer. 2) In 2000, 2005, 2010, 2015, and 2020, the carbon storage in the main urban area was 59.85, 59.29, 57.90, 56.95, and 54.07 Tg, respectively, showing an annually decreasing trend with a cumulative decrease of 5.78 Tg. The cultivated land occupation by construction land is the leading factor for the rapid decrease of carbon storage. The spatial distribution of carbon storage in the main urban area differs significantly, exhibiting a low in the middle and high in the surrounding areas. 3) In 2035, the carbon storage in the main urban area shows different degrees of decline in the Natural Trend Scenario (NTS), the Food Security Scenario (FSS) and the High Urbanization Scenario (HUS), decreasing by 3.37, 0.59, and 5.25 Tg, respectively. The only increase by 1.51 Tg is found in the Ecological Security Scenario (ESS). Therefore, under the background of the “Dual Carbon” targets and the important positioning of Chongqing as an important ecological barrier in the Yangtze River Basin, the ESS can be considered in the future development planning of the main urban area of Chongqing, which can both increase carbon sink and ensure ecological security.

Population aging has become a severe issue facing most nations and areas worldwide—with Hong Kong being no exception. For older adults, walking is among the most well-liked travel modes, boosting their overall health and wellbeing. Some studies have confirmed that the built environment has a significant (spatially fixed) influence on older adults' walking behavior. However, little consideration has been given to the potential spatial heterogeneity in such influences. Hence, this study extracted data on older adults' (outdoor) walking behavior from the 2011 Hong Kong Travel Characteristics Survey and measured a series of built environment attributes based on geo-data (e.g., Google Street View imagery). Logistic regression and geographically weighted logistic regression models were developed to unveil the complicated (including spatially fixed and heterogeneous) association between the built environment and older adults' propensity to walk. We show that population density, land-use mix, street greenery, and access to bus stops are positively connected with the propensity to walk of older adults. Intersection density seems to impact walking propensity insignificantly. All built environment attributes have spatially heterogeneous effects on older adults' walking behavior. The percentage of deviance explained is heterogeneously distributed across space.

The pandemic has impacted various industries, including the sports industry. However, corporate social responsibility (CSR) can mitigate the adverse effects of the crisis and promote the sports industry. To analyze the effect of CSR, the study examined the impact of perceived corporate social responsibility on injury prevention expectation, injury risk perception, and health up-gradation with the mediation of sports safety measures. There are 259 sportsmen of local sports bodies provided the data through a self-administered survey. Data analysis was conducted through Smart-PLS and SEM techniques. The outcome of the analysis showed that perceived corporate social responsibility leads to injury prevention expectation, injury risk perception, and health up-gradation. Also, the study found that sports safety measure mediates the relationship between perceived corporate social responsibility and injury prevention expectation, between perceived corporate social responsibility and injury risk perception, and between perceived corporate social responsibility and health up-gradation among sportsmen of local sports bodies. The theoretical implications were presented related to the significance of CSR and sports safety measure and their impact on sportsmen injury prevention expectation, health, and risk perception. The practical implications were related to the management of local sports bodies and how they can induce CSR initiatives and programs. Some limitations related to sample size, incorporating other variables, examining the model in other contexts, and using different study designs, have also been mentioned in the study.

Osteosarcoma (OS) is the most common primary malignant bone tumor with high lung metastasis and mortality rate. Neo-adjuvant chemotherapy combined with limb salvage is the main treatment strategy for OS. However, because of the tolerance to conventional chemotherapy and the cell toxicity of chemotherapy drugs, new drugs with lower toxicity for OS are urgently needed. Acacetin is a natural flavonoid compound that has inhibitory effects on many kinds of tumors. Herein, we explored the impact of acacetin on OS cell growth in vitro and in vivo. We discovered that acacetin suppressed the proliferation, migration and invasion, while promoted the apoptosis of OS cells. Notably, acacetin had little impact on proliferation and apoptosis of human normal cells. Furthermore, we confirmed that acacetin repressed the growth and metastasis of OS in xenograft mouse model in vivo. Mechanically, we discovered that acacetin activated JNK pathway and inactivated Wnt/β-catenin pathway. β-catenin over-expression or JNK inhibitor SP600125 was able to partially neutralize acacetin-induced inhibitory effect on OS cells. To sum up, our study implies that acacetin may inhibit tumor growth of human OS cells through regulating Wnt/β-catenin and JNK signaling pathways.

The intermittent hole-digging tree-planting machine shows a periodic short-time peak load law in planting operation, and the operation process is “idling” for small loads most of the time, leading to large torque fluctuations in the transmission system, unscientific power matching, and high energy consumption. To solve the above problems, this article proposes to use a series of energy-saving flywheels in the transmission system of the tree planting machine. On the premise of obtaining holes that meet the target young tree planting requirements, the optimal power compensation strategy for the flywheel system of the tree planting machine is studied to reduce torque fluctuations in the power transmission system, use smaller power drive units, and save energy. Firstly, the nonlinear multi-body dynamics simulation model of soil cutting by the hole-digging component is established. The boundary and contact conditions are set to simulate the power consumption of the hole-digging component at three rotating speeds. Based on the simulation results, the flywheel power compensation strategy is discussed, and the torque fluctuation of the flywheel balance system is analyzed. The results showed that the higher the speed, the greater the power consumption. The power value suddenly increased from 17.82 kW (1.28 s) to 27.93 kW (1.43 s) when the speed was 220 r/min. Then, the power value rapidly decreased, and the power consumption presented a short-term peak feature. The transmission system’s maximum input power is determined as 17.82 kW according to the various simulated power consumption characteristics. The part exceeding the power consumption is compensated by the energy storage flywheel. The total compensation energy was 2382.5 J. After the flywheel system was involved, the maximum output power of the tractor power output shaft decreased by 36.2%, and the peak torque decreased from 445.7 N·m to 285.1 N·m. The power consumption obtained from the field test and simulation was similar, but the energy required to overcome peak load was jointly provided by the flywheel and the engine. The actual input power of the power output shaft during the energy release period of the flywheel system was 18.51 kW when the rotating speed of the hole-digging component was 220 r/min, and the relative error with the simulation value was 2.43%. The measured actual speed reduction of the flywheel system was 8.9%. After installing an energy storage flywheel in the transmission system of the tree planting machine, the output power of the power unit can be stabilized. Tree planting machines can be equipped with smaller power units, which can reduce energy consumption and exhaust emissions.

Circumferential milling is used in wood processing, yet it generates vast quantities of dust and chips in a single pass, highlighting the need to predict chip dispersion and prevent associated hazards. This article presents findings from a theoretical and experimental analysis of chip size and kinematics of pine wood during cutting. A chip diffusion boundary surface model was established and its key parameters were determined through CCD testing. Results reveal that chip diffusion can be divided into three distinct areas based on motion state: main diffusion, random diffusion, and vortex. Notably, spindle speed and feed rate are most influential on the orthogonal diffusion angle of the main diffusion zone, whereas cutting depth most heavily impacts the top view diffusion angle. Chip scattering on the table showed an exponential increase in average chip size with sampling distance, whereas the boundary surface model accurately characterizes chip motion and demonstrates a reasonable degree of reliability, offering potential in predicting chip morphology and diffusion state. This model has important implications for wood milling practices, particularly in controlling chip dispersion.

This paper investigated the fracture toughness and enhancement mechanism for each component in bamboo-based composites at the cellular level. In situ characterization techniques identified the fracture behaviors of bamboo-based composites in three-point bending tests, and scanning electron microscope (SEM) further visualized the crack propagation of the fracture surface. In addition, the improvement mechanism of bamboo-based composites was illustrated by mechanical properties at the cellular level assisted with nanoindentation tests. Our in situ test results showed that the bamboo-based composites exhibited a longer deformation and higher bending load compared with bamboo. The fracture was non-catastrophic, and crack propagated in a tortuous manner in bamboo-based composites. Microstructural analysis revealed that phenol-formaldehyde (PF) resin pulled out and middle lamella (ML) breaking rather than transverse transwall fracturing occurred in parenchymal cells. The higher density of fibers in the bamboo-based composites triggered massive interfacial delamination in the middle lamella (ML), which was a weak mechanical interface. Furthermore, indented modulus and hardness illustrated that phenol-formaldehyde (PF) resin improved the mechanical strength of cell walls, especially parenchymal cells. The crosslinks of PF resin with the cell walls and massive fibers were the primary mechanisms responsible for the fracture toughness of bamboo-based composites, which could be helpful for advanced composites.

Gypsophila paniculata is one of the most popular cut flowers in the world whose major cultivars are blooming white. As is well known, blue flowers could be generated via the overexpression of the gene encoding flavonoid 3′5′-hydroxylase (F3′5′H) in species that naturally lack it. In this study, we established the regeneration and a genetic transformation system for the commercial cultivar ‘YX4’ of G. paniculata and introduced the F3′5′H of Platycodon grandiflorus (PgF3′5′H) successfully into ‘YX4’ using the established protocol. A total of 281 hygromycin (Hyg)-resistant plantlets were obtained, and 38 of them were polymerase chain reaction (PCR) positive, indicating a 13.5% transformation efficiency. Shoot apex without meristem was more suitable for explant due to its high regeneration capacity, and the supplement of thidiazuron (TDZ) provided the most efficient promotion of adventitious bud induction, whereas the supplement of 6-Benzyladenine (6-BA) and 1-naphthaleneacetic acid (NAA) did not affect much. Additionally, the combination of 1 day (d) pre-culture, 5 d co-culture, 10 min infection, 30 mg·L−1 additional acetosyringone (AS) supplement, and 10 mg·L−1 Hyg selection formed the optimized system for ‘YX4’ transformation. This reliable and efficient agrobacterium-mediated transformation of the valuable commercial cultivar ‘YX4’ will contribute not only to the creation and improvement of G. paniculata cultivars, but also to the function research of genes associated with important ornamental traits.