Nanoplastics induced health risk: Insights into intestinal barrier homeostasis and potential remediation strategy by dietary intervention.

Aged nanoplastics (aged-NPs) have unique characteristics endowed by environmental actions, such as rough surface, high oxygen content. Although studies have highlighted the potential hazards of aged-NPs, limited research has provided strategies for aged-NPs pollution remediation. The dietary intervention of quercetin is a novel insight to address the health risks of aged-NPs. This study explored the impact of aged-NPs on intestinal barrier homeostasis at the environmentally relevant dose and investigated the alleviating effects of quercetin on aged-NPs toxicity through transcriptomics and molecular biology analysis. It indicated that aged-NPs induced intestinal barrier dysfunction, which was characterized by higher permeability, increased inflammation, and loss of epithelial integrity, while quercetin restored it. Aged-NPs disrupted redox homeostasis, upregulated inflammatory genes controlled by AP-1, and led to Bax-dependent mitochondrial apoptosis. Quercetin intervention effectively mitigated inflammation and apoptosis by activating the Nrf2. Thus, quercetin decreased intestinal free radical levels, inhibiting the phosphorylation of p38 and JNK. This study unveiled the harmful effects of aged-NPs on intestinal homeostasis and the practicability of dietary intervention against aged-NPs toxicity. These findings broaden the understanding of the NPs toxicity and provide an effective dietary strategy to relieve the health risks of NPs. ENVIRONMENTAL IMPLICATIONS: Growing levels of NPs pollution have represented severe health hazards to the population. This study focuses on the toxic mechanism of aged-NPs on the intestinal barrier and the alleviating effect of quercetin dietary intervention, which considers the environmental action and relevant dose. It revealed the harmful effects of aged-NPs on intestinal inflammation with the key point of free radical generation. Furthermore, a quercetin-rich diet holds significant promise for addressing and reversing intestinal damage caused by aged-NPs by maintaining intracellular redox homeostasis. These findings provide an effective dietary strategy to remediate human health risks caused by NPs.

Superhydrophobic/ superoleophilic polystyrene-based porous material with superelasticity for highly efficient and continuous oil/water separation in harsh environments.

Three-dimensional separation materials with robust physical/chemical stability have great demand for effective and continuous separation of immiscible oil/water mixtures and water-in-oil emulsions, resulting from chemical leakages and discharge of industrial oily wastewaters. Herein, a superelastic polystyrene-based porous material with superhydrophobicity/superoleophilicity was designed and prepared by high internal phase emulsion polymerization to meet the aforementioned requirements. A flexible and hydrophobic aminopropyl terminated polydimethylsiloxane (NH2-PDMS-NH2) segment was introduced into the rigid styrene-divinylbenzene copolymer through 1, 4-conjugate addition reaction with trimethylolpropane triacrylate. The addition of NH2-PDMS-NH2 simultaneously improved the mechanical and hydrophobic properties of the porous material (the water contact angle from 141.2° to 152.2°). The material exhibited outstanding reversible compressibility (80% strain, even in liquid N2 environments) and superhydrophobic stability, even after being repeatedly compressed 100 times, water contact angle still remained above 150°. Meanwhile, the as-prepared material had outstanding hydrophobic stability in corrosive solutions (strong acidic, alkaline, high-salty, and even strong polar solvent), presence of mechanical interference, strong UV radiations, and high/low temperature environments. More importantly, the material could continuously and efficiently separate immiscible oil/water mixture and water-in-oil emulsions under the above conditions, showing huge potential for the large-scale remediation of complex oily wastewaters.

Multicomponent qualitative and quantitative analysis of Farfarae Flos in serum using UHPLC-Q TOF-MS.

Farfarae Flos is a traditional herb widely employed for treating coughs, bronchitis, and asthmatic disorders. In the current study, we utilized SWATH and IDA data acquisition modes in combination with multiple data processing techniques to identify Farfarae Flos metabolites in mice serum. A total of 56 compounds were characterized, including 31 phenolic acids, 13 flavonoids, 11 sesquiterpenoids and 1 alkaloid. Further quantitative analysis was conducted on 12 absorbed metabolites, utilizing a newly developed and rigorously validated analytical method. Our approach demonstrated an acceptable level of specificity, accuracy, precision, and stability. When applied to compare the serum of mice treated with FF, all 12 metabolites showed the highest concentration at 0.5 h. Overall, this study presented a novel strategy for unraveling the active compounds of FF via serum pharmacochemistry analysis, which made a foundation for exploring the pharmacodynamic material basis of FF.

KIr4O8 Nanowires with Rich Hydroxyl Promote Oxygen Evolution Reaction in Proton Exchange Membrane Water Electrolyzer.

The sluggish kinetics for anodic oxygen evolution reaction (OER) and insufficient catalytic performance over the corresponding Ir-based catalysts are still enormous challenges in proton exchange membrane water electrolyzer (PEMWE). Herein, we report that KIr4O8 nanowires anode catalyst with more exposed active sites and rich hydroxyl achieves a current density of 1.0 A/cm2 at 1.68 V and possesses excellent catalytic stability with 1230 h in PEMWE. Combining in situ Raman spectroscopy and differential electrochemical mass spectroscopy results, we propose the modified adsorbate evolution mechanism that rich hydroxyl in the inherent structure of KIr4O8 nanowires directly participates in the catalytic process for favoring the OER. Density functional theory calculation results further suggest that the enhanced proximity between Ir (d) and O (p) band center in KIr4O8 can strengthen the covalence of Ir-O, facilitate the electron transfer between adsorbents and active sites, and decrease the energy barrier of rate-determining step from OH* to O* during the OER. This article is protected by copyright. All rights reserved.

ROS-responsive thermosensitive polypeptide hydrogels for localized drug delivery and improved tumor chemoimmunotherapy.

In this study, we developed a ROS-responsive thermosensitive poly(ethylene glycol)-polypeptide hydrogel loaded with a chemotherapeutic drug, doxorubicin (Dox), an antiviral imidazoquinoline, resiquimod (R848), and antibody targeting programmed cell death protein 1 (aPD-1) for local chemoimmunotherapy. The hydrogel demonstrated controllable degradation and sustained drug release behavior according to the concentration of ROS in vitro. Following intratumoral injection into mice bearing B16F10 melanoma, the Dox/R848/aPD-1 co-loaded hydrogel effectively inhibited tumor growth, prolonged animal survival time and promoted anti-tumor immune responses with low systemic toxicity. In the postoperative model, the Dox/R848/aPD-1 co-loaded hydrogel exhibited enhanced tumor recurrence prevention and long-term immune memory effects. Thus, the hydrogel-based local chemoimmunotherapy system demonstrates potential for effective anti-tumor treatment and suppression of tumor recurrence.

Ferumoxytol-enhanced MR venography for mapping lower-extremity venous networks and evaluating varicose veins in patients with diabetes.

OBJECTIVES: Comprehensive evaluation of lower-extremity varicose veins (VVs) in patients with diabetes is crucial for treatment strategizing. The study aims to assess the feasibility of using ferumoxytol-enhanced MR venography (FE-MRV) for lower-extremity venous mapping and the detection of VVs in patients with diabetes. MATERIALS AND METHODS: As part of a phase II clinical trial of a generic brand of ferumoxytol, documented patients with diabetes were enrolled and underwent FE-MRV on a 3-Τ MRI system. Two observers assessed FE-MRV images for image quality, signal intensity ratio (SIR), perforator (PV) diameter, and luminal signal uniformity in deep-to-superficial venous networks with the assessment of intra- and inter-rater reliability. FE-MRV was used to detect lower-extremity VVs. RESULTS: Eleven patients underwent FE-MRV without adverse events. The average image quality, as scored by the two observers who assessed 275 venous segments, was 3.4 ± 0.6. Two observers strongly agreed on image quality (κ = 0.90) and SIR measurements (interclass correlation coefficient [ICC]: 0.72) and had good agreement on PV diameter (ICC: 0.64). FE-MRV revealed uniform luminal signals in deep and saphenous venous networks (0.13 ± 0.05 vs 0.08 ± 0.03). Below-knee segments exhibited a significantly higher heterogeneity index than above-knee (p = 0.039) segments. Superficial VVs were observed in 55% (12/22) of legs in 64% (7/11) of patients. Calf muscle VVs were present in 64% (14/22) of legs in 9 patients. CONCLUSION: FE-MRV safely and robustly mapped entire lower-extremity venous networks, enabling the detection and pre-treatment evaluation of both superficial, and deep VVs in patients with diabetes. CLINICAL RELEVANCE STATEMENT: Ferumoxytol-enhanced magnetic resonance venography offers a "one-stop" imaging strategy for the detection and pre-operative evaluation of both superficial and deep VVs in diabetic patients. KEY POINTS: Diabetic patients with VVs are at a higher risk of ulcer-related complications. FE-MRV allowed rapid and comprehensive visualization of the lower-limb venous networks and abdominopelvic veins in diabetic patients. This technique allowed for the detection of superficial and deep VVs in diabetic patients before the development of severe peripheral artery disease.

Intercropping with maize and sorghum-induced saikosaponin accumulation in Bupleurum chinense DC. by liquid chromatography-mass spectrometry-based metabolomics.

Bupleuri Radix is an important medicinal plant, which has been used in China and other Asian countries for thousands of years. Cultivated Bupleurum chinense DC. (B. chinense) is the main commodity of Bupleuri Radix. The benefits of intercropping with various crops for B. chinense have been recognized; however, the influence of intercropping on the chemical composition of B. chinense is still unclear yet. In this study, intercropping with sorghum and maize exhibited little effect on the root length, root diameter, and single root mass of B. chinense. Only the intercropping with sorghum increased the root length of B. chinense slightly compared to the monocropping. In addition, 200 compounds were identified by UHPLC-Q-TOF-MS, and metabolomic combined with the Venn diagram and heatmap analysis showed apparent separation between the intercropped and monocropped B. chinense samples. Intercropping with sorghum and maize could both increase the saikosaponins, fatty acyls, and organic acids in B. chinense while decreasing the phospholipids. The influence of intercropping on the saikosaponin biosynthesis was probably related with the light intensity and hormone levels in B. chinense. Moreover, we found intercropping increased the anti-inflammatory activity of B. chinense. This study provides a scientific reference for the beneficial effect of intercropping mode of B. chinense.

Structural Characterization and Screening for Anti-inflammatory Activity of Polysaccharides with Different Molecular Weights from Astragali Radix.

Astragali Radix polysaccharides (APSs) exhibit a broad spectrum of biological activity, which is mainly related to immune regulation. At present, most available studies focus on total APSs or a certain component of APSs. However, structural structure study and screening for the anti-inflammatory activity of polysaccharides with different molecular weights (MW) have yet to be conducted. In this study, lipopolysaccharide (LPS)-induced RAW264.7 macrophages were used as a model to investigate the anti-inflammatory activity of APSs and its fractions. The results revealed that fraction APS-I had better anti-inflammatory effects than APS-II. After APS-Ⅰ was hydrolyzed by trifluoroacetic acid (TFA), the resulting degradation products oligosaccharides were fully methylated. These derivatized oligosaccharides were further analyzed by MALDI-TOF-MS and UPLC-Q-Exactive-MS/MS. The results showed that APS-Ⅰ was a hetero-polysaccharide with a molecular weight of about 2.0 × 106 Da, mainly consisting of glucose (46.8%) and galactose (34.4%). The degree of polymerization of Astragali Radix oligosaccharides (APOS) was 2-16. APOS were identified as 1,4-glucooligosaccharides and 1,4-galactooligosaccharides. The findings of this study lay the foundation for further elucidation of structure-function relationships of APSs and provide guidance for the development of anti-inflammatory drugs.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia.

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

Engineering Spin Polarization of the Surface-Adsorbed Fe Atom by Intercalating a Transition Metal Atom into the MoS2 Bilayer for Enhanced Nitrogen Reduction.

The precise control of spin states in transition metal (TM)-based single-atom catalysts (SACs) is crucial for advancing the functionality of electrocatalysts, yet it presents significant scientific challenges. Using density functional theory (DFT) calculations, we propose a novel mechanism to precisely modulate the spin state of the surface-adsorbed Fe atom on the MoS2 bilayer. This is achieved by strategically intercalating a TM atom into the interlayer space of the MoS2 bilayer. Our results show that these strategically intercalated TM atoms can induce a substantial interfacial charge polarization, thereby effectively controlling the charge transfer and spin polarization on the surface Fe site. In particular, by varying the identity of the intercalated TM atoms and their vacancy filling site, a continuous modulation of the spin states of the surface Fe site from low to medium to high can be achieved, which can be accurately described using descriptors composed of readily accessible intrinsic properties of materials. Using the electrochemical dinitrogen reduction reaction (eNRR) as a prototypical reaction, we discovered a universal volcano-like relation between the tuned spin and the catalytic activity of Fe-based SACs. This finding contrasts with the linear scaling relationships commonly seen in traditional studies and offers a robust new approach to modulating the activity of SACs through interfacial engineering.

Maternal methylosome protein 50 is essential for embryonic development in medaka Oryzias latipes.

Methylosome protein 50 (Mep50) is a protein that is rich in WD40 domains, which mediate and regulate a variety of physiological processes in organisms. Previous studies indicated the necessity of Mep50 in embryogenesis in mice Mus musculus and fish. This study aimed to further understand the roles of maternal Mep50 in early embryogenesis using medaka Oryzias latipes as a model. Without maternal Mep50, medaka zygotes developed to the pre-early gastrula stage but died later. The transcriptome of the embryos at the pre-early gastrula stage was analyzed by RNA sequencing. The results indicated that 1572 genes were significantly upregulated and 741 genes were significantly downregulated in the embryos without maternal Mep50. In the differentially expressed genes (DEGs), the DNA-binding proteins, such as histones and members of the small chromosome maintenance complex, were enriched. The major interfered regulatory networks in the embryos losing maternal Mep50 included DNA replication and cell cycle regulation, AP-1 transcription factors such as Jun and Fos, the Wnt pathway, RNA processing, and the extracellular matrix. Quantitative RT-PCR verified 16 DEGs, including prmt5, H2A, cpsf, jun, mcm4, myc, p21, ccne2, cdk6, and col1, among others. It was speculated that the absence of maternal Mep50 could potentially lead to errors in DNA replication and cell cycle arrest, ultimately resulting in cell apoptosis. This eventually resulted in the failure of gastrulation and embryonic death. The results indicate the importance of maternal Mep50 in early embryonic development, particularly in medaka fish.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial.

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Robot-Assisted Radical Nephroureterectomy Using the KangDuo Surgical Robot-01 System: A Prospective, Single-Center, Single-Arm Clinical Study.

PURPOSE: To investigate the feasibility, safety, and efficacy of the KangDuo Surgical Robot-01 (KD-SR-01) system for robot-assisted radical nephroureterectomy (UTUC). MATERIALS AND METHODS: This prospective, single-center, single-arm clinical study of patients with UTUC was conducted from August 2022 to July 2023 using the KD-SR-01 system. The perioperative and follow-up data were prospectively recorded. The National Aeronautics and Space Administration Task Load Index was calculated to present ergonomics. The technique was described in detail. RESULTS: A total of 13 patients underwent RARNU. None of the cases conversed to laparoscopic surgery or open surgery. The median docking time and console time were 524 (range, 139-963) seconds and 102.2 (range, 55.3-249.3) minutes, respectively. The median estimated blood loss was 40 (range, 10-100) ml. None of the patients required intraoperative blood transfusion. The median postoperative hospital stay was 4 (range, 2-7) days. Intraoperative or postoperative complications (Clavien-Dindo grade I) occurred in 9 patients. The surgeon Task Load Index global score achieved 1.05±1.86. Three patients received the single-docking technique, demonstrating similar perioperative results compared to patients with re-docking. CONCLUSIONS: The KD-SR-01 system was feasible, safe, and effective for robot-assisted radical nephroureterectomy.

Complex association of body mass index and outcomes in patients with relapsed and refractory multiple myeloma treated with CAR-T cell immunotherapy.

BACKGROUND AIMS: Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. METHODS: We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. RESULTS: The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. CONCLUSIONS: Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes.

Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

PAX2 mediated upregulation of ESPL1 contributes to cisplatin resistance in bladder cancer through activating the JAK2/STAT3 pathway.

Extra spindle-polar body like 1 (ESPL1) is associated with the development of a variety of cancers, including bladder cancer, and is closely related to chemoresistance. In this study, we aimed to reveal the role of ESPL1 in bladder cancer progression and cisplatin (DDP) resistance. First, ESPL1 was found to be highly expressed in tumor tissues and cells of bladder cancer, and more highly expressed in cisplatin resistant tumor tissues or cells. The binding of PAX2 in ESPL1 promoter region was predicted by Jaspar database and verified by Ch-IP analysis and the luciferase reporter gene assay. Next, cisplatin-resistant T24 cells (T24/DDP) were established and transfected with ESPL1 siRNA (si-ESPL1) or overexpression vector (pcDNA-ESPL1) or co-transfected with PAX2 siRNA (si-PAX2) or overexpression vector (pcDNA-PAX2), and then treated with DDP or AG490, an inhibitor of JAK2. The results showed that silencing ESPL1 significantly reduced T24/DDP cell viability, colony formation and invasion, enhanced sensitivity to DDP, and induced cell apoptosis. Silencing PAX2 decreased ESPL1 expression, enhanced sensitivity to DDP, and induced apoptosis of T24/DDP cells, and inhibited activation of JAK2/STAT3 pathway. Overexpressing ESPL1 reversed the effect of PAX2 silencing on T24/DDP cells, while AG490 counteracted the reversal effect of overexpressing ESPL1. Finally, a xenograft tumor model was established and found that silencing ESPL1 or DDP treatment inhibited tumor growth, while silencing ESPL1 combined with DDP treatment had the best effect. In summary, this study suggested that PAX2-mediated ESPL1 transcriptional activation enhanced cisplatin resistance in bladder cancer by activating JAK2/STAT3 pathway.

Notch1 regulates hepatic thrombopoietin production.

Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-seq analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR) (asialoglycoprotein receptor 1, ASGR1) physically associates with Notch1 and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Super-Flexible Water-Proof Actuators.

Humidity-responsive materials hold broad application prospects in sensing, energy production, and other fields. Particularly, humidity-sensitive, flexibility, and water resistance are pivotal factors in the development of optimized humidity-responsive materials. In this study, hydrophobic linear polyurethane and hydrophilic 4-vinylphenylboronic acid (4-VPBA) form a semi-intercross cross-linking network. This copolymer of polyurethane exhibits excellent humidity-sensitive, mechanical properties, and water resistance. Its maximum tensile strength and maximum elongation can reach 40.56 MPa and 543.47%, respectively. After being immersed in water at various temperatures for 15 days, it exhibited a swelling ratio of only 3.28% in water at 5 °C and 9.58% in water at 70 °C. While the presence of 4-VPBA network imparts humidity-sensitive, reversible, and multidirectional bending abilities, under the stimulus of water vapor, it can bend 43° within 1.4 s. The demonstrated material surpasses current bidirectional humidity actuators in actuating ability. Based on these characteristics, automatically opening waterproof umbrellas and windows, as well as bionic-arms, crawling robots, and self-propelled boats, are successfully developed.

Non-invasive geophysical methods for monitoring the shallow aquifer based on time-lapse electrical resistivity tomography, magnetic resonance sounding, and spontaneous potential methods.

The Ningdong coalfield has played a pivotal role in advancing local economic development and meeting national energy. Nevertheless, mining operations have engendered ecological challenges encompassing subterranean water depletion, land desertification, and ground subsidence, primarily stemming from the disruption of coal seam roof strata. Consequently, the local ecosystem has incurred substantial harm. Water-preserved coal mining presently constitutes the pivotal technology in mitigating this problem. The primary challenge of this technique lies in identifying critical aquifer layers and understanding the heights of water-conducting fracture zones. To obtain a precise comprehension of the seepage patterns within the upper coal seam aquifer during mining, delineate the extent of water-conducting fracture zones, non-invasive geophysical techniques such as time-lapse electrical resistivity tomography (TL-ERT), magnetic resonance sounding (MRS), and spontaneous potential (SP) have been employed to monitor alterations within the shallow coalfield's aquifer throughout the mining process in the Ningdong coalfield. By conducting meticulous examinations of fluctuations in resistivity, moisture content, and self-potential within the superjacent strata during coal seam extraction, the predominant underground water infiltration strata were ascertained, concurrently enabling the estimation of the development elevation of water-conducting fracture zones. This outcome furnishes a geophysical underpinning for endeavors concerning local water-preserved coal mining and ecological rehabilitation.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.