Search

Poly(glycolic acid) (PGA) has displayed excellent tensile strength, degradability and renewability, but it still faces dilemmas in practical because of its low toughness, poor melt strength and the ease of thermal degradation. In this work, in order to take full advantages of its degradability and high strength, the PGA was toughened by poly(butyleneadipate-co-terephthalate) (PBAT) and reinforced by chopped carbon fibers (CFs) through melt compounding with the help of compatibilizers which facilitated the regulation of interfacial morphology and thereby performance. The evolution of tensile properties, dispersion state of PBAT domains, interface region and rheological behaviors of the blends were analyzed to explore the intrinsic improvement mechanism. Specifically, the increased grafting density of molecular chains revealed from the blend melt viscoelasticity was proposed to be responsible for the greatly enhanced toughness, resulting in an elongation at break of ∼90.45% and a toughness of 49.65 MJ/m3 which were dozens of times higher than PGA itself. Such blend is well capable of incorporating of CFs, showing an ultimate tensile strength ∼135 MPa whereas remaining ductility and aqua-degradability. Overall, this work provided a great potential in replacing metal alloys with the reinforced and toughened PGA composites for the applications of sacrificed tools.

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

Abstract Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

To improve the torque density (TD) of a permanent magnet wind turbine (PMWT), this paper proposes a magnetic pole offset semi-embedded structure based on the traditional semi-embedded structure. Firstly, the principle of how magnetic pole offset can increase the torque is explained. Then, based on the non-dominated sorting genetic algorithm II (NSGA-II), the ratio k of the inner and outer diameters of the stator is optimized to make the motor quality and efficiency reach the best state. On this basis, the TD is further optimized by utilizing the magnetic pole offset angle. The results show that when the magnetic pole offset angle is 0.5°, the TD reaches the maximum value of 13.95 Nm/kg, with an increase of 3.33%. Finally, the no-load performance and load performance of the two structures are compared to highlight the advantages of the magnetic pole offset structure.

Protein glutaminase (PG), originating from Chryseobacterium proteolyticum, can catalyze the deamidation of glutamine residues in plant proteins into glutamic acid, thus enhancing its functional properties. However, the low yield of PG limits its industrial production. In this study, the yield of PG in C. proteolyticum TM1040 increased by 121 %, up to 7.30 U/mL in a 15 L fermenter after medium optimization. Subsequently, purified PG was obtained by cation exchange chromatography (CEX) coupled with hydrophobic interaction chromatography (HIC). The degree of deamidation (DD) of wheat gluten after purified PG deamidation was 87.11 %, which is superior to chemical deamidation in safety and DD. The emulsifying and foaming properties of deamidated wheat gluten were 2.67 and 18.86 times higher, and the water- and oil-holding properties were 4.23 and 18.77 times higher, respectively. The deamidated wheat gluten with enhanced functional properties was used to improve the flavor and texture in baking cakes.

Summary: The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

Abstract Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.

Summary: Background: Although chimeric antigen receptor-modified T cells (CAR T) cell therapy has been widely reported in improving the outcomes of B-cell acute lymphoblastic leukemia (B-ALL), less research about the feasibility and safety of donor-derived CAR T after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported. Methods: This phase 1 clinical trial aims to evaluate safety and efficacy of donor-derived anti-CD19 CAR T cells (GC007g) in B-ALL patients who relapsed after allo-HSCT. This trial is registered with ClinicalTrials.gov, NCT04516551. Findings: Between 15 March 2021 and 19 May 2022, fifteen patients were screened, three patients were excluded due to withdraw of consent, donor's reason, and death, respectively. Patients received donor-derived CAR T cells infusions at 6 × 105/kg (n = 3) or 2 × 106/kg (n = 6) dose level. The median time from HSCT to relapse was 185 days (range, 81–2063). The median age of patients was 31 years (range 21–48). Seven patients (77.8%) had BCR-ABL fusion gene. CAR T cells expanded in vivo and the median time to reach Cmax was 9 days (range, 7–11). One patient had hyperbilirubinemia after GC007g infusion which was defined as a dose-limiting toxicity. All patients experienced CRS and hematological adverse events. Three patients had acute graft-versus-host-disease (grade I, n = 1; grade II, n = 1; grade IV, n = 1) and all resolved after treatment. They received CAR T cells from matched sister, haploidentical matched father and sisiter, respectively. At 28 days after infusion, all patients achieved complete remission with/without incomplete hematologic recovery (CRi/CR) with undetectable MRD. At a median follow-up of 475 days (range 322–732), seven patients remained in CR/CRi while two had CD19-negative relapse. The overall response rates (ORR) were 100% (9/9), 88.9% (8/9), and 75% (6/8) at 3 month, 6 month, and 12 month, respectively. The 1-year progression-free and overall survival were 77.8% and 85.7%, respectively. Interpretation: GC007g expanded and induced durable remission in patients with B-ALL relapsed after allo-HSCT, with manageable safety profiles. Funding: Gracell Biotechnologies Inc.

Mechanical dependence of 3D-printed thermoplastic polyurethane (TPU) reinforced with continuous carbon fibres (CCFs) on the selected printing conditions was investigated. The melt-extrusion-based 3D-printing (ME3DP) method was employed to fabricate specimens, of which the dependence of tensile, flexural and cryo-impact properties on layer thickness, printing speed and layer number was evaluated. Results showed that the printed TPU reinforced with raw CCFs revealed an over five-fold increase in tensile yield stress with the occurrence of necking phenomenon whereas those reinforced with preimpregnated CCFs (PCCFs) displayed brittle fracture which was also confirmed by the impact testing. The flexural strength and modulus of the printed CCFs/TPU were greatly raised over that of TPU and the PCCFs provided a much more enhancement. Both the increased yield stress and flexural strength implied an improved capacity for dynamic load bearing. Finally, the structure–property relationship was established via interface microstructure detection and simulation.

Abstract Background Checkpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy. Methods We recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF). Results Multiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate. Conclusion We demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.

Abstract Slowly digestible starch (SDS) has attracted increasing attention for its function of preventing metabolic diseases. Based on transglycosylation, starch branching enzymes (1,4-α-glucan branching enzymes, GBEs, EC 2.4.1.18) can be used to regulate the digestibility of starch. In this study, a GBE gene from Bacillus licheniformis (bl-GBE) was cloned, expressed, purified, and characterized. Sequence analysis and structural modeling showed that bl-GBE belong to the glycoside hydrolase 13 (GH13) family, with which its active site residues were conserved. The bl-GBE was highly active at 80 °C and a pH range of 7.5–9.0, and retained 90% of enzyme activity at 70 °C for 16 h. bl-GBE also showed high substrate specificity (80.88 U/mg) on potato starch. The stability and the changes of the secondary structure of bl-GBE at different temperature were determined by circular dichroism (CD) spectroscopy. The CD data showed a loss of 20% of the enzyme activity at high temperatures (80 °C), due to the decreased content of the α -helix in the secondary structure. Furthermore, potato starch treated with bl-GBE (300 U/g starch) showed remarkable increase in stability, solubility, and significant reduction viscosity. Meanwhile, the slowly digestible starch content of bl-GBE modified potato starch increased by 53.03% compared with native potato starch. Our results demonstrated the potential applications of thermophilic bl-GBE in food industries.

Summary: Background: Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin’s lymphoma (B-NHL). Methods: This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2 × 106/kg, 4 × 106/kg, 6 × 106/kg with three patients at each dose level, the optimal biological dose was determined to be 2 × 106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Findings: Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1–2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1–2. The most common adverse events were hematologic toxicities, including anaemia (n = 6), lymphocyte count decreased (n = 19), neutrophil count decreased (n = 17), white blood cell count decreased (n = 10), and platelet count decreased (n = 2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9–infinity), with the median overall survival not reached. Interpretation: In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Chimeric antigen receptor (CAR) T-cell based immunotherapy has shown its potential in treating blood cancers, and its application to solid tumors is currently being extensively investigated. For glioma brain tumors, various CAR T-cell targets include IL13Rα2, EGFRvIII, HER2, EphA2, GD2, B7-H3, and chlorotoxin. In this work, we are interested in developing a mathematical model of IL13Rα2 targeting CAR T-cells for treating glioma. We focus on extending the work of Kuznetsov et al. (1994) by considering binding of multiple CAR T-cells to a single glioma cell, and the dynamics of these multi-cellular conjugates. Our model more accurately describes experimentally observed CAR T-cell killing assay data than the models which do not consider multi-cellular conjugates. Moreover, we derive conditions in the CAR T-cell expansion rate that determines treatment success or failure. Finally, we show that our model captures distinct CAR T-cell killing dynamics from low to high antigen receptor densities in patient-derived brain tumor cells.

To address loess–mudstone tunnel damage resulting from mudstone swelling induced by water absorption in cold regions, model experiments and numerical simulations were employed to study the tunnel surrounding rock pressure distribution and the stress characteristics of support structures during mudstone swelling at the tunnel base. The findings reveal that the base uplift of the tunnel leads to a rapid stress increase on the arch, and the self-supporting of the interface is insufficient, causing uneven stress distribution on the tunnel. The stress peak value at the bottom of the outer arch is 30.8% of that at the inner side. The internal force of the tunnel lining at the arch crown is the largest. The compressive stress appears at the arch feet, while the tensile stress appears at the outer side of the lining. The bending moments of the inverted arch are larger than those of the arch shoulders and arch crown. The left arch shoulder and arch bottom are primarily subjected to negative bending moments, and the maximum values are about −500 kN·m and −400 kN·m, respectively. The left side of the inverted arch is first to crack, and two main cracks then appeared at the left and right arch shoulders, respectively. The formation and development of the longitudinal cracks in the arch induced by water absorption cause the inverted arch bulge failure. This study helps understand the damage mechanism of the loess–mudstone tunnel in cold regions.

Textile-based flexible Lithium-Ion Batteries (LIBs) show promising mechanical flexibility that is appealing for a wide variety of wearable and flexible electronic applications. The flexibility of flexible LIBs nowadays is still limited. In addition, their power performance is too low to enable high-speed charging, due to the low conductivity of the textiles. Here, we develop highly electrically conductive metallic fabrics, which are fabricated by coating nanostructured Ni or Cu (nano-reliefs) on woven cotton fabrics, as current collectors to enable crumpled, high-power, and safe wearable LIBs. The nanostructured metal coating not only effectively increases the contact area between current collectors and active materials, but also shortens the charge carrier transport paths, so that LIBs constructed on these nanostructured metallic cotton fabrics exhibit a high power density of 439 W/L and superior electrochemical stability under various mechanical deformations including folding, twisting, squeezing, and impacting. This type of nanostructured metallic textile is highly desirable for portable and wearable electronic applications.

Abstract Hierarchical porous carbons are the most viable electrode material for supercapacitors because of their balanced capacitive performance and chemical stability. Their pore connectivity plays a pivotal role in electrolyte transport, which is quantified by a new parameter, defined in this work as the longest possible pore separation (LPPS). Herein, we report hierarchical porous carbon nanospheres (HPC‐NS) with a unique ball‐in‐ball structure, which is achieved by the pyrolysis of a supramolecular complex of γ‐cyclodextrin (γ‐CD)/PEO‐PPO‐PEO (F127). This approach differs from the conventional soft‐templating method in that, apart from the assembly of the monomicelles that leads to the host nanospheres (approximately 300 nm), the γ‐CD‐containing monomicelles themselves are converted to small porous carbon nanospheres (

In the rapidly growing area of high-frequency communications, polyimide films with ultralow dielectric constant and dielectric loss, adequate insulating strength, and recyclability are in high demand. Using a synthesized soluble fluorinated polyimide, a series of recyclable porous dielectric films with varying porosities were fabricated in this study through nonsolvent-induced phase separation. By manipulating the mass ratio of the binary solvent used to dissolve the polyimide, the shape, size, and size distribution of the pores generated throughout the polyimide matrix can be accurately regulated. The porosity and average pore size of the as-prepared porous films were adjustable between 71% and 33% and between 9.31 and 1.00 μm, respectively, which resulted in a variable dielectric constant of 1.51–2.42 (100 kHz) and electrical breakdown strength of 30.3–119.7 kV/mm. The porous sPI film with a porosity rate of 48% displayed a low dielectric constant of 2.48 at 10 GHz. Coupled with their superior thermal stability, mechanical characteristics, and recyclability, these porous polyimide films are highly promising for constructing high-frequency microelectronic devices.

The lack of suitable lightweight current collectors is one of the primary obstacles preventing the energy density of aqueous lithium-ion batteries (ALIBs) from becoming competitive. Using silver nanowire (AgNW) films as current collectors and a molecular crowding electrolyte, we herein report the fabrication of ALIBs with relatively good energy densities. In the 2 m LiTFSI–94% PEG–6% H2O solution, the AgNW films with a sheet resistance of less than 1.0 ohm/square exhibited an electrochemical stability window as broad as 3.8 V. The LiMn2O4//Li4Ti5O12 ALIBs using AgNW films as the current collectors demonstrated an initial energy density of 70 Wh/kg weighed by the total mass of the cathode and anode, which retained 89.1% after 50 cycles.

Lightweight and flexible energy storage devices are needed to persistently power wearable devices. Here the authors employ metallized carbon fabrics as hosts for sulfur and lithium to achieve flexibility, electrochemical stability and high energy density in a lithium-sulfur battery.