Direct 4D printing of ceramics driven by hydrogel dehydration.

4D printing technology combines 3D printing and stimulus-responsive materials, enabling construction of complex 3D objects efficiently. However, unlike smart soft materials, 4D printing of ceramics is a great challenge due to the extremely weak deformability of ceramics. Here, we report a feasible and efficient manufacturing and design approach to realize direct 4D printing of ceramics. Photocurable ceramic elastomer slurry and hydrogel precursor are developed for the fabrication of hydrogel-ceramic laminates via multimaterial digital light processing 3D printing. Flat patterned laminates evolve into complex 3D structures driven by hydrogel dehydration, and then turn into pure ceramics after sintering. Considering the dehydration-induced deformation and sintering-induced shape retraction, we develop a theoretical model to calculate the curvatures of bent laminate and sintered ceramic part. Then, we build a design flow for direct 4D printing of various complex ceramic objects. This approach opens a new avenue for the development of ceramic 4D printing technology.

Dipeptidyl peptidase 4 inhibitor reduces tumor-associated macrophages and enhances anti-PD-L1-mediated tumor suppression in non-small cell lung cancer

Purpose The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model. Methods The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage. Results Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2. Conclusions Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC (AU)

Polyelectrolyte elastomer-based ionotronic sensors with multi-mode sensing capabilities via multi-material 3D printing.

Stretchable ionotronics have drawn increasing attention during the past decade, enabling myriad applications in engineering and biomedicine. However, existing ionotronic sensors suffer from limited sensing capabilities due to simple device structures and poor stability due to the leakage of ingredients. In this study, we rationally design and fabricate a plethora of architected leakage-free ionotronic sensors with multi-mode sensing capabilities, using DLP-based 3D printing and a polyelectrolyte elastomer. We synthesize a photo-polymerizable ionic monomer for the polyelectrolyte elastomer, which is stretchable, transparent, ionically conductive, thermally stable, and leakage-resistant. The printed sensors possess robust interfaces and extraordinary long-term stability. The multi-material 3D printing allows high flexibility in structural design, enabling the sensing of tension, compression, shear, and torsion, with on-demand tailorable sensitivities through elaborate programming of device architectures. Furthermore, we fabricate integrated ionotronic sensors that can perceive different mechanical stimuli simultaneously without mutual signal interferences. We demonstrate a sensing kit consisting of four shear sensors and one compressive sensor, and connect it to a remote-control system that is programmed to wirelessly control the flight of a drone. Multi-material 3D printing of leakage-free polyelectrolyte elastomers paves new avenues for manufacturing stretchable ionotronics by resolving the deficiencies of stability and functionalities simultaneously.

A volatile microemulsion method of preparing water-soluble photo-absorbers for 3D printing of high-resolution, high-water-content hydrogel structures.

Digital light processing (DLP)-based three-dimensional (3D) printing is an ideal tool to manufacture hydrogel structures in complex 3D forms. Using DLP to print hydrogel structures with high resolution requires the addition of water-soluble photo-absorbers to absorb excess light and confine photopolymerization to the desired area. However, the current photo-absorbers for hydrogel printing are neither efficient to absorb the excess light nor water-soluble. Herein, we report a volatile microemulsion template method that converts a wide range of commercial non-water-soluble photo-absorbers including Sudan orange G, quercetin, and many others to water-soluble nanoparticles with solubility above 1.0 g mL-1. After using these water-soluble photo-absorber nanoparticles, the highest lateral and vertical resolutions of printing high-water-content (70-80 wt%) hydrogels can be improved to 5 µm and 20 µm, respectively. Moreover, the quercetin nanoparticle can be easily washed out so that we achieve colorless and transparent printed hydrogel structures with excellent mechanical deformability and biocompatibility as well as thermally controllable variations on transparency and actuation. The proposed methods pave a new efficient way to develop water-soluble photo-absorbers, which helps to greatly improve the printing resolution of the high-water-content hydrogel structure and would be beneficial to extend the application scope of hydrogels.

Dipeptidyl peptidase 4 inhibitor reduces tumor-associated macrophages and enhances anti-PD-L1-mediated tumor suppression in non-small cell lung cancer.

PURPOSE: The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model. METHODS: The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage. RESULTS: Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2. CONCLUSIONS: Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC.

Multimaterial 3D printed self-locking thick-panel origami metamaterials.

Thick-panel origami has shown great potential in engineering applications. However, the thick-panel origami created by current design methods cannot be readily adopted to structural applications due to the inefficient manufacturing methods. Here, we report a design and manufacturing strategy for creating thick-panel origami structures with excellent foldability and capability of withstanding cyclic loading. We directly print thick-panel origami through a single fused deposition modeling (FDM) multimaterial 3D printer following a wrapping-based fabrication strategy where the rigid panels are wrapped and connected by highly stretchable soft parts. Through stacking two thick-panel origami panels into a predetermined configuration, we develop a 3D self-locking thick-panel origami structure that deforms by following a push-to-pull mode enabling the origami structure to support a load over 11000 times of its own weight and sustain more than 100 cycles of 40% compressive strain. After optimizing geometric parameters through a self-built theoretical model, we demonstrate that the mechanical response of the self-locking thick-panel origami structure is highly programmable, and such multi-layer origami structure can have a substantially improved impact energy absorption for various structural applications.

Multimaterial Three-Dimensional Printing of Ultraviolet-Curable Ionic Conductive Elastomers with Diverse Polymers for Multifunctional Flexible Electronics.

Ionic conductive elastomers (ICEs) are emerging stretchable and ionic conductive materials that are solvent-free and thus demonstrate excellent thermal stability. Three-dimensional (3D) printing that creates complex 3D structures in free forms is considered as an ideal approach to manufacture sophisticated ICE-based devices. However, the current technologies constrain 3D printed ICE structures in a single material, which greatly limits functionality and performance of ICE-based devices and machines. Here, we report a digital light processing (DLP)-based multimaterial 3D printing capability to seemly integrate ultraviolet-curable ICE (UV-ICE) with nonconductive materials to create ionic flexible electronic devices in 3D forms with enhanced performance. This unique capability allows us to readily manufacture various 3D flexible electronic devices. To demonstrate this, we printed UV-ICE circuits into polymer substrates with different mechanical properties to create resistive strain and force sensors; we printed flexible capacitive sensors with high sensitivity (2 kPa-1) and a wide range of measured pressures (from 5 Pa to 550 kPa) by creating a complex microstructure in the dielectric layer; we even realized ionic conductor-activated four-dimensional (4D) printing by printing a UV-ICE circuit into a shape memory polymer substrate. The proposed approach paves a new efficient way to realize multifunctional flexible devices and machines by bonding ICEs with other polymers in 3D forms.

Centrifugal multimaterial 3D printing of multifunctional heterogeneous objects.

There are growing demands for multimaterial three-dimensional (3D) printing to manufacture 3D object where voxels with different properties and functions are precisely arranged. Digital light processing (DLP) is a high-resolution fast-speed 3D printing technology suitable for various materials. However, multimaterial 3D printing is challenging for DLP as the current multimaterial switching methods require direct contact onto the printed part to remove residual resin. Here we report a DLP-based centrifugal multimaterial (CM) 3D printing method to generate large-volume heterogeneous 3D objects where composition, property and function are programmable at voxel scale. Centrifugal force enables non-contact, high-efficiency multimaterial switching, so that the CM 3D printer can print heterogenous 3D structures in large area (up to 180 mm × 130 mm) made of materials ranging from hydrogels to functional polymers, and even ceramics. Our CM 3D printing method exhibits excellent capability of fabricating digital materials, soft robots, and ceramic devices.

Overexpression of SHARPIN promotes tumor progression in ovarian cancer.

SHARPIN (Shank-associated RH domain interacting protein) plays an important role in tumorigenesis. However, its role in ovarian cancer remains largely unknown. To investigate this issue, we systematically analyzed the amplification and expression of the SHARPIN in the TCGA database. From the database, we found that SHARPIN was amplified in ovarian cancer compared to normal ovarian tissue, and the mRNA level of SHARPIN was significantly elevated in ovarian cancer compared to non-tumorigenic ovarian tissue. In addition, we observed similar results from ovarian cancer cell lines and clinical samples from ovarian cancer patients, which indicated that increased SHARPIN expression is associated with tumorigenesis in ovarian cancer. SHARPIN knockdown inhibited the migration and invasion of ovarian cancer cells, also inhibited cell cycle and promoted apoptosis, thereby suppressing cell proliferation. RNA-seq results showed that SHARPIN significantly increased the expression of P53 and P21 and decreased the expression of Cyclin D1 and c-Myc, all of which are involved in the regulation of cell proliferation. Subsequent mechanistic exploration revealed that SHARPIN knockdown increased the expression of caspases 3 and 9, leading to apoptosis of ovarian cancer cells. We also found that high expression of SHARPIN was associated with poor prognosis of ovarian cancer patients. Collectively, we demonstrated a positive correlation between SHARPIN and ovarian cancer progression and provide a basis for combined targeted therapy strategies for future ovarian cancer treatment.

Mechanically Robust and UV-Curable Shape-Memory Polymers for Digital Light Processing Based 4D Printing.

4D printing is an emerging fabrication technology that enables 3D printed structures to change configuration over "time" in response to an environmental stimulus. Compared with other soft active materials used for 4D printing, shape-memory polymers (SMPs) have higher stiffness, and are compatible with various 3D printing technologies. Among them, ultraviolet (UV)-curable SMPs are compatible with Digital Light Processing (DLP)-based 3D printing to fabricate SMP-based structures with complex geometry and high-resolution. However, UV-curable SMPs have limitations in terms of mechanical performance, which significantly constrains their application ranges. Here, a mechanically robust and UV-curable SMP system is reported, which is highly deformable, fatigue resistant, and compatible with DLP-based 3D printing, to fabricate high-resolution (up to 2 µm), highly complex 3D structures that exhibit large shape change (up to 1240%) upon heating. More importantly, the developed SMP system exhibits excellent fatigue resistance and can be repeatedly loaded more than 10 000 times. The development of the mechanically robust and UV-curable SMPs significantly improves the mechanical performance of the SMP-based 4D printing structures, which allows them to be applied to engineering applications such as aerospace, smart furniture, and soft robots.

3D printing of highly stretchable hydrogel with diverse UV curable polymers.

Hydrogel-polymer hybrids have been widely used for various applications such as biomedical devices and flexible electronics. However, the current technologies constrain the geometries of hydrogel-polymer hybrid to laminates consisting of hydrogel with silicone rubbers. This greatly limits functionality and performance of hydrogel-polymer-based devices and machines. Here, we report a simple yet versatile multimaterial 3D printing approach to fabricate complex hybrid 3D structures consisting of highly stretchable and high-water content acrylamide-PEGDA (AP) hydrogels covalently bonded with diverse UV curable polymers. The hybrid structures are printed on a self-built DLP-based multimaterial 3D printer. We realize covalent bonding between AP hydrogel and other polymers through incomplete polymerization of AP hydrogel initiated by the water-soluble photoinitiator TPO nanoparticles. We demonstrate a few applications taking advantage of this approach. The proposed approach paves a new way to realize multifunctional soft devices and machines by bonding hydrogel with other polymers in 3D forms.

The complete mitochondrial genome of Fejervarya kawamurai (Anura: Dicroglossidae) and its phylogeny.

The mitochondrial genome of Fejervarya kawamurai is a circular molecule of 17,650 bp in length, containing 13 protein-coding genes, two rRNA genes, 23 tRNA genes (including an extra tRNA-Met), and the control region. The AT content of the whole genome is 56.9%. In Bayesian inference (BI) and Maximum likelihood (ML) analyses, we found that F. kawamurai is a sister clade to F. multistriata and F. limnocharis. The monophyly of Fejervarya, Quasipaa, Nanorana was well supported (1.00 in BI and 100% in ML).