Stimuli-Triggered Multishape, Multimode, and Multistep Deformations Designed by Microfluidic 3D Droplet Printing.

Elastomers generally possess low Young's modulus and high failure strain, which are widely used in soft robots and intelligent actuators. However, elastomers generally lack diverse functionalities, such as stimulated shape morphing, and a general strategy to implement these functionalities into elastomers is still challenging. Here, a microfluidic 3D droplet printing platform is developed to design composite elastomers architected with arrays of functional droplets. Functional droplets with controlled size, composition, position, and pattern are designed and implemented in the composite elastomers, imparting functional performances to the systems. The composited elastomers are sensitive to stimuli, such as solvent, temperature, and light, and are able to demonstrate multishape (bow- and S-shaped), multimode (gradual and sudden), and multistep (one- and two-step) deformations. Based on the unique properties of droplet-embedded composite elastomers, a variety of stimuli-responsive systems are developed, including designable numbers, biomimetic flowers, and soft robots, and a series of functional performances are achieved, presenting a facile platform to impart diverse functionalities into composite elastomers by microfluidic 3D droplet printing.

CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells.

CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

Active Encapsulation in Biocompatible Nanocapsules.

Co-precipitation is generally refers to the co-precipitation of two solids and is widely used to prepare active-loaded nanoparticles. Here, it is demonstrated that liquid and solid can precipitate simultaneously to produce hierarchical core-shell nanocapsules that encapsulate an oil core in a polymer shell. During the co-precipitation process, the polymer preferentially deposits at the oil/water interface, wetting both the oil and water phases; the behavior is determined by the spreading coefficients and driven by the energy minimization. The technique is applicable to directly encapsulate various oil actives and avoid the use of toxic solvent or surfactant during the preparation process. The obtained core-shell nanocapsules harness the advantage of biocompatibility, precise control over the shell thickness, high loading capacity, high encapsulation efficiency, good dispersity in water, and improved stability against oxidation. The applications of the nanocapsules as delivery vehicles are demonstrated by the excellent performances of natural colorant and anti-cancer drug-loaded nanocapsules. The core-shell nanocapsules with a controlled hierarchical structure are, therefore, ideal carriers for practical applications in food, cosmetics, and drug delivery.

Robust Biological Fibers Based on Widely Available Proteins: Facile Fabrication and Suturing Application.

Lightweight and mechanically strong protein fibers are promising for many technical applications. Despite the widespread investigation of biological fibers based on spider silk and silkworm proteins, it remains a challenge to develop low-cost proteins and convenient spinning technology for the fabrication of robust biological fibers. Since there are plenty of widely available proteins in nature, it is meaningful to investigate the preparation of fibers by the proteins and explore their biomedical applications. Here, a facile microfluidic strategy is developed for the scalable construction of biological fibers via a series of easily accessible spherical and linear proteins including chicken egg, quail egg, goose egg, bovine serum albumin, milk, and collagen. It is found that the crosslinking effect in microfluidic chips and double-drawn treatment after spinning are crucial for the formation of fibers. Thus, high tensile strength and toughness are realized in the fibers, which are comparable or even higher than that of many recombinant spider silks or regenerated silkworm fibers. Moreover, the suturing applications in rat and minipig models are realized by employing the mechanically strong fibers. Therefore, this work opens a new direction for the production of biological fibers from natural sources.

Biocompatible and pH-Responsive Colloidal Surfactants with Tunable Shape for Controlled Interfacial Curvature.

Molecular-surfactant-stabilized emulsions are susceptible to coalescence and Ostwald ripening. Amphiphilic particles, which have a much stronger anchoring strength at the interface, could effectively alleviate these problems to form stable Pickering emulsions. Herein, we describe a versatile method to fabricate biocompatible amphiphilic dimer particles through controlled coprecipitation and phase separation. The dimer particles consist of a hydrophobic PLA bulb and a hydrophilic shellac-PEG bulb, thus resembling nonionic molecular surfactants. The size and diameter ratio of the dimer particles are readily tunable, providing flexible control over the water/oil interfacial curvature and thus the type of emulsion. The particle-stabilized emulsions were stable for a long period of time and could be destabilized through a pH-triggered response. The biocompatible amphiphilic dimer particles with tunable morphology and functionality are thus ideal colloidal surfactants for various applications.

Engineered Anisotropic Fluids of Rare-Earth Nanomaterials.

The self-assembly of inorganic nanoparticles into well-ordered structures in the absence of solvents is generally hindered by van der Waals forces, leading to random aggregates between them. To address the problem, we functionalized rigid rare-earth (RE) nanoparticles with a layer of flexible polymers by electrostatic complexation. Consequently, an ordered and solvent-free liquid crystal (LC) state of RE nanoparticles was realized. The RE nanomaterials including nanospheres, nanorods, nanodiscs, microprisms, and nanowires all show a typical nematic LC phase with one-dimensional orientational order, while their microstructures strongly depend on the particles' shape and size. Interestingly, the solvent-free thermotropic LCs possess an extremely wide temperature range from -40 °C to 200 °C. The intrinsic ordering and fluidity endow anisotropic luminescence properties in the system of shearing-aligned RE LCs, offering potential applications in anisotropic optical micro-devices.

Mechanically Strong Globular-Protein-Based Fibers Obtained Using a Microfluidic Spinning Technique.

Proteins used for the formation of light weight and mechanically strong biological fibers are typically composed of folded rigid and unfolded flexible units. In contrast to fibrous proteins, globular proteins are generally not regarded as a good candidate for fiber production due to their intrinsic structural defects. Thus, it is challenging to develop an efficient strategy for the construction of mechanically strong fibers using spherical proteins. Herein, we demonstrate the production of robust protein fibers from bovine serum albumin (BSA) using a microfluidic technique. Remarkably, the toughness of the fibers was up to 143 MJ m-3 , and after post-stretching treatment, their breaking strength increased to almost 300 MPa due to the induced long-range ordered structure in the fibers. The performance is comparable to or even higher than that of many recombinant spider silks or regenerated silkworm fibers. Thus, this work opens a new way for making biological fibers with high performance.

Glucose-dependent insulinotropic polypeptide promotes lipid deposition in subcutaneous adipocytes in obese type 2 diabetes patients: a maladaptive response.

Glucose-dependent insulinotropic polypeptide (GIP) beyond its insulinotropic effects may regulate postprandial lipid metabolism. Whereas the insulinotropic action of GIP is known to be impaired in type 2 diabetes mellitus (T2DM), its adipogenic effect is unknown. We hypothesized that GIP is anabolic in human subcutaneous adipose tissue (SAT) promoting triacylglycerol (TAG) deposition through reesterification of nonesterified fatty acids (NEFA), and this effect may differ according to obesity status or glucose tolerance. Twenty-three subjects categorized into four groups, normoglycemic lean (n = 6), normoglycemic obese (n = 6), obese with impaired glucose regulation (IGR; n = 6), and obese T2DM (n = 5), participated in a double-blind, randomized, crossover study involving a hyperglycemic clamp with a 240-min GIP infusion (2 pmol·kg-1·min-1) or normal saline. Insulin, NEFA, SAT-TAG content, and gene expression of key lipogenic enzymes were determined before and immediately after GIP/saline infusions. GIP lowered NEFA concentrations in the obese T2DM group despite diminished insulinotropic activity (mean NEFA AUC0-4 h ± SE, 41,992 ± 9,843 µmol·l-1·min-1 vs. 71,468 ± 13,605 with placebo, P = 0.039, 95% CI: 0.31-0.95). Additionally, GIP increased SAT-TAG in obese T2DM (1.78 ± 0.4 vs 0.86 ± 0.1-fold with placebo, P = 0.043, 95% CI: 0.1-1.8). Such effect with GIP was not observed in other three groups despite greater insulinotropic activity. Reduction in NEFA concentration with GIP correlated with adipose tissue insulin resistance for all subjects (Pearson, r = 0.56, P = 0.005). There were no significant gene expression changes in key SAT lipid metabolism enzymes. In conclusion, GIP appears to promote fat accretion and thus may exacerbate obesity and insulin resistance in T2DM.

Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems.

Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.

Synergistic preparation and application in PCU of α-calcium sulfate hemihydrate whiskers from phosphogypsum and electrolytic manganese residue.

The α-calcium sulfate hemihydrate whiskers (α-CSHWs) were first prepared using phosphogypsum (PG) and electrolytic manganese residue (EMR) as raw materials for coating urea, demonstrating excellent controlled-release properties. The effects of different reaction conditions on α-CSHWs, achieved by optimizing the reaction time, the concentrations of NH4+, Mn2+, and other factors, were discussed. Results showed that when the EMR content was 25 wt%, the reaction temperature was 100 °C, and the reaction time was 3 h, α-CSHWs with a length-to-diameter ratio of 39 were obtained. Through experiments and density functional theory (DFT), the mechanism of α-CSHWs preparation was elucidated. The results show that the addition of EMR reduces the content of impurity ions PO43- and F- in PG while introducing NH4+ and Mn2+. Interestingly, both NH4+ and Mn2+ can reduce the nucleation time of α-CSHWs, while PO43-, Mn2+, and F- are more likely to adsorb on the (0 0 6) crystal plane of α-CSHWs, NH4+ readily adsorbs on the (4 0 0) crystal plane. The controlled-release performance of modified α-CSHWs incorporated into polyurethane-coated urea (PCU) was investigated, and it was found that the addition of Mα significantly prolonged the nutrient release period, with the period extending up to 116 days for coatings of 5wt% and above. This work not only enhances the efficiency of PG and EMR utilization but also serves as a reference for the straightforward synthesis and application of α-CSHWs.

Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel.

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.

Highly Plasticized Lanthanide Luminescence for Information Storage and Encryption Applications.

The development of new storage media to meet the demands for diverse information storage scenarios is a great challenge. Here, a series of lanthanide-based luminescent organogels with ultrastrong mechanical performance and outstanding plasticity are developed for patterned information storage and encryption applications. The organogels possessing outstanding mechanical properties and tunable luminescent colors are prepared by electrostatic and coordinative interactions between natural DNA, synthetic ligands, and rare earth (RE) ions. The organogel-REs can be stretched by 180 times and show an ultrastrong breaking strength of 80 MPa. A series of applications with both information storage and encryption, such as self-information pattern, quick response (QR) code, and barcode, are successfully demonstrated by the organogel-REs. The developed information storage systems have various advantages of good processability, high stretchability, excellent stability, and versatile design of information patterns. Therefore, the organogel-RE-based information storage systems are suitable for applications under different scenarios, such as flexible devices under repeating rude operations. The advancements will enable the design and development of luminescent organogel-REs as information storage and encryption media for various scenarios.

Highly Stiff and Stretchable DNA Liquid Crystalline Organogels with Super Plasticity, Ultrafast Self-Healing, and Magnetic Response Behaviors.

DNA-based gels are attractive materials as they allow intuitive rational design, respond to external physicochemical stimuli, and show great potential for biomedical applications. However, their relatively poor mechanical properties currently limit their technological application considerably as the latter requires mechanical integrity and tunability. With this work, a DNA organogel is reported that gels through supramolecular interactions, which induce mesophase ordering, and that exhibits exceptional stretchability, deformability, plasticity, and biocompatibility. Moreover, the nature of the supramolecular bond enables complete self-healing within 3 s. Most importantly, the DNA-based liquid crystalline organogels exhibit impressive ultimate tensile strengths above 1 MPa, stiffness higher than 20 MPa, and toughness up to 18 MJ m-3 , rendering these materials the strongest among reported DNA networks. In addition, the facile access is demonstrated to composite DNA materials by blending magnetic nanoparticles with the organogel matrix giving access to magnetic field induced actuation. It is believed that these findings contribute significantly to the advancement of DNA gels for their use in smart materials and biomedical applications.

3D-Printed Biomimetic Systems with Synergetic Color and Shape Responses Based on Oblate Cholesteric Liquid Crystal Droplets.

Living organisms in nature have amazing control over their color, shape, and morphology in response to environmental stimuli for camouflage, communication, or reproduction. Inspired by the camouflage of the octopus via the elongation or contraction of its pigment cells, oblate cholesteric liquid crystal droplets are dispersed in a polymer matrix, serving as the role of pigment cells and showing structural color due to selective Bragg reflection by their periodic helical structure. The color of 3D-printed biomimetic systems can be tuned by changing the helical pitch via the chiral dopant concentration or temperature. When the oblate liquid crystal droplets are heated up to isotropic, the opaque and colored biomimetic systems become transparent and colorless. Meanwhile, the isotropic liquid crystal droplets tend to become spherical, causing volume contraction along the film plane and volume dilation in the perpendicular direction. The internal strain combined with the gradient distribution of the oblate isotropic liquid crystal droplets result in corresponding shape transformations. The camouflage of a biomimetic octopus and the blossom of a biomimetic flower, both of which show synergetic color and shape responses, are demonstrated to inspire the design of functional materials and intelligent devices.

Attractive Pickering Emulsion Gels.

Properties of emulsions highly depend on the interdroplet interactions and, thus, engineering interdroplet interactions at molecular scale are essential to achieve desired emulsion systems. Here, attractive Pickering emulsion gels (APEGs) are designed and prepared by bridging neighboring particle-stabilized droplets via telechelic polymers. In the APEGs, each telechelic molecule with two amino end groups can simultaneously bind to two carboxyl functionalized nanoparticles in two neighboring droplets, forming a bridged network. The APEG systems show typical shear-thinning behaviors and their viscoelastic properties are tunable by temperature, pH, and molecular weight of the telechelic polymers, making them ideal for direct 3D printing. The APEGs can be photopolymerized to prepare APEG-templated porous materials and their microstructures can be tailored to optimize their performances, making the APEG systems promising for a wide range of applications.

Transparent Impact-Resistant Composite Films with Bioinspired Hierarchical Structure.

Inspired by the helicoidally organized microstructure of stomatopods' smasher dactyl club, a type of impact-resistant composite film reinforced with periodic helicoidal nanofibers is designed and fabricated, which reproduces the structural complexity of the natural material. To periodically align nanofibers in a helicoidal structure, an electrospinning system is developed to better control the alignment of electrospun nanofibers. When the nanofiber scaffold is embedded in an epoxy matrix, the presence of a hierarchical structure allows the composite films to achieve properties well beyond their constituents. The composite film exhibits excellent optical transparency and mechanical properties, such as enhanced tensile strength, ductility, and defect tolerance. With elegant design mimicking nature's hierarchical structure at multilength scales, the composite films could effectively release the impact energy and greatly increase the impact resistance, suggesting that the transparent composite films are promising protective layers suitable for various applications.

Relative adrenal insufficiency in mice deficient in 5α-reductase 1.

Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as 'relative adrenal insufficiency'. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5ß-reductase, resulting in compensatory downregulation of the hypothalamic-pituitary-adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P<0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P<0.05), handling stress (2.5-fold lower, P<0.05) and restraint stress (43% lower, P<0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause 'relative adrenal insufficiency' in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease.

Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells.

Mitochondrial dysfunction has been associated with insulin resistance, obesity and diabetes. Hyperinsulinaemia and hyperlipidaemia are hallmarks of the insulin-resistant state. We sought to determine the contributions of high insulin and saturated fatty acid exposure to mitochondrial function and biogenesis in cultured myocytes. Differentiated C2C12 myotubes were left untreated or exposed to chronic high insulin or high palmitate. Mitochondrial function was determined assessing: oxygen consumption, mitochondrial membrane potential, ATP content and ROS (reactive oxygen species) production. We also determined the expression of several mitochondrial genes. Chronic insulin treatment of myotubes caused insulin resistance with reduced PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) signalling. Insulin treatment increased oxygen consumption but reduced mitochondrial membrane potential and ROS production. ATP cellular levels were maintained through an increased glycolytic rate. The expression of mitochondrial OXPHOS (oxidative phosphorylation) subunits or Mfn-2 (mitofusin 2) were not significantly altered in comparison with untreated cells, whereas expression of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) and UCPs (uncoupling proteins) were reduced. In contrast, saturated fatty acid exposure caused insulin resistance, reducing PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) activation while increasing activation of stress kinases JNK (c-Jun N-terminal kinase) and p38. Fatty acids reduced oxygen consumption and mitochondrial membrane potential while up-regulating the expression of mitochondrial ETC (electron chain complex) protein subunits and UCP proteins. Mfn-2 expression was not modified by palmitate. Palmitate-treated cells also showed a reduced glycolytic rate. Taken together, our findings indicate that chronic insulin and fatty acid-induced insulin resistance differentially affect mitochondrial function. In both conditions, cells were able to maintain ATP levels despite the loss of membrane potential; however, different protein expression suggests different adaptation mechanisms.