Evidence for voltage-gated potassium channel beta-subunits with oxidoreductase motifs in human and rodent pancreatic beta cells

Voltage-gated K(+) channel alpha subunits (K(V) alpha) have been previously identified in pancreatic islet beta-cells where it has been suggested they have a role in membrane repolarization and insulin secretion. Here we report the cloning of the three mammalian K(V) beta subunits, including splice variants of these subunits, from both human and rat pancreatic islets and from the rat insulinoma cell line INS-1. Two of the splice variants, K(V) beta1a and K(V) beta3, previously reported to be neuronal tissue specific, are expressed in islets and INS-1 cells. In addition, a splice variant of K(V) beta2 that lacks two potential protein kinase C phosphorylation sites at the amino terminus is present. Immunoblot analysis suggests a high level of K(V) beta2 subunit protein in rat pancreatic islets and immunoprecipitation with anti-K(V) beta2 antibody pulls down a protein from INS-1 cells that reacts with anti-aldose reductase antibody. The K(V) beta subunits, which are attached to the cytoplasmic face of the alpha subunits and are members of the aldose reductase superfamily of NADPH oxidoreductases, may have an as yet undetermined role in the regulation of insulin secretion by the intracellular redox potential. Finally, we suggest that a systematic nomenclature for K(V) beta subunits first proposed by McCormack et al. be adopted for this family of potassium channel subunits as it corresponds with the nomenclature used for their cognate K(V) alpha subunits.     

Encapsulation of Human Natural and Induced Regulatory T‐Cells in IL‐2 and CCL1 Supplemented Alginate‐GelMA Hydrogel for 3D Bioprinting

Regulatory T‐cells (Tregs) are important modulators of the immune system through their intrinsic suppressive functions. Systemic adoptive transfer of ex vivo expanded Tregs has been extensively investigated for allogeneic transplantation. Due to the time‐consuming and costly expansion protocols of Tregs, more targeted approaches could be beneficial. The encapsulation of human natural and induced Tregs for localized immunosuppression is described for the first time. Tregs encapsulated in alginate‐gelatin methacryloyl hydrogel remain viable, phenotypically stable, functional, and confined in the structure. Supplementation of the hydrogel with the Treg‐specific bioactive factors interleukin‐2 and chemokine ligand 1 improves Treg viability, suppressive phenotype, and function, and attracts to the structure CCR8⁺ T‐cells enriched with anti‐inflammatory subpopulations, including Tregs, from human peripheral blood. Furthermore, these findings are applicable to 3D bioprinting. Co‐axial printing of murine pancreatic islets with human natural and induced Tregs protects the islets from xenoresponse upon co‐culture with human peripheral blood mononuclear cells. This establishes the co‐encapsulation of Tregs by co‐axial 3D bioprinting as a valid option for providing local immune protection to allogeneic cellular transplants such as pancreatic islets.     

Delivery of iPS‐NPCs to the Stroke Cavity within a Hyaluronic Acid Matrix Promotes the Differentiation of Transplanted Cells

Stroke is the leading cause of adult disability with ≈80% being ischemic. Stem cell transplantation has been shown to improve functional recovery. However, the overall survival and differentiation of these cells is still low. The infarct cavity is an ideal location for transplantation as it is directly adjacent to the highly plastic peri‐infarct region. Direct transplantation of cells near the infarct cavity has resulted in low cell viability. Here, neural progenitor cells derived from induce pluripotent stem cells (iPS‐NPC) are delivered to the infarct cavity of stroked mice encapsulated in a hyaluronic acid hydrogel matrix to protect the cells. To improve the overall viability of transplanted cells, each step of the transplantation process is optimized. Hydrogel mechanics and cell injection parameters are investigated to determine their effects on the inflammatory response of the brain and cell viability, respectively. Using parameters that balanced the desire to keep surgery invasiveness minimal and cell viability high, iPS‐NPCs are transplanted to the stroke cavity of mice encapsulated in buffer or the hydrogel. While the hydrogel does not promote stem cell survival one week post‐transplantation, it does promote differentiation of the neural progenitor cells to neuroblasts.     

准分子激光和紫外线照射对胰岛免疫原性的影响

要新生大鼠胰岛样细胞团经准分子激光和中波紫外线照射面处理后,其免疫原性明显降低,激光组尤为显著,形态学检查显示胰岛细胞分泌颗粒和亚细胞结构保持完整无损。胰岛素分泌功能与对照组无明显差异。经STZ引致的糖尿病大鼠中胰岛异体移植,结果表明激光组受体大鼠糖尿病缓解时间较紫外线组与对照组明显延长.     

Immune-Modulating Mucin Hydrogel Microdroplets for the Encapsulation of Cell and Microtissue

Immune-modulating biomaterials used to encapsulate cells and microtissue transplants can be engineered to dampen the immune reaction and increase treatment efficacy. Mucin-derived materials have gained attention for their ability to modulate macrophage and dendritic cell activity, and to trigger mild foreign body response when implanted in vivo. In this study, the potential of mucin hydrogels (Muc-gels) as cell-encapsulating materials is investigated. When placed in contact with blood, Muc-gels trigger significantly lower complement activation, compared to clinical grade alginate hydrogels. Muc-gel is a size-selective barrier strongly hindering the diffusion of molecules with a hydrodynamic radius larger than 6 nm such as immunoglobulins. Muc-gels support the growth of MIN6m9 insulin-secreting cells into islet-like organoids and the survival of primary human pancreatic islets, which maintained glucose responsiveness. Muc-gels can be shaped into microdroplets in which MIN6m9 cells or cell aggregates can be encapsulated without loss of viability. Microdroplet encapsulation will allow transplants to be easily injected and improve their survival by favoring mass transport through the capsule. The combination of strong immune modulatory properties, appropriate selective barrier profile, biocompatibility for embedded cells Muc-gels of particular value for microencapsulating cells or microtissues for transplantation.     

Microfluidic Spinning of Cell‐Responsive Grooved Microfibers

Engineering living tissues that simulate their natural counterparts is a dynamic area of research. Among the various models of biological tissues being developed, fiber‐shaped cellular architectures, which can be used as artificial blood vessels or muscle fibers, have drawn particular attention. However, the fabrication of continuous microfiber substrates for culturing cells is still limited to a restricted number of polymers (e.g., alginate) having easy processability but poor cell–material interaction properties. Moreover, the typical smooth surface of a synthetic fiber does not replicate the micro‐ and nanofeatures observed in vivo, which guide and regulate cell behavior. In this study, a method to fabricate photocrosslinkable cell‐responsive methacrylamide‐modified gelatin (GelMA) fibers with exquisite microstructured surfaces by using a microfluidic device is developed. These hydrogel fibers with microgrooved surfaces efficiently promote cell encapsulation and adhesion. GelMA fibers significantly promote the viability of cells encapsulated in/or grown on the fibers compared with similar grooved alginate fibers used as controls. Importantly, the grooves engraved on the GelMA fibers induce cell alignment. Furthermore, the GelMA fibers exhibit excellent processability and could be wound into various shapes. These microstructured GelMA fibers have great potential as templates for the creation of fiber‐shaped tissues or tissue microstructures.     

Regulation of the Stem Cell–Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti‐Inflammatory Drug

The host immune system is known to influence mesenchymal stem cell (MSC)‐mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T‐lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro‐inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro‐inflammatory T‐lymphocyte‐induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE‐3 and CASPASE‐8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti‐inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro‐inflammatory cytokine‐induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC‐host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration.     

Rapid and Long‐Term Glycemic Regulation with a Balanced Charged Immune‐Evasive Hydrogel in T1DM Mice

Transplantation of encapsulated islets is a promising treatment for patients with type 1 diabetes mellitus. However, its long‐term clinical therapeutic efficacy is still hindered by serious immune rejection from the host immunological responses to the implanted materials, known as foreign body reaction (FBR). In this work, an anti‐biofouling balanced charged hydrogel is reported that can serve as an excellent immunoprotective material for islet transplantation therapy. It is found that the encapsulated islets can maintain their glucose‐responsive and insulin‐producing functions. Additionally, the hydrogel can effectively evade in vivo FBR after intraperitoneal implantation in an immunocompetent streptozotocin‐induced diabetic mouse model. As a result, 100% of the mice rapidly recover to normoglycemia within 2 d and stably maintain for at least 150 d without any immunosuppression treatment. These findings shed light on the “insulin independence and immunoisolation” encapsulation strategy, which can overcome the barrier of islet transplantation and holds the potential to improve current clinical therapeutic efficacy.     

Ultrathin Polymeric Coatings Based on Hydrogen‐Bonded Polyphenol for Protection of Pancreatic Islet Cells

Though transplantation of pancreatic islet cells has emerged as a promising treatment for Type 1 diabetes its clinical application remains limited due to a number of limitations including both pathogenic innate and adaptive immune responses. This paper reports on a novel type of multifunctional cytoprotective material applied to coat living pancreatic islets. The coating utilizes hydrogen‐bonded interactions of a natural polyphenol (tannic acid) with poly(N‐vinylpyrrolidone) deposited on the islet surface via non‐ionic layer‐by‐layer assembly. It is demonstrated that the coating is conformal over the surface of mammalian islets including those derived from rat, non‐human primate (NHP), and human. In contrast to unmodified controls, the coated islets maintain their viability and β‐cell functionality for at least 96 hours in vitro. It is also determined that the coating demonstrates immunomodulatory cytoprotective properties suppressing pro‐inflammatory cytokine synthesis in stimulated bone marrow‐derived macrophages and diabetogenic BDC‐2.5 T cells. The coating material combines high chemical stability under physiologically relevant conditions with capability of suppressing cytokine synthesis, crucial parameters for prolonged islet integrity, viability, and function in vivo. This study offers new opportunities in the area of advanced multifunctional materials to be used for a cell‐based transplantation therapy     

Multiscale modeling of insulin secretion

Insulin secretion from pancreatic beta cells is a fundamental physiological process, and its impairment plays a pivotal role in the development of diabetes. Mathematical modeling of insulin secretion has a long history, both on the level of the entire body and on the cellular and subcellular scale. However, little direct communication between these disparate scales has been included in mathematical models so far. Recently, we have proposed a minimal model for the incretin effect by which the gut hormone glucagon-like peptide 1 (GLP-1) enhances insulin secretion. To understand how this model couples to cellular events, we use a previously published mechanistic model of insulin secretion, and show mathematically that induction of glucose competence in beta cells by GLP-1 can underlie derivative control by GLP-1.     

海藻硫酸多糖对HPM辐射致GC-2细胞损伤保护作用研究

探讨了海藻硫酸多糖(SP)对高功率微波(HPM)致小鼠精母细胞系GC-2细胞的损伤防治作用及其机制,为新型抗电磁辐射药物开发提供基础.将GC-2细胞分为药物组、药物对照组、辐射组和正常对照组,采用平均功率密度为30 mW/cm2的S波段HPM辐照15 min,药物组和药物对照组于照射前24h加入SP(终浓度25 μg/...     

～1.2 V open-circuit voltage from organic solar cells

Organic solar cells (OSCs) have achieved rapid advance due to the continuous development of high-performance key materials.Recently,the power conversion efficiencies (PCEs)of OSCs under 1 Sun condition (AM 1.5 G,100 mW/cm2) are striving toward 19％[1-5].The PCE improvement benefits from the largely enhanced short-circuit current density (Jsc) and fill factor (FF).However,these cells show relatively low open-circuit voltage (Voc) around 0.8-0.9 V.The rise of Internet of Things (loT) industry has promoted the indoor application of solar cells.OSCs can afford higher PCEs under various indoor light as compared to 1 Sun condition[6,7],but they present lower Voc[8].Fabricating tandem devices is an effective strategy to boost the performance of OSCs.Sub-cells with syn-chronously high Voc,Jsc and FF are highly desired in tandem cells,while these sub-cells are still limited[9].Thus,improving Voc without sacrificing Jsc and FF is an urgent mission in OSCs.     

Liver‐Target and Glucose‐Responsive Polymersomes toward Mimicking Endogenous Insulin Secretion with Improved Hepatic Glucose Utilization

Oral insulin therapy that targets the liver and further mimics glucose‐responsive secretion holds promise for correcting defects in glucose metabolism caused by peripheral delivery. This work describes the construction of polymersomes (Pep‐PMS), which are composed of glucose‐responsive polymers decorated with peptides that readily bind to the ganglioside‐monosialic acid (GM1) receptor in the intestinal epithelium. Pep‐PMS are efficiently transported across the intestinal epithelium through GM1‐mediated transcytosis, leading to their abundant accumulation in the liver. Moreover, Pep‐PMS can efficiently encapsulate insulin in euglycemia and release them in hyperglycemia. Under hyperglycemic conditions, the Pep‐PMS dissociate to release the encapsulated insulin in response to glucose oxidase (GOx)‐induced H₂O₂. Surprisingly, the postprandial blood glucose levels of diabetic rats treated with Pep‐PMS can be maintained even after being challenged by glucose administration. Hepatic glucose uptake and glycogen production are also elevated after treating diabetic rats with Pep‐PMS, which is similar to glucose utilization in normal rats. Oral delivery systems that target the liver and serve as a reservoir for glucose‐responsive insulin secretion may improve the therapeutic effect in people with diabetes.     

A Melanin‐Based Natural Antioxidant Defense Nanosystem for Theranostic Application in Acute Kidney Injury

Acute kidney injury (AKI) is frequently associated with oxidative stress and causes high mortality annually in clinics. Nanotechnology‐mediated antioxidative therapy is emerging as a novel strategy for the treatment of AKI. Herein, a novel biomedical use of the endogenous biopolymer melanin as a theranostic natural antioxidant defense nanoplatform for AKI is reported. In this study, ultrasmall Mn²⁺‐chelated melanin (MMP) nanoparticles are easily prepared via a simple coordination and self‐assembly strategy, and further incorporated with polyethylene glycol (MMPP). In vitro experiments reveal the ability of MMPP nanoparticles to scavenge multiple toxic reactive oxygen species (ROS) and suppress ROS‐induced oxidative stress. Additionally, in vivo results from a murine AKI model demonstrate preferential renal uptake of MMPP nanoparticles and a subsequent robust antioxidative response with negligible side effects according to positron emission tomography/magnetic resonance (PET/MR) bimodal imaging and treatment assessment. These results indicate that the effectiveness of MMPP nanoparticles for treating AKI suggests the potential efficacy of melanin as a natural theranostic antioxidant nanoplatform for AKI, as well as other ROS‐related diseases.     

基于肠道菌群探讨葛根芩连汤治疗湿热型2型糖尿病研究进展*

摘 要: 近年来世界范围内2型糖尿病(Diabetes Mellitus type 2,T2DM)的发病率不断上升。微生态学研究证实,T2DM疾病的发生与肠道菌群数量及比例的失调有很大的关联性,这成为研究热点。现有实验发现:肠道菌群紊乱可通过短链脂肪酸学说、胆汁酸代谢学说、内毒素学说、支链氨基酸学说等机制来影响T2DM的发生发展。湿热证T2DM患者在临床最为常见,该类患者胰岛素抵抗最为严重,而动物实验研究发现葛根芩连汤可通过特定的分子机制及通路作用于肠道菌群,通过调节胰岛β细胞的功能、提高胰岛素敏感性、减轻氧化应激反应,从而调节血糖,减轻胰岛素抵抗,为临床治疗T2DM患者提供更科学的依据。但由于菌群数量庞杂,现有数据多偏重于动物实验,且研究菌群特异性不足,为此今后需进一步加强对T2DM特定菌群的研究,以及增加临床大样本数据统计。     

Realizing an Unprecedented Fill Factor of 82.2% in Ternary Organic Solar Cells via Co-Crystallization of Non-Fullerene Acceptors

Ternary strategy is demonstrated as an efficient approach to achieve high short-circuit current and open-circuit voltage to boost the performance of organic solar cells (OSCs), however, the realization of high fill-factor (FF) in ternary OSCs has been rare. In this study, three thiophene terminated non-fullerene acceptors (NFAs) with methyl or chlorine substitutions on their end-groups are designed and synthesized, and further incorporated into the state-of-the-art PM6:L8-BO system to construct ternary OSCs. Subtle changes in their chemical structures significantly modify the molecular packings of these thiophene terminated NFAs. While BTP-ThMe and BTP-ThCl have limited forms of dimer, versatile molecular dimers, including “Z” shaped D-D, “S” shaped A-A, and “F” shaped A-D packings exist in BTP-ThMeCl, which lead to the formation of compact 3D honey-comb network and this is analogous to the host acceptor L8-BO. This synergetic molecular packing between BTP-ThMeCl and L8-BO contributes to maintain the 3D charge transport network in the ternary system via the formation of NFA co-crystals at the molecular level, and consequently realizing a maximum power conversion efficiency of 19.1% with a superior FF of 82.2%, which is the highest FF reported so far for OSCs.     

From cells to laminate: probing and modeling residual stress evolution in thin silicon photovoltaic modules using synchrotron X‐ray micro‐diffraction experiments and finite element simulations

Fracture of silicon crystalline solar cells has recently been observed in increasing percentages especially in solar photovoltaic (PV) modules involving thinner silicon solar cells (<200 μm). Many failures due to fracture have been reported from the field because of environmental loading (snow, wind, etc.) as well as mishandling of the solar PV modules (during installation, maintenance, etc.). However, a significantly higher number of failures have also been reported during module encapsulation (lamination) indicating high residual stress in the modules and thus more prone to cell cracking. We report here, through the use of synchrotron X‐ray submicron diffraction coupled with physics‐based finite element modeling, the complete residual stress evolution in mono‐crystalline silicon solar cells during PV module integration process. For the first time, we unravel the reason for the high stress and cracking of silicon cells near soldered inter‐connects. Our experiments revealed a significant increase of residual stress in the silicon cell near the solder joint after lamination. Moreover, our finite element simulations show that this increase of stress during lamination is a result of highly localized bending of the cell near the soldered inter‐connects. Further, the synchrotron X‐ray submicron diffraction has proven to be a very effective way to quantitatively probe mechanical stress in encapsulated silicon solar cells. Thus, this technique has ultimately enabled these findings leading to the enlightening of the role of soldering and encapsulation processes on the cell residual stress. This model can be further used to suggest methodologies that could lead to lower stress in encapsulated silicon solar cells, which are the subjects of our continued investigations. Copyright © 2017 John Wiley & Sons, Ltd.     

Tissue Adhesive Catechol‐Modified Hyaluronic Acid Hydrogel for Effective,Minimally Invasive Cell Therapy

Current hyaluronic acid (HA) hydrogel systems often cause cytotoxicity to encapsulated cells and lack the adhesive property required for effective localization of transplanted cells in vivo. In addition, the injection of hydrogel into certain organs (e.g., liver, heart) induces tissue damage and hemorrhage. In this study, we describe a bioinspired, tissue‐adhesive hydrogel that overcomes the limitations of current HA hydrogels through its improved biocompatibility and potential for minimally invasive cell transplantation. HA functionalized with an adhesive catecholamine motif of mussel foot protein forms HA‐catechol (HA‐CA) hydrogel via oxidative crosslinking. HA‐CA hydrogel increases viability, reduces apoptosis, and enhances the function of two types of cells (human adipose‐derived stem cells and hepatocytes) compared with a typical HA hydrogel crosslinked by photopolymerization. Due to the strong tissue adhesiveness of the HA‐CA hydrogel, cells are easily and efficiently transplanted onto various tissues (e.g., liver and heart) without the need for injection. Stem cell therapy using the HA‐CA hydrogel increases angiogenesis in vivo, leading to improved treatment of ischemic diseases. HA‐CA hydrogel also improved hepatic functions of transplanted hepatocytes in vivo. Thus, this bioinspired, tissue‐adhesive HA hydrogel can enhance the efficacy of minimally invasive cell therapy.     

Injectable Stem Cell‐Laden Photocrosslinkable Microspheres Fabricated Using Microfluidics for Rapid Generation of Osteogenic Tissue Constructs

Direct injection is a minimally invasive method of stem cell transplantation for numerous injuries and diseases. However, despite its promising potential, its clinical translation is difficult due to the low cell retention and engraftment after injection. With high versatility, high‐resolution control and injectability, microfabrication of stem‐cell laden biomedical hydrogels holds great potential as minimally invasive technology. Herein, a strategy of microfluidics‐assisted technology entrapping bone marrow‐derived mesenchymal stem cells (BMSCs) and growth factors in photocrosslinkable gelatin (GelMA) microspheres to ultimately generate injectable osteogenic tissue constructs is presented. Additionally, it is demonstrated that the GelMA microspheres can sustain stem cell viability, support cell spreading inside the microspheres and migration from the interior to the surface as well as enhance cell proliferation. This finding shows that encapsulated cells have the potential to directly and actively participate in the regeneration process. Furthermore, it is found that BMSCs encapsulated in GelMA microspheres show enhanced osteogenesis in vitro and in vivo, associated with a significant increase in mineralization. In short, the proposed strategy can be utilized to facilitate bone regeneration with minimum invasiveness, and can potentially be applied along with other matrices for extended applications.     

Rapid and Continuous Hydrodynamically Controlled Fabrication of Biohybrid Microfibers

Cell encapsulation is critical for many biotechnology applications including environmental remediation, bioreactors, and regenerative medicine. Here, the development of biohybrid microfibers comprised of encapsulated bacteria in hydrogel matrices produced on‐chip using microfluidics is reported. The fiber production process utilizes hydrodynamic shaping of a cell‐laden core fluid by a miscible sheath fluid. Production of the fibers containing viable bacteria was continuous in contrast to the more typical methods in which cells infiltrated or were attached to prepared fibers. The biohybrid fibers were composed of poly (ethylene glycol dimethacrylate) matrices and individually both E. coli and B. cereus were explored as model cellular payloads. Post processing growth curves (24 h) of bacteria within fibers were in excellent agreement with that of controls suggesting minimal impact. Finally, the biohybrid fibers showed even distribution of encapsulated cells and >90% cell viability.