Pancreatic islets are surrounded by extracellular matrix (ECM) which provides mechanical and biochemical cues to the β-cells that regulate survival and insulin secretion. Changes to ECM stiffness have been correlated to dysfunction in insulin secretion that is directly coupled to glucose metabolism; however, the mechanisms of mechanotransduction regulating insulin secretion have not been studied in the islet. We hypothesize that increasing matrix stiffness will increase islet glucose sensitivity by increasing phosphofructokinase (PFK) activity. To determine the effect of changes in ECM stiffness on islet function we encapsulated mouse islets in a reverse thermal gel (RTG) scaffold with increasing stiffness as determined by rheological analysis. Glucose-stimulated insulin secretion, PFK activity, and PFK expression was measured after 24 hours of culture. Proliferation was analyzed by immunohistochemistry of Ki-67. Reactive oxygen species (ROS) were measured via confocal microscopy of islets transfected with an adenoviral ROS sensor. We found that increasing RTG wt% yielded increasing stiffness at 40°C. Insulin secretion increased as the matrix stiffness increased in basal (2mM) and high glucose (20mM) conditions. Insulin secretion at 20mM glucose normalized to 2mM glucose (stimulation index) decreases with matrix stiffness indicating dysfunction to insulin secretion. PFK activity increased in islets encapsulated in stiffer RTGs. No changes in proliferation were observed in any samples compared to controls. Our results support a role for ECM stiffness in regulating insulin secretion via PFK activity. This work provides insight into how changes in ECM stiffness contribute to islet dysfunction, as in pancreatitis and T2D. Our results will inform future development of mechanically tuned microenvironments for differentiation of iPSCs into functional β-cells and provide novel targets to protect against islet dysfunction in T2D. Disclosure C.Garcia: None. K.Holcomb: None. N.L.Farnsworth: None. Funding American Diabetes Association (7-21-JDF-020 to N.L.F.); National Institutes of Health (1F31DK132926-01A1); JDRF (3-APF-2019-749-A-N, 1-FAC-2020-891-A-N)
Over 34 years since its conception, research in educational settings has found evidence for the effectiveness of the 5E Instructional Model. Indeed, several studies have reported evidence of a better conceptual understanding of scientific ideas and models, positive effects on general achievement in science, and positive attitudes toward science. In this commentary, we would like to put forward the principles from cognitive sciences on how people learn which may underlie the 5E Model and that could theoretically contribute to the model’s effectiveness as a learning sequence. Connections to conceptual change theory are especially highlighted.
Analytic Partial Differential Equations is a treatise on the study of solutions of partial differential equations via microlocal analysis and FBI transform
C materials are being used in several demanding engineering applications owing to their superior properties that derive from a synergy between the constituent materials. There exists a size effect in materials such that the smaller a material, the stronger it tends to be; designing nanoarchitectured materials takes advantage of this phenomenon. Why not explore the concept of nanoarchitecture beyond monomaterials such as metals and ceramics, to composites? This would take advantage of the size effect and the synergy among the components to create superior properties. This was a question that Lorenzo Valdevit and his research team at the University of California, Irvine, sought to answer in their recently published article in Science Advances (https:// doi. org/ 10. 1126/ sciadv. abo30 80). “Manufacturing of dense materials at such small length scales is faced with several complexities and this has restricted the field to monomaterial cellular/porous nanoarchitectures. A suitable fabrication route is required to help exploit the potential of nanoarchitectured composites,” says Valdevit. The team utilized a two-photon direct laser writing three-dimensional printing technique to create a polymeric platform, which was then pyrolyzed to obtain a carbon shell as the reinforcement phase. Nickel was electrodeposited on the surfaces of the carbon shell and this approach resulted in a near fully dense composite with two interpenetrating phases. The researchers studied nickel/carbon interpenetrating phase composites (IPCs) with varying topologies—gyroid and spinodal surfaces. The nickel/carbon volume ratio was varied from 80/20 to 50/50, and the samples were uniaxially compressed to measure the compressive strength and strain energy absorption. The IPCs possessed a much higher compressive strength and strain energy absorption than their monolithic variants. Despite having almost 50% brittle carbon, the 52/48 gyroid IPC absorbed about five times as much strain energy as monolithic carbon and twice as much as nickel. These values were also higher than rule-of-mixture predictions (which consider the volume ratios and individual properties of the constituents). This hints at a much more complex interaction between constituents, inherent in the interpenetrating design, which significantly inhibits crack propagation and increases the strength. These IPCs also have more isotropic properties than regular fiber-reinforced composites, as well as higher specific compressive strength and strain energy absorption (normalized by density), which makes them suitable for applications requiring highperformance, lightweight materials. “Despite the challenges of scalability with the current fabrication technique, this work helps demonstrate how the concept of IPCs can be exploited to produce structures with significantly improved mechanical properties over their monolithic counterparts,” Valdevit says. “Also, by studying both highly periodic and randomly arranged topologies (gyroid and spinodal), we demonstrate[d] that the topologies of
