The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates

Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. Methods: EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Results: Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins.Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate.By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation.ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Conclusions: Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active cytokine induced caspase 3/7 apoptotic pathway and is responsive to ER stress initiation factors. The cells' ability to proliferate can be further increased by already known compounds as well as by novel peptides and proteins. Based on its robust performance during the functionality assessment assays, the EndoC-βH1 cell line was successfully used as a screening platform for identification of novel anti-diabetic drug candidates. Keywords: EndoC-βH1, Pseudoislets, Glucose stimulated insulin secretion, Somatostatin signaling, Proliferatio

Cooking a Pot of Beef Stew: Navigating Through Difficult Times Through Slow Philosophy

The Slow Movement offers feminist scholars permission to inhabit multiple identities and recognizes the inherent value of care work as work. Against an intimate living backdrop of pancreatic cancer, COVID-19, and overwork, I practice Slow scholarship by embodied caring for three elders while experiencing powerful anxiety. Identifying as a daughter, mother, carer, student, friend, leader, and scholar, I look to a variety of wisdom sources outside universal concepts of value and time to ground myself in the present. Zen, Taoism, and existentialism suggest staying with anxiety as a viable means to live in an uncomfortable present

Responsibility Ascriptions in Technology Development and Engineering: Three Perspectives

In the last decades increasing attention is paid to the topic of responsibility in technology development and engineering. The discussion of this topic is often guided by questions related to liability and blameworthiness. Recent discussions in engineering ethics call for a reconsideration of the traditional quest for responsibility. Rather than on alleged wrongdoing and blaming, the focus should shift to more socially responsible engineering, some authors argue. The present paper aims at exploring the different approaches to responsibility in order to see which one is most appropriate to apply to engineering and technology development. Using the example of the development of a new sewage water treatment technology, the paper shows how different approaches for ascribing responsibilities have different implications for engineering practice in general, and R&D or technological design in particular. It was found that there was a tension between the demands that follow from these different approaches, most notably between efficacy and fairness. Although the consequentialist approach with its efficacy criterion turned out to be most powerful, it was also shown that the fairness of responsibility ascriptions should somehow be taken into account. It is proposed to look for alternative, more procedural ways to approach the fairness of responsibility ascriptions

Connecting Higher-Order Separation Logic to a First-Order Outside World

Separation logic is a useful tool for proving the correctness of programs that manipulate memory, especially when the model of memory includes higher-order state: Step-indexing, predicates in the heap, and higher-order ghost state have been used to reason about function pointers, data structure invariants, and complex concurrency patterns. On the other hand, the behavior of system features (e.g., operating systems) and the external world (e.g., communication between components) is usually specified using first-order formalisms. In principle, the soundness theorem of a separation logic is its interface with first-order theorems, but the soundness theorem may implicitly make assumptions about how other components are specified, limiting its use. In this paper, we show how to extend the higher-order separation logic of the Verified Software Toolchain to interface with a first-order verified operating system, in this case CertiKOS, that mediates its interaction with the outside world. The resulting system allows us to prove the correctness of C programs in separation logic based on the semantics of system calls implemented in CertiKOS. It also demonstrates that the combination of interaction trees + CompCert memories serves well as a lingua franca to interface and compose two quite different styles of program verification

Verifying an HTTP Key-Value Server with Interaction Trees and VST

We present a networked key-value server, implemented in C and formally verified in Coq. The server interacts with clients using a subset of the HTTP/1.1 protocol and is specified and verified using interaction trees and the Verified Software Toolchain. The codebase includes a reusable and fully verified C string library that provides 17 standard POSIX string functions and 17 general purpose non-POSIX string functions. For the KVServer socket system calls, we establish a refinement relation between specifications at user-space level and at CertiKOS kernel-space level