Relatively Complete Counterexamples for Higher-Order Programs

In this paper, we study the problem of generating inputs to a higher-order program causing it to error. We first study the problem in the setting of PCF, a typed, core functional language and contribute the first relatively complete method for constructing counterexamples for PCF programs. The method is relatively complete in the sense of Hoare logic; completeness is reduced to the completeness of a first-order solver over the base types of PCF. In practice, this means an SMT solver can be used for the effective, automated generation of higher-order counterexamples for a large class of programs. We achieve this result by employing a novel form of symbolic execution for higher-order programs. The remarkable aspect of this symbolic execution is that even though symbolic higher-order inputs and values are considered, the path condition remains a first-order formula. Our handling of symbolic function application enables the reconstruction of higher-order counterexamples from this first-order formula. After establishing our main theoretical results, we sketch how to apply the approach to untyped, higher-order, stateful languages with first-class contracts and show how counterexample generation can be used to detect contract violations in this setting. To validate our approach, we implement a tool generating counterexamples for erroneous modules written in Racket.Comment: In Proceedings of the 36th annual ACM SIGPLAN conference on Programming Language Design and Implementation, Portland, Oregon, June 201

Stem Cell-Based Approaches for the Treatment of Diabetes

The incidence of diabetes and the associated debilitating complications are increasing at an alarming rate worldwide. Current therapies for type 1 diabetes focus primarily on administration of exogenous insulin to help restore glucose homeostasis. However, such treatment rarely prevents the long-term complications of this serious metabolic disorder, including neuropathy, nephropathy, retinopathy, and cardiovascular disease. Whole pancreas or islet transplantations have enjoyed limited success in some individuals, but these approaches are hampered by the shortage of suitable donors and the burden of lifelong immunosuppression. Here, we review current approaches to differentiate nonislet cell types towards an islet-cell phenotype which may be used for larger-scale cell replacement strategies. In particular, the differentiation protocols used to direct embryonic stem cells, progenitor cells of both endocrine and nonendocrine origin, and induced pluripotent stem cells towards an islet-cell phenotype are discussed

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

AIMS: Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. METHODS: Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. RESULTS: The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. CONCLUSIONS: Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40618-021-01620-6

Managing a Multi-Forage Rotational Stocking Unit without Farming Equipment and with the Addition of Economical Fringe Benefits

A specialized introduced forage rotational stocking grazing unit was managed without usual grassland farming equipment and with various alternative management and production techniques as fringe benefits. The forage production techniques have been successful for many years. Livestock production and economic perimeters have been average to above average. The greatest sold beef yield has been 713 pounds of beef per acre. That is excellent considering the low-capital overhead management style of the unit

Positive interplay between FFAR4/GPR120, DPP-IV inhibition and GLP-1 in beta cell proliferation and glucose homeostasis in obese high fat fed mice

G-protein coupled receptor-120 (GPR120; FFAR4) is a free fatty acid receptor, widely researched for its glucoregulatory and insulin release activities. This study aimed to investigate the metabolic advantage of FFAR4/GPR120activation using combination therapy. C57BL/6 mice, fed a High Fat Diet (HFD) for 120 days to induce obesity-diabetes, were subsequently treated with a single daily oral dose of FFAR4/GPR120 agonist Compound A (CpdA) (0.1μmol/kg) alone or in combination with sitagliptin (50mg/kg) for 21 days. After 21-days, glucose homeostasis, islet morphology, plasma hormones and lipids, tissue genes (qPCR) and protein expression (immunocytochemistry) were assessed. Oral administration of CpdA improved glucose tolerance (34%