Publications by authors named "Allison L Brill"

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E (PGE), has shown great promise as a biomarker of β-cell dysfunction in T2D.

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Elevated islet production of prostaglandin E (PGE), an arachidonic acid metabolite, and expression of prostaglandin E receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE production and signaling pathway influences nondiabetic β-cell function. In this work, plasma arachidonic acid and PGE metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation.

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Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria.

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The inhibitory G protein alpha-subunit (Gα) is an important modulator of beta-cell function. Full-body Gα-null mice are protected from hyperglycemia and glucose intolerance after long-term high-fat diet (HFD) feeding. In this study, at a time point in the feeding regimen where WT mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Gα KO mice have a dramatically altered gene expression pattern as compared with WT HFD-fed mice, with entire gene pathways not only being more strongly upregulated or downregulated versus control-diet fed groups but actually reversed in direction.

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Article Synopsis
  • Engineered heart tissues (EHTs) provide a valuable in vitro model for studying heart function, but current culture methods don't fully replicate the cardiac cycle.
  • A new bioreactor has been developed to simulate in vivo mechanics, allowing EHTs to undergo cyclic loading, which enhances their contractions and contractile work capacity.
  • The study found that mitochondrial protein levels increase with higher mechanical work in EHTs, indicating that mechanical loading significantly influences cellular adaptation in heart tissues.
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Changes in intracellular calcium (Ca ) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca -binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified.

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Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance.

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Article Synopsis
  • Polycystin 2 (PC2) is a calcium channel found on the endoplasmic reticulum and primary cilia in various cell types, primarily studied for its role in kidney function and its link to polycystic kidney disease (ADPKD).
  • This study investigates how PC2 expression changes under different pathological conditions, revealing that its levels increase during cellular stress across multiple tissues.
  • Findings suggest that PC2 plays a critical role in cellular protection, as cells lacking PC2 are more prone to stress-induced cell death, highlighting its importance in maintaining cell health in various diseases.
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Polycystin 2 (PC2) is one of two main protein types responsible for the underlying etiology of autosomal dominant polycystic kidney disease (ADPKD), the most prevalent monogenic renal disease in the world. This debilitating and currently incurable condition is caused by loss-of-function mutations in PKD2 and PKD1, the genes encoding for PC2 and Polycystin 1 (PC1), respectively. Two-hit mutation events in these genes lead to renal cyst formation and eventual kidney failure, the main hallmarks of ADPKD.

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Mitochondria and the endoplasmic reticulum (ER) have an intimate functional relationship due to tethering proteins that bring their membranes in close (~30 nm) apposition. One function of this interorganellar junction is to increase the efficiency of Ca transfer into mitochondria, thus stimulating mitochondrial respiration. Here, we showed that the ER cation-permeant channel polycystin 2 (PC2) functions to reduce mitochondria-ER contacts.

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The α-subunit of the heterotrimeric Gz protein, Gαz, promotes β-cell death and inhibits β-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional β-cell mass in the nonobese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in Gαz knockout mice.

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Prostaglandin E (PGE) is derived from arachidonic acid, whereas PGE is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE on β-cell function, particularly in the diabetic state. In this work, we determined that PGE elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state.

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A defining characteristic of type 1 diabetes mellitus (T1DM) pathophysiology is pancreatic β-cell death and dysfunction, resulting in insufficient insulin secretion to properly control blood glucose levels. Treatments that promote β-cell replication and survival, thus reversing the loss of β-cell mass, while also preserving β-cell function, could lead to a real cure for T1DM. The α-subunit of the heterotrimeric Gz protein, Gαz, is a tonic negative regulator of adenylate cyclase and downstream cAMP production.

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Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN.

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Addition of an affinity tag is a useful method for differentiating recombinant proteins expressed in bacterial and eukaryotic expression systems from the background of total cellular proteins, as well as for detecting protein-protein interactions. This overview describes the historical basis for the development of affinity tags, affinity tags that are commonly used today, how to choose an appropriate affinity tag for a particular purpose, and several recently developed affinity tag technologies that may prove useful in the near future.

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