Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells

Esters of succinic acid are potent insulin secretagogues, and have been proposed as novel antidiabetic agents for type 2 diabetes. This study examines the effects of acute and chronic exposure to succinic acid monomethyl ester (SAM) on insulin secretion, glucose metabolism and pancreatic beta cell function using the BRIN-BD11 cell line. SAM stimulated insulin release in a dose-dependent manner at both non-stimulatory (1.1mM) and stimulatory (16.7mM) glucose. The depolarizing actions of arginine also stimulated a significant increase in SAM-induced insulin release but 2-ketoisocaproic acid (KIC) inhibited SAM induced insulin secretion indicating a possible competition between the preferential oxidative metabolism of these two agents. Prolonged (18hour) exposure to SAM revealed decreases in the insulin-secretory responses to glucose, KIC, glyceraldehyde and alanine. Furthermore, SAM diminished the effects of nonmetabolized secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of BRIN-BD11 cells to oxidise glucose was unaffected by SAM culture, glucose utilization was substantially reduced. Collectively, these data suggest that while SAM may enhance the secretory potential of non-metabolized secretagogues, it may also serve as a preferential metabolic fuel in preference to other important physiological nutrients and compromise pancreatic beta cell function following prolonged exposure

Elevating zero dimensional global scaling predictions to self-consistent theory-based simulations

We have developed an innovative workflow, STEP-0D, within the OMFIT integrated modelling framework. Through systematic validation against the International Tokamak Physics Activity (ITPA) global H-mode confinement database, we demonstrated that STEP-0D, on average, predicts the energy confinement time with a mean relative error (MRE) of less than 19%. Moreover, this workflow showed promising potential in predicting plasmas for proposed fusion reactors such as ARC, EU-DEMO, and CFETR, indicating moderate H-factors between 0.9 and 1.2. STEP-0D allows theory-based prediction of tokamak scenarios, beginning with zero-dimensional (0D) quantities. The workflow initiates with the PRO-create module, generating physically consistent plasma profiles and equilibrium using the same 0D quantities as the IPB98(y,2) confinement scaling. This sets the starting point for the STEP (Stability, Transport, Equilibrium, and Pedestal) module, which further iterates between theory-based physics models of equilibrium, core transport, and pedestal to yield a self-consistent solution. Given these attributes, STEP-0D not only improves the accuracy of predicting plasma performance but also provides a path towards a novel fusion power plant (FPP) design workflow. When integrated with engineering and costing models within an optimization, this new approach could eliminate the iterative reconciliation between plasma models of varying fidelity. This potential for a more efficient design process underpins STEP-0D's significant contribution to future fusion power plant development.Comment: 12 pages, 13 figures, accepted by Physics of Plasmas 202

Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry

Background Infection with nontuberculous mycobacteria (NTM) is of growing clinical concern in people with cystic fibrosis (CF). The epidemiology of infection in children and young people remains poorly understood. Our goal was to investigate the epidemiology of NTM infection in the pediatric age group using data from the UK CF Registry. Methods Data from 2010–2015 for individuals aged <16 years (23200 observations from 5333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. The significant factors that were identified were used to generate a multivariate logistic regression model that, following step-wise removal, generated a final parsimonious model. Results The prevalence of individuals with a NTM-positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (odds ratio [OR], 2.66; P = 5.0 × 10−8), age (OR, 1.08; P = 3.4 × 10−10), and intermittent Pseudomonas aeruginosa infection (OR, 1.51; P = .004) were significantly associated with NTM infection. Conclusions NTM infection is of increasing prevalence in the UK pediatric CF population. This study highlights the urgent need for work to establish effective treatment and prevention strategies for NTM infection in young people with CF

Kinetic-Ballooning-Limited Pedestals in Spherical Tokamak Plasmas

A theoretical model is presented that for the first time matches experimental measurements of the pedestal width-height Diallo scaling in the low-aspect-ratio high-$\beta$ tokamak NSTX. Combining linear gyrokinetics with self-consistent pedestal equilibrium variation, kinetic-ballooning, rather than ideal-ballooning plasma instability, is shown to limit achievable confinement in spherical tokamak pedestals. Simulations are used to find the novel Gyrokinetic Critical Pedestal constraint, which determines the steepest pressure profile a pedestal can sustain subject to gyrokinetic instability. Gyrokinetic width-height scaling expressions for NSTX pedestals with varying density and temperature profiles are obtained. These scalings for spherical tokamaks depart significantly from that of conventional aspect ratio tokamaks.Comment: 7 pages, 5 figures. Nuclear Fusion 202

Teaching Story without Struggle: Using Graded Readers and Their Audio Packs in the EFL Classroom

In recent years the support for extensive reading (ER) in English as a second or foreign language (ESL/EFL) programs has been compelling. When practicing extensive reading, the learner reads a wide variety of texts for pleasure and achieves a general understanding of the content while deciphering unknown words through context. This approach contrasts with intensive reading, a more traditional approach based on a slow, careful reading of a text, with goals of complete comprehension and the identification of specific details and information

Probenecid Blocks Human P2X7 Receptor-Induced Dye Uptake via a Pannexin-1 Independent Mechanism

P2X7 is a ligand-gated ion channel which is activated by ATP and displays secondary permeability characteristics. The mechanism of development of the secondary permeability pathway is currently unclear, although a role for the hemichannel protein pannexin-1 has been suggested. In this study we investigated the role of pannexin-1 in P2X7-induced dye uptake and ATP-induced IL-1β secretion from human monocytes. We found no pharmacological evidence for involvement of pannexin-1 in P2X7-mediated dye uptake in transfected HEK-293 cells with no inhibition seen for carbenoxolone and the pannexin-1 mimetic inhibitory peptide, 10Panx1. However, we found that probenecid inhibited P2X7-induced cationic and anionic dye uptake in stably transfected human P2X7 HEK-293 cells. An IC50 value of 203 μM was calculated for blockade of ATP-induced responses at human P2X7. Probenecid also reduced dye uptake and IL-1β secretion from human CD14+ monocytes whereas carbenoxolone and 10Panx1 showed no inhibitory effect. Patch clamp and calcium indicator experiments revealed that probenecid directly blocks the human P2X7 receptor

Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harboring different homozygous LoF variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability, and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intrauterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 LoF in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 LoF related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction