Modeling K,ATP-Dependent Excitability in Pancreatic Islets

AbstractIn pancreatic β-cells, K,ATP channels respond to changes in glucose to regulate cell excitability and insulin release. Confirming a high sensitivity of electrical activity to K,ATP activity, mutations that cause gain of K,ATP function cause neonatal diabetes. Our aim was to quantitatively assess the contribution of K,ATP current to the regulation of glucose-dependent bursting by reproducing experimentally observed changes in excitability when K,ATP conductance is altered by genetic manipulation. A recent detailed computational model of single cell pancreatic β-cell excitability reproduces the β-cell response to varying glucose concentrations. However, initial simulations showed that the model underrepresents the significance of K,ATP activity and was unable to reproduce K,ATP conductance-dependent changes in excitability. By altering the ATP and glucose dependence of the L-type Ca2+ channel and the Na-K ATPase to better fit experiment, appropriate dependence of excitability on K,ATP conductance was reproduced. Because experiments were conducted in islets, which contain cell-to-cell variability, we extended the model from a single cell to a three-dimensional model (10×10×10 cell) islet with 1000 cells. For each cell, the conductance of the major currents was allowed to vary as was the gap junction conductance between cells. This showed that single cell glucose-dependent behavior was then highly variable, but was uniform in coupled islets. The study highlights the importance of parameterization of detailed models of β-cell excitability and suggests future experiments that will lead to improved characterization of β-cell excitability and the control of insulin secretion

Such a Tease

Burlesque has been seen in the movies and recently has been brought to life in the Des Moines art scene with Phoenix L’Amour’s show “Burlesque Baby.” The show hasn’t been in the attention of the public eye until the show on Sept. 30, when two performers received a citation for breast overexposure causing controversy to the Des Moines show

Differences in the Use and Perceptions of Evidence-Based Practice between Occupational Therapy Students and Practitioners

This study explored differences in perceptions of evidence-based practice (EBP) between occupational therapy (OT) students and practitioners. Researchers aimed to understand student and practitioner perceptions of barriers, knowledge, attitudes, and confidence in EBP. Occupational therapy students (n=61) and practitioners (n=21) completed an online researcher-created survey and the Evidence-Based Practice Confidence (EPIC) Scale survey. Results indicated practitioners were more confident in utilizing EBP than students, particularly when identifying a gap in knowledge related to a patient (p = \u3c.001) deciding on a course of action for a client (p = \u3c.001), and assessing the efficacy of EBP on client outcomes (p = \u3c.001). This finding was inconsistent with previous research, which may be due to more practitioners receiving formal education on EBP. It is critical for OT education to support student learning and application of clinical reasoning throughout the EBP process in order to increase confidence. This study was limited by the use of a homogenous population from a single university

Development of a general protocol for rapid response research on water quality disturbances and its application for monitoring the largest wildfire recorded in New Mexico, USA

Anthropogenic and natural disasters (e.g., wildfires, oil spills, mine spills, sewage treatment facilities) cause water quality disturbances in fluvial networks. These disturbances are highly unpredictable in space-time, with the potential to propagate through multiple stream orders and impact human and environmental health over days to years. Due to challenges in monitoring and studying these events, we need methods to strategize the deployment of rapid response research teams on demand. Rapid response research has the potential to close the gap in available water quality data and process understanding through time-sensitive data collection efforts. This manuscript presents a protocol that can guide researchers in preparing for and researching water quality disturbance events. We tested and refined the protocol by assessing the longitudinal propagation of water quality disturbances from the 2022 Hermit's Peak—Calf Canyon, NM, USA, the largest in the state's recorded history. Our rapid response research allowed us to collect high-resolution water quality data with semi-continuous sensors and synoptic grab sampling. The data collected have been used for traditional peer-reviewed publications and pragmatically to inform water utilities, restoration, and outreach programs

Perceptions towards established and novel dietary therapies for Crohn’s disease management among adult patients: results from a questionnaire survey

This a copy of the patient questionnaire survey

Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p \u3c .001). Children without prescriptions weighed less at baseline than children in the general population (p \u3c .001) but gained height and weight at a faster rate (p \u3c .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings

Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits, the most common mutations being SUR2[R1154Q] and SUR2[R1154W], carried by approximately 30% of patients. We used CRISPR/Cas9 genome engineering to introduce the equivalent of the human SUR2[R1154Q] mutation into the mouse ABCC9 gene. Along with minimal CS disease features, R1154Q cardiomyocytes and vascular smooth muscle showed much lower KATP current density and pinacidil activation than WT cells. Almost complete loss of SUR2-dependent protein and KATP in homozygous R1154Q ventricles revealed underlying diazoxide-sensitive SUR1-dependent KATP channel activity. Surprisingly, sequencing of SUR2 cDNA revealed 2 distinct transcripts, one encoding full-length SUR2 protein; and the other with an in-frame deletion of 93 bases (corresponding to 31 amino acids encoded by exon 28) that was present in approximately 40% and approximately 90% of transcripts from hetero- and homozygous R1154Q tissues, respectively. Recombinant expression of SUR2A protein lacking exon 28 resulted in nonfunctional channels. CS tissue from SUR2[R1154Q] mice and human induced pluripotent stem cell-derived (hiPSC-derived) cardiomyocytes showed only full-length SUR2 transcripts, although further studies will be required in order to fully test whether SUR2[R1154Q] or other CS mutations might result in aberrant splicing and variable expressivity of disease features in human CS