PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes

The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and β-cell area through increased β-cell proliferation and reduced β-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for β-cell-directed diabetes therapy

A Modular Functional Electrical Stimulation (FES) System for Gait Assistance in Pediatric Cerebral Palsy

Foot drop, the inability to lift the forefoot during gait, is a common symptom of disorders such as diabetes, stroke, spina bifida, and cerebral palsy. This condition makes walking difficult and unsafe, often resulting in stumbles and falls due to lack of ground clearance. The current standard of care is orthotic bracing, which presents donning and doffing challenges, restricts ankle motion, and contributes to social stigma in many parts of the world. Functional electrical stimulation (FES) is an alternative approach which uses small amounts of electrical current delivered through skin-surface electrodes to stimulate peripheral nerves, thus generating muscle contraction and ultimately functional movement of a human limb. When packaged in a wearable device with onboard sensors capable of detecting gait phase, stimulation current can be applied to the lower leg to cause the foot to lift during the swing phase of gait. While several FES foot-drop systems are commercially available, they cost upward of $13,000 and provide a level of adjustability and complexity not needed for many conditions. The Messiah FES team is working to develop a low-cost, portable, easy-to-use, and durable electrical stimulation device to restore legged ambulation to children with mobility impairments resulting from cerebral palsy, spina bifida, and other conditions with similar effects. Our clinical partner is CURE Ethiopia, with our primary contacts being Dr. Tim Nunn and Dr. Laurence Wicks at the CURE Ethiopia Children\u27s Hospital in Addis Ababa, Ethiopia. Funding for this work provided by The Collaboratory for Strategic Partnerships and Applied Research.https://mosaic.messiah.edu/engr2022/1007/thumbnail.jp

Glucose management for exercise using continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement of the European Association for the Study of Diabetes (EASD) and of the International Society for Pediatric and Adolescent Diabetes (ISPAD) endorsed by JDRF and supported by the American Diabetes Association (ADA)

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin‐dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

A Taxonomy of Harms Inherent in Cognitive Enhancement

Advances in neuroscience and pharmacology have led to improvements in the cognitive performance of people with neurological disease and other forms of cognitive decline. These same methods may also afford cognitive enhancement in people of otherwise normal cognitive abilities. “Cosmetic”, or supranormal, cognitive enhancement offers opportunities to enrich our social or financial status, our interactions with others, and the common wealth of our community. It is common to focus on the potential benefits of cognitive enhancement, while being less than clear about the possible drawbacks. Here I examine the harms or side-effects associated with a range of cognitive enhancement interventions. I propose a taxonomy of harms in cognitive enhancement, with harms classified as (neuro)biological, ethical, or societal. Biological harms are those that directly affect the person’s biological functioning, such as when a drug affects a person’s mood or autonomic function. Ethical harms are those that touch on issues such as fairness and cheating, or on erosion of autonomy and coercion. Societal harms are harms that affect whole populations, and which are normally the province of governments, such as the use of enhancement in military contexts. This taxonomy of harms will help to focus the debate around the use and regulation of cognitive enhancement. In particular it will help to clarify the appropriate network of stakeholders who should take an interest in each potential harm, and in minimizing the impact of these harms

Mixtures of sediment chemical contaminants at freshwater sampling sites across Europe with different contaminant burdens

Extended chemical analyses of fluvial sediments were undertaken to establish the key pollutant pressures and mixtures present across nine European Union inland waterways. A wide range of chemical components and physical parameters were investigated including substances from the EU Priority List and Watch List. The data set was examined for key indicator compounds, however it was found that a wide range of pollution pressures were present in the different sediments including organic hydrocarbons, metal(loid)s, nutrients, polycyclic aromatic hydrocarbon (PAH), polychlorinated biphenyl (PCB) compounds, perfluoroalkyl and polyfluoroalkyl substances and pesticides, some of which exceeded regulatory guidance at different sampling points. The presence of such a wide range of compounds underpins the complex chemical composition of sediments that have acted as sinks for many decades absorbing contaminants from urban, industrial and agricultural sources. This dataset has been used to describe average overall toxicity of the sediments sampled, a calculation which was based on key components identified by Principal Component Analysis (PCA) and for those that had existing freshwater sediment regulatory values. A total of 33 components were used including PCBs, PAHs, metal(iod)s and pesticides. This analysis reflected the contamination of each site, with most indicating some level of toxicity during the sampling period. Watch List chemicals triclosan (TCS) and diclofenac (DIC) were also investigated; levels were relatively low, typically 10–100's ng L−1, however they were present at all sampling sites. The dataset is available as a resource for future chemical, and toxicological, sediment analysis comparisons