Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Background: Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.

Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction.

Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory.

Lock and chop: A novel method for the generation of a PICK1 PDZ domain and piperidine-based inhibitor co-crystal structure.

The membrane protein interacting with kinase C1 (PICK1) plays a trafficking role in the internalization of neuron receptors such as the amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor. Reduction of surface AMPA type receptors on neurons reduces synaptic communication leading to cognitive impairment in progressive neurodegenerative diseases such as Alzheimer disease. The internalization of AMPA receptors is mediated by the PDZ domain of PICK1 which binds to the GluA2 subunit of AMPA receptors and targets the receptor for internalization through endocytosis, reducing synaptic communication.

Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.

Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography.

Transorbital endoscopic repair of cerebrospinal fluid leaks.

Objectives: To describe an anatomic and clinical outcome study of transorbital neuroendoscopic surgical (TONES) for the repair of complex anterior cranial fossa (ACF) cerebrospinal fluid (CSF) leaks.

Design: Anatomic cadaver investigation and clinical outcomes evaluation.

Methods: An anatomic cadaver study was undertaken to determine the anatomic feasibility of the TONES approaches for repair of CSF leaks, and determine the optimal approaches for these repairs.

Transorbital neuroendoscopic surgery.

Background: Transorbital neuroendoscopic surgery (TONES) pathways attempt to address some of the technical challenges of accessing laterally placed anterior skull base lesions or paramedian lesions that cross neurovascular structures. TONES approaches allow simultaneous coplanar visualization and working space above and below the skull base.

Objective: To present an anatomic study, a description of the surgical techniques, and an analysis of the safety and efficacy of 20 consecutive procedures using TONES for a variety of pathological conditions.

Bivalve cartilage inlay myringoplasty: an office-based procedure for closing small to medium-sized tympanic membrane perforations.

Objective: To determine whether bivalve inlay cartilage-perichondrium myringoplasty (BCM) is successful in closing tympanic membrane perforations in an office setting.

Study Design: Retrospective case review.

Subjects And Methods: Adult patients with chronic perforations underwent BCM under local and topical anesthesia.

The evaluation and treatment of lower eyelid paralysis.

The lower eyelid conforms precisely across its length to the complex topography of the cornea, conjunctiva, and globe. Along with the upper eyelid, it protects the eye from foreign bodies, prevents desiccation, and helps circulate the tear film from its origin in the lacrimal gland to its drainage at the lacrimal puncta. Paralysis of the lower eyelid may result in ectropion, lid laxity, epiphora, and lagophthalmos.

The evaluation and treatment of upper eyelid paralysis.

Patients with upper lid paralysis suffer from a loss of the blink reflex/response in the affected eye, leaving the eye vulnerable to a host of predatory insults. Partial or total impairment of the orbicularis oculi muscle, lagophthalmos, disruption of the lacrimal apparatus, upper lid retraction, and the unopposed pull of gravity on the surrounding paralyzed tissues all contribute to increased corneal exposure and an increased risk of exposure keratitis. Management of the upper lid in these patients must therefore focus on restoration of the effects of the blink reflex/response and prevention of corneal exposure.