Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome Type 1c

Because there are currently no biological treatments for deafness, we sought to advance gene therapy approaches to treat genetic deafness. We reasoned that gene delivery systems that target auditory and vestibular sensory cells with high efficiency would be required to restore complex auditory and balance function. We focused on Usher Syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and used a knock-in mouse model, Ush1c c.216G>A, which carries a cryptic splice site mutation found in French-Acadian patients with Usher Syndrome type IC (USH1C). Following delivery of wild-type Ush1c into the inner ears of neonatal Ush1c c.216G>A mice, we find recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders

Braided Carbon Fiber Rope Flow Characteristics

I am submitting the following technical subject for consideration as a thesis topic for the master degree: The reusable solid rocket motor (RSRM) nozzle internal joints are being evaluated for the incorporation of a carbon fiber rope (CFR) as a thermal barrier. The CFR is approximately 0.260 in. diameter and is composed of approximately 12,000 carbon fibers, woven in ten sheaths or layers. The CFR is manufactured by a sub-tier vendor and subsequently several of its manufacturing details are proprietary to that vendor. The CFR design intent is to prevent hot motor combustion products and slag from intruding into the joint scaling area while still approaching a vented joint design to avoid the detriments of gas jet impingement. As a member of the Heat Transfer section at Thiokol Propulsion, two main goals exist as part of this NASA funded design effort: (1) development of flow model through the CFR and (2) development of a heat transfer model through the CFR. While both models are needed and most probably interrelated, the gas flow model is being targeted as the subject matter. Essentially, the topic would be "Modeling of Gas Flow through a Braided Carbon Fiber Rope". An AIAA journal or conference paper is being considered through Thiokol/NASA as well. A sub-scale CFR flow test fixture was designed to simulate the relative levels of CFR compression. The test fixture provides the means to measure gas mass flow rate upstream of the CFR and the pressure and temperature both upstream and downstream of the CFR. The test fixture was designed to eliminate the possibility of dynamic gapping at the CFR location and provide minimal flow resistance to ambient for gases exiting the rope. The data collected in the experiment will be evaluated to define a permeability/flow resistance model. Two possibilities exist for the flow characteristics through the CFR from choked flow to strictly friction driven. A test matrix for evaluating the CFR has been compiled, which addresses both of these characteristics. The range of pressures to be tested covers a relatively low delta pressure where non-choked flow is impossible, while the high pressure shown is dictated by the RSRM joint operating pressure where choking is possible. The test matrix, was also designed for a range of rope compressions or test fixture gaps ranging from 0.025" to 0.070". These gaps are controlled by the range of RSRM full-scale hardware joint gaps that will be expected by virtue of the joint design

Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

α-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons

A higher protein intake at breakfast and lunch is associated with a higher total daily protein intake in older adults: a post-hoc cross-sectional analysis of four randomised controlled trials

Background: A protein intake of 30-40 g per meal is suggested to maximally stimulate muscle protein synthesis in older adults and could therefore contribute to the prevention of sarcopenia. Protein intake at breakfast and lunch is often low and offers a great opportunity to improve daily protein intake. Protein, however, is known for its satiating effects. Therefore, we explored the association between the amount of protein intake at breakfast and lunch and total daily protein intake in older adults. Methods: Protein intake was assessed by a 3-day food record in 498 community dwelling older adults (≥55 years) participating different lifestyle interventions. Linear mixed model analysis was used to examine the association between protein intake at breakfast or lunch and total daily protein intake, adjusted for sex, age, body mass index, smoking status, study and total energy intake. Results: After adjustment for potential confounders, a 10 g higher protein intake at breakfast was associated with a 3.2 g higher total daily protein intake (P = 0.008) for males and a 4.9 g (P < 0.001) higher total daily protein intake for females. A 10 g higher protein intake at lunch was associated with a 3.7 g higher total daily protein intake (P < 0.001) for males, and a 5.8 g higher total daily protein intake (P < 0.001) for females. Conclusions: A higher protein intake at breakfast and lunch is associated with a higher total daily protein intake in community dwelling older adults. Stimulating a higher protein intake at breakfast and lunch might represent a promising nutritional strategy to optimise the amount of protein per meal without compromising total daily protein intake