Objective: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1. Method: Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community. Results: Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry. Conclusion: Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.
Space travel increases solar particle radiation exposure to astronauts and this is significantly elevated once travel moves beyond low Earth orbit. This includes γ radiation, as well as a combinations of high energy protons and heavy ions such as 56Fe, 28Si, and 16O. There are distinct differences in the biological response to low‐energy transfer (x‐rays) or high‐energy transfer (High‐LET) (56Fe) events. Airline flight crews are chronically exposed to High‐LET and higher incidents of cancer are reported for these individuals. Much of what we know about the consequences of high‐LET exposure comes from studies of nuclear workers and atom bomb survivors. For flight crews (astronauts), most estimates of galactic radiation exposure have a low fluence rate that is much lower that patients undergoing radiotherapy or the acute exposure of those that survived the A‐bomb. However, the cumulative radiation dose is likely to have long‐term deleterious effects on the health of astronauts. And this risk increases as flight duration is increased. The underlying mechanisms for these elevated risks are unknown, although direct DNA damage and elevated oxidant stress are highly suspected. Given the relatively low fluence rate of exposure it might be possible to manage these deleterious effects using small molecules currently available. To that end we have utilized the FDA approved drug library from MedChem Express (723 drugs) to perform a high throughput screen of cultured cells following exposure to cosmic radiation. The H9c2 cell and RBL‐2H3 mast cell lines were exposed to a total of 75 cGy using a simplified 5‐ion GCR protocol developed by NASA at the NSRL facility at the Brookhaven National Laboratory. Following GCR exposure cells were split onto 96 well test plates and treated for 7 days with vehicle or 10 μM drug. Media and drugs were changed on alternate days. At harvest cells were tested for viability (MTT), oxidant stress (DHE), cellular senescence (ONPG) and mitochondrial function (ATP). Using the non‐drug treated cells as controls, Z‐scores were calculated and a composite score was developed for each drug. The top 160 composite scores were retested following a similar protocol using1 μM of each drug. Within the 160 drugs, 33 are considered to have an anti‐inflammatory capacity. 5 of the eight 5‐HT antagonists considered useful were 5‐HT3 specific. 12 of 25 angiotensin converting enzyme inhibitors or AT1 antagonists were observed to be effective while no AT2 antagonists appeared useful. 10 of 46 drugs indentified as interacting with histamine receptors were deemed effective. 7 of 54 COX inhibitors deemed effective were COX2 but not COX1 inhibitors. Collectively these findings suggest that drugs interacting with GPCR/G coupled proteins that modulate inflammation and anti‐oxidant pathways may be useful in the management of cosmic radiation exposure of long duration flight crews. Support or Funding Information Supported in part by NASA 80NSSC19K0436
Micro RNA (miRNA) are noncoding RNAs that are involved in gene silencing and transcriptional regulation. microRNAs are transcribed as long stem-loop structures (pri-miRNA). These molecules undergo double-stranded cleavage by the enzyme drosha in the nucleus to form a shorter stem-loop called pre-miRNA. After export from the nucleus to the cytoplasm, pre-miRNA undergoes another double-stranded cleavage by the enzyme dicer to eventually form mature miRNA of 20-22 nucleotide residues in length. miR-21 is considered an "onco-miR" because it is one of a family of micro RNAs that are upregulated in some cancers. To understand the structure of miR-21, we performed X-ray crystallography utilizing a general toolkit of RNA binding proteins. Here we describe the structure of nearly full-length pri-miR-21 in complex with an RNA-binding Fab solved at 1.8 Å resolution. All 55 nucleotides of the miR-21 double helical region are visible in the structure including the drosha and dicer cleavage sites. A ligand-bound ternary complex was also captured at 2.0 Å resolution using the tool compound neomycin. Neomycin binds near the dicer cleavage site and distorts the conformation of the RNA backbone near the A29 bulge region.
Due to the advancement in the science of processing and characterization of nanostructured materials, along with the industrial-scale production and decreasing cost of carbon nanotubes, their use in technologies as sensors and sensing skins is gaining popularity. With increasing Technology Readiness Levels (TRL) and field trials implemented by researchers, it is critical to characterize the sensing response of the carbon nanotube sensing skins under complex loading scenarios in order to simulate the real-life conditions. Typically, researchers describe the sensitivity (gage factor, GF) and sensing response of a carbon nanotube sensing skin based on the electrical resistance change and the longitudinal strain (ε1), not taking into consideration the effect of transverse strain (ε2) due to the Poisson's ratio of the material. Since the sensitivity of the sensor is dependent on the transverse strain, the sensitivity is affected by the properties of the substrate material. As a result, the calibration of the sensing skin is challenging. The principal objective of our research is to characterize the effect of transverse strain and develop a methodology to quantify the influence of transverse strain on the sensing response. The carbon nanotube-based sensing skins are manufactured using a scalable manufacturing technique and the effect of different loading scenarios on the sensing response are investigated. Carbon nanotubes are deposited on non-woven aramid fabrics with randomly oriented fibers and the resulting carbon nanotube-based sensing skin is bonded to steel and composite substrates which are subjected to flexural and axial loads to characterize the sensing response. A cruciform shaped specimen with a carbon nanotube sensor is tested using a biaxial testing machine and change in resistance under varying transverse loads is characterized. Key results indicate that the sensitivity of the carbon nanotube sensing skin is significantly affected by the transverse strain due to the Poisson effect which should be taken into consideration when calculating the gage factor or calibrating the sensors.
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