Topographic guidance scaffolds for peripheral nerve interfacing

In response to high and rising amputation rates, significant advances have been made in the field of prosthetic limb design. Unfortunately, there exists a lag in the neural interfacing technology required to provide an adequate link between the nervous system and this emerging generation of advanced prosthetic devices. Novel approaches to peripheral nerve interfacing are required to establish the stable, high channel count connections necessary to provide natural, thought driven control of an external prosthesis. Here, a tissue engineering-based approach has been used to create a device capable of interfacing with a regenerated portion of amputated nerve. As part of this work, a nerve guidance channel design, in which small amounts of interior scaffolding material could be precisely positioned, was evaluated. Guidance channels containing a single thin-film sheet of aligned scaffolding were shown to support robust functional nerve regeneration across extended injury gaps by minimally supplementing natural repair mechanisms. Significantly, these "thin-film enhanced nerve guidance channels" also provided the capability to guide the course of axons regenerating from a cut nerve. This capability to control axonal growth was next leveraged to create "regenerative scaffold electrodes (RSEs)" able to interface with axons regenerating from an amputated nerve. In the RSE design, low-profile arrays of interfacing electrodes were embedded within layers of aligned scaffolding material, such that regenerating axons were topographically guided by the scaffolding through the device and directly across the embedded electrodes. Chronically implanted RSEs were successfully used to record evoked neural activity from amputated nerves in an animal model. These results demonstrate that the use of topographic cues within a nerve guidance channel might offer the potential to influence the course of nerve regeneration to the advantage of a peripheral nerve interface suitable for limb amputees.PhDCommittee Chair: Ravi Bellamkonda; Committee Member: Arthur English; Committee Member: Pamela Bhatti; Committee Member: Robert Butera; Committee Member: Robert Le

Age Cohorts Impact on Public Employee Job Satisfaction through Motivation

One of the most critical issues facing government over the next decade will be filling management positions vacated by Baby Boomers. The purpose of this quantitative correlational research study was to examine how intrinsic and extrinsic motivations affect job satisfaction among different age cohorts in the public workforce. The public workforce is comprised of Baby Boomers (born 1946- 1964), Generation X (born 1965- 1980) and Generation Y (born1981 to 1996). The theoretical framework for this study was Herzberg\u27s motivation-hygiene theory. A random sample of 213 participants: Generation Y = 40, Generation X = 77, and Baby Boomers = 96, participated in an online SurveyMonkey government panel. The panel was composed of local, state, and federal employees. Participants answered the survey using the Career Goals Scale, the Job Satisfaction Scale, and a brief demographics scale. Data were analyzed using descriptive statistics as a measure of central tendency. Also, inferential statistics using Pearson product-moment correlations, simple linear regressions, and one-way multivariate analysis of variance (MANOVA) were conducted to answer three central research questions. Results revealed that both intrinsic and extrinsic motivations affect job satisfaction. Also, results of the individual one-way ANOVAs did not indicate significant differences in intrinsic motivation or job satisfaction among the age cohorts. Finally, pairwise comparisons determined that there were significant differences in extrinsic motivation between Baby Boomers and Generation Y. The information for this study may inform human resource managers in the public sector, about factors that would affect benefit plan policy, and improve recruitment and retention of employees

Skeletal immaturity, rostral sparing, and disparate hip morphologies as biomechanical causes for Legg-Calvé-Perthes’ disease

Legg-Calvé-Perthes' (Perthes') disease is a developmental disease of the hip joint that may result in numerous short and long term problems. The etiology of the disease remains largely unknown, but the mechanism is believed to be vascular and/or biomechanical in nature. There are several anatomical characteristics that tend to be prevalent in children with Perthes' disease, namely: skeletal immaturity, reduced height, and rostral sparing. We present an overview of the literature, summarizing the current understanding of the pathogenesis, particularly related to how the formation of the vasculature to the femoral epiphysis places children aged 5–8 at a higher risk for Perthes' disease, how skeletal immaturity and rostral sparing could increase the probability of developing Perthes' disease, and how animal models have aided our understanding of the disease. In doing so, we also explore why Perthes' disease is correlated to latitude, with populations at higher latitudes having higher incidence rates than populations closer to the Equator. Finally, we present five hypotheses detailing how Perthes' disease could have a biomechanical cause. Clin. Anat. 29:759–772, 2016. © 2016 Wiley Periodicals, Inc

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1(G93A) mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease

Science results from sixteen years of MRO SHARAD operations

In operation for >16 years to date, the Mars Reconnaissance Orbiter (MRO) Shallow Radar (SHARAD) sounder has acquired data at its nominal 300–450 m along-track and 3-km cross-track resolution covering >55% of the Martian surface, with nearly 100% overlap in coverage at that scale in the polar regions and in a number of smaller mid-latitude areas. While SHARAD data have opened a new window into understanding the interior structures and properties of Martian ices, volcanics, and sedimentary deposits up to a few kilometers in depth, they have also led to new revelations about the deeper interior and the behavior of the planet’s ionosphere. Here we summarize the data collected by SHARAD over this time period, the methods used in the analysis of that data, and the resulting scientific findings. The polar data are especially rich, revealing complex structures that comprise up to several dozen reflecting interfaces that extend to depths of 3 km, which inform the evolution of Martian climate in the late Amazonian period. SHARAD observations of mid-latitude lobate debris aprons and other glacier-like landforms detect strong basal reflections and low dielectric loss, confirming that they are icerich debris-covered glaciers. In other mid-latitude terrains, SHARAD data demonstrate the presence of widespread ground ices, likely at lower concentrations. SHARAD signals also probe non-icy materials, mapping out stacked lava flows, probing low-density materials thought to be ash-fall deposits, and occasionally penetrating sedimentary deposits, all of which reveal the structures and interior properties diagnostic of emplacement processes. SHARAD signals are impacted by their passage through the Martian ionosphere, revealing variations in time and space of the total electron content linked with the remanent magnetic field. Advanced techniques developed over the course of the mission, which include subband and super-resolution processing, coherent and incoherent summing, and three-dimensional (3D) radar imaging, are enabling new discoveries and extending the utility of the data. For 3D imaging, a cross-track spacing at the nominal 3-km resolution is more than sufficient to achieve good results, but finer spacing of 0.5 km or less significantly improves the spatially interpolated radar images. Recent electromagnetic modeling and a flight test show that SHARAD’s signal-to-noise ratio can be greatly improved with a large (~120◦) roll of the spacecraft to reduce interference with the spacecraft body. Both MRO and SHARAD are in remarkably fine working order, and the teams look forward to many more years in which to pursue improvements in coverage density, temporal variability in the ionosphere, and data quality that promise exciting new discoveries at Mars

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease

The Holy Grail: A road map for unlocking the climate record stored within Mars' polar layered deposits

In its polar layered deposits (PLD), Mars possesses a record of its recent climate, analogous to terrestrial ice sheets containing climate records on Earth. Each PLD is greater than 2 ​km thick and contains thousands of layers, each containing information on the climatic and atmospheric state during its deposition, creating a climate archive. With detailed measurements of layer composition, it may be possible to extract age, accumulation rates, atmospheric conditions, and surface activity at the time of deposition, among other important parameters; gaining the information would allow us to “read” the climate record. Because Mars has fewer complicating factors than Earth (e.g. oceans, biology, and human-modified climate), the planet offers a unique opportunity to study the history of a terrestrial planet’s climate, which in turn can teach us about our own planet and the thousands of terrestrial exoplanets waiting to be discovered. During a two-part workshop, the Keck Institute for Space Studies (KISS) hosted 38 Mars scientists and engineers who focused on determining the measurements needed to extract the climate record contained in the PLD. The group converged on four fundamental questions that must be answered with the goal of interpreting the climate record and finding its history based on the climate drivers. The group then proposed numerous measurements in order to answer these questions and detailed a sequence of missions and architecture to complete the measurements. In all, several missions are required, including an orbiter that can characterize the present climate and volatile reservoirs; a static reconnaissance lander capable of characterizing near surface atmospheric processes, annual accumulation, surface properties, and layer formation mechanism in the upper 50 ​cm of the PLD; a network of SmallSat landers focused on meteorology for ground truth of the low-altitude orbiter data; and finally, a second landed platform to access ~500 ​m of layers to measure layer variability through time. This mission architecture, with two landers, would meet the science goals and is designed to save costs compared to a single very capable landed mission. The rationale for this plan is presented below. In this paper we discuss numerous aspects, including our motivation, background of polar science, the climate science that drives polar layer formation, modeling of the atmosphere and climate to create hypotheses for what the layers mean, and terrestrial analogs to climatological studies. Finally, we present a list of measurements and missions required to answer the four major questions and read the climate record. 1. What are present and past fluxes of volatiles, dust, and other materials into and out of the polar regions? 2. How do orbital forcing and exchange with other reservoirs affect those fluxes? 3. What chemical and physical processes form and modify layers? 4. What is the timespan, completeness, and temporal resolution of the climate history recorded in the PLD

EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children

Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated. Method: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach. Results: The mean age of subjects was 9.8 years (range 2–19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI ≥95 and 28 ≥ 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 × 10-7 [p(rec) = 7.34 × 10-8) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p(rec) = 8.21 × 10-9]. Imputation in this region using dense 1000-Genome and Hapmap CEU samples revealed 71 SNPs with p < 10-6, all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 × 10-7, z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 × 10-6, z = -4.85), Interleukin 15 (rs2099884, p = 1.27 × 10-5, z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 × 10-9, z = 5.89]. Conclusion: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population

Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis

Objective: We report the first pediatric specific Phenome-Wide Association Study (PheWAS) using electronic medical records (EMRs). Given the early success of PheWAS in adult populations, we investigated the feasibility of this approach in pediatric cohorts in which associations between a previously known genetic variant and a wide range of clinical or physiological traits were evaluated. Although computationally intensive, this approach has potential to reveal disease mechanistic relationships between a variant and a network of phenotypes. Method: Data on 5049 samples of European ancestry were obtained from the EMRs of two large academic centers in five different genotyped cohorts. Recently, these samples have undergone whole genome imputation. After standard quality controls, removing missing data and outliers based on principal components analyses (PCA), 4268 samples were used for the PheWAS study. We scanned for associations between 2476 single-nucleotide polymorphisms (SNP) with available genotyping data from previously published GWAS studies and 539 EMR-derived phenotypes. The false discovery rate was calculated and, for any new PheWAS findings, a permutation approach (with up to 1,000,000 trials) was implemented. Results: This PheWAS found a variety of common variants (MAF > 10%) with prior GWAS associations in our pediatric cohorts including Juvenile Rheumatoid Arthritis (JRA), Asthma, Autism and Pervasive Developmental Disorder (PDD) and Type 1 Diabetes with a false discovery rate < 0.05 and power of study above 80%. In addition, several new PheWAS findings were identified including a cluster of association near the NDFIP1 gene for mental retardation (best SNP rs10057309, p = 4.33 × 10−7, OR = 1.70, 95%CI = 1.38 − 2.09); association near PLCL1 gene for developmental delays and speech disorder [best SNP rs1595825, p = 1.13 × 10−8, OR = 0.65(0.57 − 0.76)]; a cluster of associations in the IL5-IL13 region with Eosinophilic Esophagitis (EoE) [best at rs12653750, p = 3.03 × 10−9, OR = 1.73 95%CI = (1.44 − 2.07)], previously implicated in asthma, allergy, and eosinophilia; and association of variants in GCKR and JAZF1 with allergic rhinitis in our pediatric cohorts [best SNP rs780093, p = 2.18 × 10−5, OR = 1.39, 95%CI = (1.19 − 1.61)], previously demonstrated in metabolic disease and diabetes in adults. Conclusion: The PheWAS approach with re-mapping ICD-9 structured codes for our European-origin pediatric cohorts, as with the previous adult studies, finds many previously reported associations as well as presents the discovery of associations with potentially important clinical implications

The Holy Grail: A road map for unlocking the climate record stored within Mars' polar layered deposits

In its polar layered deposits (PLD), Mars possesses a record of its recent climate, analogous to terrestrial ice sheets containing climate records on Earth. Each PLD is greater than 2 ​km thick and contains thousands of layers, each containing information on the climatic and atmospheric state during its deposition, creating a climate archive. With detailed measurements of layer composition, it may be possible to extract age, accumulation rates, atmospheric conditions, and surface activity at the time of deposition, among other important parameters; gaining the information would allow us to “read” the climate record. Because Mars has fewer complicating factors than Earth (e.g. oceans, biology, and human-modified climate), the planet offers a unique opportunity to study the history of a terrestrial planet’s climate, which in turn can teach us about our own planet and the thousands of terrestrial exoplanets waiting to be discovered. During a two-part workshop, the Keck Institute for Space Studies (KISS) hosted 38 Mars scientists and engineers who focused on determining the measurements needed to extract the climate record contained in the PLD. The group converged on four fundamental questions that must be answered with the goal of interpreting the climate record and finding its history based on the climate drivers. The group then proposed numerous measurements in order to answer these questions and detailed a sequence of missions and architecture to complete the measurements. In all, several missions are required, including an orbiter that can characterize the present climate and volatile reservoirs; a static reconnaissance lander capable of characterizing near surface atmospheric processes, annual accumulation, surface properties, and layer formation mechanism in the upper 50 ​cm of the PLD; a network of SmallSat landers focused on meteorology for ground truth of the low-altitude orbiter data; and finally, a second landed platform to access ~500 ​m of layers to measure layer variability through time. This mission architecture, with two landers, would meet the science goals and is designed to save costs compared to a single very capable landed mission. The rationale for this plan is presented below. In this paper we discuss numerous aspects, including our motivation, background of polar science, the climate science that drives polar layer formation, modeling of the atmosphere and climate to create hypotheses for what the layers mean, and terrestrial analogs to climatological studies. Finally, we present a list of measurements and missions required to answer the four major questions and read the climate record. 1. What are present and past fluxes of volatiles, dust, and other materials into and out of the polar regions? 2. How do orbital forcing and exchange with other reservoirs affect those fluxes? 3. What chemical and physical processes form and modify layers? 4. What is the timespan, completeness, and temporal resolution of the climate history recorded in the PLD