A virtual laboratory system for physiology teaching

The problem of understanding physiological processes can be aided by visualization tools. Traditionally this has been achieved by the use of schematic paper diagrams. However, many physiological processes are quite complex, and in many instances students encounter difficulties in understanding the dynamics. This paper describes the rationale behind an alternative approach using interactive three‐dimensional computer‐graphics simulation to aid comprehension of scientific concepts

The Inferred Cardiogenic Gene Regulatory Network in the Mammalian Heart

Cardiac development is a complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. Approximately 200 genes of interest were input into the algorithm to generate putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of putative networks are merged and filtered to generate scale-free, hierarchical networks that are statistically significant and biologically relevant. The networks are validated with known gene interactions and used to predict regulatory pathways important for the developing mammalian heart. Area under the precision-recall curve and receiver operator characteristic curve are 9% and 58%, respectively. Of the top 10 ranked predicted interactions, 4 have already been validated. The algorithm is further tested using a network enriched with known interactions and another depleted of them. The inferred networks contained more interactions for the enriched network versus the depleted network. In all test cases, maximum performance of the algorithm was achieved when the purely data-driven method of network inference was combined with a data-independent, functional-based association method. Lastly, the network generated from the list of approximately 200 genes of interest was expanded using gene-profile uniqueness metrics to include approximately 900 additional known mouse genes and to form the most likely cardiogenic gene regulatory network. The resultant network supports known regulatory interactions and contains several novel cardiogenic regulatory interactions. The method outlined herein provides an informative approach to network inference and leads to clear testable hypotheses related to gene regulation

PERISCOPE: PERIapsis Subsurface Cave Optical Explorer

The PERISCOPE study focuses primarily on lunar caves, due to the potential for being imaged in orbital scenarios. In the intervening years, from 2012-2015, scientists developed further rationales and interest in the scientific value of lunar caves. It does not appear that they are likely to be sinks for water-ice due to the relatively warm temperatures(~-20 degrees Celsius) in the caves leading to geologically-rapid migration of unbound water due to sublimation, and inevitable loss through any skylights. However, the skylights themselves reveal apparent complex layering, which may speak to a more complex multi-stage evolution of mare flood basalts than previously considered, and so their examination may provide even more insight into the lunar mare, which in turn provide a primary record of early solar system crustal formal and evolution processes. Further extrapolation of these insights can be found within the exoplanet community of researchers,who find the information useful for calibrating star formation and planetary evolution models. In addition, catalogues of lunar and martian skylights, "caves" or "atypical pit craters" have been developed, with numbers for both bodies now in the low hundreds thanks to additional high resolution surveys and revisiting the existing image databases

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications

TransFormers for Extreme Environments: Projecting Favorable Micro-Environments Around Robots and Areas of Interest

Surviving Extreme Space Environments (EE) is one of NASAs Space Technology Grand Challenges; we propose a paradigm shift in addressing this challenge. TransFormers (TFs) transform a region of an extreme environment into a favorable micro-environment, projecting energy at the precise location where robots or humans operate. TFs often use shape transformation to control the energy projection

Activin-A and Bmp4 Levels Modulate Cell Type Specification during CHIR-Induced Cardiomyogenesis

The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin-A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To further enhance the reproducibility of CHIR-induced cardiomyogenesis, and to ultimately promote myocyte maturation, we are using exogenous growth factors to optimize cardiomyogenic signaling downstream of CHIR induction. As indicated by RNA-seq, induction with CHIR during Day 1 (Days 0–1) was followed by immediate expression of Nodal ligands and receptors, followed later by Bmp ligands and receptors. Co-induction with CHIR and high levels of the Nodal mimetic Activin-A (50–100 ng/ml) during Day 0–1 efficiently induced definitive endoderm, whereas CHIR supplemented with Activin-A at low levels (10 ng/ml) consistently improved cardiomyogenic efficiency, even when CHIR alone was ineffective. Moreover, co-induction using CHIR and low levels of Activin-A apparently increased the rate of cardiomyogenesis, as indicated by the initial appearance of rhythmically beating cells by Day 6 instead of Day 8. By contrast, co-induction with CHIR plus low levels (3–10 ng/ml) of Bmp4 during Day 0–1 consistently and strongly inhibited cardiomyogenesis. These findings, which demonstrate that cardiomyogenic efficacy is improved by optimizing levels of CHIR-induced growth factors when applied in accord with their sequence of endogenous expression, are consistent with the idea that Nodal (Activin-A) levels toggle the entry of cells into the endodermal or mesodermal lineages, while Bmp levels regulate subsequent allocation into mesodermal cell types

Human gene copy number spectra analysis in congenital heart malformations

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways

Effect of plasma surface treatment of poly (dimethylsiloxane) on the permeation of pharmaceutical compounds

This paper addresses the modification of poly(dimethylsiloxane), i.e. PDMS, using plasma surface treatment and a novel application of the membrane created. A set of model compounds were analysed to determine their permeation through PDMS both with, and without, plasma treatment. It was found that plasma treatment reduced permeation for the majority of compounds yet had little effect for some compounds, such as caffeine, with results indicating that polarity plays an important role in permeation, as is seen in human skin. Most importantly, a direct correlation was observed between plasma-modified permeation data and literature data through calculation of membrane permeability (Kp) values implying plasma-modified silicone membrane (PMSM) could be considered a suitable in vivo replacement to predict clinical skin permeatio

THEO Concept Mission: Testing the Habitability of Enceladus's Ocean

Saturn's moon Enceladus offers a unique opportunity in the search for life and habitable environments beyond Earth, a key theme of the National Research Council's 2013-2022 Decadal Survey. A plume of water vapor and ice spews from Enceladus's south polar region. Cassini data suggest that this plume, sourced by a liquid reservoir beneath the moon's icy crust, contain organics, salts, and water-rock interaction derivatives. Thus, the ingredients for life as we know it-- liquid water, chemistry, and energy sources-- are available in Enceladus's subsurface ocean. We have only to sample the plumes to investigate this hidden ocean environment. We present a New Frontiers class, solar-powered Enceladus orbiter that would take advantage of this opportunity, Testing the Habitability of Enceladus's Ocean (THEO). Developed by the 2015 Jet Propulsion Laboratory Planetary Science Summer School student participants under the guidance of TeamX, this mission concept includes remote sensing and in situ analyses with a mass spectrometer, a sub-mm radiometer-spectrometer, a camera, and two magnetometers. These instruments were selected to address four key questions for ascertaining the habitability of Enceladus's ocean within the context of the moon's geological activity: (1) How are the plumes and ocean connected? (2) Are the abiotic conditions of the ocean suitable for habitability? (3) How stable is the ocean environment? (4) Is there evidence of biological processes? By taking advantage of the opportunity Enceladus's plumes offer, THEO represents a viable, solar-powered option for exploring a potentially habitable ocean world of the outer solar system.Comment: JPL Summer School 201

Oxidation and creep behavior of Mo5Si3 based materials

Mo[subscript]5 Si[subscript]3 shows promise as a high temperature creep resistant material. The high temperature oxidation resistance of Mo[subscript]5 Si[subscript]3 has been found to be poor, however, limiting its use in oxidizing atmospheres. Mo [subscript]5Si[subscript]3 exhibits mass loss during oxidation at 800°-1200° C due to volatilization of molybdenum oxide, indicating that the silica scale that forms does not provide a passivating layer. Catastrophic \u27pest\u27 oxidation occurs at 800° C. The oxidation rate at 1200° C is on the order of 10[superscript]3 mg cm[superscript]-2 hr[superscript]-1. The addition of boron results in protective scale formation and parabolic oxidation kinetics in the temperature range of 1050°-1300° C. The oxidation rate of Mo[subscript]5 Si[subscript]3 was decreased by 5 orders of magnitude at 1200° C by doping with less than two weight percent boron. Boron doping eliminates catastrophic \u27pest\u27 oxidation at 800° C. Oxidation and scale formation on several Mo[subscript]5 Si[subscript]3 based Mo-Si-B multiphase intermetallics was studied at 600° C-1300° C using SEM, XRD, ESCA, and thermogravimetric analysis. The mechanism for the improvement in oxidation resistance was found to be scale modification by boron. Boron additions of as low as 0.14 wt% promote formation of a passivating scale by allowing viscous flow to occur;The compressive creep rate of an MoSi[subscript]3 based Mo-Si-B composition was evaluated at 1240°-1320° C and 140-180 MPa. The composition tested had a three phase microstructure composed of Mo[subscript]5 Si[subscript]3 (T1), Mo[subscript]3Si, and a ternary Mo[subscript]5( Si,B)[subscript]3 (T2) phase. The average creep stress exponent and activation energy were found to be n = 4.3 and E[subscript] a = 396 kJ/mol. The boron modified Mo[subscript]5 Si[subscript]3 was found to have approximately the same creep rate as Mo[subscript]5 Si[subscript]3 at 140 MPa. TEM analysis of the crept microstructure of the boron modified material reveals no evidence for dislocation activity in T1. Only basal slip was observed in the T2 phase. \001 dislocations and polygonal subgrain structures were observed in Mo[subscript]3 Si. Mo[subscript]3 Si and T2 were found to stop cracks that nucleate in the T1 phase during creep