Documentation of the Analyses of the Benefits and Costs of Aeronautical Research and Technology models (ABC-ART). Volume 2: Appendices

Fleet variables are defined, and source codes for each module are presented

Documentation of the analysis of the benefits and costs of aeronautical research and technology models, volume 1

The analysis of the benefits and costs of aeronautical research and technology (ABC-ART) models are documented. These models were developed by NASA for use in analyzing the economic feasibility of applying advanced aeronautical technology to future civil aircraft. The methodology is composed of three major modules: fleet accounting module, airframe manufacturing module, and air carrier module. The fleet accounting module is used to estimate the number of new aircraft required as a function of time to meet demand. This estimation is based primarily upon the expected retirement age of existing aircraft and the expected change in revenue passenger miles demanded. Fuel consumption estimates are also generated by this module. The airframe manufacturer module is used to analyze the feasibility of the manufacturing the new aircraft demanded. The module includes logic for production scheduling and estimating manufacturing costs. For a series of aircraft selling prices, a cash flow analysis is performed and a rate of return on investment is calculated. The air carrier module provides a tool for analyzing the financial feasibility of an airline purchasing and operating the new aircraft. This module includes a methodology for computing the air carrier direct and indirect operating costs, performing a cash flow analysis, and estimating the internal rate of return on investment for a set of aircraft purchase prices

Analysis of cell wall proteins regulated in stem of susceptible and resistant tomato species after inoculation with Ralstonia solanacearum: a proteomic approach

Proteomics approach was used to elucidate the molecular interactions taking place at the stem cell wall level when tomato species were inoculated with Ralstonia solanacearum, a causative agent of bacterial wilt. Cell wall proteins from both resistant and susceptible plants before and after the bacterial inoculation were extracted from purified cell wall with salt buffers and separated with 2-D IEF/SDS–PAGE and with 3-D IEF/SDS/SDS–PAGE for basic proteins. The gels stained with colloidal Coomassie revealed varied abundance of protein spots between two species (eight proteins in higher abundance in resistant and six other in susceptible). Moreover, proteins were regulated differentially in response to bacterial inoculation in resistant (seven proteins increased and eight other decreased) as well as in susceptible plants (five proteins elevated and eight other suppressed). Combination of MALDI-TOF/TOF MS and LC-ESI-IonTrap MS/MS lead to the identification of those proteins. Plants responded to pathogen inoculation by elevating the expression of pathogenesis related, other defense related and glycolytic proteins in both species. However, cell wall metabolic proteins in susceptible, and antioxidant, stress related as well as energy metabolism proteins in resistant lines were suppressed. Most of the proteins of the comparative analysis and other randomly picked spots were predicted to have secretion signals except some classical cytosolic proteins

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS

KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice.

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials

Resting-State Brain Activity in Adult Males Who Stutter

Although developmental stuttering has been extensively studied with structural and task-based functional magnetic resonance imaging (fMRI), few studies have focused on resting-state brain activity in this disorder. We investigated resting-state brain activity of stuttering subjects by analyzing the amplitude of low-frequency fluctuation (ALFF), region of interest (ROI)-based functional connectivity (FC) and independent component analysis (ICA)-based FC. Forty-four adult males with developmental stuttering and 46 age-matched fluent male controls were scanned using resting-state fMRI. ALFF, ROI-based FCs and ICA-based FCs were compared between male stuttering subjects and fluent controls in a voxel-wise manner. Compared with fluent controls, stuttering subjects showed increased ALFF in left brain areas related to speech motor and auditory functions and bilateral prefrontal cortices related to cognitive control. However, stuttering subjects showed decreased ALFF in the left posterior language reception area and bilateral non-speech motor areas. ROI-based FC analysis revealed decreased FC between the posterior language area involved in the perception and decoding of sensory information and anterior brain area involved in the initiation of speech motor function, as well as increased FC within anterior or posterior speech- and language-associated areas and between the prefrontal areas and default-mode network (DMN) in stuttering subjects. ICA showed that stuttering subjects had decreased FC in the DMN and increased FC in the sensorimotor network. Our findings support the concept that stuttering subjects have deficits in multiple functional systems (motor, language, auditory and DMN) and in the connections between them

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

Self-oscillation

Physicists are very familiar with forced and parametric resonance, but usually not with self-oscillation, a property of certain dynamical systems that gives rise to a great variety of vibrations, both useful and destructive. In a self-oscillator, the driving force is controlled by the oscillation itself so that it acts in phase with the velocity, causing a negative damping that feeds energy into the vibration: no external rate needs to be adjusted to the resonant frequency. The famous collapse of the Tacoma Narrows bridge in 1940, often attributed by introductory physics texts to forced resonance, was actually a self-oscillation, as was the swaying of the London Millennium Footbridge in 2000. Clocks are self-oscillators, as are bowed and wind musical instruments. The heart is a "relaxation oscillator," i.e., a non-sinusoidal self-oscillator whose period is determined by sudden, nonlinear switching at thresholds. We review the general criterion that determines whether a linear system can self-oscillate. We then describe the limiting cycles of the simplest nonlinear self-oscillators, as well as the ability of two or more coupled self-oscillators to become spontaneously synchronized ("entrained"). We characterize the operation of motors as self-oscillation and prove a theorem about their limit efficiency, of which Carnot's theorem for heat engines appears as a special case. We briefly discuss how self-oscillation applies to servomechanisms, Cepheid variable stars, lasers, and the macroeconomic business cycle, among other applications. Our emphasis throughout is on the energetics of self-oscillation, often neglected by the literature on nonlinear dynamical systems.Comment: 68 pages, 33 figures. v4: Typos fixed and other minor adjustments. To appear in Physics Report