Preferences for Government Size and their Effect on Labor-Leisure Decisions

While many economists have theorized and/or empirically demonstrated that labor-leisure decisions are influenced by the rate of taxation, this note introduces a new mechanism in which the collecting of taxes on income may affect such decisions. Although standard models assume that agents have no preference for the size and scope of government activity, recent and past political rhetoric suggests that preferences do exist. We examine how labor-leisure decisions can be affected when taxes are derived from income and agents' utility functions include a preference for government size.

BACE1 Gene Regulation: A Novel Drug Target in Alzheimer’s Disease

poster abstractAlzheimer’s disease (AD) is the most common form of dementia in the elderly in the United States. AD is characterized by the presence of amyloid-β (Aβ) peptide plaques. Aberrant deposition is believed to result from the misregulation of the production or the clearance of Aβ. The rate-limiting step in Aβ production is the processing of amyloid- β precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). BACE1 could play a critical role in the development of AD and is a promising drug target. In this study, we aim to reduce BACE1 enzyme levels by reducing BACE1 gene expression. We previously analyzed the promoter activity of BACE1 and the 5’ untranslated region of BACE1 mRNA. The BACE1 promoter contains many transcription factor sites including SP1, MEF2, and STAT1, which have been shown to play a role in the regulation of BACE1 gene expression. Mithramycin A (MithA) has been previously shown to selectively inhibit SP1-mediated transcriptional activation. We expect inhibition of SP1 to lead to downregulation of BACE1 and decreased Aβ, providing a novel target for AD. We have tested several BACE1 promoter-deletion constructs by DNA transfection in human neuronal cultures, treatment with MithA, and performed luciferase reporter assays. In a neuroblastoma (NB) cell line, we observed the significant increase in luciferase reporter activity of two BACE1 plasmid constructs after treatment with MithA. Treatment also correlated with an increase in BACE1 protein expression and a decrease in APP expression. This suggests that the mechanism by which MithA influences the BACE1 promoter could be complex and or due to other transcription factor sites as well. Further experiments will include using differentiated NB cells and human primary fetal neurons, along with the use of other Sp1 inhibitors including tolfenamic acid to elucidate the regulation of APP and BACE1 promoters leading to lower Aβ levels

Sleep characteristics modify the association between genetic predisposition to obesity and anthropometric measurements in 119,679 UK Biobank participants

Background - Obesity is a multifactorial condition influenced by genetics, lifestyle and environment. Objective - To investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) with body mass index (BMI) and waist circumference (WC) was modified by sleep characteristics. Design - This study included cross-sectional data from 119,859 white European adults, aged 37-73 years, participating on the UK Biobank. Interactions between GPRS-obesity, and sleep characteristics (sleep duration, chronotype, day napping, and shift work) in their effects on BMI and WC were investigated. Results - The GPRS-obesity was associated with BMI (β:0.57 kg.m-2 per standard deviation (SD) increase in GPRS, [95%CI:0.55, 0.60]; P=6.3x10-207) and WC (β:1.21 cm, [1.15, 1.28]; P=4.2x10-289). There were significant interactions between GPRS-obesity and a variety of sleep characteristics in their relationship with BMI (P-interaction <0.05). In participants who slept <7 hrs or >9 hrs daily, the effect of GPRS-obesity on BMI was stronger (β:0.60 [0.54, 0.65] and 0.73 [0.49, 0.97] kg.m-2 per SD increase in GPRS, respectively) than in normal length sleepers (7-9 hours; β:0.52 [0.49, 0.55] kg.m-2 per SD). A similar pattern was observed for shiftworkers (β:0.68 [0.59, 0.77] versus 0.54 [0.51, 0.58] kg.m-2 for non-shiftworkers) and for night-shiftworkers (β:0.69 [0.56, 0.82] versus 0.55 [0.51, 0.58] kg.m-2 for non-night- shiftworkers), for those taking naps during the day (β:0.65 [0.52, 0.78] versus 0.51 [0.48, 0.55] kg.m-2 for those who never/rarely had naps) and for those with a self-reported evening chronotype (β:0.72 [0.61, 0.82] versus β:0.52 [0.47, 0.57] kg.m-2 for morning chronotype). Similar findings were obtained using WC as the outcome. Conclusions – This study shows that the association between genetic risk for obesity and phenotypic adiposity measures is exacerbated by adverse sleeping characteristics

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Thermionic Properties of Carbon Based Nanomaterials Produced by Microhollow Cathode PECVD

Thermionic emission is the process in which materials at sufficiently high temperature spontaneously emit electrons. This process occurs when electrons in a material gain sufficient thermal energy from heating to overcome the material's potential barrier, referred to as the work function. For most bulk materials very high temperatures (greater than 1500 K) are needed to produce appreciable emission. Carbonbased nanomaterials have shown significant promise as emission materials because of their low work functions, nanoscale geometry, and negative electron affinity. One method of producing these materials is through the process known as microhollow cathode PECVD. In a microhollow cathode plasma, high energy electrons oscillate at very high energies through the Pendel effect. These high energy electrons create numerous radical species and the technique has been shown to be an effective method of growing carbon based nanomaterials. In this work, we explore the thermionic emission properties of carbon based nanomaterials produced by microhollow cathode PECVD under a variety of synthesis conditions. Initial studies demonstrate measureable current at low temperatures (approximately 800 K) and work functions (approximately 3.3 eV) for these materials

Dietary fat and total energy intake modifies the association of genetic profile risk score on obesity: evidence from 48 170 UK Biobank participants

Background: Obesity is a multifactorial condition influenced by both genetics and lifestyle. The aim of this study was to investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) and body mass index (BMI) or waist circumference (WC) was modified by macronutrient intake in a large general population study. Methods: This study included cross-sectional data from 48 170 white European adults, aged 37–73 years, participating on the UK Biobank. Interactions between GPRS-obesity, and macronutrient intake (including total energy, protein, fat, carbohydrate and dietary fibre intake) and its effects on BMI and WC were investigated. Results: The 93-SNPs genetic profile risk score was associated with a higher BMI (β:0.57 kg.m−2 per standard deviation (s.d.) increase in GPRS, [95%CI:0.53–0.60]; P=1.9 × 10−183) independent of major confounding factors. There was a significant interaction between GPRS and total fat intake (P[interaction]=0.007). Among high fat intake individuals, BMI was higher by 0.60 [0.52, 0.67] kg.m−2 per s.d. increase in GPRS-obesity; the change in BMI with GPRS was lower among low fat intake individuals (β:0.50 [0.44, 0.57] kg.m-2). Significant interactions with similar patterns were observed for saturated fat intake (High β:0.66 [0.59, 0.73] versus Low β:0.49 [0.42, 0.55] kg.m-2, P-interaction=2 × 10-4), and total energy intake (High β:0.58 [0.51, 0.64] versus Low β:0.49 [0.42, 0.56] kg.m−2, P-interaction=0.019), but not for protein intake, carbohydrate intake and fiber intake (P-interaction >0.05). The findings were broadly similar using WC as the outcome. Conclusions: These data suggest that the benefits of reducing the intake of fats and total energy intake, may be more important in individuals with high genetic risk for obesity

Demonstrating high-precision photometry with a CubeSat: ASTERIA observations of 55 Cancri e

ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) is a 6U CubeSat space telescope (10 cm x 20 cm x 30 cm, 10 kg). ASTERIA's primary mission objective was demonstrating two key technologies for reducing systematic noise in photometric observations: high-precision pointing control and high-stabilty thermal control. ASTERIA demonstrated 0.5 arcsecond RMS pointing stability and $\pm$10 milliKelvin thermal control of its camera payload during its primary mission, a significant improvement in pointing and thermal performance compared to other spacecraft in ASTERIA's size and mass class. ASTERIA launched in August 2017 and deployed from the International Space Station (ISS) November 2017. During the prime mission (November 2017 -- February 2018) and the first extended mission that followed (March 2018 - May 2018), ASTERIA conducted opportunistic science observations which included collection of photometric data on 55 Cancri, a nearby exoplanetary system with a super-Earth transiting planet. The 55 Cancri data were reduced using a custom pipeline to correct CMOS detector column-dependent gain variations. A Markov Chain Monte Carlo (MCMC) approach was used to simultaneously detrend the photometry using a simple baseline model and fit a transit model. ASTERIA made a marginal detection of the known transiting exoplanet 55 Cancri e ($\sim2$~\Rearth), measuring a transit depth of $374\pm170$ ppm. This is the first detection of an exoplanet transit by a CubeSat. The successful detection of super-Earth 55 Cancri e demonstrates that small, inexpensive spacecraft can deliver high-precision photometric measurements.Comment: 23 pages, 9 figures. Accepted in A

Initial Investigation of Reaction Control System Design on Spacecraft Handling Qualities for Earth Orbit Docking

A program of research, development, test, and evaluation is planned for the development of Spacecraft Handling Qualities guidelines. In this first experiment, the effects of Reaction Control System design characteristics and rotational control laws were evaluated during simulated proximity operations and docking. Also, the influence of piloting demands resulting from varying closure rates was assessed. The pilot-in-the-loop simulation results showed that significantly different spacecraft handling qualities result from the design of the Reaction Control System. In particular, cross-coupling between translational and rotational motions significantly affected handling qualities as reflected by Cooper-Harper pilot ratings and pilot workload, as reflected by Task-Load Index ratings. This influence is masked but only slightly by the rotational control system mode. While rotational control augmentation using Rate Command Attitude Hold can reduce the workload (principally, physical workload) created by cross-coupling, the handling qualities are not significantly improved. The attitude and rate deadbands of the RCAH introduced significant mental workload and control compensation to evaluate when deadband firings would occur, assess their impact on docking performance, and apply control inputs to mitigate that impact

Risk estimation using probability machines

BACKGROUND: Logistic regression has been the de facto, and often the only, model used in the description and analysis of relationships between a binary outcome and observed features. It is widely used to obtain the conditional probabilities of the outcome given predictors, as well as predictor effect size estimates using conditional odds ratios. RESULTS: We show how statistical learning machines for binary outcomes, provably consistent for the nonparametric regression problem, can be used to provide both consistent conditional probability estimation and conditional effect size estimates. Effect size estimates from learning machines leverage our understanding of counterfactual arguments central to the interpretation of such estimates. We show that, if the data generating model is logistic, we can recover accurate probability predictions and effect size estimates with nearly the same efficiency as a correct logistic model, both for main effects and interactions. We also propose a method using learning machines to scan for possible interaction effects quickly and efficiently. Simulations using random forest probability machines are presented. CONCLUSIONS: The models we propose make no assumptions about the data structure, and capture the patterns in the data by just specifying the predictors involved and not any particular model structure. So they do not run the same risks of model mis-specification and the resultant estimation biases as a logistic model. This methodology, which we call a “risk machine”, will share properties from the statistical machine that it is derived from