Improved Answer-Set Programming Encodings for Abstract Argumentation

The design of efficient solutions for abstract argumentation problems is a crucial step towards advanced argumentation systems. One of the most prominent approaches in the literature is to use Answer-Set Programming (ASP) for this endeavor. In this paper, we present new encodings for three prominent argumentation semantics using the concept of conditional literals in disjunctions as provided by the ASP-system clingo. Our new encodings are not only more succinct than previous versions, but also outperform them on standard benchmarks.Comment: To appear in Theory and Practice of Logic Programming (TPLP), Proceedings of ICLP 201

Spectral Functions of the Uniform Electron Gas via Coupled-Cluster Theory and Comparison to the GWGW and Related Approximations

We use, for the first time, ab initio coupled-cluster theory to compute the spectral function of the uniform electron gas at a Wigner-Seitz radius of $r_\mathrm{s}=4$. The coupled-cluster approximations we employ go significantly beyond the diagrammatic content of state-of-the-art $GW$ theory. We compare our calculations extensively to $GW$ and $GW$-plus-cumulant theory, illustrating the strengths and weaknesses of these methods in capturing the quasiparticle and satellite features of the electron gas. Our accurate calculations further allow us to address the long-standing debate over the occupied bandwidth of metallic sodium. Our findings indicate that the future application of coupled-cluster theory to condensed phase material spectra is highly promising.Comment: 6 pages, 2 figure

Phage displayed peptides/antibodies recognizing growth factors and their tyrosine kinase receptors as tools for anti-cancer therapeutics.

The basic idea of displaying peptides on a phage, introduced by George P. Smith in 1985, was greatly developed and improved by McCafferty and colleagues at the MRC Laboratory of Molecular Biology and, later, by Barbas and colleagues at the Scripps Research Institute. Their approach was dedicated to building a system for the production of antibodies, similar to a naïve B cell repertoire, in order to by-pass the standard hybridoma technology that requires animal immunization. Both groups merged the phage display technology with an antibody library to obtain a huge number of phage variants, each of them carrying a specific antibody ready to bind its target molecule, allowing, later on, rare phage (one in a million) to be isolated by affinity chromatography. Here, we will briefly review the basis of the technology and the therapeutic application of phage-derived bioactive molecules when addressed against key players in tumor development and progression: growth factors and their tyrosine kinase receptors

Unpredictable Variable Prenatal Stress Programs Expression of Genes Involved in Appetite Control and Energy Expenditure

Exposure to stress in the womb shapes neurobiological and physiological outcomes of offspring in later life, including body weight regulation and metabolic profiles. Our previous work utilizing a centrifugation-induced hypergravity demonstrated significantly increased (8-15) body mass in male, but not female, rats exposed throughout gestation to chronic 2-g from conception to birth. We reported the same outcome in adult offspring exposed throughout gestation to Unpredictable Variable Prenatal Stress (UVPS). Here we examine gene expression changes using our UVPS model to identify a potential role for prenatal stress in this hypergravity programming effect. Specifically we focused on appetite control and energy expenditure pathways in prenatally stressed adult (90-day-old) male Sprague-Dawley rats. Time-mated female rats were exposed throughout their 22-day pregnancy to UVPS consisting of white noise, strobe light, and tube restraint individually once per day on an unpredictable schedule for 15, 30 or 60 min. To control for potential changes in postnatal maternal care, newborn pups were fostered to non-manipulated, newly parturient dams. At 90-days of age, we analyzed plasma concentrations of hormones involved in appetite control and energy expenditure (leptin and adiponectin), and quantified expression of key genes in epididymal fat pads harvested from adult male offspring and controls. Leptin regulates energy balance by inhibiting hunger, and adiponectin modulates glucose levels and fatty acid breakdown. Our findings indicate significantly elevated plasma leptin concentrations and reduced expression of epididymal fat leptin (OB) and adiponectin (ADIPOQ) genes compared to controls. Analyses presently underway include quantification of plasma insulin and glucose, and the expression of ghrelin, a peptide that acts on the central nervous system and the body's perception of hunger. Collectively, these findings will further understanding of the consequences of UVPS on body weight regulation and metabolism, and provide further insight into the effect of gravity modulation on mammalian fetal development

Sex-specific Effects of Unpredictable Variable Prenatal Stress: Implications for Mammalian Developmental Programming During Spaceflight

During initial exposure and adaptation to the microgravity environment, adult mammals exhibit elevated stress, mediated by the Hypothalamic-Pituitary-Adrenal (HPA) axis. In our previous studies of pregnant rats exposed to 2-g hypergravity via continuous centrifugation, we reported changes in neuroendocrine profiles including decreased corticosterone and a concomitant increase in body mass and leptin in adult male offspring. Prenatally stressed adult offspring have been shown to exhibit an elevated stress response in adulthood, therefore we hypothesized that these changes resulted from stress exposure during fetal development. Future studies examining reproduction, gestation, and development on-orbit need to consider the unique stressors of vehicle launch, the space environment, and landing on the development of the HPA axis in animals born and raised in microgravity. In this study, we utilize Unpredictable Variable Prenatal Stress (UVPS) to simulate the stressors of spaceflight by exposing dams to three different stressors: (1) White Noise, (2) Strobe Light, and (3) Tube Restraint. Stressors were applied from Gestational Day 0 (G0), following an unpredictable schedule (morning [0600-1200hrs]; afternoon [1200-1800hrs]; evening [1800-2400hrs] in 15, 30, or 60 minute durations alongside non-stressed (NS) control dams. Following parturition, pups were fostered to non-manipulated, newly parturient dams to control for differential maternal care. On postnatal day 90 (P90), we harvested the hypothalamus, pituitary, and adrenal glands, and analyzed mRNA expression of the following genes via RT-qPCR: 1) melanocortin-2 receptor (MC2R), POMC, corticotropin-releasing hormone (CRH) in the pituitary; 2) glucocorticoid receptor (NR3C1), pro-opiomelanocortin (POMC), corticotropin-releasing hormone (CRH), brain-derived neurotropic factor (BDNF), in the hypothalamus; and 3) MC2R, tyrosine hydroxylase (TH), steroidogenic acute regulatory protein (STAR), cytochrome P450scc enzyme (CYP) in the adrenal. The identification of sex-specific fetal programming effects on adult stress response is a key step in determining potential animal behavior on-orbit, and will guide future multi-generational studies in microgravity

Sex-Specific Effects of Unpredictable Variable Prenatal Stress: Implications for Mammalian Developmental Programming During Spaceflight

During adaptation to the microgravity environment, adult mammals experience stress mediated by the Hypothalamic-Pituitary-Adrenal axis. In our previous studies of pregnant rats exposed to 2-g hypergravity via centrifugation, we reported decreased corticosterone and increased body mass and leptin in adult male, but not female, offspring. In this study, we utilized Unpredictable Variable Prenatal Stress to simulate the stressors of spaceflight by exposing dams to different stressors. Stress response modulation occurs via both positive and negative feedback in the hypothalamus, anterior pituitary gland, and adrenal cortex resulting in the differential release of corticosterone (CORT), a murine analog to human cortisol

Effects of Unpredictable Variable Prenatal Stress (UVPS) on Bdnf DNA Methylation and Telomere Length in the Adult Rat Brain

In utero exposure to stress can shape neurobiological and behavioral outcomes in offspring, producing vulnerability to psychopathology later in life. Animal models of prenatal stress likewise have demonstrated long-term alterations in brain function and behavioral deficits in offspring. For example, using a rodent model of unpredictable variable prenatal stress (UVPS), in which dams are exposed to unpredictable, variable stress across pregnancy, we have found increased body weight and anxiety-like behavior in adult male, but not female, offspring. DNA methylation (addition of methyl groups to cytosines which normally represses gene transcription) and changes in telomere length (TTAGGG repeats on the ends of chromosomes) are two molecular modifications that result from stress and could be responsible for the long-term effects of UVPS. Here, we measured methylation of brain-derived neurotrophic factor (bdnf), a gene important in development and plasticity, and telomere length in the brains of adult offspring from the UVPS model. Results indicate that prenatally stressed adult males have greater methylation in the medial prefrontal cortex (mPFC) compared to non-stressed controls, while females have greater methylation in the ventral hippocampus compared to controls. Further, prenatally stressed males had shorter telomeres than controls in the mPFC. These findings demonstrate the ability of UVPS to produce epigenetic alterations and changes in telomere length across behaviorally-relevant brain regions, which may have linkages to the phenotypic outcomes

Advancing Translational Space Research Through Biospecimen Sharing: Amplifying the Impact of Ground-Based Studies

Biospecimen Sharing Programs (BSPs) have been organized by NASA Ames Research Center since the 1960s with the goal of maximizing utilization and scientific return from rare, complex and costly spaceflight experiments. BSPs involve acquiring otherwise unused biological specimens from primary space research experiments for distribution to secondary experiments. Here we describe a collaboration leveraging Ames expertise in biospecimen sharing to magnify the scientific impact of research informing astronaut health funded by the NASA Human Research Program (HRP) Human Health Countermeasures (HHC) Element. The concept expands biospecimen sharing to one-off ground-based studies utilizing analogue space platforms (e.g., Hind limb Unloading (HLU), Artificial Gravity) for rodent experiments, thereby significantly broadening the range of research opportunities with translational relevance for protecting human health in space and on Earth. In this presentation, we will report on biospecimens currently being acquired from HHC Award Head-Down Tilt as a Model for Intracranial and Intraocular Pressures, and Retinal Changes during Spaceflight, and their availability. The BSP add-on to the project described herein has already yielded for HHC-funded investigators more than 4,700 additional tissues that would otherwise have been discarded as waste, with additional tissues available for analysis. Young (3-mo old) male and female rats and Older (9-mo old) male rats are being exposed to HLU for either 7, 14, 28, or 90 days. Additional groups are exposed to 90 days of unloading followed by either 7, 14, 28 days or 90 days of recovery (normal loading). Comparisons are made with non-suspended controls. Unused tissues are: Skin, Lungs, Thymus, Adrenals, Kidneys, Spleen, Hindlimb Muscles (Soleus, Extensor Digitorum Longus, Tibialis Anterior, Plantaris Gastrocnemius), Fat Pads, Reproductive Organs, and Intestines. Tissues are harvested, weighed, preserved then archived (with metadata) using a sample tracking system (CryoTrack). Preservation techniques include snap-freezing and RNALatersnap-freezing. Specimens were weighed at the time of dissection, and organ mass: body mass ratios analyzed to determine unloading effects across conditions and durations. The results corroborate previously reported effects of short-term exposure to microgravity or unloading exposure on various organs, and provide new insights into adaptation to long-duration unloading relevant to sustained spaceflight exposures on ISS. Supported by the Human Research Program (HRP) Human Health Countermeasures (HHC) Element and NASA Grant NNX13AD94G (CAF)

Effects of 2G on Gene Expression of Stress-Related Hormones in Rat Placenta

Understanding the effects of spaceflight on mammalian reproductive and developmental physiology is important to future human space exploration and permanent settlement beyond Earth orbit. Fetal developmental programming, including modulation of the HPA axis, is thought to originate at the placental-uterine interface, where both transfer of maternal hormones to the fetus and synthesis of endogenous hormones occurs. In healthy rats, fetal corticosterone levels are kept significantly lower by 11BetaHSD-2, which inactivates corticosterone by conversion into cortisone. Placental tissues express endogenous HPA axis-associated hormones including corticotropin-releasing hormone (CRH), pre-opiomelanocortin (POMC), and vasopressin, which may contribute to fetal programming alongside maternal hormones. DNA methylase 3A, 11BetaHSD-2, and 11BetaHSD-1, which are involved in the regulation of maternal cortisol transfer and modulation of the HPA axis, are also expressed in placental tissues along with glucocorticoid receptor and may be affected by differential gravity exposure during pregnancy. Fetuses may respond differently to maternal glucocorticoid exposure during gestation through sexually dimorphic expression of corticosterone-modulating hormones. To elucidate effects of altered gravity on placental gene expression, here we present a ground-based analogue study involving continuous centrifugation to produce 2g hypergravity. We hypothesized that exposure to 2g would induce a decrease in 11BetaHSD-2 expression through the downregulation of DNA methylase 3a and GC receptor, along with concurrent upregulation in endogenous CRH, POMC, and vasopressin expression. Timed pregnant female rats were exposed to 2G from Gestational day 6 to Gestational day 20, and comparisons made with Stationary Control (SC) and Vivarium Control (VC) dams at 1G. Dams were euthanized and placentas harvested on G20. We homogenized placental tissues, extracted and purified RNA, synthesized cDNA, and quantified the expression levels of the genes of interest relative to the GAPDH housekeeping gene, using RT-qPCR and gene-specific cDNA probes. Elucidation of glucocorticoid transfer and synthesis in the placenta can provide new insights into the unique dynamics of mammalian development in microgravity and guide future multi-generational studies in space

Characterizing the Effects of Chronic 2G Centrifugation on the Rat Skeletal System

During weightlessness, the skeletal system of astronauts is negatively affected by decreased calcium absorption and bone mass loss. Therefore, it is necessary to counteract these changes for long-term skeletal health during space flights. Our long-term plan is to assess artificial gravity (AG) as a possible solution to mitigate these changes. In this study, we aim to determine the skeletal acclimation to chronic centrifugation. We hypothesize that a 2G hypergravity environment causes an anabolic response in growing male rats. Specifically, we predict chronic 2G to increase tissue mineral density, bone volume fraction of the cancellous tissue and to increase overall bone strength. Systemically, we predict that bone formation markers (i.e., osteocalcin) are elevated and resorption markers (i.e., tartrate resistant acid phosphatase) are decreased or unchanged from controls. The experiment has three groups, each with an n8: chronic 2g, cage control (housed on the centrifuge, but not spun), and a vivarium control (normal rat caging). Pre-pubescent, male Long-Evans rats were used to assess our hypothesis. This group was subject to 90 days of 2G via centrifugation performed at the Chronic Acceleration Research Unit (CARU) at University of California Davis. After 90 days, animals were euthanized and tissues collected. Blood was drawn via cardiac puncture and the right leg collected for structural (via microcomputed tomography) and strength quantification. Understanding how counteract these skeletal changes will have major impacts for both the space-faring astronauts and the people living on Earth