The ASD Living Biology: from cell proliferation to clinical phenotype.

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child's development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD

Thermal Emission and Albedo Spectra of Super Earths with Flat Transmission Spectra

Planets larger than Earth and smaller than Neptune are some of the most numerous in the galaxy, but observational efforts to understand this population have proved challenging because optically thick clouds or hazes at high altitudes obscure molecular features (Kreidberg et al. 2014b). We present models of super Earths that include thick clouds and hazes and predict their transmission, thermal emission, and reflected light spectra. Very thick, lofted clouds of salts or sulfides in high metallicity (1000x solar) atmospheres create featureless transmission spectra in the near-infrared. Photochemical hazes with a range of particle sizes also create featureless transmission spectra at lower metallicities. Cloudy thermal emission spectra have muted features more like blackbodies, and hazy thermal emission spectra have emission features caused by an inversion layer at altitudes where the haze forms. Close analysis of reflected light from warm (~400-800 K) planets can distinguish cloudy spectra, which have moderate albedos (0.05-0.20), from hazy models, which are very dark (0.0-0.03). Reflected light spectra of cold planets (~200 K) accessible to a space-based visible light coronagraph will have high albedos and large molecular features that will allow them to be more easily characterized than the warmer transiting planets. We suggest a number of complementary observations to characterize this population of planets, including transmission spectra of hot (>1000 K) targets, thermal emission spectra of warm targets using the James Webb Space Telescope (JWST), high spectral resolution (R~10^5) observations of cloudy targets, and reflected light spectral observations of directly-imaged cold targets. Despite the dearth of features observed in super Earth transmission spectra to date, different observations will provide rich diagnostics of their atmospheres.Comment: 23 pages, 23 figures. Revised for publication in The Astrophysical Journa

Advancing a contextualized, community-centric understanding of social entrepreneurial ecosystems

We investigate what distinguishes social entrepreneurial ecosystems (SEEs) from entrepreneurial ecosystems (EEs) through appreciation of the importance of context—the multiplex of intertwined social, spatial, temporal, historical, cultural, and political influences. Community is incorporated as a key variable and hitherto overlooked dimension of the structure and influence of SEEs. We draw on extant literature and examples of a variety of SEEs to support our propositions and demonstrate why considerations of both context and community are critical to advance understanding of SEEs. We contribute to the study of SEEs by presenting a new conceptual framework and theorizing SEE as an evolving composite of interdependent actors who interact and collaborate across multiple levels to collectively generate positive externalities and drive sustainable solutions to social problems

Photoprotection:extending lessons learned from studying natural sunscreens to the design of artificial sunscreen constituents

Ultrafast pump–probe spectroscopies and computational chemistry unravel the excited state photophysics responsible for the photostability of molecules in natural and commercial sunscreens.</p

Neuron-glia crosstalk mediate the neurotoxic effects of ketamine via extracellular vesicles

Background: General anesthetics (GA) are associated with neurodevelopmental abnormalities including cell death, cognitive and behavioral changes. There is now powerful evidence for non-cell autonomous mechanisms in almost every pathological condition in the brain, especially relevant to glial cells, mainly astrocytes and microglia, that exhibit structural and functional contacts with neurons. These interactions were recently reported to occur via the secretion of extracellular vesicles (EVs). Here, we employed primary human neural cells to analyze ketamine effects focusing on the functions of glial cells and their polarization/differentiation state. We also explored the roles of extracellular vesicles (EVs) and different components of the BDNF pathway. Methods: Ketamine effects were analyzed on human neuronal and glial cell proliferation and apoptosis and astrocytic (A1/A2 ) and microglial (M1/M2) cell activation were analyzed. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell co-cultures. The role of the brainderived neurotrophic factor (BDNF) pathway, was analyzed using RT-PCR, ELISA western blot and gene silencing. EVs secreted by ketamine-treated cells were isolated, characterized and analyzed for their effects in neuron-glia cell interactions. Data were analyzed using analysis of variance or a Student\u27s t test with correction for data sets with unequal variances. Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted the expression of proinflammatory astrocytes (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and oligodendrocytes. In addition, ketamine treatment increased the lncRNA BDNF-AS levels and the secretion of pro-BDNF secretion. We found an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death by delivering BDNF-AS. Conclusions: Ketamine neurotoxicity involves both autonomous and non-cell autonomous mechanisms andomponents of the BDNF pathway expressed by neurons and glial cells represent major regulators of ketamine effects. We demonstrated for the first time a role of EVs as important mediators of ketamine effects by the delivery of specific non-coding RNAs. These results may contribute to a better understanding of cellular and molecular mechanisms underlying ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact

Prospectus, May 3, 1990

https://spark.parkland.edu/prospectus_1990/1013/thumbnail.jp

Relationship between volume status and blood pressure during chronic hemodialysis

Relationship between volume status and blood pressure during chronic hemodialysis.BackgroundThe relationship between volume status and blood pressure (BP) in chronic hemodialysis (HD) patients remains incompletely understood. Specifically, the effect of interdialytic fluid accumulation (or intradialytic fluid removal) on BP is controversial.MethodsWe determined the association of the intradialytic decrease in body weight (as an indicator of interdialytic fluid gain) and the intradialytic decrease in plasma volume (as an indicator of postdialysis volume status) with predialysis and postdialysis BP in a cross-sectional analysis of a subset of patients (N = 468) from the Hemodialysis (HEMO) Study. Fifty-five percent of patients were female, 62% were black, 43% were diabetic and 72% were prescribed antihypertensive medications. Dry weight was defined as the postdialysis body weight below which the patient developed symptomatic hypotension or muscle cramps in the absence of edema. The intradialytic decrease in plasma volume was calculated from predialysis and postdialysis total plasma protein concentrations and was expressed as a percentage of the plasma volume at the beginning of HD.ResultsPredialysis systolic and diastolic BP values were 153.1 ± 24.7 (mean ± SD) and 81.7 ± 14.8mm Hg, respectively; postdialysis systolic and diastolic BP values were 136.6 ± 22.7 and 73.9 ± 13.6mm Hg, respectively. As a result of HD, body weight was reduced by 3.1 ± 1.3kg and plasma volume was contracted by 10.1 ± 9.5%. Multiple linear regression analyses showed that eachkg reduction in body weight during HD was associated with a 2.95mm Hg (P = 0.004) and a 1.65mm Hg (P = NS) higher predialysis and postdialysis systolic BP, respectively. In contrast, each 5% greater contraction of plasma volume during HD was associated with a 1.50mm Hg (P = 0.026) and a 2.56mm Hg (P < 0.001) lower predialysis and postdialysis systolic BP, respectively. The effects of intradialytic decreases in body weight and plasma volume were greater on systolic BP than on diastolic BP.ConclusionsHD treatment generally reduces BP, and these reductions in BP are associated with intradialytic decreases in both body weight and plasma volume. The absolute predialysis and postdialysis BP levels are influenced differently by acute intradialytic decreases in body weight and acute intradialytic decreases in plasma volume; these parameters provide different information regarding volume status and may be dissociated from each other. Therefore, evaluation of volume status in chronic HD patients requires, at minimum, assessments of both interdialytic fluid accumulation (or the intradialytic decrease in body weight) and postdialysis volume overload

New Frontiers for Terrestrial-sized to Neptune-sized Exoplanets In the Era of Extremely Large Telescopes

Surveys reveal that terrestrial- to Neptune-sized planets (1 $< R <$ 4 R$_{\rm{Earth}}$) are the most common type of planets in our galaxy. Detecting and characterizing such small planets around nearby stars holds the key to understanding the diversity of exoplanets and will ultimately address the ubiquitousness of life in the universe. The following fundamental questions will drive research in the next decade and beyond: (1) how common are terrestrial to Neptune-sized planets within a few AU of their host star, as a function of stellar mass? (2) How does planet composition depend on planet mass, orbital radius, and host star properties? (3) What are the energy budgets, atmospheric dynamics, and climates of the nearest worlds? Addressing these questions requires: a) diffraction-limited spatial resolution; b) stability and achievable contrast delivered by adaptive optics; and c) the light-gathering power of extremely large telescopes (ELTs), as well as multi-wavelength observations and all-sky coverage enabled by a comprehensive US ELT Program. Here we provide an overview of the challenge, and promise of success, in detecting and comprehensively characterizing small worlds around the very nearest stars to the Sun with ELTs. This white paper extends and complements the material presented in the findings and recommendations published in the National Academy reports on Exoplanet Science Strategy and Astrobiology Strategy for the Search for Life in the Universe.Comment: Astro2020 Science White Pape

A comparative study of WASP-67b and HAT-P-38b from WFC3 data

Atmospheric temperature and planetary gravity are thought to be the main parameters affecting cloud formation in giant exoplanet atmospheres. Recent attempts to understand cloud formation have explored wide regions of the equilibrium temperature-gravity parameter space. In this study, we instead compare the case of two giant planets with nearly identical equilibrium temperature ($T_\mathrm{eq}$ $\sim 1050 \, \mathrm{K}$) and gravity ($g \sim 10 \, \mathrm{m \, s}^{-1})$. During $HST$ Cycle 23, we collected WFC3/G141 observations of the two planets, WASP-67 b and HAT-P-38 b. HAT-P-38 b, with mass 0.42 M$_\mathrm{J}$ and radius 1.4 $R_\mathrm{J}$, exhibits a relatively clear atmosphere with a clear detection of water. We refine the orbital period of this planet with new observations, obtaining $P = 4.6403294 \pm 0.0000055 \, \mathrm{d}$. WASP-67 b, with mass 0.27 M$_\mathrm{J}$ and radius 0.83 $R_\mathrm{J}$, shows a more muted water absorption feature than that of HAT-P-38 b, indicating either a higher cloud deck in the atmosphere or a more metal-rich composition. The difference in the spectra supports the hypothesis that giant exoplanet atmospheres carry traces of their formation history. Future observations in the visible and mid-infrared are needed to probe the aerosol properties and constrain the evolutionary scenario of these planets.Comment: 16 pages, 17 figures, 8 tables, accepted for publication in The Astronomical Journa