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

Preparing Your Business for Valuation

There is a tremendous need for the valuation of small businesses. Oftentimes, small businessowners do not have the wherewithal to gather the data and keep it up to date for use in situations that require valuation. Formal valuations are necessary because they provide objective evidence of value, in contrast to value set by markets on which public companies are traded. This article focuses on some factors that impact the valuation of the business and will help small businessowners feel more comfortable talking with financial professionals about how the business might be valued

Superclasses and supercharacters of normal pattern subgroups of the unipotent upper triangular matrix group

Let $U_n$ denote the group of $n\times n$ unipotent upper-triangular matrices over a fixed finite field \FF_q, and let U_\cP denote the pattern subgroup of $U_n$ corresponding to the poset \cP. This work examines the superclasses and supercharacters, as defined by Diaconis and Isaacs, of the family of normal pattern subgroups of $U_n$. After classifying all such subgroups, we describe an indexing set for their superclasses and supercharacters given by set partitions with some auxiliary data. We go on to establish a canonical bijection between the supercharacters of U_\cP and certain \FF_q-labeled subposets of \cP. This bijection generalizes the correspondence identified by Andr\'e and Yan between the supercharacters of $U_n$ and the \FF_q-labeled set partitions of $\{1,2,...,n\}$. At present, few explicit descriptions appear in the literature of the superclasses and supercharacters of infinite families of algebra groups other than \{U_n : n \in \NN\}. This work signficantly expands the known set of examples in this regard.Comment: 28 page

Stroke Quality Measures in Mexican Americans and Non-Hispanic Whites

Mexican Americans (MAs) have been shown to have worse outcomes after stroke than non-Hispanic Whites (NHWs), but it is unknown if ethnic differences in stroke quality of care may contribute to these worse outcomes. We investigated ethnic differences in the quality of inpatient stroke care between MAs and NHWs within the population-based prospective Brain Attack Surveillance in Corpus Christi (BASIC) Project (February 2009- June 2012). Quality measures for inpatient stroke care, based on the 2008 Joint Commission Primary Stroke Center definitions were assessed from the medical record by a trained abstractor. Two summary measure of overall quality were also created (binary measure of defect-free care and the proportion of measures achieved for which the patient was eligible). 757 individuals were included (480 MAs and 277 NHWs). MAs were younger, more likely to have hypertension and diabetes, and less likely to have atrial fibrillation than NHWs. MAs were less likely than NHWs to receive tPA (RR: 0.72, 95% confidence interval (CI) 0.52, 0.98), and MAs with atrial fibrillation were less likely to receive anticoagulant medications at discharge than NHWs (RR 0.73, 95% CI 0.58, 0.94). There were no ethnic differences in the other individual quality measures, or in the two summary measures assessing overall quality. In conclusion, there were no ethnic differences in the overall quality of stroke care between MAs and NHWs, though ethnic differences were seen in the proportion of patients who received tPA and anticoagulant at discharge for atrial fibrillation

Imperfect identity

Questions of identity over time are often hard to answer. A long tradition has it that such questions are somehow soft: they have no unique, determinate answer, and disagreements about them are merely verbal. I argue that this claim is not the truism it is taken to be. Depending on how it is understood, it turns out either to be false or to presuppose a highly contentious metaphysical claim

Broadband Infrared Vibrational Nano-spectroscopy Using Thermal Blackbody Radiation

Infrared vibrational nano-spectroscopy based on scattering scanning near-field optical microscopy (s-SNOM) provides intrinsic chemical specificity with nanometer spatial resolution. Here we use incoherent infrared radiation from a 1400 K thermal blackbody emitter for broadband infrared (IR) nano-spectroscopy. With optimized interferometric heterodyne signal amplification we achieve few-monolayer sensitivity in phonon polariton spectroscopy and attomolar molecular vibrational spectroscopy. Near-field localization and nanoscale spatial resolution is demonstrated in imaging flakes of hexagonal boron nitride (hBN) and determination of its phonon polariton dispersion relation. The signal-to-noise ratio calculations and analysis for different samples and illumination sources provide a reference for irradiance requirements and the attainable near-field signal levels in s-SNOM in general. The use of a thermal emitter as an IR source thus opens s-SNOM for routine chemical FTIR nano-spectroscopy