Metabolomic biomarkers in autism: identification of complex dysregulations of cellular bioenergetics.

Autism Spectrum Disorder (ASD or autism) is a phenotypically and etiologically heterogeneous condition. Identifying biomarkers of clinically significant metabolic subtypes of autism could improve understanding of its underlying pathophysiology and potentially lead to more targeted interventions. We hypothesized that the application of metabolite-based biomarker techniques using decision thresholds derived from quantitative measurements could identify autism-associated subpopulations.

Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues.

Background: The developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOX ) assay, a metabolomics-based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOX assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues.

Methods: VPA and a series of structural analogues were tested with the devTOX assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations.

microRNAs signatures as potential biomarkers of structural cardiotoxicity in human-induced pluripotent stem-cell derived cardiomyocytes.

Identification of early biomarkers of heart injury and drug-induced cardiotoxicity is important to eliminate harmful drug candidates early in preclinical development and to prevent severe drug effects. The main objective of this study was to investigate the expression of microRNAs (miRNAs) in human-induced pluripotent stem cell cardiomyocytes (hiPSC-CM) in response to a broad range of cardiotoxic drugs. Next generation sequencing was applied to hiPSC-CM treated for 72 h with 40 drugs falling into the categories of functional (i.

Robust inertial sensing with point-source atom interferometry for interferograms spanning a partial period.

Point source atom interferometry (PSI) uses the velocity distribution in a cold atom cloud to simultaneously measure one axis of acceleration and two axes of rotation from the spatial distribution of interferometer phase in an expanded cloud of atoms. Previously, the interferometer phase has been found from the phase, orientation, and period of the resulting spatial atomic interference fringe images. For practical applications in inertial sensing and precision measurement, it is important to be able to measure a wide range of system rotation rates, corresponding to interferograms with far less than one full interference fringe to very many fringes.

A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project.

Autism spectrum disorder (ASD) is biologically and behaviorally heterogeneous. Delayed diagnosis of ASD is common and problematic. The complexity of ASD and the low sensitivity of available screening tools are key factors in delayed diagnosis.

A Targeted Metabolomics-Based Assay Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Identifies Structural and Functional Cardiotoxicity Potential.

Implementing screening assays that identify functional and structural cardiotoxicity earlier in the drug development pipeline has the potential to improve safety and decrease the cost and time required to bring new drugs to market. In this study, a metabolic biomarker-based assay was developed that predicts the cardiotoxicity potential of a drug based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Assay development and testing was conducted in 2 phases: (1) biomarker identification and (2) targeted assay development.

Single-Source Multiaxis Cold-Atom Interferometer in a Centimeter-Scale Cell.

Using point-source atom interferometry (PSI), we characterize the sensitivity of a multiaxis gyroscope based on free-space Raman interrogation of a single source of cold atoms in a glass vacuum cell. The instrument simultaneously measures the acceleration in the direction of the Raman-laser beams and the projection of the rotation vector onto the plane perpendicular to that direction. The sensitivities for the magnitude and direction of the rotation-vector measurement are 0.

A cold-atom beam clock based on coherent population trapping.

We present results from an atomic clock that employs a beam of cold Rb atoms and spatially separated (Ramsey) coherent population trapping interrogation of the hyperfine clock transition at 6.834 GHz. The cold atomic beam is generated through the use of a 2D-magnetooptical trap.

Amino Acid Dysregulation Metabotypes: Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD.

Active stabilization of alkali-atom vapor density with a solid-state electrochemical alkali-atom source.

We report a demonstration of vapor-phase Rubidium (Rb) density stabilization in a vapor cell using a solid-state electrochemical Rb source device. Clear Rb density stabilization is observed. Further demonstrations show that the temperature coefficient for Rb density can be reduced more than 100 times when locked and the device's power consumption is less than 10 mW.

A human induced pluripotent stem cell-based in vitro assay predicts developmental toxicity through a retinoic acid receptor-mediated pathway for a series of related retinoid analogues.

The relative developmental toxicity potency of a series of retinoid analogues was evaluated using a human induced pluripotent stem (iPS) cell assay that measures changes in the biomarkers ornithine and cystine. Analogue potency was predicted, based on the assay endpoint of the ornithine/cystine (o/c) ratio, to be all-trans-retinoic acid>TTNPB>13-cis-retinoic acid≈9-cis-retinoic acid>acitretin>etretinate>retinol. These rankings correlate with in vivo data and demonstrate successful application of the assay to rank a series of related toxic and non-toxic compounds.

An optimized microfabricated platform for the optical generation and detection of hyperpolarized Xe.

Low thermal-equilibrium nuclear spin polarizations and the need for sophisticated instrumentation render conventional nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) incompatible with small-scale microfluidic devices. Hyperpolarized Xe gas has found use in the study of many materials but has required very large and expensive instrumentation. Recently a microfabricated device with modest instrumentation demonstrated all-optical hyperpolarization and detection of Xe gas.

Low helium permeation cells for atomic microsystems technology.

Laser spectroscopy of atoms confined in vapor cells can be strongly affected by the presence of background gases. A significant source of vacuum contamination is the permeation of gases such as helium (He) through the walls of the cell. Aluminosilicate glass (ASG) is a material with a helium permeation rate that is many orders of magnitude lower than borosilicate glass, which is commonly used for cell fabrication.

Toward Good Read-Across Practice (GRAP) guidance.

Grouping of substances and utilizing read-across of data within those groups represents an important data gap filling technique for chemical safety assessments. Categories/analogue groups are typically developed based on structural similarity and, increasingly often, also on mechanistic (biological) similarity. While read-across can play a key role in complying with legislations such as the European REACH regulation, the lack of consensus regarding the extent and type of evidence necessary to support it often hampers its successful application and acceptance by regulatory authorities.

Supporting read-across using biological data.

Read-across, i.e. filling toxicological data gaps by relating to similar chemicals, for which test data are available, is usually done based on chemical similarity.

Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children.

Background: The diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age.

Optical hyperpolarization and NMR detection of 129Xe on a microfluidic chip.

Optically hyperpolarized (129)Xe gas has become a powerful contrast agent in nuclear magnetic resonance (NMR) spectroscopy and imaging, with applications ranging from studies of the human lung to the targeted detection of biomolecules. Equally attractive is its potential use to enhance the sensitivity of microfluidic NMR experiments, in which small sample volumes yield poor sensitivity. Unfortunately, most (129)Xe polarization systems are large and non-portable.

Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening.

A metabolic biomarker-based in vitro assay utilizing human embryonic stem (hES) cells was developed to identify the concentration of test compounds that perturbs cellular metabolism in a manner indicative of teratogenicity. This assay is designed to aid the early discovery-phase detection of potential human developmental toxicants. In this study, metabolomic data from hES cell culture media were used to assess potential biomarkers for development of a rapid in vitro teratogenicity assay.

Atom number in magneto-optic traps with millimeter scale laser beams.

We measure the number of atoms N trapped in a conventional vapor-cell magneto-optic trap (MOT) using beams that have a diameter d in the range 1-5 mm. We show that the N is proportional to d(3.6) scaling law observed for larger MOTs is a robust approximation for optimized MOTs with beam diameters as small as 3 mm.

Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics.

Teratogens, substances that may cause fetal abnormalities during development, are responsible for a significant number of birth defects. Animal models used to predict teratogenicity often do not faithfully correlate to human response. Here, we seek to develop a more predictive developmental toxicity model based on an in vitro method that utilizes both human embryonic stem (hES) cells and metabolomics to discover biomarkers of developmental toxicity.

Cryogenic fountain development at NIST and INRIM: preliminary characterization.

This paper describes the new twin laser-cooled Cs fountain primary frequency standards NIST-F2 and ITCsF2, and presents some of their design features. Most significant is a cryogenic microwave interrogation region which dramatically reduces the blackbody radiation shift. We also present a preliminary accuracy evaluation of IT-CsF2.

Stemina biomarker discovery.

Stemina Biomarker Discovery was established in 2006 to commercialize technology developed by Dr Gabriela Cezar at the University of Wisconsin (WI, USA). Stemina's cell-based assays arise from the strategic convergence of two cutting edge technologies: metabolomics and human embryonic stem (hES) cells. Stemina analyzes the small molecules secreted by hES cells and differentiated cell types such as neural and heart cells derived from hES cells by liquid chromatography mass spectrometry at its state-of-the-art facilities in Madison, WI, USA.