Separating clinical antibodies from repertoire antibodies, a path to in silico developability assessment.

Approaches for antibody discovery have seen substantial improvement and success in recent years. Yet, advancing antibodies into the clinic remains difficult because therapeutic developability concerns are challenging to predict. We developed a computational model to simplify antibody developability assessment and enable accelerated early-stage screening. To this end, we quantified the ability of hundreds of sequence- and structure-based descriptors to differentiate clinical antibodies that have undergone rigorous screening and characterization for drug-like properties from antibodies in the human repertoire that are not natively paired. This analysis identified 144 descriptors capable of distinguishing clinical from repertoire antibodies. Five descriptors were selected and combined based on performance and orthogonality into a single model referred to as the Therapeutic Antibody Developability Analysis (TA-DA). On a hold-out test set, this tool separated clinical antibodies from repertoire antibodies with an AUC = 0.8, demonstrating the ability to identify developability attributes unique to clinical antibodies. Based on our results, the TA-DA score may serve as an approach for selecting lead antibodies for further development.Abbreviations: Affinity-Capture Self-Interaction Nanoparticle Spectroscopy (AC-SINS), Area Under the Curve (AUC), Complementary-Determining Region (CDR), Clinical-Stage Therapeutics (CST), Framework (FR), Monoclonal Antibodies (mAbs), Observed Antibody Space (OAS), Receiver Operating Characteristic (ROC), Size-Exclusion Chromatography (SEC), Structural Aggregation Propensity (SAP), Therapeutic Antibody Developability Analysis (TA-DA), Therapeutic Antibody Profiler (TAP), Therapeutic Structural Antibody Database (Thera-SAbDab), Variable Heavy (VH), Variable Light (VL).

Amplitude and phase retrieval with simultaneous diversity estimation using expectation maximization.

Iterative amplitude and phase retrieval algorithms have been proven to accurately reconstruct arbitrary wavefronts from multiple intensity measurements when system parameters are known exactly, given the ability to induce phase diversity between images. Such sets of intensity images with phase diversity can be generated by moving a lens in the optical system, but any position error on the lens will degenerate the reconstruction result. We demonstrate the use of an expectation-maximization algorithm with Kalman smoothing for recovering both the complex field and the lens position from a stack of intensity images. Our method successfully reduces the mean-squared-error of the estimated wavefront in comparison to an approach without position error estimation. We present and discuss the results of using a Kalman smoother and nonlinear least-squares optimization for the estimation of the moving lens position.

Automated alignment of a reconfigurable optical system using focal-plane sensing and Kalman filtering.

Automation of alignment tasks can provide improved efficiency and greatly increase the flexibility of an optical system. Current optical systems with automated alignment capabilities are typically designed to include a dedicated wavefront sensor. Here, we demonstrate a self-aligning method for a reconfigurable system using only focal plane images. We define a two lens optical system with 8 degrees of freedom. Images are simulated given misalignment parameters using ZEMAX software. We perform a principal component analysis on the simulated data set to obtain Karhunen-Loève modes, which form the basis set whose weights are the system measurements. A model function, which maps the state to the measurement, is learned using nonlinear least-squares fitting and serves as the measurement function for the nonlinear estimator (extended and unscented Kalman filters) used to calculate control inputs to align the system. We present and discuss simulated and experimental results of the full system in operation.

Tele-manufactured affordable smartphone anterior segment microscope.

The recent advances in mobile technology have made the smartphone a powerful and accessible tool. This article describe the development of a novel smartphone-based anterior segment microscope that is compatible with tele-manufacturing. The anterior segment microscope is equipped with both cobalt-blue and red-free filters that can be used for clinical photo-documentation. The digital files of the microscope are transferrable and compatible with additive-manufacturing. Therefore, the entire device can be locally manufactured with rapid prototyping techniques such as 3D printing.

Novel oxytocin gene expression in the hindbrain is induced by alcohol exposure: transgenic zebrafish enable visualization of sensitive neurons.

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported. PRINCIPAL FINDINGS: The effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area. CONCLUSIONS: Alcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders.