AOP 460: Antagonism of Smoothened receptor leading to orofacial clefting.

Sonic hedgehog (SHH) is a major intercellular signaling pathway involved in the orchestration of embryogenesis, including orofacial morphogenesis. The SHH pathway is sensitive to disruption, including both genetic predisposition and chemical-induced disruption at multiple molecular targets including antagonism of the SHH signal transducer Smoothened (SMO). Here we report the adverse outcome pathway (AOP) 460 describing the linkage between antagonism of the SMO receptor, a key intermediate in the hedgehog signaling, and orofacial clefts (OFCs).

Spatially dependent tissue distribution of thyroid hormones by plasma thyroid hormone binding proteins.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings.

Crowdsourcing AOP development: Leveraging the thesis literature review to identify knowledge gaps and facilitate research translation.

Chemical risk assessment still primarily relies on extrapolation of data from high-confidence studies. Emerging 21st Century Toxicology tools and approaches have potential to figure more prominently in chemical risk assessment, but many challenges in translating this research into assessments remain. One of these tools, the Adverse Outcome Pathway (AOP) Wiki provides a framework to map and evaluate adverse chemical dynamics, that is the biochemical and physiological effects that occur after chemical exposure.

The Asymmetry Within: A Renewed Look at Cupids Bow in Unilateral Cleft Lip.

The purpose of this study is to analyze the angular variations within Cupid's bow in patients with unoperated unilateral cleft lip (UCL). Angular features of Cupid's bow were quantified in standardized presurgical photographs of children with UCL by 5 medical professionals specializing in craniofacial anomalies. The peaks and valley of Cupid's bow were identified.

Age-Related Differences in Motor Skill Transfer with Brief Memory Reactivation.

Motor memories can be strengthened through online practice and offline consolidation. Offline consolidation involves the stabilization of memory traces in post-practice periods. Following initial consolidation of a motor memory, subsequent practice of the motor skill can lead to reactivation and reconsolidation of the memory trace.

Spatially Dependent Tissue Distribution of Thyroid Hormones by Plasma Thyroid Hormone Binding Proteins.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings.

Applied strategies of neuroplasticity.

Various levels of somatotopic organization are present throughout the human nervous system. However, this organization can change when needed based on environmental demands, a phenomenon known as neuroplasticity. Neuroplasticity can occur when learning a new motor skill, adjusting to life after blindness, or following a stroke.

A minimal human physiologically based kinetic model of thyroid hormones and chemical disruption of plasma thyroid hormone binding proteins.

The thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), are under homeostatic control by the hypothalamic-pituitary-thyroid axis and plasma TH binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB). THBPs buffer free THs against transient perturbations and distribute THs to tissues. TH binding to THBPs can be perturbed by structurally similar endocrine-disrupting chemicals (EDCs), yet their impact on circulating THs and health risks are unclear.

Development and Psychometric Testing of the Bimanual Assessment Measure for People With Chronic Stroke.

Importance: Few tools are available to assess bimanual deficits after stroke.

Objective: To develop the Bimanual Assessment Measure (BAM), which assesses a person's hand coordination in both preferred and prestroke roles (i.e.

Fresh tissue procurement and preparation for multicompartment and multimodal analysis of the prostate tumor microenvironment.

Background: Prostatic cancers include a diverse microenvironment of tumor cells, cancer-associated fibroblasts, and immune components. This tumor microenvironment (TME) is a known driving force of tumor survival after treatment, but the standard-of-care tissue freezing or fixation in pathology practice limit the use of available approaches/tools to study the TME's functionality in tumor resistance. Thus, there is a need for approaches that satisfy both clinical and laboratory endpoints for TME study.

Reward and plasticity: Implications for neurorehabilitation.

Neuroplasticity follows nervous system injury in the presence or absence of rehabilitative treatments. Rehabilitative interventions can be used to modulate adaptive neuroplasticity, reducing motor impairment and improving activities of daily living in patients with brain lesions. Learning principles guide some rehabilitative interventions.

Engineering Epithelial-Mesenchymal Microtissues to Study Cell-Cell Interactions in Development.

Intercellular signaling drives human development, but there is a paucity of in vitro models that recapitulate important tissue architecture while remaining operationally simple and scalable. As an example, formation of the upper lip and palate requires the orchestrated proliferation and fusion of embryonic facial growth centers and is dependent on paracrine epithelial-mesenchymal signaling through multiple pathways including the Sonic Hedgehog (SHH), transforming growth factor-beta (Tgf-β), bone morphogenic protein (BMP), and epidermal growth factor (EGF) pathways. We have developed a robust, throughput-compatible microphysiological system to model intercellular signaling including epithelial-mesenchymal interactions that is useful for studying both normal and abnormal orofacial development.

Enhancing motor learning in people with stroke via memory reactivation during sleep.

Purpose: Investigate the use of repetitive delivery of task-related auditory cues, known as targeted memory reactivation (TMR), throughout a 1-hour daytime nap to enhance motor learning in individuals with chronic stroke.

Research Method: Participants with a history of stroke at least 6 months prior were recruited to perform a novel overhand throwing task to randomly appearing target locations using the nonparetic upper extremity immediately before and after a 1-hour daytime nap. Half of the participants received TMR during the nap.

Crowdsourcing in Cognitive and Systems Neuroscience.

Behavioral research in cognitive and human systems neuroscience has been largely carried out in-person in laboratory settings. Underpowering and lack of reproducibility due to small sample sizes have weakened conclusions of these investigations. In other disciplines, such as neuroeconomics and social sciences, crowdsourcing has been extensively utilized as a data collection tool, and a means to increase sample sizes.

A Microphysiological Approach to Evaluate Effectors of Intercellular Hedgehog Signaling in Development.

Paracrine signaling in the tissue microenvironment is a central mediator of morphogenesis, and modeling this dynamic intercellular activity is critical to understanding normal and abnormal development. For example, Sonic Hedgehog (Shh) signaling is a conserved mechanism involved in multiple developmental processes and strongly linked to human birth defects including orofacial clefts of the lip and palate. SHH ligand produced, processed, and secreted from the epithelial ectoderm is shuttled through the extracellular matrix where it binds mesenchymal receptors, establishing a gradient of transcriptional response that drives orofacial morphogenesis.

A bioengineered organotypic prostate model for the study of tumor microenvironment-induced immune cell activation.

The prostate tumor microenvironment (TME) is strongly immunosuppressive; it is largely driven by alteration in cell phenotypes (i.e. tumor-associated macrophages and exhausted cytotoxic T cells) that result in pro-tumorigenic conditions and tumor growth.

Chronic Poststroke Deficits in Gross and Fine Motor Control of the Ipsilesional Upper Limb.

Objectives: Individuals with stroke often experience contralesional and ipsilesional arm motor deficits. The aim of this study was to compare fine and gross motor hand dexterity of the ipsilesional hand post-stroke with controls, normative values, and the contralesional hand.

Design: Data were collected from right-handed individuals with chronic stroke (n = 20), age-/sex-matched controls (n = 10), and normative values (n = 20) performing the Nine-Hole Peg Test and the Box and Blocks Test.

Engineered Perineural Vascular Plexus for Modeling Developmental Toxicity.

There is a vital need to develop in vitro models of the developing human brain to recapitulate the biological effects that toxic compounds have on the brain. To model perineural vascular plexus (PNVP) in vitro, which is a key stage in embryonic development, human embryonic stem cells (hESC)-derived endothelial cells (ECs), neural progenitor cells, and microglia (MG) with primary pericytes (PCs) in synthetic hydrogels in a custom-designed microfluidics device are cocultured. The formation of a vascular plexus that includes networks of ECs (CD31+, VE-cadherin+), MG (IBA1+), and PCs (PDGFRβ+), and an overlying neuronal layer that includes differentiated neuronal cells (βIII Tubulin+, GFAP+) and radial glia (Nestin+, Notch2NL+), are characterized.

Sensorimotor performance is improved by targeted memory reactivation during a daytime nap in healthy older adults.

Sensorimotor consolidation occurs during sleep. However, the benefit of sleep-based consolidation decreases with age due to decreased sleep quality and quantity. This study aimed to enhance sensorimotor performance through repetitive delivery of task-based auditory cues during sleep, known as targeted memory reactivation (TMR).

Modeling chemical effects on breast cancer: the importance of the microenvironment in vitro.

Accumulating evidence suggests that our ability to predict chemical effects on breast cancer is limited by a lack of physiologically relevant in vitro models; the typical in vitro breast cancer model consists of the cancer cell and excludes the mammary microenvironment. As the effects of the microenvironment on cancer cell behavior becomes more understood, researchers have called for the integration of the microenvironment into in vitro chemical testing systems. However, given the complexity of the microenvironment and the variety of platforms to choose from, identifying the essential parameters to include in a chemical testing platform is challenging.

Evaluation of PEG-based hydrogel influence on estrogen receptor driven responses in MCF7 breast cancer cells.

Extracellular matrix (ECM) mimicking hydrogel scaffolds have greatly improved the physiological relevance of assays, but introduce another dimension that creates variability in cell related readouts when compared to traditional 2D cells-on-plastic assays. We have developed a synthetic poly(ethylene glycol) (PEG) based ECM mimicking hydrogel and tested it against two gold standard animal-based naturally derived hydrogel scaffolds in MCF7 cell response. We have used the percent coefficient of variation (CV) as a metric to evaluate the reproducibility of said responses.

Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

Aromatase inhibitors are the preferred treatment for certain women with estrogen receptor (ER)-positive breast cancer, but evidence suggests that women with obesity experience aromatase inhibitor resistance at higher rates. To compare how stromal cells derived from women who are lean or obese influence response to the aromatase inhibitor (anastrazole), we incorporated patient-derived stroma in a previously characterized MCF7-derived duct model. Coculture with adipose stromal cells enabled the metabolism of testosterone (T) to E, which induced estrogen response element activity, epithelial proliferation, and hyperplasia in MCF7 cells.

Systematic Review Investigating the Effects of Nonpharmacological Interventions During Sleep to Enhance Physical Rehabilitation Outcomes in People With Neurological Diagnoses.

Objective: Conduct a systematic review of nonpharmacological interventions applied during sleep to enhance physical rehabilitation outcomes of individuals with a neurological diagnosis.

Data Sources: Three online databases were searched for original research.

Study Selection: Intervention studies were included that used outcome measures of impairment, activity, and/or participation.

Use of targeted memory reactivation enhances skill performance during a nap and enhances declarative memory during wake in healthy young adults.

Sleep is an important component of motor memory consolidation and learning, providing a critical tool to enhance training and rehabilitation. Following initial skill acquisition, memory consolidation is largely a result of non-rapid eye movement sleep over either a full night or a nap. Targeted memory reactivation is one method used to enhance this critical process, which involves the pairing of an external cue with task performance at the time of initial motor skill acquisition, followed by replay of the same cue during sleep.