Computerized Adaptive Assessment of Infant-Toddler Language Development: Demonstration and Validation of an App for Screening

We have developed a computerized adaptive test (an app), based on the MacArthur-Bates Communicative Development Inventories (CDI), that can rapidly gauge infant and toddler language development based on parent report. The app can be very useful in screening for developmental disabilities in IDEA Part C or Section 619. We will demonstrate the app and present validation data for toddlers.https://digitalcommons.library.umaine.edu/ccids_posters/1005/thumbnail.jp

Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines

A Roadmap for HEP Software and Computing R&D for the 2020s

Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment

Facial Emotion Discriminability and Binocular Rivalry for Individuals with Agenesis of the Corpus Callosum

This dissertation presents research on some of the cognitive and perceptual concomitants of agenesis of the corpus callosum (AgCC), a congenital condition in which the corpus callosum, typically the primary neural pathway connecting the two hemispheres of the brain, fails to develop between the brain\u27s hemispheres. It has been proposed that non-callosal interhemispheric pathways develop compensatory functions for individuals with AgCC. Broadly, the aim of the present research was to contribute to a greater understanding of the functional extent and limits of compensatory mechanisms for individuals with AgCC. The first study examined the ability of individuals with AgCC to identify and discriminate among basic facial expressions of emotion. Additionally, the relative durations of participants\u27 gaze toward the eyes, nose, and mouth of pictures of emotionally expressive faces were examined to assess the role of visual selective attention in emotion discriminability for individuals with AgCC. The analyses revealed that participants with AgCC exhibited impairments in the identification and discrimination of facial expressions of emotion. Additionally, participants with AgCC demonstrated atypical patterns of gaze while viewing the faces. Analysis of the effect on emotion discriminability of participants\u27 gaze to various facial features suggests that increased gaze toward the eyes and, more generally, increased gaze distributed within the T-shaped facial region comprising the eyes, nose, and mouth can yield improvements in emotion discriminability for individuals with AgCC. Overall, the results suggest that gaze atypicalities contribute to impairments in emotion discriminability for individuals with AgCC. The second study explored the perceptual grouping of visual elements during binocular rivalry, a perceptual phenomenon that occurs when each eye is presented with an image that differs from that presented to the other eye. By assessing perceptual grouping, inferences were made regarding the interhemispheric sharing of visual information for individuals with AgCC. The analysis revealed no significant grouping differences between control participants and participants with AgCC, suggesting that compensatory mechanisms facilitate interhemispheric sharing of visual information for individuals with AgCC. Additionally, the results suggest that these compensatory mechanisms can facilitate relatively long-term cooperation between the cerebral hemispheres during visual processing

Channel Expansion in the Ligand-Binding Domain of the Glucocorticoid Receptor Contributes to the Activity of Highly Potent Glucocorticoid Analogues

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR) and are commonly used as anti-inflammatory and immunosuppressant medications. Chronic GC use has been linked with unwanted complications such as steroid-induced diabetes mellitus (SIDM), although the mechanisms for these effects are not completely understood. Modification of six GC parent molecules with 2-mercaptobenzothiazole resulted in consistently less promoter activity in transcriptional activation assays using a 3xGRE reporter construct while constantly reducing inflammatory pathway activity. The most selective candidate, DX1, demonstrated a significant reduction (87%) in transactivation compared to commercially available dexamethasone. DX1 also maintained 90% of the anti-inflammatory potential of dexamethasone while simultaneously displaying a reduced toxicity profile. Additionally, two novel and highly potent compounds, DX4 and PN4, were developed and shown to elicit similar mRNA expression at attomolar concentrations that dexamethasone exhibits at nanomolar dosages. To further explain these results, Molecular Dynamic (MD) simulations were performed to examine structural changes in the ligand-binding domain of the glucocorticoid receptor in response to docking with the top ligands. Differing interactions with the transcriptional activation function 2 (AF-2) region of the GR may be responsible for lower transactivation capacity in DX1. DX4 and PN4 lose contact with Arg611 due to a key interaction changing from a stronger hydrophilic to a weaker hydrophobic one, which leads to the formation of an unoccupied channel at the location of the deacylcortivazol (DAC)-expanded binding pocket. These findings provide insights into the structure–function relationships important for regulating anti-inflammatory activity, which has implications for clinical utility