Exploring And Training Spatial Reasoning Via Eye Movements: Implications On Performance

This dissertation sought to determine if eye movements could serve as an indicator of success in spatial reasoning, and if eye movements associated with successful completion could be applied to strategically improve spatial reasoning. Using the line images of Shepard and Metzler, an electronic test of mental rotations ability (EMRT) was designed. Two versions of the test were created, allowing for both a timed (6 seconds per question) and untimed testing environment. Four experiments were designed and completed to relate mental rotation ability (MRA) scores from the EMRT, to patterns in chrononumeric and visual salience data. In each experiment, participants completed the EMRT under a different protocol. These protocols included an untimed EMRT, a timed EMRT, a within-participant crossover study where participants completed both the timed, and untimed EMRT in series, and a training crossover study where low MRA participants completed the timed EMRT in both a guided and unguided environment. In the untimed experiment, individuals of high and low MRA were asked to complete the EMRT while their eye movements were observed. As no time limit was imposed, the results allowed for observations based on MRA alone, and served to demonstrate and how individuals of different skill level differ in terms of eye movement. In the following experiment, the addition of a time limit to the EMRT revealed how individuals of high and low MRA perform when under a time restriction. The results of the Timed experiment confirmed differences between the high and low MRA group in terms of eye movements, and attention to salient regions of test images. In the third experiment, the addition of a time limit was further explored through a crossover design. By adding a time limit to an MRT, the ability of individuals to solve spatial problems is impaired, and is manifest in eye movements. Data derived from the Crossover Experiment suggested that salience-based metrics might serve to distinguish between groups of MRA, and that time restrictions may influence both participant accuracy, and identification of visually salient elements. The results from the first three experiments were then applied in the Guidance Experiment to confirm the role that visual salience plays in the context of spatial problem solving. By mapping the apprehension patterns of successful high MRA individuals onto the EMRT, low MRA individuals could be guided to salient areas on the timed EMRT. The results revealed that the application of visual guidance is an effective mechanism for MRA training. This research attends to a previously unaddressed niche in eye-movement and spatial ability training literature. As a result, it may serve as a foundation to cultivate methods of honing and improving spatial skills in the general population

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Assessing the efficacy of tablet-based simulations for learning pseudo-surgical instrumentation.

Nurses and surgeons must identify and handle specialized instruments with high temporal and spatial precision. It is crucial that they are trained effectively. Traditional training methods include supervised practices and text-based study, which may expose patients to undue risk during practice procedures and lack motor/haptic training respectively. Tablet-based simulations have been proposed to mediate some of these limitations. We implemented a learning task that simulates surgical instrumentation nomenclature encountered by novice perioperative nurses. Learning was assessed following training in three distinct conditions: tablet-based simulations, text-based study, and real-world practice. Immediately following a 30-minute training period, instrument identification was performed with comparable accuracy and response times following tablet-based versus text-based training, with both being inferior to real-world practice. Following a week without practice, response times were equivalent between real-world and tablet-based practice. While tablet-based training does not achieve equivalent results in instrument identification accuracy as real-world practice, more practice repetitions in simulated environments may help reduce performance decline. This project has established a technological framework to assess how we can implement simulated educational environments in a maximally beneficial manner

Guiding Low Spatial Ability Individuals through Visual Cueing: The Dual Importance of Where and When to Look

Research suggests that spatial ability may predict success in complex disciplines including anatomy, where mastery requires a firm understanding of the intricate relationships occurring along the course of veins, arteries, and nerves, as they traverse through and around bones, muscles, and organs. Debate exists on the malleability of spatial ability, and some suggest that spatial ability can be enhanced through training. It is hypothesized that spatial ability can be trained in low-performing individuals through visual guidance. To address this, training was completed through a visual guidance protocol. This protocol was based on eye-movement patterns of high-performing individuals, collected via eye-tracking as they completed an Electronic Mental Rotations Test (EMRT). The effects of guidance were evaluated using 33 individuals with low mental rotation ability, in a counterbalanced crossover design. Individuals were placed in one of two treatment groups (late or early guidance) and completed both a guided, and an unguided EMRT. A third group (no guidance/control) completed two unguided EMRTs. All groups demonstrated an increase in EMRT scores on their second test (P \u3c 0.001); however, an interaction was observed between treatment and test iteration (P = 0.024). The effect of guidance on scores was contingent on when the guidance was applied. When guidance was applied early, scores were significantly greater than expected (P = 0.028). These findings suggest that by guiding individuals with low mental rotation ability where to look early in training, better search approaches may be adopted, yielding improvements in spatial reasoning scores. It is proposed that visual guidance may be applied in spatial fields, such as STEMM (science, technology, engineering, mathematics and medicine), surgery, and anatomy to improve student\u27s interpretation of visual content. Anat Sci Educ. (c) 2018 American Association of Anatomists

Kinetic analysis of yersinia pestis DNA adenine methyltransferase activity using a hemimethylated molecular break light oligonucleotide

Background: DNA adenine methylation plays an important role in several critical bacterial processes including mismatchrepair, the timing of DNA replication and the transcriptional control of gene expression. The dependence of bacterial virulenceon DNA adenine methyltransferase (Dam) has led to the proposal that selective Dam inhibitors might function as broadspectrum antibiotics. Methodology/Principal Findings: herein we report the expression and purification of Yersinia pestisDam and the development of a continuous fluorescence based assay for DNA adenine methyltransferase activity that issuitable for determining the kinetic parameters of the enzyme and for high throughput screening against potential Daminhibitors. The assay utilised a hemimethylated break light oligonucleotide substrate containing a GATC methylation site.When this substrate was fully methylated by Dam, it became a substrate for the restriction enzyme DpnI, resulting inseparation of fluorophore (fluorescein) and quencher (dabcyl) and therefore an increase in fluorescence. The assays weremonitored in real time using a fluorescence microplate reader in 96 well format and were used for the kinetic characterisationof Yersinia pestis Dam, its substrates and the known Dam inhibitor, S-adenosylhomocysteine. The assay has been validated forhigh throughput screening, giving a Z-factor of 0.7160.07 indicating that it is a sensitive assay for the identification ofinhibitors. Conclusions/Significance: the assay is therefore suitable for high throughput screening for inhibitors of DNAadenine methyltransferases and the kinetic characterisation of the inhibitio