Showing papers by "Kettering University published in 2022"

CellRank for directed single-cell fate mapping

Abstract: Computational trajectory inference enables the reconstruction of cell state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank ( https://cellrank.org ) for single-cell fate mapping in diverse scenarios, including regeneration, reprogramming and disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, taking into account the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in velocity vectors. On pancreas development data, CellRank automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. Applied to lineage-traced cellular reprogramming data, predicted fate probabilities correctly recover reprogramming outcomes. CellRank also predicts a new dedifferentiation trajectory during postinjury lung regeneration, including previously unknown intermediate cell states, which we confirm experimentally.

Reconstructing Complex Cancer Evolutionary Histories from Multiple Bulk DNA Samples Using Pairtree

Abstract: Abstract Cancers are composed of genetically distinct subpopulations of malignant cells. DNA-sequencing data can be used to determine the somatic point mutations specific to each population and build clone trees describing the evolutionary relationships between them. These clone trees can reveal critical points in disease development and inform treatment. Pairtree is a new method that constructs more accurate and detailed clone trees than previously possible using variant allele frequency data from one or more bulk cancer samples. It does so by first building a Pairs Tensor that captures the evolutionary relationships between pairs of subpopulations, and then it uses these relations to constrain clone trees and infer violations of the infinite sites assumption. Pairtree can accurately build clone trees using up to 100 samples per cancer that contain 30 or more subclonal populations. On 14 B-progenitor acute lymphoblastic leukemias, Pairtree replicates or improves upon expert-derived clone tree reconstructions. Significance: Clone trees illustrate the evolutionary history of a cancer and can provide insights into how the disease changed through time (e.g., between diagnosis and relapse). Pairtree uses DNA-sequencing data from many samples of the same cancer to build more detailed and accurate clone trees than previously possible. See related commentary by Miller, p. 176. This article is highlighted in the In This Issue feature, p. 171.

Mechanical behavior and material property of low-carbon steel undergoing low-frequency vibration-assisted upsetting

Abstract: The propagation of ultrasonic wave in solids can cause a softening effect during metal deformation, and this concept has been widely exploited in micro-forming. Low-frequency vibration with micro-amplitudes was recently found to have a similar effect on metal deformation. In this study, the effects of low-frequency vibration on the mechanical behavior and microstructure of low-carbon steel DC04 during upsetting deformation was investigated. Vibration-assisted compression test results showed low-frequency vibration had a softening effect, that was proportional to vibration amplitude. Residual softening occurred in all cases during re-yield period after vibration removal. A sectional view of the deformed sample showed that vibration with larger amplitude could exacerbate the deformation of the contact area between the sample and the mold. The internal misorientation of grains in the deformation zone of the compressed sample increased significantly after large vibration treatment, indicating that low-frequency vibration promoted the occurrence of plastic deformation. A softening model considering transfer efficiency was proposed to explain the different performances under the action of small amplitude and large amplitude vibration. The residual softening effect that occurred in this study was an illusion produced by the uneven sample deformation caused by low-frequency vibration.

Nondestructive evaluation of carbon-fiber composites using digital image correlation, acoustic emission, and optical based modal analysis

Abstract: Composite materials are increasingly used in the wind industries. Damage detection and health monitoring of composite materials are challenging due to the complex internal structure and unique material properties. Digital image correlation (DIC) and acoustic emission (AE) are both used for damage detection in structures. In this work, DIC performs a full-field strain measurement on the surface of the carbon-fiber specimen while AE continuously monitors and records the AE signals generated from specimen subsurface structure failures. These health monitoring techniques are integrated and evaluated in this study to correlate surface strain measurements and acoustic emission measurements on carbon-fiber specimens. The AE measurement results show that there is a correlation between the occurrence of AE events and the timing of complete specimen failure. DIC with a high-speed stereo camera system is also adopted to extract the change in the resonance frequencies and displacement and strain mode shapes of the specimen during experiments in cyclic loading.

Molecular and genetic dissection of recursive splicing.

Abstract: Intronic ratchet points (RPs) are abundant within long introns in the Drosophila genome and consist of juxtaposed splice acceptor and splice donor (SD) sites. Although they appear to encompass zero-nucleotide exons, we recently clarified that intronic recursive splicing (RS) requires a cryptic exon at the RP (an RS-exon), which is subsequently always skipped and thus absent from mRNA. In addition, Drosophila encodes a smaller set of expressed exons bearing features of RS. Here, we investigate mechanisms that regulate the choice between RP and RS-exon SDs. First, analysis of Drosophila RP SD mutants demonstrates that SD competition suppresses inclusion of cryptic exons in endogenous contexts. Second, characterization of RS-exon reporters implicates exonic sequences as influencing choice of RS-exon usage. Using RS-exon swap and mutagenesis assays, we show exonic sequences can determine RS-exon inclusion. Finally, we provide evidence that splicing can suppress utilization of RP SDs to enable RS-exon expression. Overall, multiple factors can influence splicing of Drosophila RS-exons, which usually result in their complete suppression as zero-nucleotide RPs, but occasionally yield translated RS-exons.

Outcomes of open transverse abdominis release for ventral hernias- A systematic review, meta-analysis and meta-regression of factors affecting them

Abstract: Abstract Objectives The primary objectives were to evaluate Surgical Site Occurrences (SSO) and Surgical Site Occurrences requiring procedural Intervention (SSOPI) after open transversus abdominis release and to study various factors affecting it. Secondary objectives were to evaluate Surgical Site Infections (SSI), recurrence rates and overall complications after transversus abdominis release (TAR) and the factors responsible for those. Methods We searched PUBMED, SCOPUS and Cochrane databases with keywords “transversus abdominis release” or “TAR” OR “Surgical Site Occurrences” OR “posterior component separation AND “outcomes” as per PRISMA 2020 and MOOSE guidelines. Full texts and English literature studies were included, studies mentioning outcomes for open transversus abdominis release for ventral hernia were included and studies with robotic transversus abdominis release were excluded. Percentage occurrences of SSO, SSOPI, SSI, recurrence and overall complications after TAR were evaluated. Random effect meta-analysis with restricted maximum likehood methods was used for meta-analysis. Heterogeneity was analysed using I 2 statistics. Publication bias with eager’s test and funnel plots. Meta0regression analysis was done to evaluate factors affecting the heterogeneity. JASP 0.16.2 software was used for meta-analysis. Results Twenty two studies including 5284 patients who underwent TAR for ventral hernia were included in systematic review and meta-analysis. Overall pooled SSO, SSOPI, Overall Complications, SSI and recurrence rates were 21.72% [95% C.I 17.18-26.27%], 9.82% [95% C.I 7.64 −12%], 33.34% [95% C.I. 27.43-39.26%], 9.13% [95% 6.41-11.84] and 1.6% [0.78-2.44] respectively. Heterogeneity was significant in all the analysis. Age (p<0.001),sex (p<0.001), BMI (p<0.001),presence of comorbidities (p<0.001), prior recurrence, defect size (p<0.001) and current or past history of tobacco exposure were associated with SSO in multivariate meta-regression analysis. Defect size (p=0.04) was associated with SSOPI. Age (p=0.011), BMI (p=0.013), comorbidities (p<0.01), tobacco exposure (p=0.018),prior recurrence (p <0.01) and sex (p < 0.01) were associated with overall complications. Conclusion Open transversus abdominis release is associated with high rates of SSO, SSOPI, SSI and overall complications but recurrence rates are low. Various preoperative factors mentioned may be responsible for heterogeneity across studies.

Forced Vibrations of Damped Non-homogeneous Timoshenko Beams

Abstract: AbstractThis work is the next of a series on vibrations of non-homogeneous structures. It addresses the lateral harmonic forcing, with spatial dependencies, of a two-segment damped Timoshenko beam. In the series, frequency response functions (FRFs) were determined for segmented structures, such as rods and beams, using analytic and numerical approaches. These structures are composed of stacked cells, which are made of different materials and may have different geometric properties. The goal is the determination of frequency response functions (FRFs). Two approaches are employed. The first approach uses displacement differential equations for each segment, where boundary and interface continuity conditions are used to determine the constants involved in the solutions. Then the response, as a function of forcing frequency, can be obtained. This procedure is unwieldy, and determining particular integrals can become difficult for arbitrary spatial variations. The second approach uses logistic functions to model segment discontinuities. The result is a system of partial differential equations with variable coefficients. Numerical solutions are developed with the aid of MAPLE® software. For free/fixed boundary conditions, spatially constant force, and viscous damping, excellent agreement is found between the methods. The numerical approach is then used to obtain FRFs for cases including spatially varying load.KeywordsLayered structuresLogistic functionsNon-homogenous structures FRFsTimoshenko damped beam

The influence of context representations on cognitive control states

Abstract: Cognitive control operates via two distinct mechanisms, proactive and reactive control. These control states are engaged differentially, depending on a number of within-subject factors, but also between-group variables. While research has begun to explore if shifts in control can be experimentally modulated, little is known about whether context impacts which control state is utilized. Thus, we test if contextual factors temporarily bias the use of a particular control state long enough to impact performance on a subsequent task. Our methodology involves two parts: first participants are exposed to a context manipulation designed to promote proactive or reactive processing through amount or availability of advanced preparation within a task-switching paradigm. Then, they complete an AX-CPT task, where we assess immediate transfer on preferential adoption of one control mode over another. We present results from a Pilot Study that revealed anecdotal evidence of proactive versus reactive processing for a context manipulation using long and short preparation times. We also present data from a follow-up Registered Experiment that implements a context manipulation using long or no preparation times to assess if a more extreme context leads to pronounced differences on AX-CPT performance. Together, the results suggest that contextual representations do not impact the engagement of a particular control state, but rather, there is a general preference for the engagement of proactive control.

Regional mutational signature activities in cancer genomes

Abstract: Cancer genomes harbor a catalog of somatic mutations. The type and genomic context of these mutations depend on their causes and allow their attribution to particular mutational signatures. Previous work has shown that mutational signature activities change over the course of tumor development, but investigations of genomic region variability in mutational signatures have been limited. Here, we expand upon this work by constructing regional profiles of mutational signature activities over 2,203 whole genomes across 25 tumor types, using data aggregated by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium. We present GenomeTrackSig as an extension to the TrackSig R package to construct regional signature profiles using optimal segmentation and the expectation-maximization (EM) algorithm. We find that 426 genomes from 20 tumor types display at least one change in mutational signature activities (changepoint), and 306 genomes contain at least one of 54 recurrent changepoints shared by seven or more genomes of the same tumor type. Five recurrent changepoint locations are shared by multiple tumor types. Within these regions, the particular signature changes are often consistent across samples of the same type and some, but not all, are characterized by signatures associated with subclonal expansion. The changepoints we found cannot strictly be explained by gene density, mutation density, or cell-of-origin chromatin state. We hypothesize that they reflect a confluence of factors including evolutionary timing of mutational processes, regional differences in somatic mutation rate, large-scale changes in chromatin state that may be tissue type-specific, and changes in chromatin accessibility during subclonal expansion. These results provide insight into the regional effects of DNA damage and repair processes, and may help us localize genomic and epigenomic changes that occur during cancer development.

Cross-modality Synthesis of EM Time Series and Live Fluorescence Imaging

Abstract: Abstract Analyses across imaging modalities allow the integration of complementary spatiotemporal information about brain development, structure and function. However, systematic atlasing across modalities is limited by challenges to effective image alignment. We combine highly spatially resolved electron microscopy (EM) and highly temporally resolved time-lapse fluorescence microscopy (FM) to examine the emergence of a complex nervous system in C. elegans embryogenesis. We generate an EM pseudo time series at four classic developmental stages and create a landmark-based co-optimization algorithm for cross-modality image alignment, which handles developmental heterochrony among datasets to achieve accurate single-cell level alignment. Synthesis based on the EM series and time-lapse FM series carrying different cell-specific markers reveals critical dynamic behaviors across scales of identifiable individual cells in the emergence of the primary neuropil, the nerve ring, as well as a major sensory organ, the amphid. Our study paves the way for systematic cross-modality analysis in C. elegans and demonstrates a powerful approach that may be applied broadly. Highlights An EM time series to examine the emergence of an entire nervous system A landmark-based co-optimization algorithm for cross modality image alignment in the presence of developmental heterochrony Integration of EM and fluorescence series reveals cell behaviors at high spatial and temporal resolution Systematic single-cell annotation of EM data enables efficient navigation and targeted re-imaging

<i>Narrative in the Anthropocene.</i> By Erin James

Abstract: Erin James begins Narrative in the Anthropocene with two observations: first, the environmental humanities’ heavy focus on environmental representation has sidelined the role of narrative theory in ecocriticism; and, second, narrative theory itself has hardly engaged with environmental themes and issues. James fills this gap by offering the term Anthropocene narrative theory, a mode of textual analysis that reveals how characteristics of the Anthropocene influence narrative structure and fundamentally impact the ways in which humans tell and receive stories. James offers Anthropocene narrative theory as an analytical mode able to reveal different Anthropocene imaginaries. By focusing on unpacking the logic and flow of a text’s structure, James highlights unnarrated but tacit markers of Anthropocene thought, thereby opening for assessment how narrative structures reflect or challenge ways of thinking in the Anthropocene. An Anthropocene narrative theory reading of Jane Austen’s Mansfield Park, for example, uncovers the Western centrality and colonial violence implicit in the novel’s plot and aristocratic British setting, signaling the naturalized structure of colonial ideologies and attitudes in nineteenth-century readerships. Similarly, James’ reading of Ian McEwan’s realist climate change novel Solar suggests that the novel’s third-person limited viewpoint, grounded in the egotistical anthropocentrism of its main character, challenges readers to disrupt the self-centered, human exceptionalist values and priorities that characterize a facet of contemporary Anthropocene thought and action. Ultimately, Anthropocene narrative theory serves as a critical window into past, present, and future human cognitive structures and the worlds they build.

Inorganic polyphosphate abets silencing of a sub-telomeric gene cluster in fission yeast

Abstract: ABSTRACT Inorganic polyphosphate (PolyP) is a ubiquitous polymer that plays sundry roles in cell and organismal physiology. Whereas there is evidence for polyphosphate in the cell nucleus, it is unclear whether and how physiological levels of PolyP impact transcriptional regulation in eukarya. To address this issue, we performed transcriptional profiling of fission yeast vtc4 Δ cells, which lack the catalytic subunit of the Vtc4/Vtc2 polyphosphate polymerase complex and thus have no detectable intracellular PolyP. Deleting Vtc4 elicited the de-repression of four protein-coding genes – SPAC186 . 04c, gdt1/SPAC186 . 05, SPAC186 . 06 , and SPAC750 . 01 – located within a sub-telomeric region of the right arm of chromosome I that is known to be transcriptionally silenced by the TORC2 complex. These sub-telomeric genes were equally de-repressed in vtc2 Δ cells and in cells expressing polymerase-dead Vtc4, signifying that PolyP synthesis is necessary to abet TORC2-dependent locus-specific gene silencing.