3D Design Models to Construction (Data Centric Approach)

One aspect of e-Construction is reducing paper use, and many DOTs have successfully reduced their use of paper documents. INDOT wants to take this further by adding a data-centric approach, which focuses on the transfer of data from 3D design models to construction and then to asset management. In this presentation we discuss this initiative

INDOT Intelligent Road Design and Construction Using 3D Models

This presentation provides an update on INDOT’s e-construction and Intelligent Design and Construction initiatives. This will include a discussion of INDOT’s efforts over the past year to move toward 3D CAD models for roadway design, advancements in digital/electronic construction inspection including further development and refining of inspection checklists, continued development and testing of a mobile inspection application, and demonstration projects for e-ticketing of HMA materials delivery

INDOT Intelligent Design and Construction (IDC)

This presentation provides an update on INDOT’s e-construction initiatives. Advancements in roadway design include efforts to move toward 3D CAD models for roadway design and 3D subsurface utility design and analysis (SUDA); advancements in digital/electronic construction include the development of inspection checklists, piloting a mobile inspection application, and investigating e-ticketing for materials delivery

Mucedorus: the last ludic playbook, the first stage Arcadia

This article argues that two seemingly contradictory factors contributed to and sustained the success of the anonymous Elizabethan play Mucedorus (c. 1590; pub. 1598). First, that both the initial composition of Mucedorus and its Jacobean revival were driven in part by the popularity of its source, Philip Sidney's Arcadia. Second, the playbook's invitation to amateur playing allowed its romance narrative to be adopted and repurposed by diverse social groups. These two factors combined to create something of a paradox, suggesting that Mucedorus was both open to all yet iconographically connected to an elite author's popular text. This study will argue that Mucedorus pioneered the fashion for “continuations” or adaptations of the famously unfinished Arcadia, and one element of its success in print was its presentation as an affordable and performable version of Sidney's elite work. The Jacobean revival of Mucedorus by the King's Men is thus evidence of a strategy of engagement with the Arcadia designed to please the new Stuart monarchs. This association with the monarchy in part determined the cultural functions of the Arcadia and Mucedorus through the Interregnum to the close of the seventeenth century

I-69 Section 6 Construction Contract Update

I-69 is a high-profle, new alignment corridor project, and it’s fnal Section 6 construction is well underway in the Martinsville area. This presentation will provide an update on three Section 6 contracts, the challenges encountered, and the creative solutions employed. We will also highlight the many women employed in project leadership roles

Multi-marker quantitative radiomics for mass characterization in dedicated breast CT imaging.

PurposeTo develop and evaluate the diagnostic performance of an algorithm for multi-marker radiomic-based classification of breast masses in dedicated breast computed tomography (bCT) images.MethodsOver 1000 radiomic descriptors aimed at quantifying mass and border heterogeneity, morphology, and margin sharpness were developed and implemented. These included well-established texture and shape feature descriptors, which were supplemented with additional approaches for contour irregularity quantification, spicule and lobe detection, characterization of degree of infiltration, and differences in peritumoral compartments. All descriptors were extracted from a training set of 202 bCT masses (133 benign and 69 malignant), and their individual diagnostic performance was investigated in terms of area under the receiver operating characteristics (ROC) curve (AUC) of single-feature-based linear discriminant analysis (LDA) classifiers. Subsequently, the most relevant descriptors were selected through a multiple-step feature selection process (including stability analysis, statistical significance, evaluation of feature interaction, and dimensionality reduction), and used to develop a final LDA radiomic model for classification of benign and malignant masses, which was then tested on an independent test set of 82 cases (45 benign and 37 malignant).ResultsThe majority of the individual radiomic descriptors showed, on the training set, an AUC value deriving from a linear decision boundary higher than 0.65, with the lower limit of the associated 95% confidence interval (C.I.) not overlapping with random chance (AUC = 0.5). The final LDA radiomic model resulted in a test set AUC of 0.90 (95% C.I. 0.80-0.96).ConclusionsThe proposed multi-marker radiomic approach achieved high diagnostic accuracy in bCT mass classification, using a radiomic signature based on different feature types. While future studies with larger datasets are needed to further validate these results, quantitative radiomics applied to bCT shows potential to improve the breast cancer diagnosis pipeline

Spliceosomal Disruption of the Non-Canonical SWI/SNF Chromatin Remodeling Complex in SF3B1 Mutant Leukemias

Mutations in the RNA splicing factor SF3B1 are common in MDS and other myeloid malignancies. SF3B1 mutations promote expression of mRNAs that use an aberrant, intron proximal 3' splice site (ss). Despite the consistency of this finding, linking aberrant splicing changes to disease pathogenesis has been a challenge. Here we identify aberrant splicing and downregulated expression of BRD9, a member of the recently described ATP-dependent non-canonical BAF (ncBAF) chromatin remodeling complex, across SF3B1 mutant leukemias. In so doing, we identify a novel role for altered ncBAF function in hematopoiesis and MDS. To systematically identify functionally important aberrant splicing events created by mutant SF3B1, we integrated differential splicing events in SF3B1 mutant versus wild-type MDS with a positive enrichment CRISPR screen mimicking splicing changes induced by mutant SF3B1 that promote NMD (non-sense mediated mRNA decay). We tested whether loss of any gene functionally inactivated by SF3B1 mutations promoted transformation of Ba/F3 and 32D cells. This identified a specific NMD-inducing aberrant splicing event in BRD9 which promoted cytokine independence (Fig. A) and exhibited striking aberrant splicing across CLL and MDS and across all mutational hotspots in SF3B1 (Fig. B). SF3B1 mutations cause exonization of a normally intronic sequence in BRD9, resulting in inclusion of a poison exon that interrupts BRD9's reading frame (Fig. C) and reduced BRD9 mRNA and protein expression through NMD (Fig. D). We confirmed that mutant SF3B1 suppressed full-length BRD9 levels without generating truncated BRD9 protein. Loss of BRD9 impaired ncBAF complex formation as indicated by abolished interaction between the ncBAF specific component GLTSCR1 and the ATPase subunit BRG1 upon chemical or spliceosomal BRD9 ablation (Fig. D). Given that prior work has linked mutant SF3B1 to use of aberrant 3' ss, we sought to understand the molecular basis for aberrant exon inclusion in BRD9 by mutant SF3B1. Lariat sequencing of SF3B1 mutant versus WT K562 cells and BRD9 minigene analyses identified use of a deep intronic branchpoint adenosine by mutant SF3B1 to promote BRD9 poison exon inclusion (Fig. E). The data above suggest a role for BRD9 downregulation in SF3B1 mutant leukemia. While prior work indicated that BRD9 is required in MLL-rearranged AML (Hohmman et al. Nature Chemical Biology 2016), the role of BRD9 in normal hematopoiesis or other subtypes of myeloid neoplasms has not been evaluated. Genetic downregulation of BRD9 in normal human hematopoietic progenitors from cord blood promoted myelopoiesis while impairing megakaryopoiesis. Interestingly and unexpectedly, BRD9 loss in CD34+ cells promoted terminal erythroid differentiation in vitro. To further evaluate BRD9's role in hematopoiesis in vivo, we also generated mice with inducible knockout of the bromodomain of BRD9 (required for BRD9 function) and generation of a frameshift transcript resulting in reduced Brd9 expression (Fig. F). Loss of Brd9 resulted in macrocytosis with bone marrow erythroid dysplasia in a dosage-dependent manner, along with impaired lymphopoiesis and myeloid skewing. Moreover, competitive transplantation of hematopoietic precursors from these mice revealed that ablation of Brd9 function impaired lymphoid reconstitution while promoting advantage of myeloid cells and hematopoietic precursors (Fig. G-I). In myeloid leukemia cells, introduction of SF3B1K700E or downregulation of BRD9 resulted in increased chromatin accessibility at promoters with a significant overlap in commonly upregulated genes. This finding suggests shared epigenetic effects of SF3B1K700E mutations and BRD9 loss (Fig. J). These data identify aberrant splicing of BRD9 across the spectrum of SF3B1 mutant cancers and identify a novel role for downregulation of ncBAF function in MDS pathogenesis. Consistent with human genetic data, genetic ablation of BRD9 function in mouse and human hematopoietic cells resulted in myeloid skewing and dyserythropoiesis. These data suggest that targeted correction of aberrant BRD9 splicing might serve as a novel therapeutic approach for SF3B1-mutant leukemias. Of note, treatment with drugs impairing the binding of mutant SF3B1 to RNA resulted in a dose-dependent rescue of aberrant BRD9 splicing in vitro (Fig. K) and in treatment of an SF3B1 mutant AML patient-derived xenograft in vivo. Figure Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees

Spliceosomal disruption of the non-canonical BAF complex in cancer

SF3B1 is the most commonly mutated RNA splicing factor in cancer , but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L . Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies