Overview: Computer vision and machine learning for microstructural characterization and analysis

The characterization and analysis of microstructure is the foundation of microstructural science, connecting the materials structure to its composition, process history, and properties. Microstructural quantification traditionally involves a human deciding a priori what to measure and then devising a purpose-built method for doing so. However, recent advances in data science, including computer vision (CV) and machine learning (ML) offer new approaches to extracting information from microstructural images. This overview surveys CV approaches to numerically encode the visual information contained in a microstructural image, which then provides input to supervised or unsupervised ML algorithms that find associations and trends in the high-dimensional image representation. CV/ML systems for microstructural characterization and analysis span the taxonomy of image analysis tasks, including image classification, semantic segmentation, object detection, and instance segmentation. These tools enable new approaches to microstructural analysis, including the development of new, rich visual metrics and the discovery of processing-microstructure-property relationships.Comment: submitted to Materials and Metallurgical Transactions

Rural School District Leadership and Governance: Eating Your Veggies to Stay on the Balcony

School board trustees and superintendents must navigate overlapping roles and intersectional identities when engaging in rural school district governance work. If these individuals are not clear about the scope of their role and do not have a common understanding about the importance of high expectations for all, lack of coherent governance can negatively impact their district. Recently, one school district in rural Idaho has experienced phenomenal success. The district is in a very different place than it was just a little over five years ago. In this article insights are shared about the governance practices of trustees and the superintendent that supported their improvement

Reactive oxygen species induce virus-independent MAVS-oligomerization in systemic lupus erythematosus

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)–like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress–induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome

The Iddm14 gene is Tcrbv-13S1A1: Prevention of Autoimmune Diabetes in the Rat with an Allele-Specific Depleting Antibody That Recognizes the Vβ13a T Cell Receptor Beta Chain

To identify new intervention strategies for autoimmune type 1 diabetes (T1D), we investigated several rat models of the disorder. We dissected the powerful Iddm14 diabetes susceptibility locus in eight T1D susceptible vs. resistant rat strains by single nucleotide polymorphism (SNP) haplotyping. We identified an allele of a T cell receptor (TCR) beta chain gene, Tcrb-V13S1A1 (encoding V13βa) as a candidate gene. In three separate trials, treating LEW.1WR1 rats, which are susceptible to T1D, with a depleting anti-Vβ13 monoclonal antibody reduced diabetes frequency from 75% (N=50) to 17% (N=30, p\u3c0.001. Anti-Vβ13 monoclonal antibody also prevented T1D in spontaneously diabetic BBDP rats. We then analyzed the phenotype of infiltrating T cells recovered from the cultured islets of LEW.1WR1 rats exposed to a diabetogenic trigger. Within 5 days, up to 22% of CD4+ T cells recovered from islets were V13β+, most of these CD25+FoxP3-. We also recovered Vβ13 transcripts from pre-diabetic islets and observed a limited number of Jβ variant transcripts, indicating an oligoclonal TCR response to pancreatic beta cells. These data indicate that, in susceptible rats, V13βa on diabetogenic T cells is required to recognize a critical T1D autoantigen. Interestingly, the diabetogenic and non-diabetogenic alleles of Vβ13 have non-conservative sequence differences in both CRR1 and CDR2. The data suggest that it is possible to prevent T1D in the rat with a very narrowly targeted deletional therapy. Preliminary data suggest that a specific alpha chain may preferentially pair with Vβ13a. We are currently generating rat T cell hybridoma clones with which to analyze the interaction of putative autoantigens with a diabetogenic TCR

Use of a Multi-Reference GPS Station Network for Precise 3D Positioning in Constricted Waterways

Numerous coastal and inland marine operations, including navigation in shallow constricted waterways require time-consuming and expensive maintenance that includes frequent precise multi-beam hydrographic surveys and dredging operations. In addition, environmental and safety concerns lead to the establishment of stringent regulations regarding the minimum under keel clearance for commercial shipping operations. The clearance is partly a function of the navigation channel charting accuracy and the ability to determine the instantaneous water level in real time. The use of real-time kinematic (RTK) GPS to provide a three-dimensional accuracy of better than 10 cm has the potential to improve the effectiveness of channel maintenance and commercial navigation. In order for RTK GPS to yield such a high level of accuracy, carrier phase observables must be used. One of the most important limitations is the requirement for short distances between the ship and shore-based fixed reference stations. With the current GPS capability, the distance should be kept to less than 15 to 20 km to assure a continuous service. Establishing reference stations with such a high density is time-consuming, logistically difficult and results in high maintaining cost and operational reliability issues. In this paper a method to substantially reduce the number of reference stations is investigated through field trials conducted along the St. Lawrence Seaway, Canada, in 1998 and 1999. The proximity of the trials to a solar maximum resulted in a very high level of atmospheric activity and provided an opportunity to examine the advantages and limitations of both the conventional and multi-reference station RTK methods under such conditions. The results of the trials show that the new approach results in a substantial improvement of up to 60%

The Missing Heritability in T1D and Potential New Targets for Prevention

Type 1 diabetes (T1D) is a T cell-mediated disease. It is strongly associated with susceptibility haplotypes within the major histocompatibility complex, but this association accounts for an estimated 50% of susceptibility. Other studies have identified as many as 50 additional susceptibility loci, but the effect of most is very modest (odds ratio (OR) 5) and that deletion of V beta 13+ T cells prevents diabetes. A role for the TCR is also suspected in NOD mice, but TCR regions have not been associated with human T1D. To investigate this disparity, we tested the hypothesis in silico that previous studies of human T1D genetics were underpowered to detect MHC-contingent TCR susceptibility. We show that stratifying by MHC markedly increases statistical power to detect potential TCR susceptibility alleles. We suggest that the TCR regions are viable candidates for T1D susceptibility genes, could account for missing heritability, and could be targets for prevention

Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer\u27s disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits. Methods: Aged dogs naturally accumulate plaques and show associated cognitive declines. Low-frequency ultrasound was used to open the BBB unilaterally in aged beagles (9-11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow-up MRI exam 1 week following the final treatment. Results: The permeability of the BBB was successfully increased in all animals (mean enhancement: 19±11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0±1.4 vs 0.4±0.5/5.2±1.8 vs. 4.0±2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Aβ loads in the treated hemisphere. Conclusion: Whole-hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology

KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II

SummaryThe transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites. Here we report that the transcriptional regulator KAP1 continuously tethers the 7SK snRNP to PRG promoters to facilitate P-TEFb recruitment and productive elongation in response to stimulation. Remarkably, besides PRGs, genome-wide studies revealed that KAP1 and 7SK snRNP co-occupy most promoter-proximal regions containing paused Pol II. Collectively, we provide evidence of an unprecedented mechanism controlling 7SK snRNP delivery to promoter-proximal regions to facilitate "on-site" P-TEFb activation and Pol II elongation