Geotechnical and Groundwater Site Characterization on the UMTRA Project

Reclamation of 24 inactive uranium mill tailngs piles involves remedial work to stabilize the piles for 1000 years. Site characterization of geotechnical and groundwater conditions at each site is undertaken prior to remedial action design. This paper describes the approach to UMTRA Project site characterization. A case history, Green River, is described. Details of site characterization costs for most sites are provided

Sparse Feature Circuits: Discovering and Editing Interpretable Causal Graphs in Language Models

We introduce methods for discovering and applying sparse feature circuits. These are causally implicated subnetworks of human-interpretable features for explaining language model behaviors. Circuits identified in prior work consist of polysemantic and difficult-to-interpret units like attention heads or neurons, rendering them unsuitable for many downstream applications. In contrast, sparse feature circuits enable detailed understanding of unanticipated mechanisms. Because they are based on fine-grained units, sparse feature circuits are useful for downstream tasks: We introduce SHIFT, where we improve the generalization of a classifier by ablating features that a human judges to be task-irrelevant. Finally, we demonstrate an entirely unsupervised and scalable interpretability pipeline by discovering thousands of sparse feature circuits for automatically discovered model behaviors.Comment: Code and data at https://github.com/saprmarks/feature-circuits. Demonstration at https://feature-circuits.xy

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

Metal mixtures modeling identifies birth weight-associated gene networks in the placentas of children born extremely preterm

Prenatal exposure to toxic metals is linked to numerous adverse birth and later-in-life outcomes. These outcomes are tied to disrupted biological processes in fetal-derived tissues including the placenta and umbilical cord yet the precise pathways are understudied in these target tissues. We set out to examine the relationship between metal concentrations in umbilical cord and altered gene expression networks in placental tissue. These novel relationships were investigated in a subset of the Extremely Low Gestational Age Newborn (ELGAN) cohort (n = 226). Prenatal exposure to 11 metals/metalloids was measured using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS) in cord tissue, ensuring passage through the placental barrier. RNA-sequencing was used to quantify &gt;37,000 mRNA transcripts. Differentially expressed genes (DEGs) were identified with respect to each metal. Weighted gene co-expression analysis identified gene networks modulated by metals. Two innovative mixtures modeling techniques, namely principal components analysis and quantile-based g-computation, were employed to identify genes/gene networks associated with multi-metal exposure. Individually, lead was associated with the strongest genomic response of 191 DEGs. Joint lead and cadmium exposure was related to 657 DEGs, including DNA Methyl Transferase 1 (DNMT1). These genes were enriched for the Eukaryotic Initiation Factor 2 (EIF2) pathway. Four gene networks, each containing genes within a Nuclear Factor kappa-light-chain-enhancer of Activated B Cells (NF-kB)-mediated network, were significantly increased in average expression level in relation to increases in all metal concentrations. All four of these metal mixture-associated gene networks were negatively correlated with important predictors of neonatal health including birth weight, placenta weight, and fetal growth. Bringing together novel methodologies from epidemiological mixtures analyses and toxicogenomics, applied to a unique cohort of extremely preterm children, the present study highlighted critical genes and pathways in the placenta dysregulated by prenatal metal mixtures. These represent potential mechanisms underlying the developmental origins of metal-induced disease

Extending the Dynamic Range of Microchannel Plate Detectors Using Charge-Integration-Based Counting

Microchannel plate (MCP) detectors provide a mechanism to produce a measureable current pulse (~0.1mA over several nanoseconds) when stimulated by a single incident particle or photon. Reductions of the device's amplification factor (i.e., gain) due to high incident particle flux can lead to significant degradation of detection system performance. Here we develop a parameterized model for the variation of MCP gain with incident flux. This model provides a framework with which to quantify the limits of high-flux MCP operation. We then compare the predictions of this model to laboratory measurements of an MCP's response to a pulsed charged particle beam. Finally, we demonstrate that through integration of the MCP output current in pulsed operation, effective count rates up to ~ 1 GHz can be achieved, more than an order of magnitude increase over conventional counting techniques used for spaceflight applications