Statistical validation of risk alleles in Genetic Addiction Risk Severity (GARS) test: Early identification of risk for Alcohol Use Disorder (AUD) in 74,566 case-control subjects

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism i

Genetic addiction risk and psychological profiling analyses for preaddiction severity index

Since 1990, when our laboratory published the association of th

Compositional Falsification of Cyber-Physical Systems with Machine Learning Components

Cyber-physical systems (CPS), such as automotive systems, are starting to include sophisticated machine learning (ML) components. Their correctness, therefore, depends on properties of the inner ML modules. While learning algorithms aim to generalize from examples, they are only as good as the examples provided, and recent efforts have shown that they can produce inconsistent output under small adversarial perturbations. This raises the question: can the output from learning components can lead to a failure of the entire CPS? In this work, we address this question by formulating it as a problem of falsifying signal temporal logic (STL) specifications for CPS with ML components. We propose a compositional falsification framework where a temporal logic falsifier and a machine learning analyzer cooperate with the aim of finding falsifying executions of the considered model. The efficacy of the proposed technique is shown on an automatic emergency braking system model with a perception component based on deep neural networks

Role of an Archaeal PitA Transporter in the Copper and Arsenic Resistance of \u3ci\u3eMetallosphaera sedula\u3c/i\u3e, an Extreme Thermoacidophile

Thermoacidophilic archaea, such as Metallosphaera sedula, are lithoautotrophs that occupy metal-rich environments. In previous studies, an M. sedula mutant lacking the primary copper efflux transporter, CopA, became copper sensitive. In contrast, the basis for supranormal copper resistance remained unclear in the spontaneous M. sedula mutant, CuR1. Here, transcriptomic analysis of copper-shocked cultures indicated that CuR1 had a unique regulatory response to metal challenge corresponding to the upregulation of 55 genes. Genome resequencing identified 17 confirmed mutations unique to CuR1 that were likely to change gene function. Of these, 12 mapped to genes with annotated function associated with transcription, metabolism, or transport. These mutations included 7 nonsynonymous substitutions, 4 insertions, and 1 deletion. One of the insertion mutations mapped to pseudogene Msed_1517 and extended its reading frame an additional 209 amino acids. The extended mutant allele was identified as a homolog of Pho4, a family of phosphate symporters that includes the bacterial PitA proteins. Orthologs of this allele were apparent in related extremely thermoacidophilic species, suggesting M. sedula naturally lacked this gene. Phosphate transport studies combined with physiologic analysis demonstrated M. sedula PitA was a low-affinity, high-velocity secondary transporter implicated in copper resistance and arsenate sensitivity. Genetic analysis demonstrated that spontaneous arsenate-resistant mutants derived from CuR1 all underwent mutation in pitA and nonselectively became copper sensitive. Taken together, these results point to archaeal PitA as a key requirement for the increased metal resistance of strain CuR1 and its accelerated capacity for copper bioleaching

Multimodality Treatment for Early-Stage Hepatocellular Carcinoma: A Bridging Therapy for Liver Transplantation

Purpose: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. Materials and Methods: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4-5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. Results: During a median follow-up time of 29 (4.0-95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36(44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5-37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. Conclusion: We conclude that TACE.combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach. copyright (C) 2012 S. Karger AG, Base

Quantifying the relationship between temperature regulation in the ear and floret development stage in wheat (Triticum aestivum L.) under heat and drought stress

Thermal imaging is a valuable tool for the elucidation of gas exchange dynamics between a plant and its environment. The presence of stomata in wheat glumes and awns offers an opportunity to assess photosynthetic activity of ears up to and during flowering. The knowledge of spatial and temporal thermodynamics of the wheat ear may provide insight into interactions between floret developmental stage (FDS), temperature depression (TD) and ambient environment, with potential to be used as a high-throughput screening tool for breeders. A controlled environment study was conducted using six spring wheat (Triticum aestivum L.) genotypes of the elite recombinant inbred line Seri/Babax. Average ear temperature (AET) was recorded using a hand held infrared camera and gas exchange was measured by enclosing ears in a custom built cuvette. FDS was monitored and recorded daily throughout the study. Plants were grown in pots and exposed to a combination of two temperature and two water regimes. In the examined wheat lines, TD varied from 0.1°C to 0.6°C according to the level of stress imposed. The results indicated that TD does not occur at FDS F3, the peak of active flowering, but during the preceding stages prior to pollen release and stigma maturity (F1-F2). These findings suggest that ear temperature during the early stages of anthesis, prior to pollen release and full extension of the stigma, are likely to be the most relevant for identifying heat stress tolerant genotypes

Protein detection using hydrogel-based molecularly imprinted polymers integrated with dual polarisation interferometry

A polyacrylamide-based molecularly imprinted polymer (MIP) was prepared for bovine haemoglobin (BHb). A 3 mg/ml solution of BHb was injected over a dual polarisation interferometer (DPI) sensor to form a physisorbed layer typically of 3.5 ± 0.5 nm thickness. Onto the pre-adsorbed protein layer, MIP and NIP (non-imprinted polymer) were separately injected to monitor the interaction of BHb MIP or NIP particles under different loading conditions with the pre-adsorbed protein layer. In the case of NIP flowing of the protein layer, there was negligible surface stripping of the pre-adsorbed protein. When a protein-eluted sample of MIP particles was flowed over a pre-adsorbed protein layer on the sensor chip, the sensor detected significant decreases in both layer thickness and mass, suggestive that protein was being selectively bound to MIP after being stripped-off from the sensor surface. We also integrated thin-film MIPS for BHb and BSA onto the DPI sensor surface and were able to show that whereas BHb bound selectively and strongly to the BHb MIP thin film (resulting in a sustained increase in thickness and mass), the BHb protein only demonstrated transient and reversible binding on the BSA MIP. MIPs were also tested after biofouling with plasma or serum at various dilutions. We found that serum at 1/100 dilution allowed the MIP to still function selectively. This is the first demonstration of MIPs being integrated with DPI in the development of synthetic receptor-based optical protein sensors. © 2012 Elsevier B.V. All rights reserved

The global medial structure of regions in R^3

For compact regions Omega in R^3 with generic smooth boundary B, we consider geometric properties of Omega which lie midway between their topology and geometry and can be summarized by the term "geometric complexity". The "geometric complexity" of Omega is captured by its Blum medial axis M, which is a Whitney stratified set whose local structure at each point is given by specific standard local types. We classify the geometric complexity by giving a structure theorem for the Blum medial axis M. We do so by first giving an algorithm for decomposing M using the local types into "irreducible components" and then representing each medial component as obtained by attaching surfaces with boundaries to 4--valent graphs. The two stages are described by a two level extended graph structure. The top level describes a simplified form of the attaching of the irreducible medial components to each other, and the second level extended graph structure for each irreducible component specifies how to construct the component. We further use the data associated to the extended graph structures to compute topological invariants of Omega such as the homology and fundamental group in terms of the singular invariants of M defined using the local standard types and the extended graph structures. Using the classification, we characterize contractible regions in terms of the extended graph structures and the associated data.Comment: This is the version published by Geometry & Topology on 15 December 2006 (V3: typesetting corrections

A Human-Oriented Term Rewriting System

© Springer Nature Switzerland AG 2019. We introduce a fully automatic system, implemented in the Lean theorem prover, that solves equality problems of everyday mathematics. Our overriding priority in devising the system is that it should construct proofs of equality in a way that is similar to that of humans. A second goal is that the methods it uses should be domain independent. The basic strategy of the system is to operate with a subtask stack: whenever there is no clear way of making progress towards the task at the top of the stack, the program finds a promising subtask, such as rewriting a subterm, and places that at the top of the stack instead. Heuristics guide the choice of promising subtasks and the rewriting process. This makes proofs more human-like by breaking the problem into tasks in the way that a human would. We show that our system can prove equality theorems simply, without having to preselect or orient rewrite rules as in standard theorem provers, and without having to invoke heavy duty tools for performing simple reasoning