Halogenated ligands and their interactions with amino acids: implications for structure-activity and structure-toxicity relationships

The properties of chemicals are rooted in their molecular structure. It follows that structural analysis of specific interactions between ligands and biomolecules at the molecular level is invaluable for defining structure-activity relationships (SARs) and structure-toxicity relationships (STRs). This study has elucidated the structural and molecular basis of interactions of biomolecules with alkyl and aryl halides that are extensively used as components in many commercial pesticides, disinfectants, and drugs. We analyzed the protein structures deposited in Protein Data Bank (PDB) for structural information associated with interactions between halogenated ligands and proteins. This analysis revealed distinct patterns with respect to the nature and structural characteristics of halogen interactions with specific types of atoms and groups in proteins. Fluorine had the highest propensity of interactions for glycine, while chlorine for leucine, bromine for arginine, and iodine for lysine. Chlorine, bromine and iodine had the lowest propensity of interactions for cysteine, while fluorine had a lowest propensity for proline. These trends for highest propensity shifted towards the hydrophobic residues for all the halogens when only interactions with the side chain were considered. Halogens had equal propensities of interaction for the halogen bonding partners (nitrogen and oxygen atoms), albeit with different geometries. The optimal angle for interactions with halogens was approximately 120 degrees for oxygen atoms, and approximately 96 degrees for nitrogen atoms. The distance distributions of halogens with various amino acids were mostly bimodal, and the angle distributions were unimodal. Insights gained from this study have implications for the rational design of safer drugs and commercially important chemicals.     

Arthemis: annotation software in an integrated capturing and analysis system for colonoscopy

Colonoscopy is an endoscopic technique that allows physicians to inspect the inside of the human colon. During a colonoscopic procedure, a tiny video camera at the tip of the endoscope generates a video signal of the internal mucosa of the colon. In current practice, the entire colonoscopic procedure is not routinely captured. Software tools providing easy access to important contents of videos that are digitally captured during colonoscopy are not available. Hence, it is very time consuming to review an entire video, locate important contents, annotate them, and extract the annotated contents for research, teaching, and training purposes. Arthemis, a software application, was developed to facilitate this process. For convenient data sharing, Arthemis allows annotation according to the European Gastrointestinal Society for Endoscopy (ESGE) Minimal Standard Terminology (MST), an internationally accepted standard for digestive endoscopy. Arthemis is part of our integrated capturing and content analysis system for colonoscopy called Endoscopic Multimedia Information System (EMIS). This paper presents Arthemis as a component of EMIS, the design and implementation of Arthemis, and key lessons learned from the development process.     

Parametric embedding for class visualization

We propose a new method, parametric embedding (PE), that embeds objects with the class structure into a low-dimensional visualization space. PE takes as input a set of class conditional probabilities for given data points and tries to preserve the structure in an embedding space by minimizing a sum of Kullback-Leibler divergences, under the assumption that samples are generated by a gaussian mixture with equal covariances in the embedding space. PE has many potential uses depending on the source of the input data, providing insight into the classifier's behavior in supervised, semisupervised, and unsupervised settings. The PE algorithm has a computational advantage over conventional embedding methods based on pairwise object relations since its complexity scales with the product of the number of objects and the number of classes. We demonstrate PE by visualizing supervised categorization of Web pages, semisupervised categorization of digits, and the relations of words and latent topics found by an unsupervised algorithm, latent Dirichlet allocation.     

Proteomic analysis of the response of the human neutrophil-like cell line NB-4 after exposure to anthrax lethal toxin

We used 2‐D DIGE to analyze the early response of NB‐4 cells, a human promyelotic leukemia cell line, exposed to lethal toxin from Bacillus anthracis at the proteome level. After a 2 h exposure, cells were still viable and 43% of spots (n = 1042) showed a significant change in protein level. We identified 59 spots whose expression had changed significantly, and these reflected cytoskeleton damage, mitochondrial lysis and endoplasmic reticulum stress. Actin filament assembly was disrupted as evidenced by an increase in both actin subunits and phosphorylated cofilin, whilst levels of tropomyosin, tropomodulin and actin related protein 2/3 complex subunit decreased. Lower levels of ATP synthase subunits and mitochondrial inner membrane protein were identified as markers of mitochondrial lysis. Levels of various stress response proteins rose and, uniquely, levels of Ca²⁺ binding proteins such as translationally controlled tumor protein rose and hippocalcin‐like protein 1 decreased. This response may have mitigated effects brought about by mitochondrial lysis and endoplasmic reticulum stress, and delayed or prevented apoptosis in NB‐4 cells. These results resemble findings of similar proteomics studies in murine macrophages, although quantitative differences were observed.     

Learning and retention of associations between auditory icons and denotative referents: implications for the design of auditory warnings

OBJECTIVE: This study examined the way in which the type and preexisting strength of association between an auditory icon and a warning event affects the ease with which the icon/event pairing can be learned and retained. BACKGROUND: To be effective, an auditory warning must be audible, identifiable, interpretable, and heeded. Warnings consisting of familiar environmental sounds, or auditory icons, have potential to facilitate identification and interpretation. The ease with which pairings between auditory icons and warning events can be learned and retained is likely to depend on the type and strength of the preexisting icon/event association. METHOD: Sixty-three participants each learned eight auditory-icon/denotative-referent pairings and attempted to recall them 4 weeks later. Three icon/denotative-referent association types (direct, related, and unrelated) were employed. Participants rated the strength of the association for each pairing on a 7-point scale. RESULTS: The number of errors made while learning pairings was greater for unrelated than for either related or direct associations, whereas the number of errors made while attempting to recall pairings 4 weeks later was greater for unrelated than for related associations and for related than for direct associations. Irrespective of association type, both learning and retention performance remained at very high levels, provided the strength of the association was rated greater than 5. CONCLUSION: This suggests that strong preexisting associations are used to facilitate learning and retention of icon/denotative-referent pairings. APPLICATION: The practical implication of this study is that auditory icons having either direct or strong, indirect associations with warning events should be preferred.     

Connection and coordination: the interplay between architecture and dynamics in evolved model pattern generators

We undertake a systematic study of the role of neural architecture in shaping the dynamics of evolved model pattern generators for a walking task. First, we consider the minimum number of connections necessary to achieve high performance on this task. Next, we identify architectural motifs associated with high fitness. We then examine how high-fitness architectures differ in their ability to evolve. Finally, we demonstrate the existence of distinct parameter subgroups in some architectures and show that these subgroups are characterized by differences in neuron excitabilities and connection signs.     

Denial-of-service: courting disaster

Denial-of-service (DoS) attacks have been around for a long time. In the computer network arena, DoS attacks usually take one of two forms: 1) exploiting bugs in network clients or server applications, in an attempt to crash the application (and possibly the host on which it is running) or 2) flooding a network server with fake traffic, making it difficult or impossible for the server to receive and process legitimate traffic. The former are typically carried out by using ‘buffer overrun attacks’ in which a network application is sent a large amount of data which it fails to handle properly, instead overwriting critical information with the excess data.     

Spatial and Temporal Variabilities of Sediment Delivery Ratio

Sediment contribution of specific areas of a watershed is an important consideration, but one that is often overlooked, when developing watershed management plans. Understanding sediment delivery to the watershed outlet is one method for identifying high contribution areas. In this study, a new methodology for calculating individual subbasin sediment delivery ratio (SDR) was developed within the Soil and Water Assessment Tool (SWAT) for two Michigan watersheds. Subbasins with the greatest SDR had two defining characteristics: high erosion rates and close proximity to the watershed outlet. The impact of best management practice (BMP) implementation (no-tillage and Conservation Reserve Program) on sediment yield reduction at the watershed outlet was compared for two targeting methods (SDR and erosion rate). Identifying SDR of individual subbasins for implementation of BMPs is more effective method for addressing water quality concerns at the watershed outlet than the widely used targeting high risk erosion areas. Watershed SDR was found to be highly variable on a monthly basis, due to changes in sediment yield, which is in turn affected by factors such as precipitation and surface runoff. Finally, watershed SDR calculated using the physically-based SWAT model was compared to four empirically-based areal relationships with SDR. While some area methods reproduced the SWAT-SDR, the variations between areal methods indicate that more detailed physical characteristics should be considered in watershed SDR calculation.     

Prediction of backside micromotion in total knee replacements by finite element simulation

The micromotion at the interface between the polyethylene tibial insert and metal tibial tray [corrected] in modular total knee replacements [corrected] has been shown to contribute to wear particle-induced osteolysis and may [corrected] cause implant failure. Therefore, studying the design parameters that are involved in the backside wear process is an important task that may lead to improvement in new total knee replacements. In the present study, a finite element model was developed to predict the backside micromotion along the entire modular interface. Both the linear elastic constitutive model and non-linear J2-plasticity constitutive model were considered in the finite element model for polyethylene and were corroborated against published results obtained from displacement controlled knee simulator wear tests. The finite element simulation with the non-linear J2-plasticity constitutive model was able to predict backside micromotion [corrected] more accurately than the simulation with the linear elastic constitutive model. [corrected] The developed finite element model (including the non-linear J2-plasticity constitutive model) was then applied to assess the effects of the tibial tray locking mechanism design (dovetails versus fullperipheral [corrected] design) and different levels of interference fit on insert micromotion. The developed finite element model, implementing the non-linear J2-plasticity constitutive model, was shown to successfully predict clinical amounts of backside micromotion and could be used for the design and development of total knee replacements for the reduction of backside micromotion and polyethylene [corrected] wear.     

Examining cognitive function across the lifespan using a mobile application

Many studies conducted in a laboratory or university setting are limited by funding, personnel, space, and time constraints. In the present study, we introduce a method of data collection using a mobile application that circumvents these typical experiment administration issues. Using the application, we examined cross-sectional age differences in cognitive function. We obtained data from more than 15,000 participants and replicated specific patterns of age-related differences in cognition. Using a subset of these participants, we also examined the processing speed account of age-related cognitive differences, and the association of exercise and leisure activity with cognitive function across the lifespan. We discuss the relative advantages and disadvantages of data collection with a mobile application, and provide recommendations for the use of this method in research.