Mutation patterns of amino acid tandem repeats in the human proteome

Background: Amino acid tandem repeats are found in nearly one-fifth of human proteins. Abnormal expansion of these regions is associated with several human disorders. To gain further insight into the mutational mechanisms that operate in this type of sequence, we have analyzed a large number of mutation variants derived from human expressed sequence tags (ESTs).Results: We identified 137 polymorphic variants in 115 different amino acid tandem repeats. Of these, 77 contained amino acid substitutions and 60 contained gaps (expansions or contractions of the repeat unit). The analysis showed that at least about 21% of the repeats might be polymorphic in humans. We compared the mutations found in different types of amino acid repeats and in adjacent regions. Overall, repeats showed a five-fold increase in the number of gap mutations compared to adjacent regions, reflecting the action of slippage within the repetitive structures. Gap and substitution mutations were very differently distributed between different amino acid repeat types. Among repeats containing gap variants we identified several disease and candidate disease genes.Conclusion: This is the first report at a genome-wide scale of the types of mutations occurring in the amino acid repeat component of the human proteome. We show that the mutational dynamics of different amino acid repeat types are very diverse. We provide a list of loci with highly variable repeat structures, some of which may be potentially involved in disease.

Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters

Background: The arrangement of regulatory motifs in gene promoters, or promoterarchitecture, is the result of mutation and selection processes that have operated over manymillions of years. In mammals, tissue-specific transcriptional regulation is related to the presence ofspecific protein-interacting DNA motifs in gene promoters. However, little is known about therelative location and spacing of these motifs. To fill this gap, we have performed a systematic searchfor motifs that show significant bias at specific promoter locations in a large collection ofhousekeeping and tissue-specific genes.Results: We observe that promoters driving housekeeping gene expression are enriched inparticular motifs with strong positional bias, such as YY1, which are of little relevance in promotersdriving tissue-specific expression. We also identify a large number of motifs that show positionalbias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specificmotifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis,as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictionsfor 559 tissue-specific motifs in mouse gene promoters.Conclusion: The study shows that motif positional bias is an important feature of mammalianproximal promoters and that it affects both general and tissue-specific motifs. Motif positionalconstraints define very distinct promoter architectures depending on breadth of expression andtype of tissue.

Automatic filtering and substantiation of drug safety signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

Motivic analysis and its relevance to raga identification in carnatic music

A raga is a collective melodic expression consisting of motifs. A raga can be identified using motifs which areunique to it. Motifs can be thought of as signature prosodic phrases. Different ragas may be composed of the same setof notes, or even phrases, but the prosody may be completely different. In this paper, an attempt is made to determinethe characteristic motifs that enable identification of a raga and distinguish between them. To determine this, motifs are first manually marked for a set of five popular raga by a professional musician. The motifs are then normalisedwith respect to the tonic. HMMs are trained for each motif using 80% of the data and about 20% are used for testing. The results do indicate that about 80% of the motifs are identified as belonging to a specific raga accurately.

A knowledge based signal processing approach to tonic identification in indian classical music

In this paper, we describe several techniques for detecting tonic pitch value in Indian classical music. In Indian music, the raga is the basic melodic framework and it is built on the tonic. Tonic detection is therefore fundamental for any melodic analysis in Indian classical music. This workexplores detection of tonic by processing the pitch histograms of Indian classic music. Processing of pitch histograms using group delay functions and its ability to amplify certain traits of Indian music in the pitch histogram, is discussed. Three different strategies to detect tonic, namely, the concert method, the template matching and segmented histogram method are proposed. The concert method exploits the fact that the tonic is constant over a piece/concert.templatematchingmethod and segmented histogrammethodsuse the properties: (i) the tonic is always present in the background, (ii) some notes are less inflected and dominant, to detect the tonic of individual pieces. All the three methods yield good results for Carnatic music (90−100% accuracy), while for Hindustanimusic, the templatemethod works best, provided the v¯adi samv¯adi notes for a given piece are known (85%).

Features for analysis of Makam music

For computational studies of makam music, it is essential to gather a list of characteristics that constitute a makam and explore corresponding quantitative features for automaticanalysis. This study is such an attempt where we address the characteristics for makams as defined in theory books and deduce a list of quantitative features. The target here is to evoke discussions on some measurable features other than providing complete analysis on thediscriminative potentials of each proposed feature which could be the subject of a few larger studies.

08023-013 DMACC Lake Final Report

The DMACC Lake Watershed Improvement project will focus on water quality and quantity as well as channel and lake restoration. Roadway, parking lot, and roof drainage from the west and northwest portions of the campus add significant amounts of pollutants and silt to the lake. Severe channel erosion exists along the northern creek channel with exposed cut banks ranging from 2-10 feet in height devoid of vegetation. Heavy lake sedimentation and algae blooms are a result of accumulated sediment being conveyed to the lake. Most sections of the north channel have grades of between 0.5% and 1%. This channel receives large scouring flow velocities. There are no natural riffle or pool systems. There are five areas where these riffle and pool systems may need to be created in order to slow overall channel velocities. This will create a series of rock riffles and a still pool that will mimic the conditions that natural channels tend to create, protecting the channel from undercutting. Multiple practices will need to be implemented to address the pollutant, silt, and channel erosion. Improvements will be specifically tailored to address problems observed within the north channel, on-site drainage from the west and northwest, as well as off-site drainage to the north of the campus and east of Ankeny Blvd (Hwy 69). The result will be improved quality and quantity of site drainage and a channel with a more natural appearance and reduced scour velocities. Sections of the north channel will require grading to establish slopes that can support deep rooted vegetation and to improve maintenance access. Areas with eroded banks will require slope pull back and may also require toe armor protection to stabilize. A constructed wetland will collect and treat runoff from the west on site parking lot, before being discharged into the lake. This project will create educational opportunities to both students and the general public as well as interested parties outside of the local area for how an existing system can be retro fitted for improved watershed quality.

Iowa Motorcycle Operator's Manual, 2014

The rules and regualtions for owning and operating a motorcycle in Iowa

Geochemical evolution of active porphyry copper tailings impoundments : from alkaline deposition towards acidification

J. Smuda: Geochemical evolution of active porphyry copper tailings impoundments Thesis abstract Mine waste is the largest volume of materials handled in the world. The oxidation of sulfidic mine waste may result in the release of acid mine drainage (AMD) rich in heavy metals and arsenic to the environment, one of the major problems the mining industry is facing today. To control and reduce this environmental impact, it is crucial to identify the main geochemical and hydrological processes influencing contaminant liberation, transport, and retention. This thesis presents the results of a geochemical, mineralogical and stable isotope study (δ2H, δ18O, δ34S) from two active porphyry copper tailings impoundments in Mediterranean (Carén tailings impoundment, El Teniente mine, Central Chile) and hyper-arid climate (Talabre tailings impoundment, Chuquicamata, Northern Chile) from the deposition in alkaline environment (pH 10.5) towards acidification after several years of exposure. The major hydrological results were the identification of vertical contaminant and water transport in the uppermost, not water-saturated zone, triggered by capillary rise due to evaporation, and infiltration downwards due to new tailings deposition, and of horizontal transport in the groundwater zone. At the surface of the sedimented tailings, evaporation of pore water led to the precipitation of Na-Ca-Mg sulfates (e.g., gypsum, tenorite), in hyper-arid climate also halite. At the Carén tailings impoundment, renewed deposition in a 4-week interval inhibited a pH decrease below neutral values and the formation of an efflorescent salt crust. At the Talabre tailings impoundment, deposition breaks of several years resulted in the formation of acidic oxidation zones in the timeframe of less than 4 years. This process enabled the transport of liberated Cu, Zn, and Fe via capillary rise to the surface, where these metals precipitated as heavy-metal sulfates (e.g., devilline, krohnkite) and chlorides (eriochalcite, atacamite). Renewed depositing may dissolve efflorescent salts and transport liberated elements towards the groundwater zone. This zone was found to be highly dynamic due to infiltration and mixing with water from different sources, like groundwater, catchment water, and infiltration from superficial waters. There, Cu was found to be partially mobile due to complexation with Cl (in Cl-rich groundwater, Talabre) and dissolved organic matter (in zones with infiltration of catchment water rich in dissolved organic matter, Carén). A laboratory study on the isotopic fractionation of sulfur and oxygen of sulfate in different minerals groups (water-soluble sulfates, low- and high-crystalline Fe(III) oxyhydroxides) contributed to the use of stable isotopes as tracer of geochemical and transport processes for environmental studies. The results highlight that a detailed geochemical, stable isotope and mineralogical study permits the identification of contamination processes and pathways already during the deposition of mine tailings. This knowledge allows the early planning of adequate actions to reduce and control the environmental impact during tailings deposition and after the closing of the impoundment. J. Smuda: Geochemical evolution of active porphyry copper tailings impoundments Résumé de these Les déchets miniers constituent les plus grands volumes de matériel gérés dans le monde. L'oxydation des déchets miniers sulfuriques peut conduire à la libération de drainages miniers acides (DMA) riches en métaux et arsenic dans l'environnement, ce qui est l'un des principaux problèmes de l'industrie minière aujourd'hui. Pour contrôler et réduire ces impacts sur l'environnement, il est crucial d'identifier les principaux processus géochimiques et hydrologiques influençant la libération, le transport et la rétention des contaminants. Cette thèse présente les résultats d'une étude géochimique, minéralogique et des isotopes stables (δ2H, δ18O, δ34S) sur des déchets miniers de 2 sites de dépôt actifs en climat méditerranéen (Dépôt de déchets de Carén, mine de El Teniente, Centre du Chili) et en climat hyper-aride (Dépôt de déchets de Talabre, mine de Chuquicamata, Nord du Chili). L'objectif était d'étudier l'évolution des déchets de la déposition en milieu alcalin (pH = 10.5) vers l'acidification après plusieurs années d'exposition. Le principal résultat hydrologique a été l'identification de 2 types de transport : un transport vertical de l'eau et des contaminants dans la zone non saturée en surface, induit par la montée capillaire due à l'évaporation et par l'infiltration subséquente de la déposition de sédiments frais ; et un transport horizontal dans la zone des eaux souterraines. À la surface des déchets, l'évaporation de l'eau interstitielle conduit à la précipitation de sulfates de Na-Ca-Mg (ex. gypse, ténorite) et halite en climat hyper-aride. Dans le site de Carén, une nouvelle déposition de déchets frais à 4 semaines intervalle a empêché la baise du pH en deçà des valeurs neutres et la formation d'une croûte de sels efflorescentes en surface. Dans le site de Talabre, les fentes de dessiccation des dépôts ont entraîné la formation d'une zone d'oxydation à pH acide en moins de 4 ans. Ce processus a permis la libération et le transport par capillarité de Cu, Zn, Fe vers la surface, où ces éléments précipitent sous forme de sulfates de métaux lourds (ex., dévilline, krohnkite) de chlorures (ex. ériochalcite, atacamite). Une nouvelle déposition de sédiments frais pourrait dissoudre ces sels et les transporter vers la zone des eaux souterraines. Cette dernière zone était très dynamique en raison du mélange d'eaux provenant de différentes sources, comme les eaux souterraines, l'eau de captage et l'infiltration des eaux superficielles. Egalement dans cette zone, le cuivre était partiellement mobile à cause de la formation de complexe avec le chlore (dans les zone riche en Cl, Talabre) et avec la matière organique dissoute (dans les zones où s'infiltre l'eau de captage riche en matière organique, Carén). Une étude en laboratoire sur le fractionnement des isotopes stables de sulfure et d'oxygène des sulfates dans différents groupes de minéraux (sulfates hydrosolubles, sulfures de oxy-hydroxyde de Fe(III) faiblement ou fortement cristallins) a permis d'apporter une contribution à leur utilisation comme traceurs dans l'étude des processus géochimiques et de transport lors d'études environnementales. Les résultats montrent qu'une étude détaillée de la géochimie, des isotopes stables et de la minéralogie permet d'identifier les processus et les voies de contamination déjà pendant la période de dépôt des déchets miniers. Cette connaissance permet de planifier, dès le début de l'exploitation, des mesures adéquates pour réduire et contrôler l'impact sur l'environnement pendant la période de dépôts de déchets miniers et après la fermeture du site.

Study of the Regulatory Issues Affecting Truck Freight Movement in the Midwest, RB29-013, 2014

This project investigated regulatory issues that may affect or limit freight movement in Iowa and other Midwest states: Illinois, Kansas, Minnesota, Missouri, Nebraska, South Dakota, and Wisconsin. Current state regulations for the following are reviewed and summarized: - Vehicle dimensions - Vehicle weights - Speed limits - Weight compliance enforcement - Fees and taxes - Driver qualifications - Medical certification - Hours of service - Oversize-overweight permits

Mitochondrial dysfunction increases oxidative stress and decreases chronological life span in fission yeast

Background: Oxidative stress is a probable cause of aging and associated diseases. Reactive oxygen species (ROS) originate mainly from endogenous sources, namely the mitochondria. Methodology/Principal Findings: We analyzed the effect of aerobic metabolism on oxidative damage in Schizosaccharomyces pombe by global mapping of those genes that are required for growth on both respiratory-proficient media and hydrogen-peroxide-containing fermentable media. Out of a collection of approximately 2700 haploid yeast deletion mutants, 51 were sensitive to both conditions and 19 of these were related to mitochondrial function. Twelve deletion mutants lacked components of the electron transport chain. The growth defects of these mutants can be alleviated by the addition of antioxidants, which points to intrinsic oxidative stress as the origin of the phenotypes observed. These respiration-deficient mutants display elevated steady-state levels of ROS, probably due to enhanced electron leakage from their defective transport chains, which compromises the viability of chronologically-aged cells. Conclusion/Significance: Individual mitochondrial dysfunctions have often been described as the cause of diseases or aging, and our global characterization emphasizes the primacy of oxidative stress in the etiology of such processes.

The EU-ADR Web Platform: delivering advanced pharmacovigilance tools

PURPOSE: Pharmacovigilance methods have advanced greatly during the last decades, making post-market drug assessment an essential drug evaluation component. These methods mainly rely on the use of spontaneous reporting systems and health information databases to collect expertise from huge amounts of real-world reports. The EU-ADR Web Platform was built to further facilitate accessing, monitoring and exploring these data, enabling an in-depth analysis of adverse drug reactions risks.METHODS: The EU-ADR Web Platform exploits the wealth of data collected within a large-scale European initiative, the EU-ADR project. Millions of electronic health records, provided by national health agencies, are mined for specific drug events, which are correlated with literature, protein and pathway data, resulting in a rich drug-event dataset. Next, advanced distributed computing methods are tailored to coordinate the execution of data-mining and statistical analysis tasks. This permits obtaining a ranked drug-event list, removing spurious entries and highlighting relationships with high risk potential.RESULTS: The EU-ADR Web Platform is an open workspace for the integrated analysis of pharmacovigilance datasets. Using this software, researchers can access a variety of tools provided by distinct partners in a single centralized environment. Besides performing standalone drug-event assessments, they can also control the pipeline for an improved batch analysis of custom datasets. Drug-event pairs can be substantiated and statistically analysed within the platform's innovative working environment.CONCLUSIONS: A pioneering workspace that helps in explaining the biological path of adverse drug reactions was developed within the EU-ADR project consortium. This tool, targeted at the pharmacovigilance community, is available online at https://bioinformatics.ua.pt/euadr/. Copyright © 2012 John Wiley & Sons, Ltd.

Fuzzy logic algorithm to extract specific interaction forces from atomic force microscopy data

The atomic force microscope is not only a very convenient tool for studying the topography of different samples, but it can also be used to measure specific binding forces between molecules. For this purpose, one type of molecule is attached to the tip and the other one to the substrate. Approaching the tip to the substrate allows the molecules to bind together. Retracting the tip breaks the newly formed bond. The rupture of a specific bond appears in the force-distance curves as a spike from which the binding force can be deduced. In this article we present an algorithm to automatically process force-distance curves in order to obtain bond strength histograms. The algorithm is based on a fuzzy logic approach that permits an evaluation of "quality" for every event and makes the detection procedure much faster compared to a manual selection. In this article, the software has been applied to measure the binding strength between tubuline and microtubuline associated proteins.

Chances and limits of method restriction: a detailed analysis of suicide methods in Switzerland.

The objective of this study was to estimate the potential of method restriction as a public health strategy in suicide prevention. Data from the Swiss Federal Statistical Office and the Swiss Institutes of Forensic Medicine from 2004 were gathered and categorized into suicide submethods according to accessibility to restriction of means. Of suicides in Switzerland, 39.2% are accessible to method restriction. The highest proportions were found in private weapons (13.2%), army weapons (10.4%), and jumps from hot-spots (4.6%). The presented method permits the estimation of the suicide prevention potential of a country by method restriction and the comparison of restriction potentials between suicide methods. In Switzerland, reduction of firearm suicides has the highest potential to reduce the total number of suicides.

Do protein–protein interaction databases identify moonlighting proteins?

One of the most striking results of the human (and mammalian) genomes is the low number of protein-coding genes. To-date, the main molecular mechanism to increase the number of different protein isoforms and functions is alternative splicing. However, a less-known way to increase the number of protein functions is the existence of multifunctional, multitask, or ‘‘moonlighting’’, proteins. By and large, moonlighting proteins are experimentally disclosed by serendipity. Proteomics is becoming one of the very active areas of biomedical research, which permits researchers to identify previously unseen connections among proteins and pathways. In principle, protein–protein interaction (PPI) databases should contain information on moonlighting proteins and could provide suggestions to further analysis in order to prove the multifunctionality. As far as we know, nobody has verified whether PPI databases actually disclose moonlighting proteins. In the present work we check whether well-established moonlighting proteins present in PPI databases connect with their known partners and, therefore, a careful inspection of these databases could help to suggest their different functions. The results of our research suggest that PPI databases could be a valuable tool to suggest multifunctionality.