Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene.

We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Gestão Documental: Gestão de Processos de Aposentação usando a Plataforma IBM FileNet na Direcção Geral de Administração Pública

Ainda, nos nossos dias, o papel como sendo base de suporte das informações, é o maior problema operacional na maioria das empresas, órgãos governamentais e instituições. A administração pública cabo-verdiana lida anualmente com um grande volume de documentos e, a dificuldade de se lidar cada vez mais com os documentos produzidos é crescente. Daí, a necessidade de estabelecer princípios de racionalidade administrativa, a partir da intervenção nas etapas do ciclo de produção, utilização, conservação e destinação dos documentos de arquivo - a Gestão Documental. Com a evolução das Tecnologias da Informação e Comunicação (TIC) é contínua, igualmente a gestão da informação precisa adaptar-se a cada nova onda de mudança. A utilização de sistemas de gestão de conteúdos e de processos constituem ferramentas indispensáveis para o desenvolvimento de modernos sistemas de informação, agilizando assim os processos críticos nas instituições, de forma a optimizar o binómio produtividade - qualidade. Este trabalho faz referência à utilização da IBM FileNet, para modelação do processo de pedido de aposentação na Administração Pública. Ficou comprovado que o sistema de gestão de Workflow - Bussiness Process Management (BPM) da IBM, é capaz de automatizar o procedimento dos processos, gerir a sequência de actividades de trabalho e chamar (ou invocar) os recursos humanos e electrónicos apropriados, associados aos vários passos de actividades numa instituição. As evidências da plataforma FileNet como solução de Gestão de Conteúdos, e Gestão de Processos na nossa Administração Pública, demonstram vantagens consideráveis em todos os níveis. Para além de dinamizar e automatizar os processos críticos, o FileNet BPM pode permitir a optimização das operações e melhorar a capacidade de tomar decisões rápidas e acertadas, capacitando a instituição, para tomar decisões atempadas, baseadas na mais rigorosa informação disponível.

Intraoperative angiography reloaded: a new hybrid operating theater for combined endovascular and surgical treatment of cerebral arteriovenous malformations: a pilot study on 25 patients.

BACKGROUND: Multimodality treatment suites for patients with cerebral arteriovenous malformations (AVM) have recently become available. This study was designed to evaluate feasibility, safety and impact on treatment of a new intraoperative flat-panel (FP) based integrated surgical and imaging suite for combined endovascular and surgical treatment of cerebral AVM. METHODS: Twenty-five patients with AVMs to treat with combined endovascular and surgical interventions were prospectively enrolled in this consecutive case series. The hybrid suite allows combined endovascular and surgical approaches with intraoperative scanner-like imaging (XperCT®) and intraoperative 3D rotational angiography (3D-RA). The impact of intraoperative multimodal imaging on feasibility, workflow of combined interventions, surgery, and unexpected imaging findings were analyzed. RESULTS: Twenty-five patients (mean age 38 ± 18.6 year) with a median Spetzler-Martin grade 2 AVM (range 1-4) underwent combined endovascular and surgical procedures. Sixteen patients presented with a ruptured AVM and nine with an unruptured AVM. In 16 % (n = 4) of cases, intraoperative imaging visualized AVM remnants ≤3 mm and allowed for completion of the resections in the same sessions. Complete resection was confirmed in all n = 16 patients who had follow-up angiography one year after surgery so far. All diagnostic and therapeutical steps, including angiographic control, were performed without having to move the patients CONCLUSION: The hybrid neurointerventional suite was shown to be a safe and useful setup which allowed for unconstrained combined microsurgical and neuroradiological workflow. It reduces the need for extraoperative angiographic controls and subsequent potential surgical revisions a second time, as small AVM remnants can be detected with high security.

3D seismic facies characterization and geological patterns recognition (Australian North West Shelf)

EXECUTIVE SUMMARY This PhD research, funded by the Swiss Sciences Foundation, is principally devoted to enhance the recognition, the visualisation and the characterization of geobodies through innovative 3D seismic approaches. A series of case studies from the Australian North West Shelf ensures the development of reproducible integrated 3D workflows and gives new insight into local and regional stratigraphic as well as structural issues. This project was initiated in year 2000 at the Geology and Palaeontology Institute of the University of Lausanne (Switzerland). Several collaborations ensured the improvement of technical approaches as well as the assessment of geological models. - Investigations into the Timor Sea structural style were carried out at the Tectonics Special Research Centre of the University of Western Australia and in collaboration with Woodside Energy in Perth. - Seismic analysis and attributes classification approach were initiated with Schlumberger Oilfield Australia in Perth; assessments and enhancements of the integrated seismic approaches benefited from collaborations with scientists from Schlumberger Stavanger Research (Norway). Adapting and refining from "linear" exploration techniques, a conceptual "helical" 3D seismic approach has been developed. In order to investigate specific geological issues this approach, integrating seismic attributes and visualisation tools, has been refined and adjusted leading to the development of two specific workflows: - A stratigraphic workflow focused on the recognition of geobodies and the characterization of depositional systems. Additionally, it can support the modelling of the subsidence and incidentally the constraint of the hydrocarbon maturity of a given area. - A structural workflow used to quickly and accurately define major and secondary fault systems. The integration of the 3D structural interpretation results ensures the analysis of the fault networks kinematics which can affect hydrocarbon trapping mechanisms. The application of these integrated workflows brings new insight into two complex settings on the Australian North West Shelf and ensures the definition of astonishing stratigraphic and structural outcomes. The stratigraphic workflow ensures the 3D characterization of the Late Palaeozoic glacial depositional system on the Mermaid Nose (Dampier Subbasin, Northern Carnarvon Basin) that presents similarities with the glacial facies along the Neotethys margin up to Oman (chapter 3.1). A subsidence model reveals the Phanerozoic geodynamic evolution of this area (chapter 3.2) and emphasizes two distinct mode of regional extension for the Palaeozoic (Neotethys opening) and Mesozoic (abyssal plains opening). The structural workflow is used for the definition of the structural evolution of the Laminaria High area (Bonaparte Basin). Following a regional structural characterization of the Timor Sea (chapter 4.1), a thorough analysis of the Mesozoic fault architecture reveals a local rotation of the stress field and the development of reverse structures (flower structures) in extensional setting, that form potential hydrocarbon traps (chapter 4.2). The definition of the complex Neogene structural architecture associated with the fault kinematic analysis and a plate flexure model (chapter 4.3) suggest that the Miocene to Pleistocene reactivation phases recorded at the Laminaria High most probably result from the oblique normal reactivation of the underlying Mesozoic fault planes. This episode is associated with the deformation of the subducting Australian plate. Based on these results three papers were published in international journals and two additional publications will be submitted. Additionally this research led to several communications in international conferences. Although the different workflows presented in this research have been primarily developed and used for the analysis of specific stratigraphic and structural geobodies on the Australian North West Shelf, similar integrated 3D seismic approaches will have applications to hydrocarbon exploration and production phases; for instance increasing the recognition of potential source rocks, secondary migration pathways, additional traps or reservoir breaching mechanisms. The new elements brought by this research further highlight that 3D seismic data contains a tremendous amount of hidden geological information waiting to be revealed and that will undoubtedly bring new insight into depositional systems, structural evolution and geohistory of the areas reputed being explored and constrained and other yet to be constrained. The further development of 3D texture attributes highlighting specific features of the seismic signal, the integration of quantitative analysis for stratigraphic and structural processes, the automation of the interpretation workflow as well as the formal definition of "seismo-morphologic" characteristics of a wide range of geobodies from various environments would represent challenging examples of continuation of this present research. The 21st century will most probably represent a transition period between fossil and other alternative energies. The next generation of seismic interpreters prospecting for hydrocarbon will undoubtedly face new challenges mostly due to the shortage of obvious and easy targets. They will probably have to keep on integrating techniques and geological processes in order to further capitalise the seismic data for new potentials definition. Imagination and creativity will most certainly be among the most important quality required from such geoscientists.

Genome-wide arrays in routine diagnostics of hematological malignancies.

Over the last three decades, cytogenetic analysis of malignancies has become an integral part of disease evaluation and prediction of prognosis or responsiveness to therapy. In most diagnostic laboratories, conventional karyotyping, in conjunction with targeted fluorescence in situ hybridization analysis, is routinely performed to detect recurrent aberrations with prognostic implications. However, the genetic complexity of cancer cells requires a sensitive genome-wide analysis, enabling the detection of small genomic changes in a mixed cell population, as well as of regions of homozygosity. The advent of comprehensive high-resolution genomic tools, such as molecular karyotyping using comparative genomic hybridization or single-nucleotide polymorphism microarrays, has overcome many of the limitations of traditional cytogenetic techniques and has been used to study complex genomic lesions in, for example, leukemia. The clinical impact of the genomic copy-number and copy-neutral alterations identified by microarray technologies is growing rapidly and genome-wide array analysis is evolving into a diagnostic tool, to better identify high-risk patients and predict patients' outcomes from their genomic profiles. Here, we review the added clinical value of an array-based genome-wide screen in leukemia, and discuss the technical challenges and an interpretation workflow in applying arrays in the acquired cytogenetic diagnostic setting.

Electronic Construction Collaboration System – Phase III, December 2011

This phase of the electronic collaboration project involved two major efforts: 1) implementation of AEC Sync (formerly known as Attolist), a web-based project management system (WPMS), on the Broadway Viaduct Bridge Project and the Iowa Falls Arch Bridge Project and 2) development of a web-based project management system for bridge and highway construction projects with less than $10 million in contract value. During the previous phase of this project (fiscal year 2010), the research team helped with the implementation process for AEC Sync and collected feedback from the Broadway Viaduct project team members before the start of the project. During the 2011 fiscal year, the research team collected the post-project surveys from the Broadway Viaduct project members and compared them to the pre-project survey results. The results of the AEC Sync implementation on the Broadway project were positive. The project members were satisfied with the performance of the AEC Sync software and how it facilitated document management and its transparency. In addition, the research team distributed, collected, and analyzed the pre-project surveys for the Iowa Falls Arch Bridge Project. The implementation of AEC Sync for the Iowa Falls Arch Bridge Project appears to also be positive, based on the pre-project surveys. The fourth phase of this electronic collaboration project involves the identification and implementation of a WPMS solution for smaller bridge and highway projects. The workflow for the shop drawing approval process for sign truss projects was documented and used to identify possible WPMS solutions. After testing and evaluating several WPMS solutions, Microsoft SharePoint Foundation’s site pages were selected to be pilot-tested on sign truss projects. Due to the limitation on the SharePoint license that the Iowa Department of Transportation (DOT) has, a file transfer protocol (FTP) site will be developed alongside this site to allow contractors to upload shop drawings to the Iowa DOT. The SharePoint site pages are expected to be ready for implementation during the 2012 calendar year.

Maintenance Asset Management Project -- Phase II, July 31, 2013

Expanded abstract: Iowa Department of Transportation (IA DOT) is finalizing research to streamline field inventory/inspection of culverts by Maintenance and Construction staff while maximizing the use of tablet technologies. The project began in 2011 to develop some new best practices for field staff to assist in the inventory, inspection and maintenance of assets along the roadway. The team has spent the past year working through the complexities of identifying the most appropriate tablet hardware for field data collection. A small scale deployment of tablets occurred in spring of 2013 to collect several safety related assets (culverts, signs, guardrail, and incidents). Data can be collected in disconnected or connected modes and there is an associated desktop environment where data can be viewed and queried after being synced into the master database. The development of a deployment plan and related workflow processes are underway; which will eventually feed information into IA DOTs larger asset management system and make the information available for decision making. The team is also working with the IA DOT Design Office on Computer Aided Drafting (CAD) data processing and the IA DOT Construction office with a new digital As-Built plan process to leverage the complete data life-cycle so information can be developed once and leveraged by the Maintenance staff farther along in the process.

Identification of human IKK-2 inhibitors of natural origin (Part II): in Silico prediction of IKK-2 inhibitors in natural extracts with known anti-inflammatory activity.

Human inhibitor NF-κB kinase 2 (hIKK-2) is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Thus, synthetic ATP-competitive inhibitors for hIKK-2 have been developed as anti-inflammatory compounds. We recently reported a virtual screening protocol (doi:10.1371/journal.pone.0016903) that is able to identify hIKK-2 inhibitors that are not structurally related to any known molecule that inhibits hIKK-2 and that have never been reported to have anti-inflammatory activity. In this study, a stricter version of this protocol was applied to an in-house database of 29,779 natural products annotated with their natural source. The search identified 274 molecules (isolated from 453 different natural extracts) predicted to inhibit hIKK-2. An exhaustive bibliographic search revealed that anti-inflammatory activity has been previously described for: (a) 36 out of these 453 extracts; and (b) 17 out of 30 virtual screening hits present in these 36 extracts. Only one of the remaining 13 hit molecules in these extracts shows chemical similarity with known synthetic hIKK-2 inhibitors. Therefore, it is plausible that a significant portion of the remaining 12 hit molecules are lead-hopping candidates for the development of new hIKK-2 inhibitors.

A 3 years retrospective study of survival for zirconia-based single crowns fabricated from intraoral digital impressions.

OBJECTIVE: To evaluate the clinical performance of glass-ceramic/zirconia crowns fabricated using intraoral digital impressions - a retrospective study with a three-year follow-up. METHODS: 70 consecutive patients with a total of 86 glass-ceramic/zirconia crowns were treated by a single clinician using standardized clinical and laboratory protocols. A complete digital workflow was adopted for the purpose except for the veneering procedure for the glass-ceramic crowns. Occlusal adjustments were made before the ceramic glazing procedure. Before cementation, all abutments where carefully cleaned with a 70% alcoholic solution and air dried. Cementation was performed using dual-curing, self-adhesive resin cement. Patients were re-examined after 12, 24 and 36 months, to assess crown chipping/fractures. RESULTS: After the three-year follow-up, none of the zirconia-based restoration was lost ("apparent" survival rate 100%) otherwise, the chipping rate of the veneering material increased from 9.3% after 12 months, to 14% after 24 months to 30.2% after 36 months. As a consequence, the "real" success rate after 3 years was 69.8%. CONCLUSIONS: After 3 years the success rate of zirconia-based crowns was 69.8%, while the incidence of the chipping was 30.2%. Assuming an exponential increase in chipping rate between 12 and 36 months it can be argued that, among others, the fatigue-mechanism could be advocated as the main factor for the failure of glass-ceramic veneered zirconia especially after 24 months.

An efficient algorithm to perform multiple testing in epistasis screening

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. Gene-gene interaction studies will require a memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MBMDR-3.0.3. We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn’s disease. Results: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999 permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four Quad-Core AMD Opteron(tm) Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn’s disease (CD) data. Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the context of Crohn’s disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype higher-order associations.

Practical considerations for improving the productivity of mass spectrometry-based proteomics.

Mass spectrometry (MS) is currently the most sensitive and selective analytical technique for routine peptide and protein structure analysis. Top-down proteomics is based on tandem mass spectrometry (MS/ MS) of intact proteins, where multiply charged precursor ions are fragmented in the gas phase, typically by electron transfer or electron capture dissociation, to yield sequence-specific fragment ions. This approach is primarily used for the study of protein isoforms, including localization of post-translational modifications and identification of splice variants. Bottom-up proteomics is utilized for routine high-throughput protein identification and quantitation from complex biological samples. The proteins are first enzymatically digested into small (usually less than ca. 3 kDa) peptides, these are identified by MS or MS/MS, usually employing collisional activation techniques. To overcome the limitations of these approaches while combining their benefits, middle-down proteomics has recently emerged. Here, the proteins are digested into long (3-15 kDa) peptides via restricted proteolysis followed by the MS/MS analysis of the obtained digest. With advancements of high-resolution MS and allied techniques, routine implementation of the middle-down approach has been made possible. Herein, we present the liquid chromatography (LC)-MS/MS-based experimental design of our middle-down proteomic workflow coupled with post-LC supercharging.

Automatic quality assessment in structural brain magnetic resonance imaging

MRI has evolved into an important diagnostic technique in medical imaging. However, reliability of the derived diagnosis can be degraded by artifacts, which challenge both radiologists and automatic computer-aided diagnosis. This work proposes a fully-automatic method for measuring image quality of three-dimensional (3D) structural MRI. Quality measures are derived by analyzing the air background of magnitude images and are capable of detecting image degradation from several sources, including bulk motion, residual magnetization from incomplete spoiling, blurring, and ghosting. The method has been validated on 749 3D T(1)-weighted 1.5T and 3T head scans acquired at 36 Alzheimer's Disease Neuroimaging Initiative (ADNI) study sites operating with various software and hardware combinations. Results are compared against qualitative grades assigned by the ADNI quality control center (taken as the reference standard). The derived quality indices are independent of the MRI system used and agree with the reference standard quality ratings with high sensitivity and specificity (>85%). The proposed procedures for quality assessment could be of great value for both research and routine clinical imaging. It could greatly improve workflow through its ability to rule out the need for a repeat scan while the patient is still in the magnet bore.

Decision-theoretic reflections on processing a fingermark

A recent publication in this journal [Neumann et al., Forensic Sci. Int. 212 (2011) 32-46] presented the results of a field study that revealed the data provided by the fingermarks not processed in a forensic science laboratory. In their study, the authors were interested in the usefulness of this additional data in order to determine whether such fingermarks would have been worth submitting to the fingermark processing workflow. Taking these ideas as a starting point, this communication here places the fingermark in its context of a case brought before a court, and examines the question of processing or not processing a fingermark from a decision-theoretic point of view. The decision-theoretic framework presented provides an answer to this question in the form of a quantified expression of the expected value of information (EVOI) associated with the processed fingermark, which can then be compared with the cost of processing the mark.

Service Management for Service Desk

Palvelunhallinnan kehittäminen Service Desk ympäristöön johtaa parempaan työnkulun hallintaan. Service Deskin päätehtävänä on toimia ainoana yhteyspisteenä asiakkaalta tietohallinto-osastolle. Jokainen yhteydenottopitää kirjata ja se pitäisi olla jäljitettävissä. Tapahtumien eli insidenttien kirjaaminen tapahtuu pääasiassa Service Desk -funktiossa, joka omistaa niistä jokaisen. Tapahtumien hallintaprosessin tehtävänä on etsiä loppukäyttäjän tai IT-infrastruktuurin monitorointityökalun ilmoittamalle insidentille mahdollisimman nopea ratkaisu. Insidentit saattavat johtaa ongelmiin, jotka käsitellään erillisessä prosessissa. Ongelmien hallintaprosessi yrittää etsiä vikatilanteen pohjimmaisen syyn. Kun pohjimmaisin syy on löytynyt, prosessi lähettää muutospyynnön muutosten hallintaprosessille. Jotta päästään mahdollisimman hyvään tehokkuuteen, pitää määrittää asiakasrajapinta sekä mittarit. ITIL-malli tarjoaa prosessit IT-palvelunhallinnan kehittämiselle. Kansainvälisesti tunnettuna 'de factO' standardina sitä voidaan soveltaa globaaleissa yrityksissä. Tässä työssä keskitytään erään lääkkeiden jakelussa toimivan yrityksen tietohallinto-osaston Help Deskin nykytilan määrittämiseen. Työssä myös kuvataan tietohallinto-osaston tavoitetila, jossa keskitytään Service Deskin IT palvelunhallinnan kehittämiseen. Muut prosessit ja mittarit on kuvattu niiltä osin, jotka tulee huomioida Service Deskin seuraamisen ja ohjaamisen kannalta.

Ohutlevyn taivuttaminen pienerätuotannossa

Tutkimuksessa on selvitetty ohutlevyn taivuttamismenetelmien tärkeimmät kustannustekijät ja menetelmien taloudelliset käyttöalueet. Vertailtavina menetelminä on käsinsärmäys, robotisoitu särmäys, taivutusautomaatti ja taivutuskone. Tulosta on sovellettu Hackman Metos Oy:n keittiölaitteiden tuotantoon. Tutkimusmenetelminä oli haastattelututkimus, kirjallisuustutkimus, työntutkimustulosten käyttö, ryhmäteknologian soveltaminen ja kokeellinen tutkimus. Särmäysrobotin tärkein kustannustekijä on ohjelmointiaika, mikä vaikuttaa ratkaisevasti sen soveltuvuuteen pienerätuotantoon. Nykyisten särmäyssolujen taloudellinen käyttöalue on tuhansien kappaleiden vuosivolyymi satojen kappaleiden eräkoolla. taivutusautomaatin ohjelmointi- ja asetusajat ovat erittäin lyhyet ja sen tärkein kustannustekijä on käyttöaste. Mikäli käyttöaste on korkea, taivutusautomaatti on kannattava pienerätuotannossa pienille vuosivolyymeille. Taivutusautomaatin käyttöönotossa tuotteiden suunnittelu on tärkeä tekijä, sillä särmättäväksi suunnitellut osat eivät välttämättä sovellu taivutusautomaatilla taivutettavaksi. Taivutuskoneen investointikustannus on alhaisempi kuin särmäyspuristimen, mutta sillä on paljon tuotteen valmistettavuuden liittyviä rajoituksia. Taivutuskone on kannattava investointi, mikäli tuotannossa on paljon levyjä, joiden taivutukset ovat samaan suuntaan ja ne vaativat kaksi särmääjää. Tutkimuksen perusteella Hackman Metso Oy:ssä teknis-taloudellisin taivutusmenetelmä on käsinsärmäys. Tuotannon kasvaessa taivutusautomaatti tulee olemaan särmäysrobottia edullisempi. Taivutuskoneella on niin paljon valmistettavuusrajoituksia, että se ei sovellu yrityksen tuotantoon.