15,202 research outputs found

    Shuffled ATG8 interacting motifs form an ancestral bridge between UFMylation and autophagy

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    UFMylation involves the covalent modification of substrate proteins with UFM1 (Ubiquitin‐fold modifier 1) and is important for maintaining ER homeostasis. Stalled translation triggers the UFMylation of ER‐bound ribosomes and activates C53‐mediated autophagy to clear toxic polypeptides. C53 contains noncanonical shuffled ATG8‐interacting motifs (sAIMs) that are essential for ATG8 interaction and autophagy initiation. However, the mechanistic basis of sAIM‐mediated ATG8 interaction remains unknown. Here, we show that C53 and sAIMs are conserved across eukaryotes but secondarily lost in fungi and various algal lineages. Biochemical assays showed that the unicellular alga Chlamydomonas reinhardtii has a functional UFMylation pathway, refuting the assumption that UFMylation is linked to multicellularity. Comparative structural analyses revealed that both UFM1 and ATG8 bind sAIMs in C53, but in a distinct way. Conversion of sAIMs into canonical AIMs impaired binding of C53 to UFM1, while strengthening ATG8 binding. Increased ATG8 binding led to the autoactivation of the C53 pathway and sensitization of Arabidopsis thaliana to ER stress. Altogether, our findings reveal an ancestral role of sAIMs in UFMylation‐dependent fine‐tuning of C53‐mediated autophagy activation

    Monocular 3D Human Pose Estimation for Sports Broadcasts using Partial Sports Field Registration

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    The filming of sporting events projects and flattens the movement of athletes in the world onto a 2D broadcast image. The pixel locations of joints in these images can be detected with high validity. Recovering the actual 3D movement of the limbs (kinematics) of the athletes requires lifting these 2D pixel locations back into a third dimension, implying a certain scene geometry. The well-known line markings of sports fields allow for the calibration of the camera and for determining the actual geometry of the scene. Close-up shots of athletes are required to extract detailed kinematics, which in turn obfuscates the pertinent field markers for camera calibration. We suggest partial sports field registration, which determines a set of scene-consistent camera calibrations up to a single degree of freedom. Through joint optimization of 3D pose estimation and camera calibration, we demonstrate the successful extraction of 3D running kinematics on a 400m track. In this work, we combine advances in 2D human pose estimation and camera calibration via partial sports field registration to demonstrate an avenue for collecting valid large-scale kinematic datasets. We generate a synthetic dataset of more than 10k images in Unreal Engine 5 with different viewpoints, running styles, and body types, to show the limitations of existing monocular 3D HPE methods. Synthetic data and code are available at https://github.com/tobibaum/PartialSportsFieldReg_3DHPE.Comment: accept at "9th International Workshop on Computer Vision in Sports (CVsports) at CVPR 2023

    Four Lectures on the Random Field Ising Model, Parisi-Sourlas Supersymmetry, and Dimensional Reduction

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    Numerical evidence suggests that the Random Field Ising Model loses Parisi-Sourlas SUSY and the dimensional reduction property somewhere between 4 and 5 dimensions, while a related model of branched polymers retains these features in any dd. These notes give a leisurely introduction to a recent theory, developed jointly with A. Kaviraj and E. Trevisani, which aims to explain these facts. Based on the lectures given in Cortona and at the IHES in 2022.Comment: 55 pages, 11 figures; v2 - minor changes, mentioned forthcoming work by Fytas et a

    Neuroanatomical and gene expression features of the rabbit accessory olfactory system. Implications of pheromone communication in reproductive behaviour and animal physiology

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    Mainly driven by the vomeronasal system (VNS), pheromone communication is involved in many species-specific fundamental innate socio-sexual behaviors such as mating and fighting, which are essential for animal reproduction and survival. Rabbits are a unique model for studying chemocommunication due to the discovery of the rabbit mammary pheromone, but paradoxically there has been a lack of knowledge regarding its VNS pathway. In this work, we aim at filling this gap by approaching the system from an integrative point of view, providing extensive anatomical and genomic data of the rabbit VNS, as well as pheromone-mediated reproductive and behavioural studies. Our results build strong foundation for further translational studies which aim at implementing the use of pheromones to improve animal production and welfare

    Procedure-Aware Pretraining for Instructional Video Understanding

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    Our goal is to learn a video representation that is useful for downstream procedure understanding tasks in instructional videos. Due to the small amount of available annotations, a key challenge in procedure understanding is to be able to extract from unlabeled videos the procedural knowledge such as the identity of the task (e.g., 'make latte'), its steps (e.g., 'pour milk'), or the potential next steps given partial progress in its execution. Our main insight is that instructional videos depict sequences of steps that repeat between instances of the same or different tasks, and that this structure can be well represented by a Procedural Knowledge Graph (PKG), where nodes are discrete steps and edges connect steps that occur sequentially in the instructional activities. This graph can then be used to generate pseudo labels to train a video representation that encodes the procedural knowledge in a more accessible form to generalize to multiple procedure understanding tasks. We build a PKG by combining information from a text-based procedural knowledge database and an unlabeled instructional video corpus and then use it to generate training pseudo labels with four novel pre-training objectives. We call this PKG-based pre-training procedure and the resulting model Paprika, Procedure-Aware PRe-training for Instructional Knowledge Acquisition. We evaluate Paprika on COIN and CrossTask for procedure understanding tasks such as task recognition, step recognition, and step forecasting. Paprika yields a video representation that improves over the state of the art: up to 11.23% gains in accuracy in 12 evaluation settings. Implementation is available at https://github.com/salesforce/paprika.Comment: CVPR 202

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 β chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IκB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de referência para doentes com estenose aórtica e visa a eliminação da sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica. Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os mecanismos biológicos subjacentes a uma remodelagem reversa incompleta ainda não são claros. Além disso, não dispomos de ferramentas de prognóstico definitivos nem de terapias auxiliares para melhorar a condição dos pacientes indicados para substituição da válvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica para a caracterização, respetivamente, do miocárdio e do líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas desreguladas foram detetadas. As análises de anotação de genes, de enriquecimento de vias celulares e discriminativa corroboram um cenário de aumento da expressão de genes pro-hipertróficos e de síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos apontou para a cadeia β do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma, sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição dos pacientes indicados para intervenção. Em particular, a avaliação funcional de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver força (tensão ativa). Este estudo levanta várias hipóteses na investigação da remodelagem reversa. No futuro, estudos de ganho e/ou perda de função realizados em cardiomiócitos isolados ou em modelos animais de banding-debanding da aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos encontrados. Além disso, estudos clínicos em coortes de maior dimensão trarão conclusões definitivas quanto ao valor de prognóstico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    Exploring experiences of ‘inclusive’ education in international schools from the perspective of parents who have children labeled with SEN/D

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    This thesis reports on a study that explored experiences of ‘inclusive’ education in international schools from the perspective of parents who have children labeled with SEN/D. I interviewed ten parents who had enrolled their child with an SEN/D label in an international school in Amman, Jordan. I analyzed this data within a critical disability studies theoretical framework to highlight the relations to neoliberalism, neocolonialism, and ableism. This approach enabled an analysis of how parents revealed support for different ideas within disability studies. This analysis highlighted their contradictions and resistance to previous understandings of disability, inclusion, and SEN/D. I analyzed the data in relation to literature from three distinct fields of scholarship: disability studies, international schooling, and school choice literature. By bringing together these three divergent fields, a novel and significant contribution to knowledge forms. The purpose of bringing together these three fields, and completing this study using a critical disability studies theoretical framework, was to highlight the unique concerns of parents of children labeled with SEN/D within the international school market and the formative processes these parents experience in relation to their desire to school their children across ‘inclusive’ international schools. The findings from the study indicate that while parents of SEN/D children do experience exclusion repeatedly across multiple international schools which market themselves as ‘inclusive,’ they largely accept this as part of the process and believe that exclusion was a necessary part of international schools being inclusive

    Substrate-specificity of the DNA-protein crosslink repair protease SPRTN

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    Registration accuracy of the optical navigation system for image-guided surgery

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    Abstract. During the last decades, image-guided surgery has been a vastly growing method during medical operations. It provides a new opportunity to perform surgical operations with higher accuracy and reliability than before. In image-guided surgery, a navigation system is used to track the instrument’s location and orientation during the surgery. These navigation systems can track the instrument in many ways, the most common of which are optical tracking, mechanical tracking, and electromagnetic tracking. Usually, the navigation systems are used primarily in surgical operations located in the head and spine area. For this reason, it is essential to know the registration accuracy and thus the navigational accuracy of the navigation system, and how different registration methods might affect them. In this research, the registration accuracy of the optical navigation system is investigated by using a head phantom whose coordinate values of holes in the surface are measured during the navigation after different registration scenarios. Reference points are determined using computed tomography images taken from the head phantom. The absolute differences of the measured points to the corresponding reference points are calculated and the results are illustrated using bar graphs and three-dimensional point clouds. MATLAB is used to analyze and present the results. Results show that registration accuracy and thus also navigation accuracy are primarily affected by how the first three registration points are determined for the navigation system at the beginning of the registration. This should be considered in future applications where the navigation system is used in image-guided surgery.Kuvaohjatun kirurgian optisen navigointilaitteen rekisteröintitarkkuus. Tiivistelmä. Viimeisten vuosikymmenien aikana kuvaohjattu kirurgia on yleistynyt laajalti lääketieteellisten toimenpiteiden aikana ja se tarjoaa entistä paremman mahdollisuuden tarkkaan ja luotettavaan hoitoon. Kuvaohjatussa kirurgiassa navigointilaitteisto seuraa käytetyn instrumentin paikkaa ja orientaatiota operaation aikana. Navigointilaitteistoilla on erilaisia toimintaperiaatteita, joiden perusteella ne seuraavat instrumenttia. Yleisimmin käytetyt navigointilaitteistot perustuvat optiseen, mekaaniseen, tai sähkömagneettiseen seurantaan. Yleensä kuvaohjattua kirurgiaa käytetään pään ja selkärangan alueen kirurgisissa operaatioissa, joten on erittäin tärkeää, että navigointilaitteiston rekisteröinti- ja siten myös navigointitarkkuus tunnetaan, sekä erilaisten rekisteröintitapojen mahdolliset vaikutukset kyseisiin tarkkuuksiin. Tässä tutkimuksessa optisen navigointilaitteen rekisteröintitarkkuutta tutkitaan päämallin avulla, jonka pintaan luotujen reikien koordinaattiarvot mitataan navigointitilanteessa erilaisten rekisteröintitapojen jälkeen. Referenssipisteet kyseisille mittauspisteille määritetään päämallin tietokonetomografiakuvista. Mitattujen pisteiden, sekä vastaavien referenssipisteiden väliset absoluuttiset erot lasketaan ja tulokset esitetään palkkikuvaajien, sekä kolmiulotteisten pistepilvien avulla käyttäen apuna MATLAB-ohjelmistoa. Tulokset osoittavat, että rekisteröintitarkkuuteen ja siten navigointitarkkuuteen vaikuttaa eniten rekisteröintitilanteen alussa määritettävien kolmen ensimmäisen rekisteröintipisteen sijainti ja tämä tuleekin ottaa huomioon jatkossa tilanteissa, joissa navigointilaitetta käytetään kuvaohjatussa kirurgiassa
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