38 research outputs found

    A Meeting of Minds: In Recognition of the Contributions of Randall J. Cohrs

    Get PDF
    A Special Issue in memory of Randall J. Cohrs, Ph.D. Topics include original research reports on a variety of viruses as well as reviews and commentaries on Randy’s contributions to many investigations

    Texture and Colour in Image Analysis

    Get PDF
    Research in colour and texture has experienced major changes in the last few years. This book presents some recent advances in the field, specifically in the theory and applications of colour texture analysis. This volume also features benchmarks, comparative evaluations and reviews

    Merging the Real and the Virtual: An Exploration of Interaction Methods to Blend Realities

    Get PDF
    We investigate, build, and design interaction methods to merge the real with the virtual. An initial investigation looks at spatial augmented reality (SAR) and its effects on pointing with a real mobile phone. A study reveals a set of trade-offs between the raycast, viewport, and direct pointing techniques. To further investigate the manipulation of virtual content within a SAR environment, we design an interaction technique that utilizes the distance that a user holds mobile phone away from their body. Our technique enables pushing virtual content from a mobile phone to an external SAR environment, interact with that content, rotate-scale-translate it, and pull the content back into the mobile phone. This is all done in a way that ensures seamless transitions between the real environment of the mobile phone and the virtual SAR environment. To investigate the issues that occur when the physical environment is hidden by a fully immersive virtual reality (VR) HMD, we design and investigate a system that merges a realtime 3D reconstruction of the real world with a virtual environment. This allows users to freely move, manipulate, observe, and communicate with people and objects situated in their physical reality without losing their sense of immersion or presence inside a virtual world. A study with VR users demonstrates the affordances provided by the system and how it can be used to enhance current VR experiences. We then move to AR, to investigate the limitations of optical see-through HMDs and the problem of communicating the internal state of the virtual world with unaugmented users. To address these issues and enable new ways to visualize, manipulate, and share virtual content, we propose a system that combines a wearable SAR projector. Demonstrations showcase ways to utilize the projected and head-mounted displays together, such as expanding field of view, distributing content across depth surfaces, and enabling bystander collaboration. We then turn to videogames to investigate how spectatorship of these virtual environments can be enhanced through expanded video rendering techniques. We extract and combine additional data to form a cumulative 3D representation of the live game environment for spectators, which enables each spectator to individually control a personal view into the stream while in VR. A study shows that users prefer spectating in VR when compared with a comparable desktop rendering

    Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation - Volume II

    Get PDF
    Eukaryotic cells contain distinct membrane-bound organelles, which compartmentalize cellular proteins to fulfil a variety of vital functions. In contrast to being isolated and static entities (e.g., peroxisomes, mitochondria, lipid droplets), organelles rather display dynamic changes, interact with each other, share certain proteins and show metabolic cooperation and cross talk. Despite great advances in the identification and characterization of essential components and molecular mechanisms associated with the biogenesis and function of organelles, investigating how organelles interact and are incorporated into metabolic pathways and signaling networks has become a novel focus in the field of cellular biology. Organelle cooperation requires sophisticated targeting systems, which regulate the proper distribution of shared proteins to more than one organelle. Organelle motility and membrane remodeling support organelle interaction and contact. This contact can be mediated by membrane proteins residing on different organelles, which can serve as molecular tethers to physically link opposing membranes. They can also contribute to the exchange of metabolites and ions, or act in the assembly of signaling platforms. In this regard, organelle communication events have been associated with important cellular functions such as apoptosis, antiviral defense, organelle division/biogenesis, ROS metabolism and signaling, and various metabolic pathways such as synthesis and breakdown of lipids including cholesterol. In this Research Topic, we will focus on recent novel findings on the underlying molecular mechanisms and physiological significance of organelle interaction and cooperation with a particular focus on mitochondria, peroxisomes, endoplasmic reticulum, lysosomes and lipid droplets and their impact on the regulation of cellular homeostasis. Our understanding of how organelles physically interact and use cellular signaling systems to coordinate functional networks between each other is still far from being fully understood. Nevertheless, recent discoveries of defined membrane structures such as the mitochondria-ER associated membranes (MAM) are revealing how membrane domains enriched in specific proteins transmit signals across organelle boundaries, allowing one organelle to influence the function of another. In addition to its role as a mediator between mitochondria and the ER, contacts between the MAM and peroxisomes contribute to antiviral signaling, and specialized regions of the ER are supposed to initiate peroxisome biogenesis, whereas membrane contacts between peroxisomes, lipid droplets, lysosomes and the ER mediate lipid metabolism. A number of tethering complexes facilitating such contacts have been identified in recent years and more will likely follow in the near future. Additionally, the first human genetic disorders with mutations in tethering proteins have been reported. Despite these findings, the functional significance of most contact sites is still far from being understood and knowledge about the regulation of their formation and detachment is still scarce. Identifying the key molecular players of such specialized membrane structures is a prerequisite to understand how organelle communication is physically accomplished and will lead to the identification of new regulatory networks. Cytosolic messenger systems (e.g., kinase/phosphatase systems or redox signaling) may contribute to the general coordination of organelle communication but may also have a direct impact on the formation of tethering complexes. This Research Topic will integrate new findings from both modes of communication and will provide new perspectives for the functional significance of cross talk among organelles

    Monoclonal Antibodies and Their Functional Fragments in Research, Diagnosis and Therapy

    Get PDF
    This book is a compendium of scientific articles submitted to a Special Issue of International Journal of Molecular Sciences, fostered by MDPI and curated by Dr. Annamaria Sandomenico and Dr. Menotti Ruvo from the Institute of Biostructure and Bioimaging of the National Research Council. All articles underwent a rigorous peer review and were selected to highlight the properties that make monoclonal antibodies and their functional fragments some of the most useful and versatile assets in therapy and diagnosis

    Drug development progress in duchenne muscular dystrophy

    Get PDF
    Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space

    Recent Advances in Antibody Therapeutics

    Get PDF
    Since first receiving approval in 1986, antibody-based therapeutics have been the most successful modality for the treatment of various diseases. This Special Issue of IJMS, “Recent Advances in Antibody Therapeutics”, presents leading-edge articles and reviews for discovery, development, and clinical applications of therapeutic antibodies, covering antibody drug conjugates (ADCs), GPCR-targeting antibodies, a functional antibody screening, bioassay of bispecific antibodies, antibody applications for cardiovascular diseases, antibody delivery to CNS, etc. The excellent studies in this Special Issue would valuable insight for scientists and clinicians in the field of therapeutic antibodie

    Combination and integration to redirect NK cells for cancer immunotherapy

    Get PDF
    Cancer is a disease with still a high mortality. The number of new cases is still increasing globally despite current treatments. Therefore, new therapies with high specificity and efficiency to control the progress of cancer are urgently needed in the clinic. Nowadays, new cancer treatments emerged that are based on the immune system that have achieved encouraging outcomes. Together these modalities are called tumour immunotherapy. In this current PhD thesis, we have continued our group’s previous research on developing novel approaches for cancer immunotherapies are based on natural killer (NK) cells. This research demonstrated multiple methods to enhance the anti-tumour capacities of NK cells: 1) a combination with an anti-tumour antibody, 2) introduced an activation chimeric antigen receptor (CAR), 3) CRISPR/Cas9 genetic deletion of an inhibitory signal. These NK cell combinatorial approaches are ready for scale-up to be implemented into clinical treatments to the ultimate benefit of patients

    Mucopolysaccharidosis type IIIC : molecular defects and pathophysiological mechanism

    Full text link
    La mucopolysaccharidose de type IIIC (MPS IIIC), ou le syndrome de Sanfilippo type C, est une maladie pĂ©diatrique rare et grave, provoquant une dĂ©tĂ©rioration neurologique progressive, affectant initialement l'acquisition de la parole et le comportement, et conduisant finalement Ă  la dĂ©mence, aux dĂ©ficits moteurs et Ă  une mort prĂ©maturĂ©e. Des variants pathogĂ©niques dans le gĂšne HGSNAT sont responsables de la dĂ©ficience de l’enzyme hĂ©parane sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase impliquĂ©e dans le catabolisme lysosomal de l’hĂ©parane sulfate (HS). La connaissance limitĂ©e de la pathophysiologie de la maladie jusqu'Ă  prĂ©sent a empĂȘchĂ© le dĂ©veloppement de thĂ©rapies efficaces. Afin de mieux comprendre les mĂ©canismes pathogĂ©niques Ă  l'origine de la maladie, en particulier la neurodĂ©gĂ©nerescence progressive, nous avons caractĂ©risĂ© le premier modĂšle animal du syndrome de Sanfilippo type C, une souris Hgsnat Knockout (chapitre II). Nous avons montrĂ© que le modĂšle murin de MPS IIIC reproduit les Ă©tapes progressives de la maladie humaine. Les souris affectĂ©es prĂ©sentent une hyperactivitĂ© et une rĂ©duction de l’anxiĂ©tĂ© comme symptĂŽmes initiaux, suivis d’une dĂ©ficience de la mĂ©moire spatiale et de l’apprentissage, d’une dĂ©marche anormale Ă  un stade ultĂ©rieur de la maladie et une espĂ©rance de vie rĂ©duite. À travers cette Ă©tude, nous avons dĂ©montrĂ© que le dĂ©ficit en HGSNAT entraĂźne la surcharge de HS dans les lysosomes des microglies depuis le plus jeune Ăąge et dĂ©clenche une rĂ©ponse neuroinflammatoire chronique, caractĂ©risĂ©e par une micro- et astrogliose et la production de cytokines. Au niveau des neurones, l’accumulation d’HS est dĂ©tectĂ© plus tard et est accompagnĂ© de l'accumulation d’organelles dysfonctionnelles, y compris des mitochondries gonflĂ©es avec une structure anormale, ce qui entraĂźne probablement une dĂ©ficience du mĂ©tabolisme Ă©nergĂ©tique mitochondriale dans le cerveau des souris MPS IIIC. En outre, des niveaux accrus d'ubiquitine, LC3-II, des protĂ©ines tau phosphorylĂ©e et amyloĂŻde-ÎČ susceptibles Ă  l’agrĂ©gation, et des protĂ©ines modifiĂ©es par O-GlcNAc dans les neurones suggĂšrent une protĂ©olyse cellulaire dĂ©ficitaire. Nos rĂ©sultats suggĂšrent que l'accumulation de mitochondries endommagĂ©es peut largement contribuer Ă  la perte neuronale dĂ©tectĂ©e dans les souris MPS IIIC et serait la consĂ©quence d'une neuroinflammation chronique et d'un dĂ©ficit de la mitophagie. Dans le deuxiĂšme projet de cette thĂšse, nous avons Ă©tudiĂ© et caractĂ©risĂ© les dĂ©fauts gĂ©nĂ©tiques d’une large cohorte de nouveaux patients Sanfilippo C de diffĂ©rentes origines gĂ©ographiques, incluant des pays oĂč des patients n’avait jamais encore Ă©tĂ© identifiĂ©s (chapitre III). La caractĂ©risation molĂ©culaire de 27 nouveaux patients a permis, pour la premiĂšre fois, l'identification de variants pathogĂ©niques dans HGSNAT chez des patients du BrĂ©sil, d’AlgĂ©rie, d’AzerbaĂŻdjan et d’Iran et l'Ă©largissement du spectre mutationnel au Canada, la Colombie, la Turquie et les USA. De plus, nous avons identifiĂ© six nouveaux variants causant la maladie, montrant, Ă  travers des analyses in silico et d’études fonctionnelles in vitro, qu'ils interfĂšrent avec la production ou le repliement des protĂ©ines HGSNAT mutantes. Cette Ă©tude nous a aussi permis de diffĂ©rencier deux groupes de patients en fonction de l'apparition et de la progression de la maladie, potentiellement associĂ©s Ă  diffĂ©rents types de variants pathogĂ©niques. Enfin, l’analyse d’haplotypes portant sur le plus grand groupe de patients Ă©tudiĂ©s Ă  ce jour, 78 cas provenant de 22 pays diffĂ©rents, a rĂ©vĂ©lĂ© la mĂȘme origine pour plusieurs variants pathogĂ©niques du gĂšne HGSNAT dĂ©tectĂ©s dans diffĂ©rentes populations, et l'existence de plusieurs mutations fondatrices. En conclusion, la caractĂ©risation du premier modĂšle murin MPS IIIC a permis d'identifier diffĂ©rents mĂ©canismes physiopathologiques sous-jacents Ă  la maladie, qui peuvent reprĂ©senter des cibles thĂ©rapeutiques clĂ©s. Ce modĂšle animal est Ă©galement un outil utile pour l'Ă©valuation de l'efficacitĂ© de nouvelles thĂ©rapies. En outre, cette thĂšse a ainsi contribuĂ© Ă  la connaissance de la rĂ©partition gĂ©ographique et de la frĂ©quence des variants pathogĂ©niques du gĂšne HGSNAT et Ă  l'identification des effets fondateurs, ce qui peut contribuer Ă  un diagnostic prĂ©coce des patients atteints de MPS IIIC.Mucopolysaccharidosis III type C (MPS IIIC), or Sanfilippo syndrome type C, is a rare and severe pediatric disease causing progressive neurological deterioration, initially affecting speech acquisition and behavior, and ultimately leading to dementia, motor deficits and premature death. Pathogenic variants in the HGSNAT gene are responsible for the deficiency of heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulfate (HS). The limited knowledge of the pathophysiology of the disease has so far precluded the development of effective therapies. In order to understand the pathogenic mechanisms underlying the disease, in particular the neurodegenerative process, we have characterized the first animal model of Sanfilippo syndrome type C, an Hgsnat Knockout mouse (chapter II). We have shown that the MPS IIIC murine model recapitulates human disease progression, presenting hyperactivity and reduced anxiety as initial symptoms, followed by an impaired spatial memory and learning, abnormal gait at a later stage, and reduced lifespan. Through this study, we have demonstrated that HGSNAT deficiency leads to the storage of HS in brain microglial lysosomes from an early age, triggering a chronic neuroinflammatory response characterized by micro- and astrogliosis and cytokine production. In neurons, the storage of HS is detected at a later stage and it is accompanied by the accumulation of dysfunctional organelles, including swollen, structurally abnormal mitochondria, likely responsible for the impaired mitochondrial energy metabolism in the brain of MPS IIIC mice. Furthermore, augmented levels of intraneuronal ubiquitin, LC3-II, the aggregate prone-proteins phosphorylated tau and amyloid-ÎČ, and O-GlcNAc-modified proteins are suggestive of a defective cellular proteolysis. Altogether, our findings suggest that accumulation of damaged mitochondria is the consequence of chronic neuroinflammation and mitophagy impairment, and may largely contribute to the neuronal loss detected in MPS IIIC mice. In the second project of this thesis, we investigated and characterized the molecular defects in a large cohort of new Sanfilippo C patients from different geographic origins, including countries where MPS IIIC patients had not yet been reported (chapter III). The molecular characterization of the 27 new patients enabled, for the first time, the identification of HGSNAT disease‐causing variants in patients from Brazil, Algeria, Azerbaijan, and Iran and to extend their spectrum within Canada, Colombia, Turkey and the USA. Besides, we have identified six novel pathogenic variants showing, through in silico and in vitro functional studies, that they interfere with the production or folding of the resulting HGSNAT mutant proteins. This study also allowed the differentiation of two groups of patients based on the onset and progression of the disease, potentially associated to different types of pathogenic variants. Finally, a haplotype study on the largest group of patients studied so far, 78 cases from 22 different countries, revealed the same origin for several HGSNAT pathogenic variants detected in different populations, and the existence of several founder mutations. In conclusion, the characterization of the first MPS IIIC murine model enabled the identification of different pathophysiological mechanisms underlying the disease, which may represent key therapeutic targets. This animal model is also a useful tool for the evaluation of the effectiveness of novel therapies. Furthermore, this thesis has also contributed to the knowledge of the worldwide geographic distribution and frequency of HGSNAT disease-causing variants, and the identification of founder effects, which may contribute to an early diagnosis of MPS IIIC patients
    corecore