The emergence and improvement of Additive Manufacturing technologies allow the fabrication of complex shapes so far inconceivable. However, to produce those intricate geometries, support structures ...are required. Besides wasting unnecessary material, these structures are consuming valuable production and post-processing times. This paper proposes a new framework to optimize the geometry and topology of inner and outer support structures. Starting from a uniform lattice structure filling both the inner and outer areas to be supported, the approach removes a maximum number of beams so as to minimize the volume of the support. The most suited geometry for the initial lattice structure is defined at the beginning considering the possibilities of the manufacturing technologies. Then, the pruning of the structure is performed through a genetic algorithm, for which the control parameters values have been tuned through a design of experiments. The proposed approach is validated on several test cases of various geometries, containing both inner and outer areas to be supported. The generated support structures are compared to the ones obtained by several state-of-the-art support structure strategies and are proved to have lower material consumption.
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•A framework generating aperiodic, low volume support structures is proposed.•A lattice is optimized to create these supports.•A Genetic Algorithm (GA) finds a solution to a Directed Steiner Tree (DST) problem.•The parameters of the GA have been tuned through a Design of Experiments (DoE).•These supports are proved to have a low volume in comparison to other supports.
Adeno-associated viruses (AAVs) are small, nonenveloped single-stranded DNA viruses that require helper viruses to facilitate efficient replication. Despite the presence of humoral responses to the ...wild-type AAV in humans, AAV remains one of the most promising candidates for therapeutic gene transfer to treat many genetic and acquired diseases. Characterization of the IgG subclass responses to AAV and study of the prevalence of both IgG and neutralizing factors to AAV types 1, 2, 5, 6, 8, and 9 in the human population are of importance for the development of new strategies to overcome these immune responses. Natural exposure to AAV types 1, 2, 5, 6, 8, and 9 can result in the production of antibodies from all four IgG subclasses, with a predominant IgG1 response and low IgG2, IgG3, and IgG4 responses. Prevalences of anti-AAV1 and -AAV2 total IgG determined by enzyme-linked immunosorbent assay were higher (67 and 72%) than those of anti-AAV5 (40%), anti-AAV6 (46%), anti-AAV8 (38%), and anti-AAV9 (47%). Furthermore, data showed that cross-reactions are important. The two highest neutralizing factor seroprevalences were observed for AAV2 (59%) and AAV1 (50.5%) and the lowest were observed for AAV8 (19%) and AAV5 (3.2%). Vectors based on AAV5, AAV8, and AAV9 may have an advantage for gene therapy in humans. Furthermore, among individuals seropositive for AAV5, AAV8, and AAV9, about 70-100% present low titers. Better characterization of the preexisting humoral responses to the AAV capsid and cross-reactivity will allow development of new strategies to circumvent AAV acquired immune responses.
Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and ...recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.
Recombinant adeno-associated virus (AAV) vectors have been broadly adopted as a gene delivery tool in clinical trials, owing to their high efficiency of transduction of several host tissues and their ...low immunogenicity. However, a considerable proportion of the population is naturally exposed to the WT virus from which AAV vectors are derived, which leads to the acquisition of immunological memory that can directly determine the outcome of gene transfer. Here, we show that prior exposure to AAV drives distinct capsid immunity profiles in healthy subjects. In peripheral blood mononuclear cells (PBMCs) isolated from AAV-seropositive donors, recombinant AAV triggered TNF-α secretion in memory CD8+ T cells, B cell differentiation into antibody-secreting cells, and anti-capsid antibody production. Conversely, PBMCs isolated from AAV-seronegative individuals appeared to carry a population of NK cells reactive to AAV. Further, we demonstrated that the AAV capsid activates IL-1β and IL-6 cytokine secretion in monocyte-related dendritic cells (moDCs). IL-1β and IL-6 blockade inhibited the anti-capsid humoral response in vitro and in vivo. These results provide insights into immune responses to AAV in humans, define a possible role for moDCs and NK cells in capsid immunity, and open new avenues for the modulation of vector immunogenicity.
This paper conducts a comparative evaluation between Neural Radiance Fields (NeRF) and photogrammetry for 3D reconstruction in the cultural heritage domain. Focusing on three case studies, of which ...the Terpsichore statue serves as a pilot case, the research assesses the quality, consistency, and efficiency of both methods. The results indicate that, under conditions of reduced input data or lower resolution, NeRF outperforms photogrammetry in preserving completeness and material description for the same set of input images (with known camera poses). The study recommends NeRF for scenarios requiring extensive area mapping with limited images, particularly in emergency situations. Despite NeRF’s developmental stage compared to photogrammetry, the findings demonstrate higher potential for describing material characteristics and rendering homogeneous textures with enhanced visual fidelity and accuracy; however, NeRF seems more prone to noise effects. The paper advocates for the future integration of NeRF with photogrammetry to address respective limitations, offering more comprehensive representation for cultural heritage preservation tasks. Future developments include extending applications to planar surfaces and exploring NeRF in virtual and augmented reality, as well as studying NeRF evolution in line with emerging trends in semantic segmentation and in-the-wild scene reconstruction.
In the field of digital cultural heritage (DCH), 2D/3D digitization strategies are becoming more and more complex. The emerging trend of multimodal imaging (i.e., data acquisition campaigns aiming to ...put in cooperation multi-sensor, multi-scale, multi-band and/or multi-epochs concurrently) implies several challenges in term of data provenance, data fusion and data analysis. Making the assumption that the current usability of multi-source 3D models could be more meaningful than millions of aggregated points, this work explores a “reduce to understand” approach to increase the interpretative value of multimodal point clouds. Starting from several years of accumulated digitizations on a single use-case, we define a method based on density estimation to compute a Multimodal Enhancement Fusion Index (MEFI) revealing the intricate modality layers behind the 3D coordinates. Seamlessly stored into point cloud attributes, MEFI is able to be expressed as a heat-map if the underlying data are rather isolated and sparse or redundant and dense. Beyond the colour-coded quantitative features, a semantic layer is added to provide qualitative information from the data sources. Based on a versatile descriptive metadata schema (MEMoS), the 3D model resulting from the data fusion could therefore be semantically enriched by incorporating all the information concerning its digitization history. A customized 3D viewer is presented to explore this enhanced multimodal representation as a starting point for further 3D-based investigations.
Adeno-associated viruses (AAV) are small, nonenveloped single-stranded DNA viruses which require helper viruses to facilitate efficient replication. These recombinant viruses are some of the most ...promising candidates for therapeutic gene transfer to treat many genetic and acquired diseases. Nevertheless, the presence of humoral responses to the wild-type AAV common among humans is one of the limitations of in vivo transduction efficacy in humans using cognate recombinant vector. In this study, based on the serum samples that we were able to collect from various clinical situations, we studied the impact of one to five plasmapheresis (PP), at 1–5 day intervals on neutralizing factor (NAF) titers specific for AAV types 1, 2, 6, and 8 in seropositive patients with diverse pathologies and immunosuppressor treatments. We show that frequent sessions of PP result in drastic reduction of NAF specific for AAV1, 2, 6, and 8 to undetectable levels or titers <1:5, mainly when initial titers, i.e., before the first PP were ≤1:20. Altogether, these results show that the use of PP and its possible association with pharmacological immunosuppressive treatments may help to design optimal management of seropositive patients for AAV gene therapy treatments.
The combination of LiDAR with other technologies for numerisation is increasingly applied in the field of building, design, and geoscience, as it often brings time and cost advantages in 3D data ...survey processes. In this paper, the reconstruction of 3D point cloud datasets is studied, through an experimental protocol evaluation of new LiDAR sensors on smartphones. To evaluate and analyse the 3D point cloud datasets, different experimental conditions are considered depending on the acquisition mode and the type of object or surface being scanned. The conditions allowing us to obtain the most accurate data are identified and used to propose which acquisition protocol to use. This protocol seems to be the most adapted when using these LiDAR sensors to digitise complex interior buildings such as railway stations. This paper aims to propose: (i) a methodology to suggest the adaptation of an experimental protocol based on factors (distance, luminosity, surface, time, and incidence) to assess the precision and accuracy of the smartphone LiDAR sensor in a controlled environment; (ii) a comparison, both qualitative and quantitative, of smartphone LiDAR data with other traditional 3D scanner alternatives (Faro X130, VLX, and Vz400i) while considering three representative building interior environments; and (iii) a discussion of the results obtained in a controlled and a field environment, making it possible to propose recommendations for the use of the LiDAR smartphone at the end of the numerisation of the interior space of a building.
Imaging techniques and Image Based-Modeling (IBM) practices in the field of Cultural Heritage (CH) studies are nowadays no longer used as one-shot applications but as various and complex scenarios ...involving multiple modalities; sensors, scales, spectral bands and temporalities utilized by various experts. Current use of Structure from Motion and photogrammetric methods necessitates some improvements in iterative registration to ease the growing complexity in the management of the scientific imaging applied on heritage assets. In this context, the co-registration of photo-documentation among other imaging resources is a key step in order to move towards data fusion and collaborative semantic enrichment scenarios. This paper presents the recent development of a Totally Automated Co-registration and Orientation library (TACO) based on the interoperability of open-source solutions to conduct photogrammetric-based registration. The proposed methodology addresses and solves some gaps in term of robustness and versatility in the field of incremental and global orientation of image-sets dedicated to CH practices.
Dendritic cells constitutively secrete a population of small (50-90 nm diameter) Ag-presenting vesicles called exosomes. When sensitized with tumor antigenic peptides, dendritic cells produce ...exosomes, which stimulate anti-tumor immune responses and the rejection of established tumors in mice. Using a systematic proteomic approach, we establish the first extensive protein map of a particular exosome population; 21 new exosomal proteins were thus identified. Most proteins present in exosomes are related to endocytic compartments. New exosomal residents include cytosolic proteins most likely involved in exosome biogenesis and function, mainly cytoskeleton-related (cofilin, profilin I, and elongation factor 1alpha) and intracellular membrane transport and signaling factors (such as several annexins, rab 7 and 11, rap1B, and syntenin). Importantly, we also identified a novel category of exosomal proteins related to apoptosis: thioredoxin peroxidase II, Alix, 14-3-3, and galectin-3. These findings led us to analyze possible structural relationships between exosomes and microvesicles released by apoptotic cells. We show that although they both represent secreted populations of membrane vesicles relevant to immune responses, exosomes and apoptotic vesicles are biochemically and morphologically distinct. Therefore, in addition to cytokines, dendritic cells produce a specific population of membrane vesicles, exosomes, with unique molecular composition and strong immunostimulating properties.
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