In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for small-scale active pharmaceutical ingredient production. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the formation of free-flowing particles. We introduce a novel continuous nucleator designed based on solubility data and produced via 3D printing, enabling a fast and precise small-scale manufacturing of a nucleator meeting the requirements for nucleation and for the further growth processes. The nucleator was evaluated with regard to its suitability for continuous long-term operation across various coupled crystallizers. As a practical application example it is connected to a slug flow crystallizer to enable high-quality continuous crystallization. Additionally, the full integration of downstream processes using the continuous vacuum screw filter to achieve free-flowing product particles is realized. Even under non-optimized process conditions, with the help of in-situ generation of nuclei free-flowing product particles were successfully obtained. This is particularly useful during drug development when no material is available for seed addition and quickly obtain product for further characterization.

ORF6 is responsible for suppressing the immune response of cells infected by the SARS-CoV-2 virus. It is also the most toxic protein of SARS-CoV-2, and its actions are associated with the viral pathogenicity. Here we study in silico and in vitro the structure of the protein, its interaction with RAE1, and the mechanism of action behind its high toxicity. We show both computationally and experimentally that SARS-CoV-2 ORF6, embedded in the membranes of the endoplasmic reticulum, binds to RAE1 and sequesters it in the cytoplasm, thus depleting its availability in the nucleus and impairing nucleocytoplasmic mRNA transport. This negatively affects the cellular genome stability by compromising the cell cycle progression into the S-phase and by promoting the accumulation of RNA-DNA hybrids. Understanding the multiple ways in which ORF6 affects DNA replication may also have important implications for elucidating the pathogenesis of SARS-CoV-2 and developing therapeutic strategies to mitigate its deleterious effects on host cells.

The 21^st century has witnessed precipitous changes spanning from the way of life to the technologies that emerged. We have entered a nascent paradigm shift (industry 4.0) where science fictions have become science facts, and technology fusion is the main driver. Thus, ensuring that any advancement in technology reach and benefit all is the ideal opportunity for everyone. In this study, disruptive technologies of industry 4.0 was explored and quantified in terms of the number of their appearances in published literature. The study aimed at identifying industry 4.0 key technologies which have been ill-defined by previous researchers and to enumerate the required skills of industry 4.0. Comprehensive literature survey covering the field of engineering, production, and management was done from multidisciplinary databases: Google scholar, ScienceDirect, Scopus, Sage, Taylor & Francis and Emerald insight. Results of the electronic survey showed that 35 disruptive technologies were quantified and 13 key technologies: Internet of things, Big data, 3D printing, Cloud computing, Autonomous robots, Virtual and Augmented reality, Cyber physical system, Artificial intelligence, Smart sensors, Simulation, Nanotechnology, Drones and Biotechnology were identified. Both technical and personal skills to be imparted into the human workforce for industry 4.0 were reported. The study identified the need to investigate the capability and the readiness of developing countries in adapting industry 4.0 in terms of the changes in the education systems and industrial manufacturing settings. The study proposes the need to address integration of industry 4.0 concepts into the current education system.

Biomimicry in additive manufacturing often refers to topology optimization and the use of lattice structures, due to the organic shape of the topology-optimized designs, and the lattices often looking similar to many light-weight structures found in nature such as trabecular bone, wood, sponges, coral, to name a few. Real biomimetic design however involves the use of design principles taken in some way from natural systems. In this work we use a methodology whereby high resolution 3D analysis of a natural material with desirable properties is “reverse-engineered” and the design tested for the purpose. This allows more accurate replication of the desired properties, and adaption of the design parameters to the material used for production (which usually differs from the biological material). One such example is the impact-protective natural design of the glyptodont body armour. In this paper we report on the production of body armour models in metal (Ti4Al4V) and analyze the resulting mechanical properties, assessing their potential for impact protective applications. This is the first biomimetic study using metal additive manufacturing to date.

Dams are a critical infrastructure system for many communities, but they are also one of the most challenging to inspect. Dams are typically very large and complex structures, and the result is that inspections are often time-intensive and require expensive, specialized equipment and training to provide inspectors with comprehensive access to the structure. The scale and nature of dam inspections also introduces additional safety risks to the inspectors. Unmanned aerial vehicles (UAV) have the potential to address many of these challenges, particularly when used as a data acquisition platform for photogrammetric three-dimensional (3D) reconstruction and analysis, though the nature of both UAV and modern photogrammetric methods necessitates careful planning and coordination for integration. This paper presents a case study on one such integration at the Brighton Dam, a large-scale concrete gravity dam in Maryland, USA. A combination of multiple UAV platforms and multi-scale photogrammetry was used to create two comprehensive and high-resolution 3D point clouds of the dam and surrounding environment at intervals. These models were then assessed for their overall quality, as well as their ability to resolve flaws and defects that were artificially applied to the structure between inspection intervals. The results indicate that the integrated process is capable of generating models that accurately render a variety of defect types with sub-millimeter accuracy. Recommendations for mission planning and imaging specifications are provided as well.

Different notions of entropy can be identified in different communities: (i) the thermodynamic sense, (ii) the information sense, (iii) the statistical sense, (iv) the disorder sense, and (v) the homogeneity sense. Especially the “disorder sense” and the “homogeneity sense” relate to and require the notion of space and time. One of the few prominent examples relating entropy to geometry and to space is the Bekenstein-Hawking entropy of a Black Hole. Although being developed for the description of a physics object—a black hole—having a mass, a momentum, a temperature, a charge etc. absolutely no information about these attributes of this object can eventually be found in the final formula. In contrast, the Bekenstein-Hawking entropy in its dimensionless form is a positive quantity only comprising geometric attributes like an area A—which is the area of the event horizon of the black hole-, a length L_P—which is the Planck length - and a factor ¼. A purely geometric approach towards this formula will be presented. The approach is based on a continuous 3D extension of the Heaviside function, with this extension drawing on the phase-field concept of diffuse interfaces. Entropy enters into the local, statistical description of contrast respectively gradient distributions in the transition region of the extended Heaviside function definition. The structure of the Bekenstein-Hawking formula eventually is derived for a geometric sphere based on mere geometric-statistic considerations.

Tailings generated by mining account for the largest proportion of global waste from industrial activities. Copper is relatively uncommon world-wide, with low concentrations in sediments and waters, yet is very elevated around mining sites. On the Keweenaw Peninsula of Michigan, USA, jutting out into Lake Superior, 140 mines extracted native copper from the Portage Lake Volcanic Series, part of an intercontinental rift system. Between 1901-1932, two mills at Gay (Mohawk, Wolverine) sluiced 22.7 million metric tonnes (MMT) of copper-rich tailings (stamp sands) into Grand (Big) Traverse Bay. Here we examine: 1) 3D coastal elevation and reef bathymetry, 2) particle dispersal, 3) copper concentrations and leaching, plus 4) shoreline toxicity. About 10 MMT of tailings created a migrating coastal beach that stretches 7 km from the Gay pile to the Traverse River Seawall. Another 10 MMT are moving underwater on the coastal shelf, threatening Buffalo Reef, an important lake trout and whitefish breeding ground. Aerial photos, ALS (plane) LiDAR, and relatively inexpensive UAS (drone) surveys characterize shoreline structure and aid initial remediation. Because sands (natural beach quartz, stamp sand basalt) are silicates of similar density, particle dispersal is similar and challenging. However, stamp sand beaches contrast greatly with natural sand beaches in both physical profile and chemistry. Dispersing particles retain copper, and release toxic concentrations. Leaching is elevated by exposure to high DOC and low pH waters. Field experiments, shoreline seining, and benthic sampling confirm serious impacts on aquatic biota, supporting tailings removal.

The exploration of three-dimensional (3D) DNA structures marks a pivotal shift in genomics, offering unprecedented insights into the intricacies of cellular regulation, disease genesis, and the potential for novel diagnostic and therapeutic strategies. This study delves into the dynamic nature of 3D genome organization, investigating how these structures influence cellular functions in response to environmental changes and over time. Through a combination of real-time imaging and advanced computational models, we aim to unravel the complex interplay between 3D DNA structures, non-coding RNAs, and chromatin organization, and their collective impact on gene expression and cellular differentiation. A significant focus is placed on understanding the role of 3D DNA structures in the development and progression of genetic disorders. By employing comprehensive genomic and epigenomic profiling, this research seeks to identify structural aberrations linked to diseases, paving the way for the development of targeted diagnostics and therapies. Additionally, the study explores the potential of genome editing technologies, such as CRISPR-Cas systems, in correcting these structural abnormalities, while also addressing the ethical, legal, and social implications (ELSI) of such interventions. Integrating data from various genomic analyses, we propose the development of advanced computational models to predict the effects of 3D DNA structures on gene expression and cellular function. This integrative approach not only promises to enhance our understanding of genomic regulation but also sets the stage for groundbreaking advances in genomics-based diagnostics and therapeutics. The findings of this study have the potential to revolutionize our approach to treating genetic disorders, offering a new frontier in personalized medicine.

A novel approach for the long-term medical treatment of the inner ear is the diffusion of drugs through the round window membrane from a patient-individualized, drug-eluting implant, which is inserted in the middle ear. In this study, drug-loaded (10 wt% Dexamethasone) guinea pig round window niche implants (GP-RNIs, ~1.30 mm x 0.95 mm x 0.60 mm) were manufactured with high precision via micro injection molding (µIM, Tmold = 160 °C, crosslinking time of 120 s). The medical grade silicone elastomer MED-4244 (NuSil Technology LLC, Radnor, PA, USA) was used. Molds for µIM were 3D printed from a commercially available resin PlasGRAY V2 (Asiga, Alexandria, Australia, TG = 84 °C) via a high-resolution DLP process (xy-resolution of 32 µm, z-resolution of 10 µm, 3D printing time of about 6 h). Drug release, biocompatibility, and bio-efficacy of the GP-RNIs were investigated in vitro. GP-RNIs could be successfully produced. Wear of the molds due to thermal stress was observed. However, the molds are suitable for single use in the µIM process. About 10% of the drug load (8.2 ± 0.6 µg) was released after 6 weeks (medium: isotonic saline). The implants showed high biocompatibility over a time of 28 days (lowest cell viability ~80%). Moreover, we found anti-inflammatory effects over a time of 28 days in a TNF-α-reduction test. These results are promising for the development of long-term drug-releasing implants for human inner ear therapy.

Height assignment is an important problem for satellite measurements of Atmospheric Motion Vectors (AMVs) that are interpreted as winds by forecast and assimilation systems. Stereo methods assign heights to AMVs from the parallax observed between observations from different vantage points in orbit while tracking cloud or moisture features. In this paper, we fully develop the stereo method to jointly retrieve wind vectors with their geometric heights from geostationary satellite pairs. Synchronization of observations between observing systems is not required. NASA and NOAA stereo-winds codes have implemented this method and we have processed large datasets from GOES-16, -17, and Himawari-8. Our retrievals are validated against rawinsonde observations and demonstrate the potential to improve forecast skill. Stereo winds also offer an important mitigation for the loop heat pipe anomaly on GOES-17 during times when warm focal plane temperatures cause infra-red channels that are needed for operational height assignments to fail. We also examine several application areas, including deep convection in tropical cyclones, planetary boundary layer dynamics, and fire smoke plumes, where stereo methods provide insights into atmospheric processes. The stereo method is broadly applicable across the geostationary ring where systems offering similar Image Navigation and Registration (INR) performance as GOES-R are deployed.

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. Properties of three-dimensional tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a tumoroid-based screening system. We screened 6 pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The effects of one of the hit compounds were examined on tumor formation and progression in vitro and in vivo. Antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and properties of cancer stem cells / cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

Psoriasis is a chronic immune-mediated skin disease that involves interaction of both immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation and angiogenesis. Because available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can rescind molecular defects associated with psoriasis and could be developed for its management. Fisetin (3,7,3′,4′- tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables has demonstrated pro-apoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological and tissue-engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC) and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α-stimulated NHEKs significantly inhibited the activation of p38 and JNK, but had no effect on ERK1/2. In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFNγ and IL-17A by 12-O- tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in-vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in-vivo human psoriatic skin-lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify pro-differentiative, anti-proliferative and anti-inflammatory effects of fisetin, via modulation of PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin model of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.

Background: The CoBaTrICE initiative standardized intensive care training throughout Europe. Pericardiocentesis, an important yet infrequent operation, poses unique training challenges often unmet by conventional methods. This study evaluates the efficacy of virtual reality (VR) simulations and 3D-printed mannequins in pericardiocentesis training, both crafted from scratch using highly affordable materials and free software. Methods: Thirty-five final-year medical students participated in this prospective, quasi-experimental study. Initially, students underwent VR simulation training, followed by training using 3D-printed self-made mannequins. Learning outcomes were assessed using the Objective and Structured Clinical Examination (OSCE) questionnaire. Heart rate variability (HRV) analysis was employed to monitor stress responses, while the NASA Task Load Index (NASA-TLX) was used to gauge self-perceived difficulty. Results: Although the mannequin model induced more stress reactions, it excelled in tasks requiring fine motor skills, such as correct placement and asepsis maintenance. In contrast, lower NASA-TLX scores indicated that the VR model imposed less mental demand and effort, reflecting a reduced cognitive load. Conclusion: Both VR simulations and 3D-printed mannequins effectively taught pericardiocentesis skills, each offering distinct advantages. Mannequins enhanced fine motor skills, whereas VR reduced cognitive load and increased engagement. The combination of both approaches could maximize training outcomes, particularly in resource-constrained environments, thus broadening access to advanced simulation education.

The bi- or multi-nucleated Reed-Sternberg cell (RS) is the diagnostic cornerstone of EBV-positive and EBV-negative classical Hodgkin lymphoma (cHL). cHL is a germinal center (GC) derived B-cell disease. Hodgkin cells (H) are the mononuclear precursors of RS. An experimental model has to fulfill three conditions to qualify as common pathogenic denominator: i) to be of germinal center-derived B-cell origin, ii) to be EBV-negative to avoid EBV latency III expression, and iii) to support permanent LMP1 expression upon induction. These conditions are unified in the EBV-, Diffuse Large B-Cell Lymphoma (DLBCL) cell line BJAB-tTA-LMP1. 3D reconstuctive nanotechnology revealed spatial, quantititive and qualitative disturbance of telomere/shelterin interactions in mononuclear H-like cells, further progression during transition to RS-like cells, including progressive complexity of the karytotype with every mitotic cycle, due to BBF (breakage/bridge/fusion) events. The findings of this model were confirmed on diagnostic patient samples and correlate with clincal outcome. Moreover, in vitro signficant disturbance of the lamin AC/telomere interaction progressively occured. In summary, our research over the past three decades identifed cHL as the first lymphoid maligancy driven by a disturbed telomere/shelterin/lamin AC interaction, generating the diagnostic RS. Our findings may act as trailblazer for tailored therapies in refractory cHL.

Glial cells provide physical and chemical support and protection for neurons. Secreted neurotrophic factors, scaffolds and vesicles regulate in addition to normal homeostasis, repair following neural tissue injury or degeneration. We previously demonstrated that human CNS glia have revascularization capacity by inducing endothelial cell sprouting and microchanneling driven by glial cell secreted components. The clinical potential of using secreted factors and vesicles generated by glial cells in conditioned media was shown by their re-normalization of pathological blood vessels and 3D tissue wound healing and remodeling capacity. To identify secreted components of glial cells and how CNS and PNS glial cells differentially regulate neural tissue homeostasis, disease and injury response, we developed a novel culture method for various types of glial cells that allow for isolating and characterizing secreted glial components, free of animal factors and contaminants normally associated with serum-based culture conditions. Our culture method will enable to identify secreted components using ultrasensitive RNA, glycoconjugate and protein analysis technologies. The characterization of glial secreted factors involved microchanneling may help in development of new clinical therapies for glial and neural cells or axons to migrate and reform connections.

This paper presents a proof-of-concept study on the biocolonization of 3D-printed hydroxyapatite scaffolds with mesenchymal stem cells (MSCs). Three-dimensional (3D) printed biomimetic bone structure made of Calcium Deficient HydroxyApatite (CDHA) intended as future bone graft was made from newly developed composite material for FDM printing. The biopolymer polyvinyl alcohol serves in this material as a thermoplastic binder for 3D molding of the printed object with a passive function and is completely removed during sintering. The study presents the material, the process of fused deposition modeling (FDM) of CDHA scaffolds and its post-processing at three temperatures (1200, 1300, 1400 °C), as well it evaluates the cytotoxicity and biocompatibility of scaffolds with MTT and LDH release assays after 14 days. The study also includes a morphological evaluation of the cellular colonization with scanning electron microscopy (SEM) in two different filament orientations (rectilinear and gyroid). The results of the MTT assay showed that the tested material was not toxic, and cells were preserved in both orientations, with most cells present on the material fired at 1300°C. Results of the LDH release assay showed a slight increase in LDH leakage from all samples. Visual evaluation of SEM confirmed the ideal post-processing temperature of the 3D-printed FDM framework for samples fired at 1300°C and 1400°C, with a porosity of 0.3 mm between filaments. In conclusion, the presented fabrication and colonization of CDHA scaffolds have great potential to be used in the tissue engineering of bones.

In the current industrial landscape, increasingly pervaded by technological innovations, the adoption of optimized strategies for asset management is becoming a critical key success factor. Among the various strategies available, the “Prognostics and Health Management” strategy is able to support maintenance management decisions more accurately, through continuous monitoring of equipment health and “Remaining Useful Life” forecasting. In the present study, Convolutional Neural Network-based Deep Neural Network techniques are investigated for the Remaining Useful Life prediction of a punch tool, whose degradation is caused by working surface deformations during the machining process. Surface deformation is determined using a 3D scanning sensor capable of returning point clouds with micrometric accuracy during the operation of the punching machine, avoiding both downtime and human intervention. The 3D point clouds thus obtained are transformed into bidimensional image-type maps, i.e., maps of depths and normal vectors, to fully exploit the potential of convolutional neural networks for extracting features. Such maps are then processed by comparing 15 genetically optimized architectures with the transfer learning of 19 pre-trained models, using a classic machine learning approach, i.e., Support Vector Regression, as a benchmark. The achieved results clearly show that, in this specific case, optimized architectures provide performance far superior (MAPE=0.058) to that of transfer learning which, instead, remains at a lower or slightly higher level (MAPE=0.416) than Support Vector Regression (MAPE=0.857).

Based on the minimum conduction band edge caused by the minimum channel potential resulting from the quasi-3D scaling theory and the 3D density of state (DOS) accompanied by the Fermi-Dirac distribution function on the source and drain sides, a unified semiconductor-device-physics-based ballistic model is developed for the threshold voltage of modern multiple-gate (MG) transistors, including FinFET, W-gate MOSFET, and Nanosheet (NS) MOSFET. It is shown that the thin silicon, thin gate oxide, and high work function will alleviate the ballistic effects and resist the threshold voltage degradation. Besides, as the device dimension is further reduced to give rise to the 2D/1D DOS, the lowest conduction band edge is hence increased to resist the threshold voltage degradation. The nanosheet MOSFET exhibits the largest threshold voltage among the three transistors due to the smallest minimum conduction band edge caused by the quasi-3D minimum channel potential. Compared to P-type MOSFET (P-FET), the N-FET shows more threshold voltage because the electron has a more effective mass than the hole

Article explores participant specific study of muscle inherehit dynamics hidden inside the diognostic electromyography (D-EMG) signals during load pull exercises, aiming to uncover underlying patterns and nonlinear behaviors. Employing a multi-step analytical framework, the study first evaluates signal stationarity through Quantile-Quantile (Q-Q) plot and surrogate data analyses, revealing insights into signal stability. Subsequent use of phase space reconstruction techniques exposes intrinsic dynamics within the EMG signals, visualized through Poincar´e maps, elucidating attractor geometry and system dynamics. Histogram analysis further dissects the Poincar´e maps, offering insights into signal behavior relative to physiological processes. Additionally, the study quantifies the largest Lyapunov exponent from the Poincar´e maps, providing a measure of dynamical complexity within the muscle EMG signals during load pull exercises. By integrating these methods, this research sheds light on the nuanced interplay between EMG signals and muscle activity during dynamic exercises, offering valuable insights for rehabilitation strategies.

The aim of the work is to study the effect of the 3D printing process on the microstructural and hydrophilic properties of polylactic acid (PLA) samples with various model printing patterns obtained from the black Filament PLA by sequentially applying polymer layers using the FDM (Fused Deposition Modeling) method. X-ray phase analysis revealed partial crystallization of PLA polymer chains in printed samples, which occurs under thermal and mechanical action on the original amorphous PLA filament during 3D printing to varying degrees, depending on the geometry of the pattern and the morphology of its surface. At the same time, IR spectroscopy data indicate the preservation of all intrastructural chemical bonds of polylactide. Measured at the original installation, the values of the wetting edge angles on the surface of the printed samples are in the range φ = 50-60°, which is significantly less than the right angle. This indicates the hydrophilic properties of all samples’ surface. At the same time, the influence of different geometries of model drawings in printed samples was found not only on the morphology of the samples’ surface according to SEM data, but also on its wettability.

Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.

Congenital breast asymmetry represents a particular challenge to the classical techniques of plastic surgery due to a young group of patients. This study compares traditional breast augmentation using silicone implants to the more innovative lipograft technique regarding long-term results. To achieve this, we not only captured subjective parameters like satisfaction with outcome and symmetry, but also objective parameters such as breast volume and anthropometric measurements. Objective examination was performed manually and by using the Vectra® H2 photogrammetry scanning system. Patients who underwent implant augmentation and lipograft both showed no significant differences in patient´s satisfaction with surgical outcome (p = 0.55) and symmetry (p = 0.69). Furthermore, a breast symmetry of 93 % in both groups was reported. Likewise, no statistically significant volume difference between left and right breast was observed in both groups (p<0.41). However, on average, lipograft patients needed 1.3 procedures more until the desired result was achieved. In contrast, patients treated with implant-based breast augmentation usually need several implant changes during their life. In conclusion, both methods should be considered for patients with congenital breast asymmetry.

The poly lactic acid (PLA) is one of the most used bio-derived thermoplastic polymers in 3D and 4D printing applications. The determination of PLA surface properties is of capital importance in 3D/4D printing technology. (1) Background: The surface thermodynamic properties of PLA polymer were determined by using the inverse gas chromatography (IGC) technique at infinite dilution. The determination of the retention volume of polar and non-polar molecules adsorbed on the PLA particles filling the column allowed us to obtain the dispersive, polar, and Lewis’s acid-base surface properties at different temperatures from 40 °C to 100 °C. (2) Methods: the applied surface method was based on our recent model that used the London dispersion equation and the new chromatographic parameter function of the deformation polarizability and the harmonic mean of the ionization energies of the PLA polymer and organic molecules. (3) Results: The application of this new method led to the determination of the dispersive and polar free surface energy of adsorption of molecules on the polymeric material, as well as the glass transition and the Lewis acid-base constants. (4) Conclusions: four interval temperatures were distinguished showing four zones of the variations of the surface properties of PLA as a function of the temperature before and after the glass transition.

The safe and reliable operation of autonomous vehicles in complex and dynamic environments is heavily dependent upon exteroceptive and proprioceptive sensors. A LiDAR system generates accurate 3D point clouds, which are crucial for the detection, classification, and tracking of multiple targets. LiDAR data, however, presents significant challenges due to its density, noise, and varying sampling rates. In this study, various clustering and MTT techniques for LiDAR point clouds will be identified and classified within the context of autonomous driving to assess the state-of-the-art methods’ key challenges and their performances. We have categorized clustering and MTT methods used in AV applications, identified research gaps and challenges and analyzed existing algorithms and their challenges in detail. Researchers and practitioners in the field of autonomous driving will find this review to be a valuable resource.

Bottlenose dolphin (Tursiops truncatus) belongs to the Cetartiodactyla and similarly to the other cetaceans represent the most successful mammalian colonization of the aquatic environment. Here we report a genomic, evolutionary and expression study of Tursiops truncatus T cell receptor beta (TRB) genes. Although the organization of the dolphin TRB locus is similar to that of the other artiodactyl species, with three in tandem D-J-C clusters located at its 3’ end, its uniqueness is given by the reduction of the total length due essentially to the absence of duplications and to the deletions that have drastically reduced the number of the germline TRBV genes. We have analyzed the relevant mature transcripts from two subjects. The simultaneous availability of rearranged TRA and TRB cDNA from the peripheral blood of one of the two specimens, and the human/dolphin amino acids multi sequence alignments, allowed us to calculate the most likely interactions at the protein interface between the alpha/beta heterodimer in complex with major histocompatibility class I (MH1) protein. Interacting amino acids located in the CDR-IMGT of the dolphin variable V alpha and beta domains were identified. According to comparative modelisation, the atome pair contact sites analysis between the human MH1 grove (G) domains and the TR V domains confirms conservation of the structure of the dolphin TR/pMH.

Rapid developments in the field of underwater photogrammetry have given scientists1the ability to produce accurate 3-dimensional (3D) models which are now increasingly used in the representation and study of local areas of interest. This paper addresses the lack of systematic analysis of 3D reconstruction and navigation fusion strategies, as well as associated error evaluation of models produced at larger scales in GPS-denied environments using a monocular camera (often in deep-sea scenarios). Based on our prior work on automatic scale estimation of Structure from Motion (SfM)-based 3D models using laser scalers, an automatic scale accuracy framework is presented. The confidence level for each of the scale error estimates is independently assessed through the propagation of the uncertainties associated with image features and laser spot detections using a Monte Carlo simulation. The number of iterations used in the simulation was validated through the analysis of the final estimate behaviour. To facilitate the detection and uncertainty estimation of even greatly attenuated laser beams, an automatic laser spot detection method, mitigating the effects of scene texture, was developed, with the main novelty of estimating the uncertainties based on the recovered characteristic shapes of laser spots with radially decreasing1 intensities. The effects of four different reconstruction strategies resulting from the combinations of Incremental/GlobalSfM, and thea priori/a posterioriuse of navigation data were analyzed using two distinct survey scenarios captured during the SUBSAINTES 2017 cruise (doi: 10.17600/17001000). The study demonstrates that surveys with multiple overlaps of non-sequential images result in a nearly identical solution regardless of the strategy (SfM or navigation fusion), while surveys with weakly connected sequentially acquired images are prone to produce broad-scale deformation (doming effect) when navigation is not included in the optimization. Thus the scenarios with complex survey patterns substantially benefit from using multi-objective BA navigation fusion. In all cases, the errors in the models are inferior to 5%, with errors often being around 1%. The effects of combining data from multiple surveys were also evaluated. The introduction of additional vectors in the optimization of multi-survey problems successfully accounted for offset changes present in the underwater USBL-based navigation data and thus minimize the effect of contradicting navigation priors. Our results also illustrate the importance of collecting a multitude of evaluation data at different locations and moments during the survey.

This study investigates the application of deep residual networks for predicting the dynamics of interacting three-dimensional rigid bodies. We present a framework combining a 3D physics simulator implemented in C++ with a deep learning model constructed using PyTorch. The simulator generates training data encompassing linear and angular motion, elastic collisions, fluid friction, gravitational effects, and damping. Our deep residual network, consisting of an input layer, multiple residual blocks, and an output layer, is designed to handle the complexities of 3D dynamics. We evaluate the network's performance using a dataset of 10,000 simulated scenarios, each involving 3-5 interacting rigid bodies. The model achieves a mean squared error of 0.015 for position predictions and 0.022 for orientation predictions, representing a 25% improvement over baseline methods. Our results demonstrate the network's ability to capture intricate physical interactions, with particular success in predicting elastic collisions and rotational dynamics. This work significantly contributes to physics-informed machine learning by showcasing the immense potential of deep residual networks in modeling complex 3D physical systems. We discuss our approach's limitations and propose future directions for improving generalization to more diverse object shapes and materials.

Artificial intelligence (AI) and 3D printing (3DP) play critical roles in what is known as the 4th Industrial Revolution by developing data- and machine-intelligence-based integrated production technologies. This shift has led to increasingly complex design requirements and fabrication methods, posing several challenges for implementing design, fabrication process, and architectural quality standardization. This paper systematically reviews AI techniques applied in diverse stages of 3DP production in architecture. The research goals are to (1) offer a comprehensive critical analysis of the body of literature; (2) identify and categorize approaches to integrating AI in the production of 3D-printed structures; (3) identify and discuss challenges and opportunities of AI integration in architectural production of 3DP structures; and (4) identify gap and provide recommendations for future research. The findings indicate that topics related to AI applications are current and trending, receiving increasing attention from researchers in general and particularly those working in machine and deep learning, artificial neural networks, and pattern recognition. However, the potential of the application of AI in architectural production using additive manufacturing still needs to be explored. Considering this, the paper emphasizes the necessity of redefining traditional field boundaries and opening new opportunities in the sector.

Three-dimensional (3D) printing technologies are transforming the design and manufacture of components and products across a variety of disciplines, however their application in the construction industry is still limited. Material deposition processes can achieve infinite geometries and have advanced from rapid prototyping and model-scale markets to their application in fabricating functional products, large objects and the construction of full-scale buildings. Many international projects have recently been realized and the construction industry is beginning to utilise these dynamic technologies. The potential advantages for integrating 3D printing into house construction are significant, these include the capacity for mass customization of designs and parameters for functional and aesthetic purposes, reduction in construction waste from highly precise material placement, and the use of recycled waste products in layer deposition materials. With the ultimate goal of improving construction efficiency and decreasing building costs, applying Strand7 Finite Element Analysis software, a numerical model was designed specifically for 3D printing in a cement mix incorporated with recycled waste product High Density Polyethylene (HDPE) and found that construction of an arched truss-like roof was structurally feasible without the need for steel reinforcements. The lab sizes prototypes were manufactured based on the destined numerical model by using a 3D printing technology. Currently available 3D printing technologies can be adopted for building construction and this paper discusses the applications, advantages, limitations and future directions of 3D printing as an innovative and viable solution for affordable house construction.

As UAVs are increasingly employed across various industries, the demand for robust and accurate detection has become crucial. LiDAR has developed as a vital sensor technology because to its ability to offer rich 3D spatial information, particularly in applications such as security and airspace monitoring. This review systematically explores recent innovations in LiDAR-based drone detection, deeply focusing on the principle and components of LiDAR sensor, its classifications based on different parameters and scanning mechanisms, as well as the approaches for processing LiDAR data. The review briefly compares several deep learning approaches, including point-based, voxel-based, and hybrid models, that have improved drone detection, tracking, and classification. We also explore the integration of multi-modal sensor fusion, which combines LiDAR data with other complimentary modalities to improve UAV detection and tracking in complex environments such as GNSS-denied zones.

In plants, water flows are the major driving force behind the growth and play a crucial role in the life cycle. To study hydrodynamics, methods based on tracking small particles inside water flows occupy a special place. Due to these tools, it is possible to get information about the dynamics of the spatial distribution of the fluxes characteristics. In this paper, using contrast-enhanced MRI, we have shown that gadolinium chelate, used as an MRI contrast agent, marks the structural characteristics of xylem bundles of maize stem nodes and internodes. Supplementing MRI data, a high-precision visualization of xylem vessels by laser scanning microscopy was used to reveal structural and dimensional characteristics of the stem vascular system. In addition, we proposed the concept of using the prototype "Y-type xylem vascular bundles" as a model of the elementary connection of vessels within the vascular system. A Reynolds number can match the microchannel model with the real xylem vessels.

Advanced methods of treatment are needed to fight the threats of virus-transmitted deseases and pandemics. Often they are based on an improved biophysical understanding of virus replication strategies and processes in their host cells. For instance, an essential component of the replication of the Hepatitis C virus (HCV) proceeds under the influence of non-structural HCV proteins (NSPs) that are anchored to the endoplasmatic reticulum (ER), such as the NS5a protein. The diffusion of NSPs has been studied by in-vitro fluorescence recovery after photobleaching (FRAP) experiments. The diffusive evolution of the concentration field of NSPs on the ER can be described by means of surface partial differential equations (sufPDE). Knodel et al, Viruses 2018, 10, 28 estimated the diffusion coefficient of the NS5a protein by minimizing the discrepancy of an extended set of sufPDE simulations and experimental FRAP time series data. Here, we provide a scaling analysis of the sufPDEs that describe the diffusive evolution of the concentration field of NSPs on the ER. This analysis provides an estimate of the diffusion coefficient that is based only on the ratio of the membrane surface area in the FRAP region and its contour length. The quality of this estimate is explored by comparison to numerical solutions of the sufPDE for a flat geometry and for ten different 3D embedded 2D ER grids that are derived from fluorescence z-stack data of the ER. Finally, we apply the new data analysis to the experimental FRAP time-series data analyzed in our previous paper, and we discuss the opportunities of the new approach.

Very well into the dawn of the fourth industrial revolution (industry 4.0), we hardly distinguish between what is artificial and what is natural (e.g. man-made virus and natural virus). Thus, the level of discombobulation among people, companies or countries is indeed unprecedented. The fact that industry 4.0 is explosively disrupting or retrofitting each and every industrial sector, makes industry 4.0 the famous buzzword amongst researchers today. However, the insight of industry 4.0 disruption in the industrial sectors remains ill-defined in both academic and non-academic literature. The present study aimed at identifying industry 4.0 neologisms, understanding the industry 4.0 disruption and illustrating the disruptive technologies convergence in the major industrial sectors. A total of 99 neologisms of industry 4.0 were identified. Industry 4.0 disruption in Education industry (Education 4.0), Energy industry (Energy 4.0), Agriculture industry (Agriculture 4.0), Healthcare industry (Healthcare 4.0), and Logistics industry (Logistics 4.0) are described. The convergence of 12 disruptive technologies including 3D printing, Artificial intelligence, Augmented reality, Big Data, Blockchain, Cloud computing, Drones, Internet of things, Nanotechnology, Robotics, Simulation and Synthetic biology in agriculture, healthcare and logistics industries are illustrated.

Clock Network Design (CDN) is a critical step while designing any Integrated-Circuits (ICs). It holds vital importance in the performance of entire circuit. Due to continuous scaling, 3D ICs stacked with TSV are gaining importance, with an objective to continue with the Moore's law. Through-Silicon-Via (TSV) provides the vertical interconnection between two die, which allows the electrical signal to flow through it. 3D ICs has many advantages over conventional 2D planar ICs like reduced power, area, cost, wire-length etc. The proposed work is mainly focused on power reduction and obstacle avoidance for 3D ICs. Various techniques have already been introduced for minimizing clock power within specified clock constraints of the 3D CND network. Proposed 3D Clock Tree Synthesis (CTS) is a combination of various algorithms with an objective to meet reduction in power as well as avoidance of obstacle or blockages while routing the clock signal from one sink to other sink. These blockages like RAM, ROM, PLL etc. are fixed during the placement process. The work is carried out mainly in three steps- first is Generation of 3D Clock tree avoiding the blockages, then Buffering and Embedding and finally validating the results by SPICE simulation. The experimental result shows that our CTS approach results in significant 9% reduction in power as compare to the existing work.

The war to technology and economic power have been the driver for industrialization in most developed countries. The first industrial revolution (industry 1.0) earned millions for textile mill owners while the second industrial revolution (industry 2.0) opened the way for tycoons and captains of industry like John D. Rockefeller, J.P. Morgan and Henry Ford. The third industrial revolution (industry 3.0) engendered technology giants like Apple and Microsoft, and made magnates of men like Steve Jobs and Bill Gates. Now, the race for the fourth industrial revolution (industry 4.0) is on and there is no option, every country whether developed or developing must participate. Many countries have positively responded to industry 4.0 by developing strategic initiatives to strengthen industry 4.0 implementation. Unlocking the country’s potential to industry 4.0 has been of interest to researchers in the recent past. However, the extent to which industry 4.0 initiatives being launched globally has never been revealed. Therefore, the present study aimed at exploring industry 4.0 initiatives through comprehensive electronic survey of literature to estimate the extend of its launching in different regions. Inferences were drawn from industry 4.0 initiatives in developed nations to be used as the recommendations for East Africa Community. Results of the survey revealed that 117 industry 4.0 initiatives have been launched in 56 countries worldwide consisting of five regions. The country’s percent of industry 4.0 initiatives as per region were: Latin America and the Caribbean (15%), North America (40%), Europe (53%), Asia and Oceania (25%), Middle East and Africa (11%). While the worldwide percent was estimated as 25%. This revealed that the big gap is existing between countries towards the race for industry 4.0.

Power sources that can consistently deliver high levels of energy over extended periods are crucial for various space applications. Among the many methods of energy generation, direct heat-to-electricity conversion without intermediate steps or moving components shows particular promise but also presents significant challenges. The aim of this research is to address these challenges by enhancing the energy efficiency of thermionic conversion, which transforms thermal energy into electrical energy, through the development and utilization of a novel class of emission nanomaterials known as multilayer carbyne-enriched 3D-shaped nano-interfaces. By manipulating the topological, physicochemical, and functional characteristics of these interfaces, we seek to optimize their thermionic conversion capabilities. Building on the recent discovery of collective atomic vibrations called phonon waves within transition domains of multilayer nanostructures, we have devised a new approach to enhance the efficiency of thermionic energy converters. This involves unlocking the predictive functionality of 2D-ordered linear-chain carbon-based multilayer emitters through the excitation and fine-tuning of collective atomic vibrations and nanoarchitecture. To achieve this, we propose employing a combination of techniques that leverage interface effects, enable phonon wave propagation, facilitate energy exchange, and capitalize on synergistic effects offered by the multilayer nano-enhanced interfaces. The resulting devices for thermionic energy conversion have the potential to significantly surpass the efficiency of existing plasma thermionic converters by several orders of magnitude. Moreover, these electricity-generating sources based on thermionic conversion represent fundamental options for the advancement of Lunar and Martian research missions, opening up possibilities for sustainable energy production in extraterrestrial environments.

This case study explores the transformative effects of emergent digital technologies, particularly augmented reality (AR), on literacy engagement and reading for pleasure. The United Arab Emirates Ministry of Education implemented the UAE Storytime programme, utilising AR to create an interactive literacy experience for young learners. The programme incorporated bilingual episodes, featuring stories based on local and global contexts, with 3D objects and interactive games to enhance understanding. The results indicate a positive correlation between the use of AR and literacy engagement. A high proportion of learners scanned the QR codes to access the AR objects, which enhanced their engagement and understanding of the stories. The programme fostered a learner agency, engaged family members in the learning process, and established a sense of global community. The study recommends the integration of similar initiatives into the curriculum to promote collaboration, creativity, and holistic learning experiences.