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Background: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required. Methods: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2). Results: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron. Conclusions: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.

Abstract Inherited Retinal Diseases (IRDs) are considered one of the leading causes of blindness worldwide. However, the majority of them still lack a safe and effective treatment due to their complexity and genetic heterogeneity. Recently, gene therapy is gaining importance as an efficient strategy to address IRDs which were previously considered incurable. The development of the clustered regularly-interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system has strongly empowered the field of gene therapy. However, successful gene modifications rely on the efficient delivery of CRISPR-Cas9 components into the complex three-dimensional (3D) architecture of the human retinal tissue. Intriguing findings in the field of nanoparticles (NPs) meet all the criteria required for CRISPR-Cas9 delivery and have made a great contribution toward its therapeutic applications. In addition, exploiting induced pluripotent stem cell (iPSC) technology and in vitro 3D retinal organoids paved the way for prospective clinical trials of the CRISPR-Cas9 system in treating IRDs. This review highlights important advances in NP-based gene therapy, the CRISPR-Cas9 system, and iPSC-derived retinal organoids with a focus on IRDs. Collectively, these studies establish a multidisciplinary approach by integrating nanomedicine and stem cell technologies and demonstrate the utility of retina organoids in developing effective therapies for IRDs.

The brain is the center of the nervous system controlling other organs. The brain is characterized by extreme complexity of its structure and delicate texture, which makes it difficult to investigate by invasive methods. The advances in semiconductor manufacturing technology led to the development of implantable microelectromechanical system (MEMS)-based devices that can be implanted into the brain with reduced risk of damage to the brain tissue due to their small size and low stiffness. Such devices are now widely applied in the clinic and brain research for understanding brain functions, diagnosing brain-related diseases, and pursuing innovative therapies. Inevitably, these invasive devices cause damage to the brain tissue, such as wounds, inflammation, and scars, eventually leading to dysfunction of the device. Therefore, it is vital to find an optimal design solution for such devices taking into consideration such parameters as size, stiffness and biocompatibility. In this review, we focus on three main brain applications of such devices: detection of electrical signals, intracranial pressure (ICP), and optogenetics. We summarize the current application scope of such MEMS-based devices in brain research and clinical application, and compare them based on their mechanical and biological properties. The understanding of the device design, methods of application, and current development can support neuroscientists and neurologists to make revolutionary discoveries in the brain research field.

In a biomedical diagnosis with a limited sample volume and low concentration, droplet-based microfluidics, also called digital microfluidics, becomes a very attractive approach. Previously, our group developed a magnetic-beads-based digital microfluidic immunoassay with a bead number of around 100, requiring less than 1 μL of sample volume to achieve a pg/mL level limit of detection (LOD). However, the bead number in each measurement was not the same, causing an unstable coefficient of variation (CV) in the calibration curve. Here, we investigated whether a fixed number of beads in this bead-based digital microfluidic immunoassay could provide more stable results. First, the bead screening chips were developed to extract exactly 100, 49, and 25 magnetic beads with diameters of less than 6 μm. Then, four calibration curves were established. One calibration curve was constructed by using varying bead numbers (50–160) in the process. The other three calibration curves used a fixed number of beads, (100, 49, and 25). The results indicated that the CVs for a fixed number of beads were evidently smaller than the CVs for varying bead numbers, especially in the range of 1 pg/mL to 100 pg/mL, where the CVs for 100 beads were less than 10%. Furthermore, the calculated LOD, based on the composite calibration curves, could be reduced by three orders, from 3.0 pg/mL (for the unfixed bead number) to 0.0287 pg/mL (for 100 beads). However, when the bead numbers were too high (more than 500) or too low (25 or fewer), the bead manipulation for aggregation became more difficult in the magnetic-beads-based digital microfluidic immunoassay chip.

At present, intramedullary interlocking nails are widely used for bone-fracture fixation in orthopedic surgeries. Surgeons often use X-ray imaging to find the actual location of the distal screw-holes of the nail after the nail is inserted into the medullary canal of a bone for fixation. Thus, the patients and medical team are inevitably exposed to radioactivity. In this paper, we report a radiation-free electromagnetic/magnetic-coupled targeting system to locate the distal screw-holes of the nail used in interlocking-nail surgery. The targeting system consists of a c-shaped electromagnet with a pick-up coil, a highly permeable curved silicon-steel strip embedded on the nail, a guiding mechanism, and electronic measuring instruments. An alternative current is applied to the electromagnet to generate a uniform magnetic field/flux in the electromagnet's air gap. When the nail inserted into the medullary canal of a bone is scanned through or rotated in the air gap of the electromagnet, the magnetic flux in the air gap is influenced by the silicon-steel strip embedded on the nail. The variation of the magnetic flux induces a voltage response in the pick-up coil due to electromagnetic induction. The pattern of the voltage response is analyzed to establish a criterion for screw-hole targeting. The results obtained using this criterion reveal that the maximum targeting error of the location and orientation targeting for a screw-hole with a diameter of 5 mm is <;2 mm and 10°, respectively. Thus, the system/approach is sufficiently simple and accurate to be used by surgeons in clinical surgery. [ABSTRACT FROM PUBLISHER]

This paper shows an application of fuzzy logic in designing and fabricating an intelligent robotic fish with multiple actuators which can swim freely and autonomously avoid obstacles in water. The multiple actuators on the robotic fish consist of two pectoral fins, one on each side of the fish, two tail sections, a center of gravity adjuster for the head of the fish, and a pump used to draw in or expel water. Based on the multiple actuators having adequate controls, the fish can swim forward, turn to the right, turn to the left, rise, and sink with high agility. The two main functions of the robotic fish are obstacle avoidance and target tracking. The distance between the fish and the obstacle is detected and measured by four infrared sensors on the fish's body. The fish can then avoid the obstacle autonomously when it approaches the obstacle. Obstacle avoidance is achieved using fuzzy control technique. As shown in the simulation and practical experiment, the path of obstacle avoidance using fuzzy control is much smoother than that using intuitive control. The other function is target tracking, in which the robotic tracker fish can track the robotic target fish autonomously and due to the obstacle avoidance function the two will not collide. All of the above motion controls are implemented by FPGA with the aids of several sensors. [ABSTRACT FROM AUTHOR]

This paper introduces the implementation of a fuzzy control based intelligent robot fish. The robot fish can swim autonomously or be controlled through remote control. Possible actions of the robot fish by remote control include swimming forward, turning left, turning right, sinking, and rising. It also includes automatic electrical power sensing functions. When electricity is low, the robot fish will surface to recharge electricity. Furthermore, the robot fish can perform some independent functions, such as obstacle avoidance and target tracking. A camera inside the fish can monitor underwater surroundings and also track targets in the water. This work uses two control methods, intuitive control and fuzzy control, to avoid obstacle and track targets, and then compares both of them by computer simulations and practical experiment. The comparison results show that fuzzy control fish performs better than the intuitive control fish. In order to prove the adaptability of the robot fish to different environments, the robot fish was tested not only in the pool of the laboratory, but also in various outdoor environments. The results show that the robot fish can be operated in all of the tested environments. [ABSTRACT FROM AUTHOR]