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In a neonatal mouse model of sterile sepsis, LPS-induced FOXC2 binding to FBE and FOXC2 expression in lung EC was attenuated with garcinol treatment. These data reveal a new mechanism of LPS-induced histone acetylation-dependent FOXC2 autoregulation.Aberrant ceramide build-up in preeclampsia, a serious disorder of pregnancy, causes exuberant autophagy-mediated trophoblast cell death. The significance of ceramide accumulation for lysosomal biogenesis in preeclampsia is unknown. Here we report that lysosome formation is markedly increased in trophoblast cells of early-onset preeclamptic placentae, in particular in syncytiotrophoblasts. This is accompanied by augmented levels of transcription factor EB (TFEB). In vitro and in vivo experiments demonstrate that ceramide increases TFEB expression and nuclear translocation and induces lysosomal formation and exocytosis. Further, we show that TFEB directly regulates the expression of lysosomal sphingomyelin phosphodiesterase (L-SMPD1) that degrades sphingomyelin to ceramide. In early-onset preeclampsia, ceramide-induced lysosomal exocytosis carries L-SMPD1 to the apical membrane of the syncytial epithelium, resulting in ceramide accumulation in lipid rafts and release of active L-SMPD1 via ceramide-enriched exosomes into the maternal circulation. The SMPD1-containing exosomes promote endothelial activation and impair endothelial tubule formation in vitro. Both exosome-induced processes are attenuated by SMPD1 inhibitors. These findings suggest that ceramide-induced lysosomal biogenesis and exocytosis in preeclamptic placentae contributes to maternal endothelial dysfunction, characteristic of this pathology.Newly differentiated pancreatic β cells lack proper insulin secretion profiles of mature functional β cells. The global gene expression differences between paired immature and mature β cells have been studied, but the dynamics of transcriptional events, correlating with temporal development of glucose-stimulated insulin secretion (GSIS), remain to be fully defined. This aspect is important to identify which genes and pathways are necessary for β-cell development or for maturation, as defective insulin secretion is linked with diseases such as diabetes. In this study, we assayed through RNA sequencing the global gene expression across six β-cell developmental stages in mice, spanning from β-cell progenitor to mature β cells. A computational pipeline then selected genes differentially expressed with respect to progenitors and clustered them into groups with distinct temporal patterns associated with biological functions and pathways. PMX-53 Inflamm inhibitor These patterns were finally correlated with experimental GSIS, calcium influx, temporal gene expression pattern analysis provided a comprehensive database of the underlying molecular components and biological mechanisms driving β-cell maturation at different temporal stages, which are fundamental for better control of the in vitro production of functional β cells from human embryonic stem/induced pluripotent cell for transplantation-based type 1 diabetes therapy.Progressive myoclonic epilepsy (PME) is a rare neurodegenerative disease, characterized by myoclonic seizures and tonic clonic seizures, with genetical and phenotypical heterogeneity. The semaphorin 6B (SEMA6B) gene has been recently reported a causal gene of PME. Independent studies are warranted to further support these findings. Here we report that one nonsense variant in NM_032108.3 exon17 c.2056C > T (p.Gln686∗) and one missense variant in exon14 c.1483G > T (p.Gly495Trp) of SEMA6B, both occurring de novo, underlie early-onset epilepsy with variable severity and different response to treatment in two patients. In vitro analyses have demonstrated that the nonsense variant, p.Gln686∗, results in a truncated protein with remarkably increased expression compared to that of the wild type. The truncated protein presented more homogeneous and failed to locate in the plasma membrane. The missense variant p.Gly495Trp affects evolutionarily conserved amino acid and is located in the sema domain, a key functional domain of SEMA6B. It was predicted to perturb the SEMA6B function by altering the tertiary structure of mutant protein, although neither change of protein length and expression nor difference of cellular distribution was observed. Co-immunoprecipitation studies have demonstrated that both variants influence protein binding of SEMA6B and PlxnA2 with varying degrees. Our results provide further evidence to support the initial findings of SEMA6B being causal to epilepsy and indicate that mediating Semaphorin/Plexin signaling is the potential mechanism of the SEMA6B-related disease.The chicken egg is a well-known complete food of human daily consumption which serves as a cost-effective, high-quality nutrient resource. About 30% of table eggs are directed to breaker plants in developed countries, leading to the generation of substantial eggshell (ES) waste, which is increasingly explored for potential value-added applications. The number of patents describing ES-based applications has increased dramatically in recent years. This review provides insight into the most recent patents published between 2015 and 2020, with focus on different engineering technologies for the screening, separation, and processing of ES. Screening technologies include detection of ES surface spots and glossiness, ES cracks, and mechanical properties, along with identification of chicken breed and enumeration of surface bacterial count. Collection and separation technologies describe separation strategies of ES from egg white (EW), egg yolk (EY), liquid egg, eggshell membrane (ESM), hatchlings, and cooked egg. Separation of ES from liquid eggs utilizes gravity, rotational forces, or air pressure. Processing of ES involves washing and sterilization along with cutting, crushing, and pulverization technologies that enable the collection of ES suitable for value-added applications. In addition, ES carving (mechanical and laser) opens up the realm of artwork and decoration. Furthermore, intact ES can be utilized for food serving. The exponential increase in innovative screening, separation, collection, and processing technologies reflects industrial interest to upscale low-value ES waste material, and is a first crucial step in the emergence of advanced technologies that exploit the biomedical, chemical, engineering, and environmental applications for ES.Pulmonary drug delivery has recognized benefits for both local and systemic treatments. Dry powder inhalers (DPIs) are convenient, portable and environmentally friendly devices, becoming an optimal choice for patients. The tailoring of novel formulations for DPIs, namely in the form of porous particles, is stimulating in the pharmaceutical research area to improve delivery efficiency. Suitable powder technological approaches are being sought to design such formulations. Namely, aerogel powders are nanostructured porous particles with particularly attractive properties (large surface area, excellent aerodynamic properties and high fluid uptake capacity) for these purposes. In this review, the most recent development on powder technologies used for the processing of particulate porous carriers are described via updated examples and critically discussed. A special focus will be devoted to the most recent advances and uses of aerogel technology to obtain porous particles with advanced performance in pulmonary delivery.Biomaterials play a core role in cartilage repair and regeneration. The success or failure of an implanted biomaterial is largely dependent on host response following implantation. Host response has been considered to be influenced by numerous factors, such as immune components of materials, cytokines and inflammatory agents induced by implants. Both synthetic and native materials involve immune components, which are also termed as immunogenicity. Generally, the innate and adaptive immune system will be activated and various cytokines and inflammatory agents will be consequently released after biomaterials implantation, and further triggers host response to biomaterials. This will guide the constructive remolding process of damaged tissue. Therefore, biomaterial immunogenicity should be given more attention. Further understanding the specific biological mechanisms of host response to biomaterials and the effects of the host-biomaterial interaction may be beneficial to promote cartilage repair and regeneration. In this review, we summarized the characteristics of the host response to implants and the immunomodulatory properties of varied biomaterial. We hope this review will provide scientists with inspiration in cartilage regeneration by controlling immune components of biomaterials and modulating the immune system.Central to the investigation of the biomechanics of traumatic brain injury (TBI) and the assessment of injury risk from head impact are finite element (FE) models of the human brain. However, many existing FE human brain models have been developed with simplified representations of the parenchyma, which may limit their applicability as an injury prediction tool. Recent advances in neuroimaging techniques and brain biomechanics provide new and necessary experimental data that can improve the biofidelity of FE brain models. In this study, the CAB-20MSym template model was developed, calibrated, and extensively verified. To implement material heterogeneity, a magnetic resonance elastography (MRE) template image was leveraged to define the relative stiffness gradient of the brain model. A multi-stage inverse FE (iFE) approach was used to calibrate the material parameters that defined the underlying non-linear deviatoric response by minimizing the error between model-predicted brain displacements and experimental t data. Strains predicted by the calibrated model under non-injurious rotational impacts in human volunteers (N = 6) also demonstrated similar biofidelity compared to in vivo measurements obtained from tagged magnetic resonance imaging studies. In addition to serving as an anatomically accurate model for further investigations of TBI biomechanics, the MRE-based framework for implementing material heterogeneity could serve as a foundation for incorporating subject-specific material properties in future models.Protein-protein interactions (PPIs) are well-established as a class of promising drug targets for their implications in a wide range of biological processes. However, drug development toward PPIs is inevitably hampered by their flat and wide interfaces, which generally lack suitable pockets for ligand binding, rendering most PPI systems "undruggable." Here, we summarized drug design strategies for developing peptide-based PPI inhibitors. Importantly, several quintessential examples toward well-established PPI targets such as Bcl-2 family members, p53-MDM2, as well as APC-Asef are presented to illustrate the detailed schemes for peptide-based PPI inhibitor development and optimizations. This review supplies a comprehensive overview of recent progresses in drug discovery targeting PPIs through peptides or peptidomimetics, and will shed light on future therapeutic agent development toward the historically "intractable" PPI systems.