ABSTRACT
BACKGROUND: Atogepant, an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist, is being investigated for the treatment of migraine. METHODS: We collected data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Four algorithms (ROR, PRR, BCPNN, and EBGM) were used as measures to detect signals of atogepant-associated adverse events (AEs) in real-world data. RESULT: Of the 3,552,072 reports, 2876 expressly stated the use of atogepant. Women accounted for the majority of adverse events (AEs), with a notable age concentration of 45-65 years. The percentage of reported adverse events was the highest in the United States. Significant system organ categories (SOC) included nervous system disorders, gastrointestinal disorders, nervous system disorders, surgical and medical procedures, ear and labyrinth disorders. Notably, preferred terms (PTs) related to atogepant include migraine, constipation, nausea, vertigo, somnolence, decreased appetite, dizziness and fatigue. Unexpected adverse events such as abnormal dreams, self-injurious ideation, brain fog, tension headache, nightmare, brain neoplasm, feeling abnormal, euphoric mood, hyperacusis and post concussion syndrome were also identified. CONCLUSIONS: The present investigation has detected new and unexpected signals of atogepant-related adverse drug reactions (ADRs). In order to confirm these solve safety issues that were previously overlooked, more research is necessary.
ABSTRACT
Acute kidney injury (AKI) is common and an independent risk factor for mortality in patients with paraquat (PQ) poisoning. Currently, no specific antidote is available. Synaptotagmin-1 (SYT1) has been identified as a key protein that facilitates PQ efflux in PQ-resistant A549 cells, thereby preventing PQ-induced lung injury. However, the protective effect of STY1 on PQ-induced AKI remains to be elucidated. This study exposed human kidney 2 (HK-2) cells overexpressing SYT1 to PQ. These cells exhibited significantly lower levels of growth inhibition, reactive oxygen species production, early apoptosis, and PQ accumulation compared to the parent HK-2 cells. Transcriptomic screening and Western blot analysis revealed that SYT1 overexpression significantly promoted the expression of glucose transporter 2 (GLUT2). Inhibition of GLUT2 completely abolished the protective effects of SYT1 overexpression in HK-2 cells and restored intracellular PQ concentrations. Further immunoprecipitation-shotgun and RNA interference experiments revealed that SYT1 binds to and stabilizes the protein SERPINE1 mRNA-binding protein 1 (SERBP1), enhancing the stability of GLUT2 mRNA and its protein levels. In summary, SYT1 antagonizes PQ intracellular accumulation and prevents nephrocyte toxicity by up-regulating SERBP1/GLUT2 expression. This study identifies a potential target for the treatment of PQ-induced AKI.
Subject(s)
Glucose Transporter Type 2 , Paraquat , Synaptotagmin I , Up-Regulation , Humans , Paraquat/toxicity , Synaptotagmin I/metabolism , Synaptotagmin I/genetics , Up-Regulation/drug effects , Cell Line , Glucose Transporter Type 2/metabolism , Glucose Transporter Type 2/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Apoptosis/drug effects , Reactive Oxygen Species/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/chemically induced , Acute Kidney Injury/pathologyABSTRACT
Bubbles are ubiquitous in the natural environment, where different substances and phases of the same substance forms globules due to differences in pressure and surface tension. Total internal reflection occurs at the interface of a bubble, where light travels from the higher refractive index material outside a bubble to the lower index material inside a bubble at appropriate angles of incidence, which can lead to a phase shift in the reflected light. Linearly polarized skylight can be converted to elliptically polarized light with efficiency up to 53% by single scattering from the water-air interface. Total internal reflection from air bubble in water is one of the few sources of elliptical polarization in the natural world. Stationary and dynamic scenes of air bubbles in water in both indoor and outdoor settings are studied using an imaging polarimeter. Our results are important for studies in fluid dynamics, remote sensing, and polarimetry.
ABSTRACT
Total internal reflection occurs when light is incident on the interface of high- and low-refractive-index materials at an angle greater than the critical angle. Sunlight with high degree of linear polarization, such as atmospheric scattered skylight, can be converted with a high efficiency up to 53% to circular and elliptical polarizations by total internal reflection under water in the region outside Snell's window. The degree of circular polarization is observed to be inversely dependent on the albedo of underwater objects and is shown to be a direct consequence of the Umov effect. Our results are important for underwater polarimetry, surveillance applications and studies of marine animals' polarized vision near the water-air interface.
ABSTRACT
Display devices, or displays, such as those utilized extensively in cell phones, computer monitors, televisions, instrument panels, and electronic signs, are polarized light sources. Most displays are designed for direct viewing by human eyes, but polarization imaging of reflected light from a display can also provide valuable information. These indirect (reflected/scattered) photons, which are often not in direct field-of-view and mixed with photons from the ambient light, can be extracted to infer information about the content on the display devices. In this work, we apply Stokes algebra and Mueller calculus with the edge overlap technique to the problem of extracting indirect photons reflected/scattered from displays. Our method applies to recovering information from linearly and elliptically polarized displays that are reflected by transmissive surfaces, such as glass, and semi-diffuse opaque surfaces, such as marble tiles and wood furniture. The technique can further be improved by applying Wiener filtering.
ABSTRACT
Cross-presentation is the mechanism by which exogenous Ag is processed for recognition by CD8(+) T cells. Murine CD8α(+) DCs are specialized at cross-presenting soluble and cellular Ag, but in humans this process is poorly characterized. In this study, we examined uptake and cross-presentation of soluble and cellular Ag by human blood CD141(+) DCs, the human equivalent of mouse CD8α(+) DCs, and compared them with human monocyte-derived DCs (MoDCs) and blood CD1c(+) DC subsets. MoDCs were superior in their capacity to internalize and cross-present soluble protein whereas CD141(+) DCs were more efficient at ingesting and cross-presenting cellular Ag. Whilst cross-presentation by CD1c(+) DCs and CD141(+) DCs was dependent on the proteasome, and hence cytosolic translocation, cross-presentation by MoDCs was not. Inhibition of endosomal acidification enhanced cross-presentation by CD1c(+) DCs and MoDCs but not by CD141(+) DCs. These data demonstrate that CD1c(+) DCs, CD141(+) DCs, and MoDCs are capable of cross-presentation; however, they do so via different mechanisms. Moreover, they demonstrate that human CD141(+) DCs, like their murine CD8α(+) DC counterparts, are specialized at cross-presenting cellular Ag, most likely mediated by an enhanced capacity to ingest cellular Ag combined with subtle changes in lysosomal pH during Ag processing and use of the cytosolic pathway.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Endocytosis , Phosphoproteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Viral Matrix Proteins/metabolism , Antigens, CD1/metabolism , Antigens, Surface/metabolism , Blood Circulation , Cell Line , Cross-Priming , Humans , Monocytes/immunology , Necrosis , Protein Transport , Solubility , ThrombomodulinABSTRACT
We demonstrated a continuous-wave (cw) and pulsed optical vortex with topological charges driven by heat generated during the lasing process without introducing the astigmatism effect and reducing lasing efficiency. During the lasing process, the topological charges were changeable by the thermal-induced lens and selected by the mode-matching between the pump and oscillating beams. With a graphene sample as the saturable absorber, a pulsed optical vortex was achieved at a wavelength of 1.36 µm, which identified that graphene could be used as a pulse modulator for the generation of a pulsed optical vortex. Thermally driven cw and pulsed optical vortexes should have various promising applications based on the compact structure, changeable topological charges, and specific wavelength.
ABSTRACT
We established a humanized mouse model incorporating FLT3-ligand (FLT3-L) administration after hematopoietic cell reconstitution to investigate expansion, phenotype, and function of human dendritic cells (DC). FLT3-L increased numbers of human CD141(+) DC, CD1c(+) DC, and, to a lesser extent, plasmacytoid DC (pDC) in the blood, spleen, and bone marrow of humanized mice. CD1c(+) DC and CD141(+) DC subsets were expanded to a similar degree in blood and spleen, with a bias toward expansion of the CD1c(+) DC subset in the bone marrow. Importantly, the human DC subsets generated after FLT3-L treatment of humanized mice are phenotypically and functionally similar to their human blood counterparts. CD141(+) DC in humanized mice express C-type lectin-like receptor 9A, XCR1, CADM1, and TLR3 but lack TLR4 and TLR9. They are major producers of IFN-λ in response to polyinosinic-polycytidylic acid but are similar to CD1c(+) DC in their capacity to produce IL-12p70. Although all DC subsets in humanized mice are efficient at presenting peptide to CD8(+) T cells, CD141(+) DC are superior in their capacity to cross-present protein Ag to CD8(+) T cells following activation with polyinosinic-polycytidylic acid. CD141(+) DC can be targeted in vivo following injection of Abs against human DEC-205 or C-type lectin-like receptor 9A. This model provides a feasible and practical approach to dissect the function of human CD141(+) and CD1c(+) DC and evaluate adjuvants and DC-targeting strategies in vivo.
Subject(s)
Adjuvants, Immunologic/pharmacology , Antigens, CD1/metabolism , Antigens, Surface/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Glycoproteins/metabolism , Membrane Proteins/pharmacology , Adjuvants, Immunologic/administration & dosage , Animals , Antigen Presentation/immunology , Antigens, CD/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Adhesion Molecule-1 , Cell Adhesion Molecules/metabolism , Female , Humans , Immunoglobulins/metabolism , Interferon-gamma/metabolism , Interleukin-12/metabolism , Lectins, C-Type/immunology , Lectins, C-Type/metabolism , Lymphocyte Activation/immunology , Membrane Proteins/administration & dosage , Mice , Mice, Inbred NOD , Mice, SCID , Minor Histocompatibility Antigens , Poly I-C/immunology , Receptors, Cell Surface/immunology , Receptors, Chemokine/metabolism , Thrombomodulin , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 9/metabolismABSTRACT
Human blood myeloid DCs can be subdivided into CD1c (BDCA-1)(+) and CD141 (BDCA-3)(+) subsets that display unique gene expression profiles, suggesting specialized functions. CD1c(+) DCs express TLR4 while CD141(+) DCs do not, thus predicting that these two subsets have differential capacities to respond to Escherichia coli. We isolated highly purified CD1c(+) and CD141(+) DCs and compared them to in vitro generated monocyte-derived DCs (MoDCs) following stimulation with whole E. coli. As expected, MoDCs produced high levels of the proinflammatory cytokines TNF, IL-6, and IL-12, were potent inducers of Th1 responses, and processed E. coli-derived Ag. In contrast, CD1c(+) DCs produced only low levels of TNF, IL-6, and IL-12 and instead produced high levels of the anti-inflammatory cytokine IL-10 and regulatory molecules IDO and soluble CD25. Moreover, E. coli-activated CD1c(+) DCs suppressed T-cell proliferation in an IL-10-dependent manner. Contrary to their mouse CD8(+) DC counterparts, human CD141(+) DCs did not phagocytose or process E. coli-derived Ag and failed to secrete cytokines in response to E. coli. These data demonstrate substantial differences in the nature of the response of human blood DC subsets to E. coli.
Subject(s)
Antigens, Surface/analysis , Dendritic Cells/immunology , Escherichia coli/immunology , Interleukin-10/biosynthesis , Myeloid Cells/immunology , Antigens, CD1 , Dendritic Cells/metabolism , Glycoproteins , Humans , Interleukin-10/metabolism , Lymphocyte Activation , Phenotype , T-Lymphocytes/immunology , ThrombomodulinABSTRACT
Dendritic cells (DC) are a heterogeneous population of bone marrow derived leucocytes that are essential in the initiation of primary T lymphocyte responses. DC are identified as Lineage negative, HLA-DR(+) blood cells that can be further subdivided by CD11c to distinguish CD11c(+) DC and the CD11c(-) plasmacytoid DC. Plasmacytoid DC are the primary IFNα producing cells and express CD303, CD304 and CD123. The CD11c(+) myeloid DC can be divided into populations by CD1c, CD16 and CD141 expression. Despite DC being a functionally unique population, they share many cell surface antigens with myeloid lineage cells and B lymphocytes. We used flow cytometry to screen fresh human blood DC populations with the HLDA9 panel of 63 directly labelled mAb which included mAb specific for a number of B lymphocyte antigens. Of this panel, 23 mAb did not bind Lin(-)HLA-DR(+) DC and 10 bound all four populations. Eight mAb bound to the three CD11c(+) DC populations whilst no mAb tested bound to only pDC. Some of the mAb expected to bind to DC populations failed in this analysis. Overall, this screening highlighted similarities between the CD11c(+) DC subsets and the relatively immature state of peripheral blood DC.
Subject(s)
Dendritic Cells/immunology , Antibodies, Monoclonal/immunology , CD11c Antigen/immunology , Cells, Cultured , Humans , Immunophenotyping , Protein Binding , ProteomeABSTRACT
The CD300 glycoproteins are a family of related leucocyte surface molecules that modulate a diverse array of cell processes via their paired triggering and inhibitory receptor functions. All family members have a single Ig-V like domain and they share a common evolutionary pathway. At least one member of the family has undergone significant positive selection (ranked second in the top 50) indicating a need to maintain some crucial function. Here we have reviewed the CD300 family members, and their expression on cells of the monocyte and dendritic cell lineages. The consequences of CD300 molecule expression by these leucocyte lineages are only now beginning to be understood. The ability to fine tune monocyte and dendritic cell function and immune responses highlights several potential options to exploit these molecules as therapeutic targets in chronic inflammatory diseases, allergy and other disease states.