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BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.
Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.
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Lithium (Li) metal negative electrodes have attracted wide attention for high-energy-density batteries. However, their low coulombic efficiency (CE) due to parasitic electrolyte reduction has been an alarming concern. Concentrated electrolytes are one of the promising concepts that can stabilize the Li metal/electrolyte interface, thus increasing the CE; however, its mechanism has remained controversial. In this work, we used a combination of LiN(SO2F)2 (LiFSI) and weakly solvating 1,2-diethoxyethane (DEE) as a model electrolyte to study how its liquid structure changes upon increasing salt concentration and how it is linked to the Li plating/stripping CE. Based on previous works, we focused on the Li electrode potential (ELi with reference to the redox potential of ferrocene) and solid-electrolyte-interphase (SEI) formation. Although ELi shows a different trend with DEE compared to conventional 1,2-dimethoxyethane (DME), which is accounted for by different ion-pair states of Li+ and FSI-, the ELi-CE plots overlap for both electrolytes, suggesting that ELi is one of the dominant factors of the CE. On the other hand, the extensive ion pairing results in the upward shift of the FSI- reduction potential, as demonstrated both experimentally and theoretically, which promotes the FSI--derived inorganic SEI. Both ELi and SEI contribute to increasing the Li plating/stripping CE.
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[This corrects the article DOI: 10.1021/acscatal.3c03951.].
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Li-mediated ammonia synthesis is, thus far, the only electrochemical method for heterogeneous decentralized ammonia production. The unique selectivity of the solid electrode provides an alternative to one of the largest heterogeneous thermal catalytic processes. However, it is burdened with intrinsic energy losses, operating at a Li plating potential. In this work, we survey the periodic table to understand the fundamental features that make Li stand out. Through density functional theory calculations and experimentation on chemistries analogous to lithium (e.g., Na, Mg, Ca), we find that lithium is unique in several ways. It combines a stable nitride that readily decomposes to ammonia with an ideal solid electrolyte interphase, balancing reagents at the reactive interface. We propose descriptors based on simulated formation and binding energies of key intermediates and further on hard and soft acids and bases (HSAB principle) to generalize such features. The survey will help the community toward electrochemical systems beyond Li for nitrogen fixation.
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Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.
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Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Vipoma , Femenino , Humanos , Persona de Mediana Edad , Vipoma/cirugía , Vipoma/diagnóstico , Vipoma/patología , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Péptido Intestinal Vasoactivo , Neoplasias Pancreáticas/diagnóstico , DiarreaRESUMEN
BACKGROUND: 25-hydroxycholesterol (25HC), produced by cholesterol 25-hydroxylase (CH25H) in macrophages, has been reported to inhibit the replication of viral pathogens such as severe acute respiratory syndrome coronavirus-2. Also, CH25H expression in macrophages is robustly induced by interferons (IFNs). OBJECTIVE: To better understand the serum level increase of 25HC in coronavirus disease 2019 (COVID-19) and how it relates to the clinical picture. METHODS: We measured the serum levels of 25HC and five other oxysterols in 17 hospitalized COVID-19 patients. RESULTS: On admission, 25HC and 27-hydroxycholesterol (27HC) serum levels were elevated; however, 7-ketocholesterol (7KC) levels were lower in patients with COVID-19 than in the healthy controls. There was no significant correlation between 25HC serum levels and disease severity markers, such as interferon-gamma (IFN-γ) and interleukin 6. Dexamethasone effectively suppressed cholesterol 25-hydroxylase (CH25H) mRNA expression in RAW 264.7 cells, a murine leukemia macrophage cell line, with or without lipopolysaccharide or IFNs; therefore, it might mitigate the increasing effects of COVID-19 on the serum levels of 25HC. CONCLUSIONS: Our results highlighted that 25HC could be used as a unique biomarker in severe COVID-19 and a potential therapeutic candidate for detecting the severity of COVID-19 and other infectious diseases.
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Antivirales , COVID-19 , Humanos , Animales , Ratones , Antivirales/farmacología , Replicación Viral , Línea CelularRESUMEN
The development of high-rate lithium-ion batteries is required for automobile applications. To this end, internal resistances must be reduced, among which Li+ transfer resistance at electrode/electrolyte interfaces is known to be the largest. Hence, it is of urgent significance to understand the mechanism and kinetics of the interfacial Li+ transfer. This Spotlight on Applications presents recent progress in the analysis and mechanical understanding of interfacial Li+ transfer. First, we review the reported activation energies (Ea) at various solid/liquid interfaces. On this basis, the mechanism and rate-determining step of the interfacial Li+ transfer are discussed from the viewpoints of the desolvation of Li+, the nature of the solid electrolyte interphase (SEI), and the surface structural features of electrodes. After that, we introduce promising strategies to reduce the Ea, highlighting some specific cases that give remarkably low Ea. We also note the variations in frequency factors or pre-exponential factors (A) of the interfacial Li+ transfer, which are primarily dominated by the number of Li+ intercalation sites on electrode surfaces. The current understanding and improvement strategies of interfacial Li+ transfer kinetics presented herein will be a foundation for designing high-rate lithium-ion batteries.
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Helicobacter suis, a zoonotic infection-related bacterium, induces gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. However, a lack of suitable animal models complicates the detailed analysis of this disease. Here, we describe the generation of a gastric MALT lymphoma mouse model. We then detail the use of this model combined with an immunostaining protocol to identify the cell populations that constitute gastric MALT lymphoma. This protocol can be used to identify the constituent cells of human MALT lymphoma. For complete details on the use and execution of this profile, please refer to Yamamoto et al. (2021).
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Infecciones por Helicobacter , Helicobacter heilmannii , Linfoma de Células B de la Zona Marginal , Neoplasias Gástricas , Animales , Modelos Animales de Enfermedad , Infecciones por Helicobacter/complicaciones , Linfoma de Células B de la Zona Marginal/complicaciones , Linfoma no Hodgkin , Ratones , Neoplasias Gástricas/complicacionesRESUMEN
Fluoride ions are used in battery electrolytes in fluoride shuttle batteries. Since organic solvents are used in battery electrolytes, there is a growing demand to develop appropriate methods for quantifying fluoride ion concentration in organic solvents. In this study, a fluoride ion-selective electrode (ISE) for organic solutions is proposed as an electrode of the second kind. A Ag|AgF electrode was made via the anodization of a silver wire in propylene carbonate (PC) containing dissolved fluoride ions. The resultant electrode exhibits a stable linear response of the open circuit potential to the logarithm of the fluoride ion concentration in PC solutions over a range of 10-4-10-2 mol dm-3. The lower and upper limits of the linear response were interpreted in terms of the solubility and the formation of a silver fluoride complex. The use of this electrode of the second kind is suitable for the analysis of fluoride ions in organic solutions and is a promising concept for the development of ISEs for the detection of ions in organic solutions under highly restrictive conditions.
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Helicobacter suis, a zoonotic infection-related bacterium, can induce gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. Recently, we reported that the formation of gastric MALT lymphoma after H. suis infection is induced by interferon (IFN)-γ activation. Here, we revealed that activation of the Toll-like receptor (TLR) 4-Toll/IL-1 receptor domain-containing adapter-inducing interferon-ß (TRIF) pathway after H. suis infection is associated with the production of type 1 IFNs (IFN-α, IFN-ß) by gastric epithelial cells. Additionally, these type 1 IFNs interact with type 1 IFN receptors on gastric B cells, facilitating the secretion of IFN-γ and the activation of which is enhanced by positive feedback regulation in B cells. These results suggest that the TLR4-TRIF-type 1 IFN-IFN-γ pathway is crucial in the development of gastric MALT lymphoma after H. suis infection and may, therefore, represent a therapeutic target for the prevention of this condition.
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This study attempted to stabilize the nanosurface of LiNiO2 (LNO) electrodes by varying the electrolyte concentration, significantly influencing its initial electrochemical behaviors for use in aqueous lithium-ion batteries. The charge/discharge capacities, reversibility, and cyclability of LNO were improved during initial cycles with an increase in the concentration of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI). As determined by the galvanostatic intermittent titration technique, the superior diffusivity of Li+ ions in the LNO electrode is also obtained in the concentrated electrolyte. Nanoscale observation of the LNO surface revealed that its morphology is maintained relatively well in the concentrated electrolyte while it is destroyed in dilute electrolytes after the initial electrochemical cycles. These results are considered to be attributable to the variation of the interface condition in the electrical double layer with an increase in the electrolyte concentration, thus stabilizing the nanosurface of LNO by suppressing the dissolution of Ni ions from the surface. Additionally, in situ X-ray diffraction analysis demonstrated that LNO shows more stable phase transitions and volume changes as the electrolyte concentration increases, indicating that its structural changes in bulk can be directly related to the state of the nanosurface, which has a positive impact on the initial electrochemical behaviors in this system.
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Carbon nanosphere (CNS) electrodes are the candidate of sodium-ion battery (SIB) negative electrodes with small internal resistances due to their small particle sizes. Electrochemical properties of low-crystallized CNS electrodes in dilute and concentrated sodium bis(trifluoromethanesulfonyl) amide/ethylene carbonate + dimethyl carbonate (NaTFSA/EC + DMC) were first investigated. From the cyclic voltammograms, both lithium ion and sodium ion can reversibly insert into/from CNSs in all of the electrolytes used here. The cycling stability of CNSs in concentrated electrolytes was better than that in dilute electrolytes for the SIB system. The interfacial charge-transfer resistances at the interface between CNSs and organic electrolytes were evaluated using electrochemical impedance spectroscopy. In the Nyquist plots, the semicircles at the middle-frequency region were assigned to the parallel circuits of charge-transfer resistances and capacitances. The interfacial sodium-ion transfer resistances in concentrated organic electrolytes were much smaller than those in dilute electrolytes, and the rate capability of CNS electrodes in sodium salt-concentrated electrolytes might be better than in dilute electrolytes, suggesting that CNSs with concentrated electrolytes are the candidate of SIB negative electrode materials with high rate capability. The calculated activation energies of interfacial sodium-ion transfer were dependent on electrolyte compositions and similar to those of interfacial lithium-ion transfer.
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Human (h) carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) function depends upon IgV-mediated homodimerization or heterodimerization with host ligands, including hCEACAM5, hTIM-3, PD-1, and a variety of microbial pathogens. However, there is little structural information available on how hCEACAM1 transitions between monomeric and dimeric states which in the latter case is critical for initiating hCEACAM1 activities. We therefore mutated residues within the hCEACAM1 IgV GFCC' face including V39, I91, N97, and E99 and examined hCEACAM1 IgV monomer-homodimer exchange using differential scanning fluorimetry, multi-angle light scattering, X-ray crystallography and/or nuclear magnetic resonance. From these studies, we describe hCEACAM1 homodimeric, monomeric and transition states at atomic resolution and its conformational behavior in solution through NMR assignment of the wildtype (WT) hCEACAM1 IgV dimer and N97A mutant monomer. These studies reveal the flexibility of the GFCC' face and its important role in governing the formation of hCEACAM1 dimers and selective heterodimers.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Antígenos CD/química , Antígenos CD/genética , Moléculas de Adhesión Celular/química , Moléculas de Adhesión Celular/genética , Cristalografía por Rayos X , Dispersión Dinámica de Luz , Fluorometría , Humanos , Espectroscopía de Resonancia Magnética , Mutación , Conformación Proteica , Multimerización de Proteína , Relación Estructura-ActividadRESUMEN
This study investigated the fundamental mechanisms of the loss of capacity of LiNiO2 (LNO) electrodes for Li+ insertion/deinsertion with a special focus on the origin of this deterioration in an aqueous system. In situ Raman spectra revealed that the intercalation of H+ ions formed a NiOOHx film at the surface of LNO during the initial electrochemical cycles; this NiOOHx film was also confirmed by X-ray photoelectron spectroscopy and transmission electron microscopy analysis. The formation of an electrochemically inactive spinel-like phase (Ni3O4) at the subsurface was triggered by the absence of Li in the NiOOHx film at the surface. These structural changes of LNO, accelerated by the intercalation of H+ ions, were considered to be the fundamental cause of the greater loss of capacity in the aqueous system.
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Invited for this month's cover are the groups of Shih-kang Lin at the National Cheng Kung University and Takeshi Abe at Kyoto University. The image shows how interfacial chemistry design can play a role in unlocking higher-energy-density and fast-charging Li4 Ti5 O12 -based lithium-ion batteries for electric vehicle applications. The Full Paper itself is available at 10.1002/cssc.202001086.
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Charge-transfer kinetics between electrodes and electrolytes critically determines the performance of lithium-ion batteries (LIBs). Lithium titanate defect spinel (Li4 Ti5 O12 , LTO) is a safe and durable anode material, but its relatively low energy density limits the range of applications. Utilizing the low potential region of LTO is a straightforward strategy for increasing energy density. However, the electrochemical characteristics of LTO at low potentials and the properties of the solid-electrolyte interphase (SEI) on LTO are not well understood. Here, we investigate the charge-transfer kinetics of the SEI formed between model LTO thin-film electrodes and organic electrolytes with distinct solvation ability using AC impedance spectroscopy whereas their stability was assessed by cyclic voltammetry of ferrocene. With the SEI film on LTO, the Li+ desolvation was rate-determining step but with larger activation energies, which showed a strong dependence on the solvation ability of electrolyte. The activation energies of desolvation for the fluoroethylene carbonate+dimethyl carbonate- and ethylene carbonate+diethyl carbonate-based systems increased from 35 and 55 to 44 and 67â kJ mol-1 , respectively, and that for the propylene carbonate-based system did not noticeably change at around 67â kJ mol-1 . In addition, the SEI passivation of LTO was much slower than that of graphite, and the rate also strongly depended on the solvation ability of the electrolyte. Understanding the surface properties of LTO at low potentials opens the door for high-energy-density LTO-based LIBs.
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T-cell immunoglobulin and mucin domain containing protein-3 (TIM-3) is an important immune regulator. Here, we describe a novel high resolution (1.7 Å) crystal structure of the human (h)TIM-3 N-terminal variable immunoglobulin (IgV) domain with bound calcium (Ca++) that was confirmed by nuclear magnetic resonance (NMR) spectroscopy. Significant conformational differences were observed in the B-C, C'-Câ³ and C'-D loops of hTIM-3 compared to mouse (m)TIM-3, hTIM-1 and hTIM-4. Further, the conformation of the C-C' loop of hTIM-3 was notably different from hTIM-4. Consistent with the known metal ion-dependent binding of phosphatidylserine (PtdSer) to mTIM-3 and mTIM-4, the NMR spectral analysis and crystal structure of Ca++-bound hTIM-3 revealed that residues in the hTIM-3 F-G loop coordinate binding to Ca++. In addition, we established a novel biochemical assay to define hTIM-3 functionality as determined by binding to human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). These studies provide new insights useful for understanding and targeting hTIM-3.
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Cristalografía por Rayos X/métodos , Receptor 2 Celular del Virus de la Hepatitis A/química , Resonancia Magnética Nuclear Biomolecular/métodos , Linfocitos T/metabolismo , Secuencia de Aminoácidos , Animales , Humanos , Ratones , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
AIM: To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. METHODS: The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed. RESULTS: The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients' GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01). CONCLUSION: Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms.