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1.
Cell ; 185(8): 1414-1430.e19, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35325595

RESUMEN

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This "cytokine med-chem" approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems.


Asunto(s)
COVID-19 , Citocinas , Humanos , Interleucina-2/farmacología , Células Asesinas Naturales , Ligandos , Receptores de Interleucina-10 , SARS-CoV-2
2.
Semin Immunol ; 69: 101814, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37542986

RESUMEN

Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.


Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Humanos , Anciano , Envejecimiento , Senescencia Celular/fisiología , Linfocitos T , Inflamación
3.
Environ Res ; 246: 118148, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38191040

RESUMEN

Interpreting the biogeographic distribution and underlying mechanisms of functional traits not only contributes to revealing the spatiotemporal dynamics of species biodiversity but also helps to maintain ecological stability during environmental variations. However, little is known about the functional profiles of diatom communities over large river systems. Herein, we provided the first blueprints about the spatiotemporal distributions and driving forces of functional traits for both planktonic and sedimentary diatoms over the 6030 km continuum of the Yangtze River, with the help of the high-throughput sequencing and functional identification. By investigating the 28 functional traits affiliated into five categories, we found that planktonic diatom functions showed clearer landform-heterogeneity patterns (ANOSIM R = 0.336) than sedimentary functions (ANOSIM R = 0.172) along the river, represented by life-forms and ecological-guilds prominent in water-plateau as well as cell-sizes and life-forms particularly in sediment-plateau. Planktonic diatom functions also displayed higher richness and network complexity in plateau (richness: 58.70 ± 9.30, network edges: 65) than in non-plateau regions (23.82 ± 13.16, 16), promoting the stability and robustness of diatom functions against the high-radiation and low-temperature plateau environment. Environmental selection (mainly exerted by PAR, UV, and Tw) played crucial roles in determining the functional variations of planktonic diatoms (explaining 80.5%) rather than sedimentary diatoms (14.5%) between plateau and non-plateau regions. Meanwhile, planktonic diatom traits within life-forms were identified to be well responsive to the ecological environment quality (r = 0.56-0.60, P < 0.001) in the Yangtze. This study provided comprehensive insights into the multifunctionality of diatoms and their responses to environmental disturbance and environment quality, which helps to develop effective strategies for maintaining ecological stability in changing river environments.


Asunto(s)
Diatomeas , Plancton , Ecosistema , Monitoreo del Ambiente , Biodiversidad , Ríos
4.
Proc Natl Acad Sci U S A ; 118(15)2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33876762

RESUMEN

Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP51-486), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP51-486 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.


Asunto(s)
Proteínas de Unión al GTP/química , Multimerización de Proteína , Sitios de Unión , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Células HEK293 , Humanos , Simulación de Dinámica Molecular , Unión Proteica , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo
5.
Angew Chem Int Ed Engl ; : e202411029, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38955769

RESUMEN

Graphite (Gr)-based lithium-ion batteries with admirable electrochemical performance below -20 °C are desired but are hindered by sluggish interfacial charge transport and desolvation process. Li salt dissociation via Li+-solvent interaction enables mobile Li+ liberation and contributes to bulk ion transport, while is contradictory to fast interfacial desolvation. Designing kinetically-stable solid electrolyte interphase (SEI) without compromising strong Li+-solvent interaction is expected to compatibly improve interfacial charge transport and desolvation kinetics. However, the relationship between physicochemical features and temperature-dependent kinetics properties of SEI remains vague. Herein, we propose four key thermodynamics parameters of SEI potentially influencing low-temperature electrochemistry, including electron work function, Li+ transfer barrier, surface energy, and desolvation energy. Based on the above parameters, we further define a novel descriptor, separation factor of SEI (SSEI), to quantitatively depict charge (Li+/e-) transport and solvent deprivation processes at Gr/electrolyte interface. A Li3PO4-based, inorganics-enriched SEI derived by Li difluorophosphate (LiDFP) additive exhibits the highest SSEI (4.89×103) to enable efficient Li+ conduction, e- blocking and rapid desolvation, and as a result, much suppressed Li-metal precipitation, electrolyte decomposition and Gr sheets exfoliation, thus improving low-temperature battery performances. Overall, our work originally provides visualized guides to improve low-temperature reaction kinetics/thermodynamics by constructing desirable SEI chemistry.

6.
J Transl Med ; 21(1): 805, 2023 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-37951977

RESUMEN

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease. Clinical models to accurately evaluate the prognosis of IPF are currently lacking. This study aimed to construct an easy-to-use and robust prediction model for transplant-free survival (TFS) of IPF based on clinical and radiological information. METHODS: A multicenter prognostic study was conducted involving 166 IPF patients who were followed up for 3 years. The end point of follow-up was death or lung transplantation. Clinical information, lung function tests, and chest computed tomography (CT) scans were collected. Body composition quantification on CT was performed using 3D Slicer software. Risk factors in blood routine examination-radiology-pulmonary function (BRP) were identified by Cox regression and utilized to construct the "BRP Prognosis Model". The performance of the BRP model and the gender-age-physiology variables (GAP) model was compared using time-ROC curves, calibration curves, and decision curve analysis (DCA). Furthermore, histopathology fibrosis scores in clinical specimens were compared between the different risk stratifications identified by the BRP model. The correlations among body composition, lung function, serum inflammatory factors, and profibrotic factors were analyzed. RESULTS: Neutrophil percentage > 68.3%, pericardial adipose tissue (PAT) > 94.91 cm3, pectoralis muscle radiodensity (PMD) ≤ 36.24 HU, diffusing capacity of the lung for carbon monoxide/alveolar ventilation (DLCO/VA) ≤ 56.03%, and maximum vital capacity (VCmax) < 90.5% were identified as independent risk factors for poor TFS among patients with IPF. We constructed a BRP model, which showed superior accuracy, discrimination, and clinical practicability to the GAP model. Median TFS differed significantly among patients at different risk levels identified by the BRP model (low risk: TFS > 3 years; intermediate risk: TFS = 2-3 years; high risk: TFS ≈ 1 year). Patients with a high-risk stratification according to the BRP model had a higher fibrosis score on histopathology. Additionally, serum proinflammatory markers were positively correlated with visceral fat volume and infiltration. CONCLUSIONS: In this study, the BRP prognostic model of IPF was successfully constructed and validated. Compared with the commonly used GAP model, the BRP model had better performance and generalization with easily obtainable indicators. The BRP model is suitable for clinical promotion.


Asunto(s)
Fibrosis Pulmonar Idiopática , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Pronóstico , Capacidad Vital , Biomarcadores , Fibrosis , Estudios Retrospectivos
7.
J Autoimmun ; 137: 102947, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36357240

RESUMEN

Immune aging is a complex process rendering the host susceptible to cancer, infection, and insufficient tissue repair. Many autoimmune diseases preferentially occur during the second half of life, counterintuitive to the concept of excess adaptive immunity driving immune-mediated tissue damage. T cells are particularly susceptible to aging-imposed changes, as they are under extreme proliferative pressure to fulfill the demands of clonal expansion and of homeostatic T cell repopulation. T cells in older adults have a footprint of genetic and epigenetic changes, lack mitochondrial fitness, and fail to maintain proteostasis, diverging them from host protection to host injury. Here, we review recent progress in understanding how the human T-cell system ages and the evidence detailing how T cell aging contributes to autoimmune conditions. T cell aging is now recognized as a risk determinant in two prototypic autoimmune syndromes; rheumatoid arthritis and giant cell arteritis. The emerging concept adds susceptibility to autoimmune and autoinflammatory disease to the spectrum of aging-imposed adaptations and opens new opportunities for immunomodulatory therapy by restoring the functional intactness of aging T cells.


Asunto(s)
Enfermedades Autoinmunes , Autoinmunidad , Humanos , Anciano , Autoinmunidad/fisiología , Linfocitos T , Envejecimiento , Senescencia Celular , Factores de Riesgo
8.
J Cell Mol Med ; 26(1): 99-107, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34889029

RESUMEN

Inhalation of crystalline silica causes silicosis, the most common and serious occupational disease, which is characterized by progressive lung inflammation and fibrosis. Recent studies revealed the anti-inflammatory and anti-fibrosis role of Caveolin-1 (Cav-1) in lung, but this role in silicosis has not been investigated. Thus, this study evaluated Cav-1 regulatory effects in silicosis. It was found that Cav-1 levels were significantly reduced in the lung from silicosis patients and silicotic mice. The silicosis models were established in C57BL/6 (wild-type) and Cav-1 deficiency (Cav-1-/- ) mice, and Cav-1-/- mice displayed wider alveolar septa, increased collagen deposition and more silicotic nodules. The mice peritoneal-derived macrophages were used to explore the role of Cav-1 in silica-induced inflammation, which plays a central role in mechanism of silicosis. Cav-1 inhibited silica-induced infiltration of inflammatory cells and secretion of inflammatory factors in vitro and in vivo, partly by downregulating NF-κB pathway. Additionally, silica uptake and expression of 4-hydroxynonenal in silicotic mice were observed, and it was found that Cav-1 absence triggered excessive silica deposition, causing a stronger oxidative stress response. These findings demonstrate the protective effects of Cav-1 in silica-induced lung injury, suggesting its potential therapeutic value in silicosis.


Asunto(s)
Fibrosis Pulmonar , Silicosis , Animales , Caveolina 1/genética , Caveolina 1/metabolismo , Modelos Animales de Enfermedad , Fibrosis , Humanos , Inflamación/patología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Dióxido de Silicio/toxicidad , Silicosis/metabolismo
9.
EMBO J ; 37(3): 351-366, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29288164

RESUMEN

The RIG-I-like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine-rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR-mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15-associated RIG-I to promote interaction between RIG-I and the autophagic cargo receptor p62 and to mediate RIG-I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG-I-p62 interaction as well as the autophagic degradation of RIG-I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG-I delivery to autophagosomes for degradation in a p62-dependent manner.


Asunto(s)
Autofagia/inmunología , Proteína 58 DEAD Box/metabolismo , Interferón Tipo I/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Células COS , Línea Celular , Chlorocebus aethiops , Citocinas/metabolismo , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Unión Proteica/inmunología , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptores Inmunológicos , Transducción de Señal/inmunología , Ubiquitinas/metabolismo , Virus de la Estomatitis Vesicular Indiana/inmunología
10.
EMBO J ; 37(18)2018 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-30065070

RESUMEN

Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non-structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11-linked poly-ubiquitin chains from caspase-1 at Lys134, thus inhibiting the proteasomal degradation of caspase-1. The enhanced stabilization of caspase-1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKVin vitro and in vivo Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future.


Asunto(s)
Caspasa 1/inmunología , Evasión Inmune , Nucleotidiltransferasas/inmunología , Proteolisis , Transducción de Señal/inmunología , Proteínas no Estructurales Virales/inmunología , Virus Zika/inmunología , Animales , Caspasa 1/genética , Chlorocebus aethiops , Endopeptidasas/genética , Endopeptidasas/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/inmunología , Células HEK293 , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Ratones , Ratones Noqueados , Nucleotidiltransferasas/genética , Transducción de Señal/genética , Células THP-1 , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/inmunología , Células Vero , Proteínas no Estructurales Virales/genética , Virus Zika/genética
11.
Anal Bioanal Chem ; 413(30): 7509-7520, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34643770

RESUMEN

Accurate measurement of plasma metanephrines (MNs) including metanephrine (MN) and normetanephrine (NMN) is crucial for the screening and diagnosis in pheochromocytomas and paragangliomas (PPGLs). Although the number of laboratories using liquid chromatography tandem mass spectrometry (LC-MS/MS) method to measure MNs has been increasing rapidly, those laboratory-developed assays showed incomparable results. There are no reference measurement procedures (RMPs) or reference materials (RMs) for MNs in Joint Committee for Traceability in Laboratory Medicine (JCTLM), which hindered the standardization of MNs measurement. We established a candidate RMP (cRMP) based on isotope dilution liquid chromatography tandem mass spectrometry (ID-LC/MS/MS) method for plasma MNs measurement. Plasma samples were spiked with MN-D3 and NMN-D3 as internal standards; protein precipitation and ion-exchange solid phase extraction (SPE) were performed to extract samples, eventually analyzed by LC-MS/MS. The cRMP was applied to evaluate two routine ID-LC/MS/MS methods through split-sample comparisons. Fifty-three individual patient samples were determined by cRMP and two routine ID-LC/MS/MS methods; results were analyzed by ordinary linear regression and Bland-Altman plots. The cRMP exhibited desirable imprecision, with intra-run and total imprecision (coefficient variation, CV) for MN being 0.79-1.36% and 1.53-1.87% and for NMN being 1.10-1.34% and 1.15-1.64%. The analytical recoveries of MN and NMN ranged from 98.3 to 101.7% and from 98.5 to 101.9%, respectively. Significant calibrator biases and sample-specific deviations were observed in method comparison. An accurate, precise, and reliable cRMP for plasma MNs was developed, and RMs with value assigned following the cRMP would help minimize the calibration bias and improve the comparability of different measuring systems.


Asunto(s)
Cromatografía Liquida/métodos , Metanefrina/sangre , Calibración , Humanos , Técnicas de Dilución del Indicador , Límite de Detección , Metanefrina/normas , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem
12.
Scand J Clin Lab Invest ; 81(3): 218-224, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33755506

RESUMEN

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) published the reference measurement procedure (RMP) for ALP measurement in 2011. However, the RMP is of high requirements for laboratories, complicated, time-consuming and high cost of reagents. Many manufacturers do not trace results to the higher procedure. And there is currently no designated comparison method (DCM) for ALP measurement. Thus, the standardization of ALP measurement is hindered. Automatic biochemical analyzers are easy to operate and widely used in clinical laboratories. Therefore, according to the RMP, establishing a DCM based on an automatic biochemical analyzer will be a practical way to establish traceability to the accuracy base and promote the standardization of ALP measurement. On the basis of conforming to the RMP recommended by IFCC as far as possible, the DCM was established based on a Thermo Indiko automatic biochemical analyzer. Performances of the method were validated. The DCM repeatability and within laboratory imprecision was <1% and <2.5%, respectively. For evaluation of trueness, the biases were within the equivalent limits. Measurement procedure comparisons and biases estimation were carried out between the DCM, the RMP, and the six routine methods using a panel of 40 individual human serum samples. The comparisons between the DCM and the RMP gave satisfying results. Compared with the DCM, the relative biases of some routine methods failed to meet the bias limit derived from biological variation.


Asunto(s)
Fosfatasa Alcalina/sangre , Análisis Químico de la Sangre/métodos , Análisis Químico de la Sangre/instrumentación , Análisis Químico de la Sangre/normas , Humanos , Laboratorios Clínicos/normas , Reproducibilidad de los Resultados
13.
BMC Med Educ ; 21(1): 194, 2021 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-33823845

RESUMEN

BACKGROUND: We combined anatomy with imaging, transformed the 2D information of various imaging techniques into 3D information, and form the assessment system of real medical imaging cases in order to make up for the deficiencies in the current teaching of the medical imaging technology students. METHODS: A total of 460 medical imaging students were selected and randomly divided into two groups. The research group received the teaching of the fusion of the original CT and MR data 3D model and the original image combined with 3D anatomical image. CT and MRI data are imported through load DICOM of 3D slicer. Different tissues and organs are segmented by threshold and watershed algorithm of segment editor module. Models are exported through export / import models and label maps in segmentation. Save the NHDR file of the original data and Obj file of the corresponding model through save the NHDR and corresponding Obj files are loaded into probe 1.0 software. The software can give different colors to the three-dimensional models of different organs or tissues to display the stereo models and related data, and display the hook edges of organ models on coronal, sagittal and axial images. At the same time, annotation can be established in the corresponding anatomical position. Finally, it can be saved as a single file of Hwl, and the teaching can be opened at any time through the program of probe 1.0. Statistical analysis Academic self-efficacy scale and Self-directed learning ability scale was adopted by self-directed learning evaluation scale between two groups. RESULTS: Compare the theoretical scores and case analysis scores of the two groups. The scores of the study and control groups were significantly higher than those of the control group. Before the experiment, no significant difference was detected in the self-efficacy of learning ability and learning behavior between the two groups, while after the experiment, these differences between the two groups were statistically significan. Moreover, the learning ability self-efficacy and learning behavior of the two groups of students after the experiment was significantly higher than that before the experiment. The self-efficacy of the learning behavior of the control group was higher after the experiment than that before the experiment, albeit the difference was not statistically significant. CONCLUSIONS: The modern, information-based and humanized experimental teaching mode will be constantly improved under the support of PACS system in order to optimize the medical imaging teaching activities for the development of modern medical education.


Asunto(s)
Imagenología Tridimensional , Estudiantes de Medicina , Humanos , Aprendizaje , Imagen por Resonancia Magnética , Enseñanza , Tecnología
14.
Beilstein J Org Chem ; 15: 2847-2855, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31839830

RESUMEN

A novel anthracene-based tetraperimidine hexafluorophosphate 3 was prepared, and its structure was determined through X-ray analysis, HRMS as well as 1H and 13C NMR spectroscopy. In the cationic moiety of 3, two (N-ethylperimidinyl-C2H4)2NCH2- arms were attached to the 9- and 10-positions of anthracene. In addition, compound 3 was used as a chemosensor to research the ability to recognize Cr3+ through fluorescence and UV titrations, HRMS, as well as 1H NMR and IR spectroscopy. The results indicate that 3 is an effective chemosensor for Cr3+.

15.
Beilstein J Org Chem ; 11: 563-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25977729

RESUMEN

A novel fluorescence sensor (BIP) bearing NH and OH subunits displayed a highly selective and sensitive recognition property for fluoride over other anions. Fluoride-driven ESPT, poorly used in anion recognition and sensing, was suggested to be responsible for the fluorescence enhancement with a blue shift of 35 nm in the emission spectrum.

16.
Bioorg Med Chem Lett ; 24(13): 2885-91, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24835984

RESUMEN

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.


Asunto(s)
Descubrimiento de Drogas , Proteínas Plasmáticas de Unión al Retinol/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Vitamina A/sangre
17.
Sci Rep ; 14(1): 3918, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38365929

RESUMEN

The multi-motor servo system (MMSS) is an electro-mechanical system widely used in various fields, including electric vehicles, robotics, and industrial machinery. Depending on the application, the number of motors in the system can range from several dozens to tens of thousands, which imposes additional communication demands. Thus, ensuring synchronization and control precision of the system requires addressing the challenge of guaranteeing the performance and reliability of communication among motors in the MMSS. In this paper, we design a smart servo motor (SSM) to upgrade the system to the multi-smart-motor servo system (MSMSS) based on a distributed real-time field bus architecture, namely, Multi-Motor Bus (MMB) architecture. The proposed MMB architecture is lightweight and stable, providing real-time support for Control Area Network connections to a central user computer and inter-integrated circuit connections to SSM units. This MMB architecture facilitates the synchronization of command transmission across SSMs and ensures the consistency of motors in the MSMSS. Additionally, a serial experiments to examine 3 key system performance and reliability characteristics are conducted, including command transmission time, transmission jitters, and rotation consistency. The analysis of these characteristics demonstrates the system's potential and feasibility to be applicable in industry.

18.
J Inflamm Res ; 17: 3159-3171, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38774448

RESUMEN

Background: Sepsis is a life-threatening clinical syndrome caused by dysregulated host response to infection. The mechanism underlying sepsis-induced immune dysfunction remains poorly understood. Natural killer T (NKT) cells are cytotoxic lymphocytes that bridge the innate and adaptive immune systems, the role of NKT cells in sepsis is not entirely understood, and NKT cell cluster differences in sepsis remain unexplored. Methods: Mendelian randomization (MR) analyses were first conducted to investigate the causal relationship between side scatter area (SSC-A) on NKT cells and 28-day mortality of septic patients. A prospective and observational study was conducted to validate the relationship between the percentage of NKT cells and 28-day mortality of sepsis. Then, the single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) from healthy controls and septic patients were profiled. Results: MR analyses first revealed the protective roles of NKT cells in the 28-day mortality of sepsis. Then, 115 septic patients were enrolled. NKT percentage was significantly higher in survivors (n = 84) compared to non-survivors (n = 31) (%, 5.00 ± 3.46 vs 2.18 ± 1.93, P < 0.0001). Patients with lower levels of NKT cells exhibited a significantly increased risk of 28-day mortality. According to scRNA-seq analysis, NKT cell clusters exhibited multiple distinctive characteristics, including a distinguishing cluster defined as FOS+NKT cells, which showed a significant decrease in sepsis. Pseudo-time analysis showed that FOS+NKT cells were characterized by upregulated expression of crucial functional genes such as GZMA and CCL4. CellChat revealed that interactions between FOS+NKT cells and adaptive immune cells including B cells and T cells were decreased in sepsis compared to healthy controls. Conclusion: Our findings indicate that NKT cells may protect against sepsis, and their percentage can predict 28-day mortality. Additionally, we discovered a unique FOS+NKT subtype crucial in sepsis immune response, offering novel insights into its immunopathogenesis.

19.
ACS Appl Mater Interfaces ; 16(2): 2932-2939, 2024 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-38179712

RESUMEN

Black silicon (BS), a nanostructured silicon surface containing highly roughened surface morphology, has recently emerged as a promising candidate for field emission (FE) cathodes in novel electron sources due to its huge number of sharp tips with ease of large-scale fabrication and controllable geometrical shapes. However, evaluating the FE performance of BS-based nanostructures with high accuracy is still a challenge due to the increasing complexity in the surface morphology. Here, we demonstrate a 3D modeling methodology to fully characterize highly disordered BS-based field emitters randomly distributed on a roughened nonflat surface. We fabricated BS cathode samples with different morphological features to demonstrate the validity of this method. We utilize parametrized scanning electron microscopy images that provide high-precision morphology details, successfully describing the electric field distribution in field emitters and linking the theoretical analysis with the measured FE property of the complex nanostructures with high precision. The 3D model developed here reveals a relationship between the field emission performance and the density of the cones, successfully reproducing the classical relationship between current density J and electric field E (J-E curve). The proposed modeling approach is expected to offer a powerful tool to accurately describe the field emission properties of large-scale, disordered nano cold cathodes, thus serving as a guide for the design and application of BS as a field electron emission material.

20.
Adv Sci (Weinh) ; 11(22): e2400615, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38489666

RESUMEN

Selenium (Se), the world's oldest optoelectronic material, has been widely applied in various optoelectronic devices such as commercial X-ray flat-panel detectors and photovoltaics. However, despite the rare and widely-dispersed nature of Se element, a sustainable recycling of Se and other valuable materials from spent Se-based devices has not been developed so far. Here a sustainable strategy is reported that makes use of the significantly higher vapor pressure of volatile Se compared to other functional layers to recycle all of them from end-of-life Se-based devices through a closed-space evaporation process, utilizing Se photovoltaic devices as a case study. This strategy results in high recycling yields of ≈ 98% for Se and 100% for other functional materials including valuable gold electrodes and glass/FTO/TiO2 substrates. The refabricated photovoltaic devices based on these recycled materials achieve an efficiency of 12.33% under 1000-lux indoor illumination, comparable to devices fabricated using commercially sourced materials and surpassing the current indoor photovoltaic industry standard of amorphous silicon cells.

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