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The interplay between immune checkpoints KLRB1 and CLEC2D is crucial for tumor progression and immune evasion, yet the interaction dynamics are not fully understood. This study aims to elucidate the interaction across various cancers and identify small molecule inhibitors that can disrupt it. We perform a comprehensive pan-cancer analysis of the KLRB1-CLEC2D pair, including mRNA expression patterns, pathological stages, survival outcomes, and single-cell omics, immune infiltration, copy number variations, and DNA methylation profiles. Our findings reveal a consistently higher CLEC2D/KLRB1 ratio in most cancer types compared to normal tissues, and this ratio also increased with advancing pathological stages. Lower KLRB1 expression correlated with higher mortality in most cancers, opposite to CLEC2D. Expression variations were attributed to differential lymphocyte infiltration, CNV, and DNA methylation. Structure-based virtual screening analysis identified compounds including forsythiaside A and RGD peptides as effective inhibitors of the KLRB1-CLEC2D interaction, validated through microscale thermophoresis. This research advances understanding of the KLRB1-CLEC2D interaction within the tumor microenvironment and introduces novel therapeutic strategies to modulate this interaction.
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BACKGROUND: Dietary Reference Intake (DRI) Recommendations for total sulfur amino acids (TSAA; methionine + cysteine) during pregnancy are based on factorial calculations using data from adult males. To date, no data exist on TSAA requirements obtained directly during pregnancy. OBJECTIVE: The objective of this study was to examine whether TSAA requirement during early (11-20 wk) and late (31-40 wk) gestation in healthy females with singleton pregnancies, are different than current recommendations, and different between early and late gestation using the indicator amino acid oxidation (IAAO) technique. METHODS: Twenty-five females 20-40 y with a healthy singleton pregnancy were studied using the IAAO technique in a repeated measures design for a total of 70, 8-hour days. On each study day a methionine test intake (range: 0 - 40 mgâ kg-1â day-1) was provided in 8 hourly, isonitrogenous and isocaloric meals with cysteine excluded from the diet. Breath samples were collected at baseline and isotopic steady state of orally provided L-1-13C-Phenylalanine for measurement of phenylalanine oxidation. Requirement was determined using biphasic linear regression crossover analysis to identify a breakpoint in 13CO2 production, representing the estimated average requirement (EAR). RESULTS: The TSAA requirement in healthy pregnant participants in early gestation was 11.1 mgâ kg-1â day-1 (R2m=0.79, R2c=0.79; 95% CI [8.9, 13.3 mgâ kg-1â day-1]) and 15.0 mgâ kg-1â day-1 (R2m=0.72, R2c=0.79; 95% CI [13.0, 17.0 mgâ kg-1â day-1]) in late gestation. Difference between Confidence Intervals (DCI) of the two breakpoints was = -3.9 ± 3.0, and statistically different. CONCLUSIONS: We directly measured TSAA requirements in healthy pregnant mothers and our findings suggest that requirements are lower than current DRI recommendations of 20 and 25 mgâ kg-1â day-1, as the EAR, and Recommended Dietary Allowance (RDA), respectively. Late gestation TSAA needs are significantly different and increased 35% compared to early gestation. Recommendations for TSAA intake need to be tailored for gestational stage. CLINICAL TRIAL REGISTRY NUMBER: NCT04326322 clinicaltrials.gov.
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BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).
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Antidepresivos , Depresión , Medicamentos Herbarios Chinos , Inflamasomas , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/complicaciones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Ratas , Depresión/tratamiento farmacológico , Depresión/etiología , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Masculino , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND: Fat grafting is widely used in breast reconstruction and aesthetic plastic surgery. However, the success rate and effects of fat grafting, especially in elderly female donors, are observed. This study aimed to explore the difference in the survival rate of donor fat from elderly women and young women in fat grafting. METHODS: We collected adipose tissue samples from two healthy Chinese women: a young woman and an elderly woman. In addition, adipose tissue samples were collected from female nude mice in four experimental groups-CON-Y, CON-O, OVX-Y, and OVX-O-after fat transplantation. Grafts were harvested, weighed, and subjected to assessment of histology and angiogenesis. RESULTS: An ovariectomy model was successfully established to validate the effect of low estrogen levels on fat grafting results. Due to the influence of low estrogen levels, the graft survival rate of donor site fat was significantly higher in elderly women than in young women, accompanied by a lesser degree of angiogenesis. Low estrogen levels led to adipocyte hypertrophy, which may be related to decreased AQP-7 expression. CONCLUSIONS: AQP-7 downregulation due to low estrogen levels induces adipocyte hypertrophy, and donor fat from elderly women exhibits a higher survival rate after fat transplantation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Tejido Adiposo , Estrógenos , Supervivencia de Injerto , Humanos , Femenino , Tejido Adiposo/trasplante , Animales , Factores de Edad , Ratones , Anciano , Ratones Desnudos , Adulto , Mamoplastia/métodos , Ovariectomía , Persona de Mediana EdadRESUMEN
The objective of this study was to assess the relationship between the triglyceride-glucose (TyG) index, a recently proposed marker of insulin resistance, and the occurrence of diabetic retinopathy (DR), a complication associated with cardiovascular risk. This systematic review and meta-analysis aimed to evaluate the association between the TyG index and DR. To achieve the objective of the meta-analysis, an extensive search was conducted on databases such as PubMed, Embase, and Web of Science to identify observational studies with longitudinal follow-up. Random-effects models were employed to combine the findings, taking into account the potential influence of heterogeneity. Twelve observational studies from 11 reports were included in the meta-analysis, which involved 16 259 patients with type 2 diabetes (T2D). Among them, 4302 (26.5%) were diagnosed as DR. Pooled results showed that a higher TyG index was associated with a higher risk of DR [odds ratio (OR) for the fourth versus the first quartile of TyG index: 1.91, 95% confidence interval (CI): 1.44 to 2.53, p<0.001; I2=72%]. Meta-analysis of TyG index analyzed in continuous variable showed consistent results (OR for per 1 unit increment of TyG index: 1.41, 95% CI: 1.08 to 1.86, p=0.01; I2=82%). Subgroup analysis showed that adjustment of HbA1c or the duration of diabetes did not significantly affect the results (p for subgroup difference all>0.05). In conclusion, a high TyG index was associated with the risk of DR in T2D patients.
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Flagella play a crucial role in the invasion process of Salmonella and function as a significant antigen that triggers host pyroptosis. Regulation of flagellar biogenesis is essential for both pathogenicity and immune escape of Salmonella. We identified the conserved and unknown function protein STM0435 as a new flagellar regulator. The ∆stm0435 strain exhibited higher pathogenicity in both cellular and animal infection experiments than the wild-type Salmonella. Proteomic and transcriptomic analyses demonstrated dramatic increases in almost all flagellar genes in the ∆stm0435 strain compared to wild-type Salmonella. In a surface plasmon resonance assay, purified STM0435 protein-bound c-di-GMP had an affinity of ~8.383 µM. The crystal structures of apo-STM0435 and STM0435&c-di-GMP complex were determined. Structural analysis revealed that R33, R137, and D138 of STM0435 were essential for c-di-GMP binding. A Salmonella with STM1987 (GGDEF protein) or STM4264 (EAL protein) overexpression exhibits completely different motility behaviours, indicating that the binding of c-di-GMP to STM0435 promotes its inhibitory effect on Salmonella flagellar biogenesis.
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Proteínas Bacterianas , GMP Cíclico/análogos & derivados , Proteómica , Animales , Virulencia , Proteínas Bacterianas/genética , Biopelículas , Salmonella/metabolismo , GMP Cíclico/análisis , GMP Cíclico/metabolismo , Regulación Bacteriana de la Expresión GénicaRESUMEN
In this study, the performance of a zero-gap flow-through reactor with three-dimensional (3D) porous Ti/RuO2-TiO2@Pt anodes was systematically investigated for the electrocatalytic oxidation of phenolic wastewater, considering phenol and 4-nitrophenol (4-NP) as the target pollutants. The optimum parameters for the electrochemical oxidation of phenol and 4-NP were examined. For phenol degradation, at an initial concentration of 50 mg/L, initial pH of 7, NaCl concentration of 10.0 g/L, current density of 10 mA/cm2, and retention time of 30 min, the degradation efficiency achieved was 95.05%, with an energy consumption of 15.39 kWh/kg; meanwhile, for 4-NP, the degradation efficiency was 98.42% and energy consumption was 19.21 kWh/kg (at an initial concentration of 40 mg/L, initial pH of 3, NaCl concentration of 10.0 g/L, current density of 10 mA/cm2, and retention time of 30 min). The electrocatalytic oxidation of phenol and 4-NP conformed to the pseudo-first-order kinetics model, and the k values were 0.2562 min-1 and 0.1736 min-1, respectively, which are 1.7 and 3.6-times higher than those of a conventional electrolyzer. Liquid chromatography-mass spectrometry (LC-MS) was used to verify the intermediates formed during the degradation of phenol or 4-NP and a possible degradation pathway was provided. The extremely narrow electrode distance and the flow-through configuration of the zero-gap flow-through reactor were thought to be essential for its lower energy consumption and higher mass transfer efficiency. The zero-gap flow-through reactor with a novel 3D porous Ti/RuO2-TiO2@Pt electrode is a superior alternative for the treatment of industrial wastewater.
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The intestinal pathogen Salmonella enterica rapidly enters the bloodstream after the invasion of intestinal epithelial cells, but how Salmonella breaks through the gut-vascular barrier is largely unknown. Here, we report that Salmonella enters the bloodstream through intestinal CX3CR1+ macrophages during early infection. Mechanistically, Salmonella induces the migration/invasion properties of macrophages in a manner dependent on host cell actin and on the pathogen effector SteC. SteC recruits host myosin light chain protein Myl12a and phosphorylates its Ser19 and Thr20 residues. Myl12a phosphorylation results in actin rearrangement, and enhanced migration and invasion of macrophages. SteC is able to utilize a wide range of NTPs other than ATP to phosphorylate Myl12a. We further solved the crystal structure of SteC, which suggests an atypical dimerization-mediated catalytic mechanism. Finally, in vivo data show that SteC-mediated cytoskeleton manipulation is crucial for Salmonella breaching the gut vascular barrier and spreading to target organs.
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Cadenas Ligeras de Miosina , Salmonella enterica , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Actinas/metabolismo , Células Epiteliales/metabolismo , Macrófagos/metabolismoRESUMEN
In this study, a zero-gap flow-through microfluidic reactor was constructed for the degradation of tetracycline and norfloxacin in water using a porous Ti/RuO2-IrO2@Pt electrode as the anode and porous titanium plate as the cathode. The operation parameters included electrolyte type, electrolyte concentration, current density, initial concentration of pollutants and pH, were investigated. The degradation efficiency and energy consumption were calculated and compared with traditional electrolyzer. In the zero-gap flow-through microfluidic reactor, 100 % of both tetracycline and norfloxacin can be decomposed in 15â min, and high mineralization rate were achieved under the optimized reaction condition. And the reaction was consistent with pseudo-first-order kinetics with k value of 0.492â cm-1 and 1.010â cm-1, for tetracycline and norfloxacin, respectively. In addition, the energy consumption was 28.33â kWh â kg-1 TC and 8.36â kWh â kg-1 NOR, for tetracycline and norfloxacin, respectively, which was much lower than that of traditional electrolyzer. The LC-MS results showed that tetracycline underwent a series of demethylation, dehydration and deamination reactions, and the norfloxacin went through ring opening reaction, decarboxylation and hydroxylation reaction, and finally both produced CO2 and H2O.
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Porcine epidemic diarrhea virus (PEDV) is an acute and highly contagious porcine enteric coronavirus. It has caused serious economic losses of pig industry in China. Here we insolated a current PEDV field strain named GS2022, analyzed the characters of genetic variation and pathogenicity. The results demonstrated that the GS2022 strain was belong to a newly defined subgroup G2 d, forming an independent branch which mainly contains strains isolated in China from 2017 to 2023. Notably, there are multiple mutations and extensive N-glycosylation compared to CV777 strain and PT-P5 strain, therefore the structure of GS2022 strain is different from 6U7K and 7W6M. Animal pathogenicity test showed that GS2022 strain could cause severe clinical signs and the high level of virus shedding in 7-day-old piglets. But recovery of diarrhea after 5 days, and no pathological damage to important organs. Further study on 3-day-old piglets also indicated GS2022 strain have pathogenicity. In this study no piglets died, which make it possible for that GS2022 strain become a candidate vaccine. These results are helpful to understand the epidemiology, molecular characteristics, evolution, and antigenicity of PEDV circulating in China. It also provides reference for designing effective vaccines against PEDV.
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Infecciones por Coronavirus , Virus de la Diarrea Epidémica Porcina , Enfermedades de los Porcinos , Animales , Porcinos , Virulencia , Filogenia , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/veterinaria , China/epidemiología , Recombinación Genética , Diarrea/veterinariaRESUMEN
Colorectal cancer (CRC) is currently the third leading cancer and commonly develops from chronic intestinal inflammation. A strong association was found between gut microbiota and intestinal inflammation and carcinogenic risk. Flavonoids, which are abundant in vegetables and fruits, can inhibit inflammation, regulate gut microbiota, protect gut barrier integrity, and modulate immune cell function, thereby attenuating colitis and preventing carcinogenesis. Upon digestion, about 90% of flavonoids are transported to the colon without being absorbed in the small intestine. This phenomenon increases the abundance of beneficial bacteria and enhances the production of short-chain fatty acids. The gut microbe further metabolizes these flavonoids. Interestingly, some metabolites of flavonoids play crucial roles in anti-inflammation and anti-tumor effects. This review summarizes the modulatory effect of flavonoids on gut microbiota and their metabolism by intestinal microbe under disease conditions, including inflammatory bowel disease, colitis-associated cancer (CAC), and CRC. We focus on dietary flavonoids and microbial interactions in intestinal mucosal barriers as well as intestinal immune cells. Results provide novel insights to better understand the crosstalk between dietary flavonoids and gut microbiota and support the standpoint that dietary flavonoids prevent intestinal inflammation and carcinogenesis.
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Colitis , Microbiota , Humanos , Inflamación , Polifenoles , Flavonoides/farmacología , CarcinogénesisRESUMEN
With an increasing number of patients with gastrointestinal cancer, effective and accurate early diagnostic clinical tools are required provide better health care for patients with gastrointestinal cancer. Recent studies have shown that artificial intelligence (AI) plays an important role in the diagnosis and treatment of patients with gastrointestinal tumors, which not only improves the efficiency of early tumor screening, but also significantly improves the survival rate of patients after treatment. With the aid of efficient learning and judgment abilities of AI, endoscopists can improve the accuracy of diagnosis and treatment through endoscopy and avoid incorrect descriptions or judgments of gastrointestinal lesions. The present article provides an overview of the application status of various artificial intelligence in gastric and colorectal cancers in recent years, and the direction of future research and clinical practice is clarified from a clinical perspective to provide a comprehensive theoretical basis for AI as a promising diagnostic and therapeutic tool for gastrointestinal cancer.
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Unlike what happens in conventional ferroics, the ferrorotational (FR) domain manipulation and visualization in FR materials are nontrivial as they are invariant under both space-inversion and time-reversal operations. FR domains have recently been observed by using the linear electrogyration (EG) effect and X-ray diffraction (XRD) diffraction mapping. However, ferrorotational selectivity, such as the selective processing of the FR domains and direct visualization of the FR domains, e.g., under an optical microscope, would be the next step to study the FR domains and their possible applications in technology. Unexpectedly, we discovered that the microscopic FR structural distortions in ilmenite crystals can be directly coupled with macroscopic mechanical rotations in such a way that FR domains can be visualized under an optical microscope after innovative rotational polishing, a combined ion milling with a specific rotational polishing, or a twisting-induced fracturing process. Thus, the FR domains could be a unique medium to register the memory of a rotational mechanical process due to a novel selective coupling between its microscopic structural rotations and an external macroscopic rotation. Analogous to the important enantioselectivity in modern chemistry and the pharmaceutical industry, this newly discovered ferrorotational selectivity opens up opportunities for FR manipulation and new FR functionality-based applications.
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This experiment aimed to investigate the protective effect of sea buckthorn (Hipphophae rhamnoides) extract on an animal model of NAFLD induced by high-fat and cholesterol diet. Twenty-five SPF-grade male KM mice were randomly divided into the blank control group, high-fat model group, sea-buckthorn low-dose group, sea-buckthorn medium-dose group, and sea-buckthorn high-dose group. During the whole experiment, the high-fat model group and sea-buckthorn treatment group were fed high-fat and high-cholesterol diet to build the fatty liver model, whereas the blank control group was fed ordinary diet. The high-fat model group and blank control group were intragastrically given normal saline, and each sea buckthorn treatment group was intragastrically given different concentrations of sea buckthorn extract. After 5 weeks of intervention using the abovementioned method, the experiment was completed; relevant serological indexes were determined, and the liver coefficient was calculated. Our results demonstrated that the liver coefficient in the high-dose sea buckthorn group was extremely significantly decreased (P < 0.01) compared with that in the high-fat model group. In addition, the concentration of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in serum of mice was decreased by the intervention of sea buckthorn extract, whereas the concentration of high-density lipoprotein cholesterol (HDL-C) was increased. Significant differences were observed between the sea-buckthorn high-dose treatment group and the high-fat model group (P < 0.05). The extracts of sea buckthorn had a certain protective effect on non-alcoholic fatty liver. This study lays an important foundation in developing and using sea buckthorn extract as a clinical drug and guiding people to take health care products reasonably.
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Hippophae , Enfermedad del Hígado Graso no Alcohólico , Humanos , Ratones , Masculino , Animales , Dieta Alta en Grasa/efectos adversos , Hígado , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Colesterol/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.
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Electrocatalytic oxidation (ECO) has attracted attention because of its high efficiency and environmental friendliness in water treatment. The preparation of anodes with high catalytic activity and long service lifetimes is a core part of electrocatalytic oxidation technology. Here, porous Ti/RuO2-IrO2@Pt, Ti/RuO2-TiO2@Pt, and Ti/Y2O3-RuO2-TiO2@Pt anodes were fabricated by means of modified micro-emulsion and vacuum impregnation methods with high porosity titanium plates as substrates. The scanning electron microscopy (SEM) images showed that RuO2-IrO2@Pt, RuO2-TiO2@Pt, and Y2O3-RuO2-TiO2@Pt nanoparticles were coated on the inner surface of the as-prepared anodes to form the active layer. Electrochemical analysis revealed that the high porosity substrate could result in a large electrochemically active area, and a long service life (60 h at 2 A cm-2 current density, 1 mol L-1 H2SO4 as the electrolyte, and 40 °C). The degradation experiments conducted on tetracycline hydrochloride (TC) showed that the porous Ti/Y2O3-RuO2-TiO2@Pt had the highest degradation efficiency for tetracycline, reaching 100% removal in 10 min with the lowest energy consumption of 167 kWh kg-1 TOC. The reaction was consistent with the pseudo-primary kinetics results with a k value of 0.5480 mol L-1 s-1, which was 16 times higher than that of the commercial Ti/RuO2-IrO2 electrode. The fluorospectrophotometry studies verified that the degradation and mineralization of tetracycline were mainly ascribed to the â¢OH generated in the electrocatalytic oxidation process. This study thus presents a series of alternative anodes for future industrial wastewater treatment.
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The discovery of pathogenic variants provided biological insight into the role of host genetic factors in generalized pustular psoriasis (GPP). However, not all those affected by GPP carry variants in the reported genes. To comprehensively explore the molecular pathogenesis of GPP, whole-exome sequencing was performed, and two loci were identified with exome-wide significance through single variant association analysis: rs148755083 in the IL36RN gene (Pcombined = 1.19 × 10-18, OR = 8.26) and HLA-C∗06:02 within the major histocompatibility complex region (Pcombined = 8.38 × 10-12, OR = 2.98). Gene burden testing revealed that BTN3A3 correlated with GPP (Pcombined = 1.14 × 10-10, OR = 5.59). Subtype analysis showed that IL36RN and BTN3A3 were both significantly associated with GPP alone and GPP with psoriasis vulgaris, whereas a correlation with HLA-C∗06:02 was only observed in GPP with psoriasis vulgaris. Functional analysis revealed that BTN3A3 regulated cell proliferation and inflammatory balance in GPP. In particular, loss of function of BTN3A3 activated NF-κB and promoted the production of inflammatory cytokines by inhibiting IL-36Ra expression to disturb the IL-1/IL-36 inflammatory axis and enhance the TNF-α-mediated pathway. Our findings identify BTN3A3 as, to our knowledge, a previously unreported pathogenic determinant, expanding our understanding of the genetic basis of GPP.
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Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Pueblos del Este de Asia , Pruebas Genéticas , Antígenos HLA-C/genética , Interleucinas/genética , Psoriasis/genética , Psoriasis/patología , Enfermedades Cutáneas Vesiculoampollosas/genética , Butirofilinas/genéticaRESUMEN
Airy beams, accelerating optical beams with exotic properties of self-bending, self-healing and non-diffraction, are essential for a wide range of photonics applications. Recently, metasurfaces have provided an efficient platform for generating desired Airy beams within a thin thickness, but they suffer from the narrow bandwidth, especially for two-dimensional (2D) Airy beams. Here, we propose an amplitude-tailorable polarization-converting metasurface to enable ultra-wideband 2D Airy beam generation. The amplitude and phase profiles for the 2D Airy beam can be realized by tuning only the orientation of the multi-resonant meta-atom, which can operate in the range of 6.6â GHz to 23.7â GHz, or fractional bandwidth of 113%. An exemplary prototype is measured to validate the design principle, which is in agreement with the simulation results. The proposed method holds great promise for wavefront shaping, and may facilitate the uses of Airy beam for practical applications.
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When Salmonella enters host cells, the synthesis of flagella is quickly turned off to escape the host immune system. In this study, we investigated the cooperative regulatory mechanism of flagellar synthesis by two EAL-like proteins, STM1344 and STM1697, in Salmonella. We found that Salmonella upregulated the expression of both STM1344 and STM1697 to various degrees upon invading host cells. Importantly, deletion of STM1697 or STM1344 led to failure of Salmonella flagellar control within host cells, suggesting that the two factors are not redundant but indispensable. STM1697 was shown to modulate Salmonella flagellar biogenesis by preventing the flagellar master protein FlhDC from recruiting RNA polymerase. However, STM1344 was identified as a bifunctional factor that inhibits RNA polymerase recruitment of FlhDC at low molar concentrations and the DNA binding activity of FlhDC at high molar concentrations. Structural analysis demonstrated that STM1344-FlhD binds more tightly than STM1697-FlhD, and size exclusion chromatography (SEC) experiments showed that STM1344 could replace STM1697 in a STM1697-FlhDC complex. Our data suggest that STM1697 might be a temporary flagellar control factor upon Salmonella entry into the host cell, while STM1344 plays a more critical role in persistent flagellar control when Salmonella organisms survive and colonize host cells for a long period of time. Our study provides a more comprehensive understanding of the complex flagellar regulatory mechanism of Salmonella based on regulation at the protein level of FlhDC. IMPORTANCE Salmonella infection kills more than 300,000 people every year. After infection, Salmonella mainly parasitizes host cells, as it prevents host cell pyroptosis by turning off the synthesis of flagellar antigen. Previous studies have determined that there are two EAL-like proteins, STM1344 and STM1697, encoded in the Salmonella genome, both of which inhibit flagellar synthesis by interacting with the flagellar master protein FlhDC. However, the expression order and simultaneous mechanism of STM1344 and STM1697 are not clear. In this study, we determined the expression profiles of the two proteins after Salmonella infection and demonstrated the cooperative mechanism of STM1344 and STM1697 interaction with FlhDC. We found that STM1344 might play a more lasting regulatory role than STM1697. Our results reveal a comprehensive flagellar control process after Salmonella entry into host cells.