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1.
Nature ; 621(7979): 586-591, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37704725

RESUMEN

Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells1,2. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and plants3-5. The widely conserved AvrE-family effectors, including DspE in Erwinia amylovora and AvrE in Pseudomonas syringae, have a central role in the pathogenesis of diverse phytopathogenic bacteria6. These conserved effectors are involved in the induction of 'water soaking' and host cell death that are conducive to bacterial multiplication in infected tissues. However, the exact biochemical functions of AvrE-family effectors have been recalcitrant to mechanistic understanding for three decades. Here we show that AvrE-family effectors fold into a ß-barrel structure that resembles bacterial porins. Expression of AvrE and DspE in Xenopus oocytes results in inward and outward currents, permeability to water and osmolarity-dependent oocyte swelling and bursting. Liposome reconstitution confirmed that the DspE channel alone is sufficient to allow the passage of small molecules such as fluorescein dye. Targeted screening of chemical blockers based on the predicted pore size (15-20 Å) of the DspE channel identified polyamidoamine dendrimers as inhibitors of the DspE/AvrE channels. Notably, polyamidoamines broadly inhibit AvrE and DspE virulence activities in Xenopus oocytes and during E. amylovora and P. syringae infections. Thus, we have unravelled the biochemical function of a centrally important family of bacterial effectors with broad conceptual and practical implications in the study of bacterial pathogenesis.


Asunto(s)
Proteínas Bacterianas , Células Vegetales , Enfermedades de las Plantas , Porinas , Agua , Animales , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Muerte Celular , Fluoresceína/metabolismo , Liposomas/metabolismo , Oocitos/metabolismo , Oocitos/microbiología , Células Vegetales/metabolismo , Células Vegetales/microbiología , Enfermedades de las Plantas/microbiología , Porinas/química , Porinas/metabolismo , Pliegue de Proteína , Soluciones/metabolismo , Agua/metabolismo , Xenopus laevis , Concentración Osmolar
2.
Proc Natl Acad Sci U S A ; 121(4): e2317344121, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38241440

RESUMEN

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.


Asunto(s)
Quistes , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Ratones , Animales , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/metabolismo , Proliferación Celular , Enfermedades Renales Poliquísticas/metabolismo , Apoptosis , Estrés Oxidativo , Quistes/metabolismo , ADN/metabolismo , Riñón/metabolismo , Canales Catiónicos TRPP/genética
3.
Nucleic Acids Res ; 52(14): 8370-8384, 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-38888121

RESUMEN

The Klebsiella pneumoniae (K. pneumoniae, Kp) populations carrying both resistance-encoding and virulence-encoding mobile genetic elements (MGEs) significantly threaten global health. In this study, we identified a new anti-CRISPR gene (acrIE10) on a conjugative plasmid with self-target sequence in K. pneumoniae with type I-E* CRISPR-Cas system. AcrIE10 interacts with the Cas7* subunit of K. pneumoniae I-E* CRISPR-Cas system. The crystal structure of the AcrIE10-KpCas7* complex suggests that AcrIE10 suppresses the I-E* CRISPR-Cas by binding directly to Cas7 to prevent its hexamerization, thereby preventing the surveillance complex assembly and crRNA loading. Bioinformatic and functional analyses revealed that AcrIE10 is functionally widespread across diverse species. Our study reports a novel anti-CRISPR and highlights its potential role in spreading resistance and virulence among pathogens.


Asunto(s)
Proteínas Bacterianas , Sistemas CRISPR-Cas , Klebsiella pneumoniae , Plásmidos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efectos de los fármacos , Plásmidos/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Virulencia/genética , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/genética
5.
Carcinogenesis ; 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39180262

RESUMEN

Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products (RAGE), activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 (timo A3) could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.

6.
Mol Carcinog ; 63(7): 1392-1405, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38651944

RESUMEN

Na, K-ATPase interaction (NKAIN) is a transmembrane protein family, which can interact with Na, K-ATPase ß1 subunit. NKAIN1 plays an important role in alcohol-dependent diseases such as endometrial and prostate cancers. However, the relationship between NKAIN1 and human breast cancer has not been studied. Hence, this study aimed to explore the relationship between NKAIN1 expression and breast cancer. Data used in this study were mainly from the Cancer Genome Atlas, including differential expression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, multiple Cox regression analysis, co-expression gene analysis, and gene set enrichment analysis. Analyses were performed using reverse transcription-quantitative polymerase chain reaction, western blot analysis, and immunohistochemistry on 46 collected samples. The knockdown or overexpression of NKAIN1 in vitro in MCF-7 and MDA-MB-231 cell lines altered the proliferation and migration abilities of tumor cells. In vivo experiments further confirmed that NKAIN1 knockdown effectively inhibited the proliferation and migration of cancer cells. Therefore, our study identified NKAIN1 as an oncogene that is highly expressed in breast cancer tissues. The findings highlight the potential of NKAIN1 as a molecular biomarker of breast cancer.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Pronóstico , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ratones , Línea Celular Tumoral , Oncogenes , Ratones Desnudos , Células MCF-7 , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Persona de Mediana Edad
7.
Opt Express ; 32(9): 16319-16332, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38859262

RESUMEN

Oversampled modulation (OM) and undersampled modulation (UM) are two commonly used optical camera communication (OCC) modulation schemes for high-speed communication in short-range and reliable communication at long distances, respectively. However, the relationship between these two schemes and the tradeoff in performance for arbitrary communication distances have not been thoroughly investigated. In this study, we analyze the impact of distance and modulation parameters on pixel efficiency and packet delivery rate performance, demonstrating the underlying unity of traditional OM and UM schemes. Furthermore, we propose a generalized modulation scheme that allows for achieving predefined link performance at a given distance by adjusting the modulation parameters, such as packet length and repetition counts. Simulation and experimental results show that the proposed generalized modulation scheme provides OCC with a unique distance-aware capability other than the traditional OM and UM schemes, which are two special cases focusing on effectiveness and reliability, respectively. This research enhances our understanding of OCC data modulation and establishes a theoretical foundation for achieving efficient and reliable OCC transmission in complex environments.

8.
BMC Cancer ; 24(1): 1177, 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39334019

RESUMEN

OBJECTIVE: The brachytherapy (BT) and radical prostatectomy (RP) are two methods recommended in current guidelines for the treatment of localized prostate cancer (PCa). It is difficult to compare the oncological results of these two treatments because of differences in baseline characteristics and treatment selection.we sought to compare the efficacy of BT and RP after propensity score matching(PSM)analysis. METHODS: Between January 2009 and December 2021, our institution treated 657 patients with localized PCa (BT: n = 198; RP: n = 459)and followed up for > 2 years. Biochemical recurrence was defined as prostate-specific antigen (PSA) levels of nadir plus 2 ng/ml or higher (Phoenix definition) for BT, and as PSA0.2 ng/ml or greater for RP. PSM was applied based on the age, body mass index, PSA, prostate volume, clinical T-stage, Gleason grade, percentage of positive puncture needles ≥ 1/2, maximum tumor diameter ≥ 5 mm, and follow-up period. RESULTS: Median follow-up was 63 months for BT and 52 months for RP. After propensity score adjustment, a total of 294 (147 each) patients remained for further analysis.Kaplan-Meier curves showed no statistically significant difference in clinical relapse-free survivals (cRFS) (p = 0.637),overall survival (OS) (p = 0.726),and cancer-specific survival (CSS) (p = 0.505).BT was associated with improved biochemical relapse-free survivals (bRFS) compared to RP (p = 0.022), Logistic multivariate analysis based on the whole cohort revealed that clinical T stage ≥ T2b (p = 0.043) and tumor maximum diameter ≥ 5 mm (p = 0.044) were associated with significantly bRFS. CONCLUSION: The BT and RP group patients exhibited similar cRFS, OS, and CSS. However, patients in the BT groups exhibited better bRFS than those in the RP group.Clinical T stage ≥ T2b and a maximum tumor diameter ≥ 5 mm were independent prognostic factors.


Asunto(s)
Braquiterapia , Puntaje de Propensión , Prostatectomía , Neoplasias de la Próstata , Humanos , Masculino , Braquiterapia/métodos , Prostatectomía/métodos , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/mortalidad , Anciano , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Recurrencia Local de Neoplasia , Resultado del Tratamiento , Estudios Retrospectivos , Clasificación del Tumor , Estudios de Seguimiento , Estadificación de Neoplasias , Estimación de Kaplan-Meier
9.
Cerebellum ; 2024 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-39379642

RESUMEN

Cerebellar transcranial direct current stimulation (tDCS) has been shown to influence movement functions, but little is known about the specific effects of stimulation polarity on balance control. This study investigated the impact of bilateral cerebellar tDCS on balance functions as a function of stimulation polarity. In this randomized, controlled trial, thirty-nine healthy young adults were assigned to one of three groups: right anodal/left cathodal cerebellar stimulation (AC group), right cathodal/left anodal cerebellar stimulation (CA group), and a control sham group. Each participant underwent a daily 30-minute session of tDCS at 2 mA for one week. Balance function was assessed pre- and post-intervention and the data were analyzed using generalized estimating equations. The CA group exhibited a significant reduction in sway area when standing on the left leg and on both stable and unstable surfaces with eyes open, compared to both the AC and sham groups. However, there were no significant differences among the groups in terms of sway length, anteroposterior velocity, or mediolateral velocity. Our results indicate the polarity-dependent effects of bilateral cerebellar tDCS on balance functions, with enhanced stability observed only following cathodal tDCS over the right cerebellum paired with anodal tDCS over the left cerebellum. This polarity-specific modulation may have implications for developing cerebellar neuromodulation interventions for movement disorders.

10.
Acta Pharmacol Sin ; 45(1): 209-222, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37749236

RESUMEN

Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 µM. Furthermore, we found that S670 (6 µM) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg·kg-1·d-1, i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.


Asunto(s)
Neoplasias Encefálicas , Ferroptosis , Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Autofagosomas/metabolismo , Amidas/farmacología , Transducción de Señal , Lisosomas/metabolismo , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas Qa-SNARE
11.
PLoS Genet ; 17(7): e1009677, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34237075

RESUMEN

Pyrethrum extract from dry flowers of Tanacetum cinerariifolium (formally Chrysanthemum cinerariifolium) has been used globally as a popular insect repellent against arthropod pests for thousands of years. However, the mechanistic basis of pyrethrum repellency remains unknown. In this study, we found that pyrethrum spatially repels and activates olfactory responses in Drosophila melanogaster, a genetically tractable model insect, and the closely-related D. suzukii which is a serious invasive fruit crop pest. The discovery of spatial pyrethrum repellency and olfactory response to pyrethrum in D. melanogaster facilitated our identification of four odorant receptors, Or7a, Or42b, Or59b and Or98a that are responsive to pyrethrum. Further analysis showed that the first three Ors are activated by pyrethrins, the major insecticidal components in pyrethrum, whereas Or98a is activated by (E)-ß-farnesene (EBF), a sesquiterpene and a minor component in pyrethrum. Importantly, knockout of Or7a, Or59b or Or98a individually abolished fly avoidance to pyrethrum, while knockout of Or42b had no effect, demonstrating that simultaneous activation of Or7a, Or59b and Or98a is required for pyrethrum repellency in D. melanogaster. Our study provides insights into the molecular basis of repellency of one of the most ancient and globally used insect repellents. Identification of pyrethrum-responsive Ors opens the door to develop new synthetic insect repellent mixtures that are highly effective and broad-spectrum.


Asunto(s)
Chrysanthemum cinerariifolium/metabolismo , Repelentes de Insectos/química , Receptores Odorantes/metabolismo , Animales , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Flores , Repelentes de Insectos/metabolismo , Insecticidas/química , Odorantes/análisis , Piretrinas/química , Piretrinas/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/fisiología , Sesquiterpenos/química
12.
J Am Soc Nephrol ; 34(9): 1521-1534, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37332102

RESUMEN

SIGNIFICANCE STATEMENT: Heterozygous DNAJB11 mutation carriers manifest with small cystic kidneys and renal failure in adulthood. Recessive cases with prenatal cystic kidney dysplasia were recently described. Our in vitro and mouse model studies investigate the proposed disease mechanism as an overlap of autosomal-dominant polycystic kidney disease and autosomal-dominant tubulointerstitial kidney disease pathogenesis. We find that DNAJB11 loss impairs cleavage and maturation of the autosomal-dominant polycystic kidney disease protein polycystin-1 (PC1) and results in dosage-dependent cyst formation in mice. We find that Dnajb11 loss does not activate the unfolded protein response, drawing a fundamental contrast with the pathogenesis of autosomal-dominant tubulointerstitial kidney disease. We instead propose that fibrosis in DNAJB11 -kidney disease may represent an exaggerated response to polycystin-dependent cysts. BACKGROUND: Patients with heterozygous inactivating mutations in DNAJB11 manifest with cystic but not enlarged kidneys and renal failure in adulthood. Pathogenesis is proposed to resemble an overlap of autosomal-dominant polycystic kidney disease (ADPKD) and autosomal-dominant tubulointerstitial kidney disease (ADTKD), but this phenotype has never been modeled in vivo . DNAJB11 encodes an Hsp40 cochaperone in the endoplasmic reticulum: the site of maturation of the ADPKD polycystin-1 (PC1) protein and of unfolded protein response (UPR) activation in ADTKD. We hypothesized that investigation of DNAJB11 would shed light on mechanisms for both diseases. METHODS: We used germline and conditional alleles to model Dnajb11 -kidney disease in mice. In complementary experiments, we generated two novel Dnajb11-/- cell lines that allow assessment of PC1 C-terminal fragment and its ratio to the immature full-length protein. RESULTS: Dnajb11 loss results in a profound defect in PC1 cleavage but with no effect on other cystoproteins assayed. Dnajb11-/- mice are live-born at below the expected Mendelian ratio and die at a weaning age with cystic kidneys. Conditional loss of Dnajb11 in renal tubular epithelium results in PC1 dosage-dependent kidney cysts, thus defining a shared mechanism with ADPKD. Dnajb11 mouse models show no evidence of UPR activation or cyst-independent fibrosis, which is a fundamental distinction from typical ADTKD pathogenesis. CONCLUSIONS: DNAJB11 -kidney disease is on the spectrum of ADPKD phenotypes with a PC1-dependent pathomechanism. The absence of UPR across multiple models suggests that alternative mechanisms, which may be cyst-dependent, explain the renal failure in the absence of kidney enlargement.


Asunto(s)
Quistes , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Insuficiencia Renal , Ratones , Animales , Riñón Poliquístico Autosómico Dominante/patología , Canales Catiónicos TRPP/metabolismo , Riñón/patología , Enfermedades Renales Poliquísticas/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Renal/complicaciones , Quistes/genética
13.
J Am Soc Nephrol ; 34(1): 110-121, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36270750

RESUMEN

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1 α -XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1 . METHODS: We engineered a Pkd1 REJ domain missense murine model, Pkd1 R2216W , on the basis of the orthologous human hypomorphic allele Pkd1 R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression. RESULTS: Expression of active XBP1 in cultured cells bearing PC1 R2216W mutations increased levels and ciliary trafficking of PC1 R2216W . Mice homozygous for Pkd1 R2216W or heterozygous for Pkd1 R2216Win trans with a conditional Pkd1 fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters. CONCLUSIONS: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.


Asunto(s)
Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Adulto , Ratones , Humanos , Animales , Riñón Poliquístico Autosómico Dominante/metabolismo , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismo , Modelos Animales de Enfermedad , Enfermedades Renales Poliquísticas/metabolismo , Mutación , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo
14.
Clin Exp Immunol ; 213(3): 317-327, 2023 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-37191481

RESUMEN

Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive cartilage erosion and joint destruction. Synovial fibroblasts (SFs) play a crucial role in the pathogenesis of RA. This study aims to explore the function and mechanism of CD5L during RA progression. We examined the levels of CD5L in synovial tissues and SFs. The collagen-induced arthritis (CIA) rat models were used to investigate the effect of CD5L on RA progression. We also investigated the effects of exogenous CD5L on the behavior and activity of RA synovial fibroblasts (RASFs). Our results showed that CD5L expression was significantly upregulated in synovium of RA patients and CIA-rats. Histology and Micro-CT analysis showed that synovial inflammation and bone destruction were more severe in CD5L-treated CIA rats compared with control rats. Correspondingly, CD5L blockade alleviated bone damage and synovial inflammation in CIA-rats. The exogenous CD5L treatment promoted RASFs proliferation invasion and proinflammatory cytokine production. Knockdown of CD5L receptor by siRNA significantly reversed the effect of CD5L treatment on RASFs. Moreover, we observed that CD5L treatment potentiated PI3K/Akt signaling in the RASFs. The promoted effects of CD5L on IL-6 and IL-8 expression were significantly reversed by PI3K/Akt signaling inhibitor. In conclusion, CD5L promote RA disease progression via activating RASFs. CD5L blocking is a potential therapeutic approach for RA patients.

15.
BMC Microbiol ; 23(1): 197, 2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37488503

RESUMEN

BACKGROUND: The traditional Sichuan Sun-dried vinegar (SSV) with unique flavor and taste is believed to be generated by the solid-state fermentation craft. However, how microorganisms and their metabolites change along with fermentation has not yet been explored. RESULTS: In this study, our results demonstrated that the middle and late stages of SSV fermentation were the periods showing the largest accumulation of organic acids and amino acids. Furthermore, in the bacterial community, the highest average relative abundance was Lactobacillus (ranging from 37.55 to 92.50%) in all fermentation stages, while Acetobacters ranked second position (ranging from 20.15 to 0.55%). The number of culturable lactic acid bacteria is also increased during fermentation process (ranging from 3.93 to 8.31 CFU/g). In fungal community, Alternaria (29.42%), Issatchenkia (37.56%) and Zygosaccharomyces (69.24%) were most abundant in different fermentation stages, respectively. Interestingly, Zygosaccharomyces, Schwanniomyces and Issatchenkia were first noticed as the dominant yeast genera in vinegar fermentation process. Additionally, spearman correlation coefficients exhibited that Lactobacillus, Zygosaccharomyces and Schwanniomyces were significant correlation with most metabolites during the fermentation, implying that these microorganisms might make a significant contribution to the flavor formation of SSV. CONCLUSION: The unique flavor of SSV is mainly produced by the core microorganisms (Lactobacillus, Zygosaccharomyces and Schwanniomyces) during fermentation. This study will provide detailed information related to the structure of microorganism and correlation between changes in metabolites and microbial succession in SSV. And it will be very helpful for proposing a potential approach to monitor the traditional fermentation process.


Asunto(s)
Ácido Acético , Alimentos Fermentados , Fermentación , Ácido Acético/química , Lactobacillus/metabolismo , Zygosaccharomyces/metabolismo , Saccharomycetales/metabolismo , Aminoácidos/metabolismo , Fenoles/análisis , Flavonoides/análisis , Alimentos Fermentados/microbiología
16.
Opt Lett ; 48(13): 3419-3422, 2023 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-37390145

RESUMEN

The exposure effect of cameras in optical camera communication (OCC) distorts the received light pulses and generates inter-symbol interference (ISI), which adversely affects the bit error rate (BER) performance. In this Letter, we derive an analytical expression of BER based on the pulse response model of the camera-based OCC channel and analyze the impact of exposure time on BER performance considering asynchronous transmission characteristics. Numerical simulations and experimental results demonstrate that a long exposure time is beneficial in a noise-dominant communication scenario, while a short exposure time is preferable when ISI is dominant. This Letter provides a comprehensive analysis of the influence of exposure time on BER performance, offering a theoretical foundation for the design and optimization of OCC systems.


Asunto(s)
Dispositivos Ópticos
17.
Microb Ecol ; 86(3): 1881-1892, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36799977

RESUMEN

Halobacteriovorax are predatory bacteria that have a significant ecological role in marine environments. However, understanding of dynamics of populations, driving forces, and community composition of Halobacteriovorax groups in natural marine environments is still limited. Here, we used high-throughput sequencing to study the underlying mechanisms governing the diversity and assembly of the Halobacteriovorax community at spatiotemporal scales in a subtropical estuary. Phylogenetic analysis showed that 10 of 15 known Halobacteriovorax clusters were found in the studied estuary. Halobacteriovorax α-diversity and ß-diversity exhibited significant seasonal variation. Variation partitioning analysis showed that the effect of nutrients was greater than that of other measured water properties on Halobacteriovorax community distribution. The results of Spearman's and Mantel's tests indicated that the trophic pollutants dissolved inorganic phosphorus (DIP) and NH4+-N in the estuary were the key factors that significantly affected Halobacteriovorax species and community diversity. In addition, this work indicated that the biological stoichiometry (especially N/P) of nutrients exerted a significant influence on the Halobacteriovorax community. Furthermore, we found that both deterministic and stochastic processes contributed to the turnover of Halobacteriovorax communities, and environmental filtering dominated the assembly of estuarine Halobacteriovorax communities. Overall, we provide new insights into the mechanisms in the generation and maintenance of the Halobacteriovorax community in marine environments.


Asunto(s)
Ecosistema , Estuarios , Estaciones del Año , Filogenia , Proteobacteria
18.
Microb Ecol ; 85(2): 495-507, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35195737

RESUMEN

Revealing planktonic fungal ecology under coastal eutrophication is crucial to our understanding of microbial community shift in marine pollution background. We investigated the diversity, putative interspecies interactions, assembly processes and environmental responses of abundant and rare planktonic fungal communities along a eutrophication gradient present in the Beibu Gulf. The results showed that Dothideomycetes and Agaricomycetes were the predominant classes of abundant and rare fungi, respectively. We found that eutrophication significantly altered the planktonic fungal communities and affected the abundant taxa more than the rare taxa. The abundant and rare taxa were keystone members in the co-occurrence networks, and their interaction was enhanced with increasing nutrient concentrations. Stochastic processes dominated the community assembly of both abundant and rare planktonic fungi across the eutrophication gradient. Heterogeneous selection affected abundant taxa more than rare taxa, whereas homogenizing dispersal had a greater influence on rare taxa. Influences of environmental factors involving selection processes were detected, we found that abundant fungi were mainly influenced by carbon compounds, whereas rare taxa were simultaneously affected by carbon, nitrogen and phosphorus compounds in the Beibu Gulf. Overall, these findings highlight the distinct ecological adaptations of abundant and rare fungal communities to marine eutrophication.


Asunto(s)
Microbiota , Micobioma , Plancton , Eutrofización , Nitrógeno
19.
Thromb J ; 21(1): 116, 2023 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-37950211

RESUMEN

OBJECTIVES: Cerebral venous sinus thrombosis (CVST) can cause sinus obstruction and stenosis, with potentially fatal consequences. High-resolution magnetic resonance imaging (HRMRI) can diagnose CVST qualitatively, although quantitative screening methods are lacking for patients refractory to anticoagulation therapy and who may benefit from endovascular treatment (EVT). Thus, in this study, we used radiomic features (RFs) extracted from HRMRI to build machine learning models to predict response to drug therapy and determine the appropriateness of EVT. MATERIALS AND METHODS: RFs were extracted from three-dimensional T1-weighted motion-sensitized driven equilibrium (MSDE), T2-weighted MSDE, T1-contrast, and T1-contrast MSDE sequences to build radiomic signatures and support vector machine (SVM) models for predicting the efficacy of standard drug therapy and the necessity of EVT. RESULTS: We retrospectively included 53 patients with CVST in a prospective cohort study, among whom 14 underwent EVT after standard drug therapy failed. Thirteen RFs were selected to construct the RF signature and CVST-SVM models. In the validation dataset, the sensitivity, specificity, and area under the curve performance for the RF signature model were 0.833, 0.937, and 0.977, respectively. The radiomic score was correlated with days from symptom onset, history of dyslipidemia, smoking, fibrin degradation product, and D-dimer levels. The sensitivity, specificity, and area under the curve for the CVST-SVM model in the validation set were 0.917, 0.969, and 0.992, respectively. CONCLUSIONS: The CVST-SVM model trained with RFs extracted from HRMRI outperformed the RF signature model and could aid physicians in predicting patient responses to drug treatment and identifying those who may require EVT.

20.
J Nat Prod ; 86(4): 739-750, 2023 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-36888988

RESUMEN

Eleven new pyridone alkaloids, penicipyridones A-K (1-11), and three new tetramic acids, tolypocladenols D-F (12-14), were isolated from rice media cultures of the marine-derived fungus Penicillium oxalicum QDU1. Their structures, including absolute configurations, were determined by comprehensive analyses of spectroscopic data, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction data. Interestingly, several of the penicipyridones undergo interconversions between hydroxy and methoxy groups at C-4 in acidic MeOH solution. Furthermore, in an acidic aqueous solution, OH-4 could be replaced by diverse substituent groups. Compounds 1, 4, 5, 8, 10, 11, and 14 exhibited moderate inhibitory effects on NO production in the LPS-induced RAW264.7 macrophages, with IC50 values ranging from 9.2 to 19 µM.


Asunto(s)
Alcaloides , Penicillium , Alcaloides/química , Penicillium/química , Hongos , Piridonas/química , Estructura Molecular
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