RESUMEN
Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+ , ALDH+ , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
Asunto(s)
Carcinogénesis/genética , Células Madre Neoplásicas/fisiología , Antígeno AC133/genética , Aldehído Deshidrogenasa/genética , Animales , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Regulación hacia Arriba/genética , Proteínas Wnt/genéticaRESUMEN
BACKGROUND: Tubular senescence is a major determinant of chronic kidney disease (CKD) and identification of potential therapeutic targets involved in senescent tubular epithelial cells has clinical importance. Lysosomal-associated protein transmembrane 5 (LAPTM5) is a key molecule related to T and B cell receptor expression and inflammation. However, the expression pattern of LAPTM5 in the kidney and the contribution of LAPTM5 to the development of CKD keep unknown. METHODS: LAPTM5-/- mice and tubule specific-LAPTM5 knockout mice were used to examine the role of LAPTM5 in tubular senescence by establishing different experimental mouse CKD models. RESULTS: LAPTM5 expression was significantly induced in the kidney, especially in proximal tubules and distal convoluted tubules, from mice with aristolochic acid nephropathy, bilateral ischemia/reperfusion injury (IRI)-induced CKD or unilateral ureter obstruction (UUO). Tubule-specific deletion of LAPTM5 inhibited senescence of tubular epithelial cells and alleviated tubulointerstitial fibrosis in aged mice. Moreover, LAPTM5 deficiency ameliorated kidney injury and tubular senescence in mice with CKD. Mechanistically, LAPTM5 inhibited ubiquitination of NICD1 by mediating WWP2 lysosomal degradation, then leading to cellular senescence in tubular epithelial cells. Notably, we also observed a higher expression of LAPTM5 in tubules from individuals with CKD and the level of LAPTM5 was correlated with kidney fibrosis and tubular senescence in people with CKD. CONCLUSIONS: LAPTM5 contributed to tubular senescence by regulating WWP2/NICD1 signaling pathway and exacerbated kidney injury during the progression of CKD.
RESUMEN
The water oxidation reaction, a crucial process for solar energy conversion, has garnered significant research attention. Achieving efficient energy conversion requires the development of cost-effective and durable water oxidation catalysts. To design effective catalysts, it is essential to have a fundamental understanding of the reaction mechanisms. This review presents a comprehensive overview of recent advancements in the understanding of the mechanisms of water oxidation using transition metal-based heterogeneous electrocatalysts, including Mn, Fe, Co, Ni, and Cu-based catalysts. It highlights the catalytic mechanisms of different transition metals and emphasizes the importance of monitoring of key intermediates to explore the reaction pathway. In addition, advanced techniques for physical characterization of water oxidation intermediates are also introduced, for the purpose of providing information for establishing reliable methodologies in water oxidation research. The study of transition metal-based water oxidation electrocatalysts is instrumental in providing novel insights into understanding both natural and artificial energy conversion processes.
RESUMEN
Poor water stability and single luminous color are the major drawbacks of the most phosphors reported. Therefore, it is important to realize multicolor luminescence in a phosphor with single host and single activator as well as moisture resistance. LaF3 :Pr3+ @SiO2 yolk-shell nanospheres are facilely obtained by a designing new technology of a simple and cost-effective electrospray ionization combined with a dicrucible fluorating technique without using protective gas. In addition, tunable photoluminescence, especially white-light emission, is successfully obtained in LaF3 :Pr3+ @SiO2 yolk-shell nanospheres by adjusting Pr3+ ion concentrations, and the luminescence mechanism of Pr3+ ion is advanced. Compared with the counterpart LaF3 :Pr3+ nanospheres, the water stability of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres is improved by 15% after immersion in water for 72 h, and the fluorescence intensity can be maintained at 86% of the initial intensity. Furthermore, by treating the yolk-shell nanospheres with hydrofluoric acid, it is not only demonstrated that the shell-layer is SiO2 but also core-LaF3 :Pr3+ nanospheres are obtained. Particularly, only fluorination procedure among the halogenation can produce such special yolk-shell nanospheres, the formation mechanism of yolk-shell nanospheres is proposed detailedly based on the sound experiments and a corresponding new technology is built. These findings broaden practical applications of LaF3 :Pr3+ @SiO2 yolk-shell nanospheres.
RESUMEN
BACKGROUND: An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. METHODS: Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. RESULTS: Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. CONCLUSION: This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer.
Asunto(s)
Linfocitos T CD8-positivos , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Subfamília C de Receptores Similares a Lectina de Células NK , Neoplasias Gástricas , Humanos , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Regulación Neoplásica de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteínas de Punto de Control Inmunitario/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
The silkworm, Bombyx mori, is a complete metamorphosed economic insect, and the silk gland is a significant organ for silk protein synthesis and secretion. The silk gland completely degenerates during pupation, but the regulatory mechanism of programmed cell death (PCD) has not yet been understood. In the present study, we investigated the non-genetic pathway of 20E-induced PCD in the posterior silk gland (PSG) based on intracellular Ca2+ levels. Silk gland morphology and silk gland index indicated rapid degeneration of silk gland during metamorphosis from mature silkworm (MS) to pupal day 1 (P1), and Ca2+ levels within the PSG were found to peak during the pre-pupal day 1 (PP1) stage. Moreover, the results of autophagy and apoptosis levels within the PSG showed that autophagy was significantly increased in MS-PP1 periods, and significantly decreased in PP2 and P1 periods. Apoptosis was almost absent in MS-PP1 periods and significantly increased in PP2 and P1 periods. Additionally, western blotting results showed that autophagy preceded apoptosis, and the autophagy-promoting ATG5 was cleaved by calpain to the autophagy-inhibiting and apoptosis-promoting NtATG5 since PP1 period, while decreased autophagy was accompanied by increased apoptosis. Collectively, these findings suggest that Ca2+ is a key factor in the shift from autophagy to apoptosis.
RESUMEN
INTRODUCTION: Progestin, commonly used in oral contraception and preventing preterm birth, elicits various off-target side effects on brain and gastrointestinal (GI) functions, yet the precise mechanisms remain elusive. This study aims to probe progestin's impact on GI function and anxiety-like behaviors in female mice. METHODS: Colon stem cells were utilized to explore the mechanism underlying progestin 17-hydroxyprogesterone caproate (17-OHPC)-mediated suppression of claudin-1 (CLDN1), crucial for epithelial integrity. Chromatin immunoprecipitation and luciferase assays identified potential progestin-response elements on the CLDN1 promoter, with subsequent assessment of oxidative stress and pro-inflammatory cytokine release. Manipulation of vitamin D receptor (VDR) or estrogen receptor ß (ERß) expression elucidated their roles in 17-OHPC-mediated effects. Intestine-specific VDR deficient mice were generated to evaluate 17-OHPC's impact on GI dysfunction and anxiety-like behaviors in female mice. Additionally, gene expression was analyzed in various brain regions, including the amygdala, hypothalamus, and hippocampus. RESULTS: Exposure to 17-OHPC suppressed CLDN1 expression via epigenetic modifications and VDR dissociation from the CLDN1 promoter. Furthermore, 17-OHPC intensified oxidative stress and pro-inflammatory cytokine release. VDR knockdown partly mimicked, while overexpression of either VDR or ERß partly restored 17-OHPC-mediated effects. Intestinal VDR deficiency partly mirrored 17-OHPC-induced GI dysfunction, with minimal impact on 17-OHPC-mediated anxiety-like behaviors. CONCLUSIONS: 17-OHPC suppresses CLDN1 expression through VDR, contributing to GI dysfunction in female mice, distinct from 17-OHPC-induced anxiety-like behaviors. This study reveals a new mechanism and potential negative impact of progestin exposure on the GI tract, alongside inducing anxiety-like behaviors in female mice.
Asunto(s)
Ansiedad , Claudina-1 , Receptores de Calcitriol , Animales , Femenino , Ansiedad/inducido químicamente , Ansiedad/metabolismo , Ratones , Receptores de Calcitriol/metabolismo , Claudina-1/metabolismo , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos , Receptor beta de Estrógeno/metabolismo , Progestinas/farmacologíaRESUMEN
Antimicrobial peptide (AMP) is an important component of crustaceans' innate immune system. In this study, a short neuropeptide F (sNPF) gene (Pc-sNPF) and a Forkhead box O (FOXO) gene (PcFOXO) from Procambarus clarkii were identified. Analysis findings showed that the expression level of AMP genes differed between male and female P. clarkii. Furthermore, Pc-sNPF and PcFOXO were related to the sex dimorphism of AMP. Knockdown of Pc-sNPF in the eyestalk significantly upregulated the expression of PcFOXO and two anti-lipopolysaccharide factors (PcALF4 and PcALFL) in the intestine of P. clarkii. The expression of PcFOXO in the intestine of female P. clarkii was higher than in that of males. Results from RNA interference revealed that PcFOXO positively regulated the expression of PcALF4 and PcALFL in the intestine of male and female P. clarkii. In summary, our study showed that differences in Pc-sNPF expression in eyestalk of male and female P. clarkii leading to sex dimorphism of AMP expression in the intestine are mediated by the sNPF-FOXO-AMP signal pathway called the eyestalk-intestine axis.
Asunto(s)
Proteínas de Artrópodos , Regulación de la Expresión Génica , Neuropéptidos , Caracteres Sexuales , Animales , Masculino , Femenino , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Proteínas de Artrópodos/metabolismo , Regulación de la Expresión Génica/inmunología , Neuropéptidos/genética , Neuropéptidos/metabolismo , Astacoidea/genética , Astacoidea/inmunología , Intestinos , Péptidos Antimicrobianos/genética , Péptidos Antimicrobianos/metabolismo , Inmunidad Innata/genética , Filogenia , Perfilación de la Expresión Génica , Secuencia de Aminoácidos , Alineación de SecuenciaRESUMEN
Cervical cancer is the second most common malignancy of the female reproductive tract worldwide. Although cervical cancer is caused by human papillomavirus (HPV) infection, its underlying pathogenesis requires further investigation. The present study investigated the role of kinetochore associated protein 1 (KNTC1) in cervical cancer and its association with the key virus oncoprotein, HPV E7. A series of bioinformatic analyses revealed that KNTC1 might be involved in the tumorigenesis of multiple human malignancies, including cervical cancer. Tissue microarray analysis showed that in vivo KNTC1 expression was higher in high-grade squamous intraepithelial lesions (HSILs) than in normal cervix and even higher in cervical cancer. In vitro silencing of KNTC1 increased the proliferation, invasion and migration of cervical cancer cell lines. Although not affecting apoptosis, KNTC1 silencing significantly promoted G1/S phase transition of the cell cycle. High-throughput analysis of mRNA expression showed that KNTC1 could regulate its downstream target protein Smad2 at the transcriptional level. Moreover, as the key oncoprotein of the virus, HPV E7 could inhibit the expression of KNTC1 protein, and decrease Smad2 protein expression with or without the aid of KNTC1. These results indicated that KNTC1 is a novel tumor suppressor that can impede the initiation and progression of cervical carcinoma, providing insight into the molecular mechanism by which HPV induces cervical cancer.
Asunto(s)
Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/patología , Infecciones por Papillomavirus/genética , Proteínas E7 de Papillomavirus/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Carcinogénesis/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMEN
BACKGROUND AND AIMS: This study aimed to explore the association between hyperuricemia and heart failure (HF) readmission in HF patients with preserved ejection fraction (HFpEF) because the impact of hyperuricemia on the prognosis of these patients has not been fully understood. METHODS AND RESULTS: This retrospective observational study included 538 hospitalized patients diagnosed with HFpEF. A total of 57.6 % of patients with HFpEF suffered from hyperuricemia (serum uric acid (SUA) was >7 mg/dL in men and >6 mg/dL in women). Compared to those without hyperuricemia, patients with hyperuricemia were more likely to be female (62.6 % vs. 53.9 %, p = 0.044) and older (78.0 ± 8.4 vs. 75.9 ± 9.0 years, p = 0.008). Our Cox analysis revealed that SUA level (hazard ratio (HR) = 1.158, 95 % confidence interval (CI): 1.087-1.234, p<0.001) and hyperuricemia (HR = 1.846, 95 % CI: 1.308-2.606, p<0.001) were associated with HF readmission in patients with HFpEF, respectively. Kaplan-Meier analysis showed that patients with hyperuricemia had a significantly worse prognosis (p<0.001). The receiver operating characteristic analysis revealed that the area under the ROC curve of SUA for predicting HF readmission was 0.6276 (95 % CI: 0.5763-0.6790) and a designated cut-off value of 7.53 mg/dL. CONCLUSIONS: Hyperuricemia is a common comorbidity among patients with HFpEF. Moreover, SUA level and hyperuricemia have been shown to be associated with HF readmission. Therefore, it is meaningful to monitor SUA levels in patients with HFpEF during the whole treatment period of HF. Whereas, whether intervention of hyperuricemia could benefit patients with HFpEF needs further studies.
Asunto(s)
Insuficiencia Cardíaca , Hiperuricemia , Femenino , Humanos , Masculino , China/epidemiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiología , Readmisión del Paciente , Volumen Sistólico , Ácido Úrico , Anciano , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: This study aimed to investigate the association of cystatin C, serum creatinine and sarcopenia index with cardiovascular and all-cause death in general population. METHODS: Data of participants from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2004 were used and all participants were followed up regularly until December 31, 2019. Multivariable Cox analysis was used to investigate the association of cystatin C, serum creatinine and sarcopenia index with cardiovascular and all-cause death. Restricted cubic spline was conducted to evaluate the nonlinear association. RESULTS: A total of 9894 participants with a mean age of 45.64 years were enrolled and followed up for a mean duration of 15.62 ± 4.68 years. Approximately 50.3% were male and there were a total of 2681 all-cause deaths and 691 cardiovascular deaths recorded during the follow-up period. In final adjusted model, compared with the first quartile of cystatin C (< 0.659 mg/L), the risk of cardiovascular and all-cause death increased 2.36-fold and 1.71-fold for participants in the fourth quartile (≥ 0.877 mg/L) (HR: 3.36, 95% CI: 2.06-5.46, P < 0.001; HR: 2.71, 95% CI: 2.17-3.38, P < 0.001; respectively). Furthermore, a higher sarcopenia index (< 88.41 vs. ≥125.52) was associated with the reduced risk of cardiovascular death (HR: 0.41, 95% CI: 0.31-0.53, P < 0.001) as well as all-cause death (HR: 0.41, 95% CI: 0.35-0.49, P < 0.001). Additionally, restricted cubic splines showed that there was a nonlinear relationship between sarcopenia index levels and all-cause death while there was a linear relationship between sarcopenia index levels and cardiovascular death. CONCLUSIONS: Higher sarcopenia index was associated with the decreased risk of cardiovascular and all-cause death in general population in the United States. Elevated cystatin C was positively associated with cardiovascular and all-cause death.
Asunto(s)
Enfermedades Cardiovasculares , Causas de Muerte , Cistatina C , Encuestas Nutricionales , Sarcopenia , Humanos , Cistatina C/sangre , Masculino , Sarcopenia/mortalidad , Sarcopenia/epidemiología , Sarcopenia/sangre , Femenino , Persona de Mediana Edad , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Estados Unidos/epidemiología , Adulto , Creatinina/sangre , Factores de Riesgo , Biomarcadores/sangreRESUMEN
Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.
Asunto(s)
Transducción de Señal , Estilbenos , Ratones , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Estilbenos/farmacología , FN-kappa B/metabolismo , Lipopolisacáridos/farmacologíaRESUMEN
Objective: To assess the effectiveness of perioperative nursing interventions in improving outcomes and satisfaction for patients undergoing laparoscopic surgery for ovarian endometriosis. Methods: From July 2021 to September 2022, 80 patients with endometriosis underwent laparoscopic surgery at Shijiazhuang Fourth Hospital and were randomly assigned to the conventional (n=40) and experimental (n=40) groups. During the perioperative period, patients in the conventional group received standard nursing interventions, while patients in the experimental group received comprehensive nursing interventions. The two groups were compared in terms of postoperative clinical indicators, self-rated anxiety scale (SAS) and self-rated depression scale (SDS) scores, nursing compliance, complications, and nursing satisfaction. Results: comprehensive nursing resulted in better postoperative clinical indices (time to get out of bed, hospital stay) versus routine nursing (all P < .001). The comprehensive nursing led to significantly lower SAS and SDS scores versus routine nursing. The nursing compliance of the patients in the experimental group was significantly higher than that of the patients in the conventional group (P < .001). Comprehensive nursing was associated with a significantly lower incidence of complications versus routine nursing (P < .001). Comprehensive nursing contributed to significantly higher nursing satisfaction versus routine nursing (P < .001). Conclusion: Comprehensive perioperative nursing interventions for patients with ovarian endometriosis undergoing laparoscopic surgery considerably accelerate patient recovery and enhance nursing compliance, as well as minimize patient negative emotions and improve patient satisfaction with nursing. The comprehensive approach addresses the specific needs of patients during the recovery period, minimizing postoperative complications, accelerating patient recovery, and improving overall quality of life. By integrating psychological support, tailored strategies for pain management, early mobilization, and prompt intervention for complications, this intervention sets a benchmark for holistic care in gynecological surgery.
RESUMEN
The transition period in dairy cows is a critical stage and peripartum oxidative status, negative energy balance (NEB), and inflammation are highly prevalent. Fecal microbial metabolism is closely associated with blood oxidative status and nonesterified fatty acids (NEFA) levels. Here, we investigated dynamic changes in total oxidative status markers and NEFA in blood, fecal microbiome, and metabolome of 30 dairy cows during transition (-21, -7, +7, +21 d relative to calving). Then the Bayesian network and 9 machine-learning algorithms were applied to dismantle their relationship. Our results show that the oxidative status indicator (OSI) of -21, -7, +7 d was higher than +21 d. The plasma concentration of NEFA peaked on +7 d. For fecal microenvironment, a decline in bacterial α diversity was observed at postpartum and in bacterial interactions at +7 d. Conversely, microbial metabolites involved in carbohydrate, lipid, and energy metabolism increased on +7 d. A correlation analysis revealed that 11 and 10 microbial metabolites contributed to OSI and NEFA variations, respectively (arc strength >0.5). The support vector machine (SVM) radial model showed the highest average predictive accuracy (100% and 88.9% in the test and external data sets) for OSI using 1 metabolite and 3 microbiota. The SVM radial model also showed the highest average diagnostic accuracy (100% and 91% in the test and external data sets) for NEFA with 2 metabolites and 3 microbiota. Our results reveal a relationship between variation in the fecal microenvironment and indicators of oxidative status, NEB, and inflammation, which provide a theoretical basis for the prevention and precise regulation of peripartum oxidative status and NEB.
Asunto(s)
Ácidos Grasos no Esterificados , Periodo Periparto , Femenino , Bovinos , Animales , Teorema de Bayes , Periodo Posparto , Inflamación/veterinaria , Estrés Oxidativo , Lactancia/fisiología , Ácido 3-HidroxibutíricoRESUMEN
The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin-induced IL-1ß secretion and anti-cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti-inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS-induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.
RESUMEN
Proposed by Ginzberg nearly 60 years ago, surface superconductivity refers to the emergent phenomenon that the electrons on or near the surface of a material becomes superconducting despite its bulk is nonsuperconducting. Here, based on first-principles calculations within density functional theory, we predict that the superconducting transition temperature Tc at the surfaces of CanBn+1Cn+1 (n = 1, 2, 3, ...) films can be drastically enhanced to â¼90 K from 8 K for bulk CaBC. Our detailed analyses reveal that structural symmetry reduction at surfaces induces pronounced carrier self-doping into the surface B-C layer of the films and shifts the σ-bonding states toward the Fermi level; furthermore, the in-plane stretching modes of the surface layers experience significant softening. These two effects work collaboratively to strongly enhance the electron-phonon coupling, which in turn results in much higher Tc values than the McMillian limit. These findings point to new material platforms for realizing unusually high-Tc surface superconductivity.
RESUMEN
Prime editing is a versatile CRISPR/Cas-based precise genome-editing technique for crop breeding. Four new types of prime editors (PEs) named PE6a-d were recently generated using evolved and engineered reverse transcriptase (RT) variants from three different sources. In this study, we tested the editing efficiencies of four PE6 variants and two additional PE6 constructs with double-RT modules in transgenic rice (Oryza sativa) plants. PE6c, with an evolved and engineered RT variant from the yeast Tf1 retrotransposon, yielded the highest prime-editing efficiency. The average fold change in the editing efficiency of PE6c compared with PEmax exceeded 3.5 across 18 agronomically important target sites from 15 genes. We also demonstrated the feasibility of using two RT modules to improve prime-editing efficiency. Our results suggest that PE6c or its derivatives would be an excellent choice for prime editing in monocot plants. In addition, our findings have laid a foundation for prime-editing-based breeding of rice varieties with enhanced agronomically important traits.
RESUMEN
OBJECTIVE: To understand the health status, influencing factors and spatial distribution of the Chinese floating population and to evaluate the health equity of the floating population. METHODS: All the data were collected from the 2017 Migrant Population Dynamic Monitoring Survey in China, binary Logistic regression was used to analyze the factors that might affect the health of the floating population, and the concentration index method was used to evaluate the health equity of the floating population. Spatial autocorrelation analyses the spatial aggregation of health status and health equity. RESULTS: The unhealthy rate of the floating population in China was 2.71%. Age and gender show a statistically significant impact on self-rated health; that is, as age increases, the self-rated health of the migrant population gradually deteriorates, and women are more likely to think that they are unhealthy. Fairness analysis shows that the concentration index of the floating population is 0.021 7, the urban household registration floating population is 0.021 6, and the rural household registration floating population is 0.021 9. It is shown that the fairness of the health status of the floating population is biased towards the high-income class, and the rural household registration floating population' s health unfairness is greater than that of the urban household registration migration population. Moreover, Moran' s i=0.211 for self-rated health and Moran' s i=0.291 for the unhealthy rate indicate that self-rated health has a spatial aggregation trend. Moran' s i=0.136 showed the characteristics of spatial clustering, and the two-week prevalence fairness of the floating population was mainly in the northern and southeastern coastal areas. CONCLUSION: In general, the health status of the floating population in China is relatively good. The main influencing factors of health included gender and age. The central tendency of health inequity is reflected in the southeast coastal and northern regions, which are characterized by poverty. Attention to spatial aggregation is not only helpful to analyze the reasons of floating population, but also to study the health differences between different regions and health-related factors, to improve the overall health level of the whole population.
Asunto(s)
Sistemas de Información Geográfica , Población Rural , Humanos , Femenino , China/epidemiología , Población Urbana , Estado de SaludRESUMEN
BRD4 protein plays a pivotal role in cell cycle regulation and differentiation. Disrupting the activity of BRD4 has emerged as a promising strategy for inhibiting the growth and proliferation of cancer cells. Herein, we introduced a BRD4-targeting photothermal agent for controlled protein degradation, aiming to enhance low-temperature photothermal therapy (PTT) for cancer treatment. By incorporating a BRD4 protein inhibitor into a cyanine dye scaffold, the photothermal agent specifically bond to the bromodomain of BRD4. Upon low power density laser irradiation, the agent induced protein degradation, directly destroying the BRD4 structure and inhibiting its transcriptional regulatory function. This strategy not only prolonged the retention time of the photothermal agent in cancer cells but also confined the targeted protein degradation process solely to the tumor tissue, minimizing side effects on normal tissues through the aid of exogenous signals. This work established a simple and feasible platform for future PTT agent design in clinical cancer treatment.
Asunto(s)
Proteínas de Ciclo Celular , Proteolisis , Factores de Transcripción , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteolisis/efectos de los fármacos , Terapia Fototérmica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones , Animales , Proteínas que Contienen BromodominioRESUMEN
Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.