RESUMEN
RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.
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Proteínas Adaptadoras del Transporte Vesicular , Inflamación , Necroptosis , Proteínas de Unión al ARN , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Transducción de Señal , Animales , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Ratones , Inflamación/metabolismo , Inflamación/inmunología , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/genética , Muerte Celular , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Dominios Proteicos , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Apoptosis , Mutación , Proteína de Dominio de Muerte Asociada a Receptor de TNFRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1-3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6-8. ZBP1 mediates host defence against some viruses6,7,9-14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Zα-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Zα-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions-particularly in individuals with mutations in RIPK1 and CASP817-20.
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Inflamación/metabolismo , Necroptosis , Proteínas de Unión al ARN/metabolismo , Transporte Activo de Núcleo Celular , Animales , Caspasa 8/metabolismo , Femenino , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ácidos Nucleicos/metabolismo , ARN Bicatenario/metabolismo , Proteínas de Unión al ARN/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Enfermedades de la Piel/genética , Enfermedades de la Piel/metabolismo , Enfermedades de la Piel/patologíaRESUMEN
Tranexamic acid (TXA) is widely used among young women because of its ability to whiten skin and treat menorrhagia. Nevertheless, its potential effects on oocyte maturation and quality have not yet been clearly clarified. Melatonin (MT) is an endogenous hormone released by the pineal gland and believed to protect cells from oxidative stress injury. In the present study, we used in vitro maturation model to investigate the toxicity of TXA and the protective role of MT in mouse oocyte. Compared with the control group, TXA-exposed group had significantly lower nuclear maturation (57.72% vs. 94.08%, P < 0.001) and early embryo cleavage rates (38.18% vs. 87.66%, P < 0.001). Further study showed that spindle organization (52.56% vs. 18.77%, P < 0.01) and chromosome alignment (33.23% vs. 16.66%, P < 0.01) were also disrupted after TXA treatment. Mechanistically, we have demonstrated that TXA induced early apoptosis of oocytes (P < 0.001) by raising the level of ROS (P < 0.001), which was consistent with an increase in mitochondrial damage (P < 0.01). Fortunately, all these effects except the spindle defect were successfully rescued by an appropriate level of MT. Collectively, our findings indicate that MT could partially reverse TXA-induced oocyte quality deterioration in mouse by effectively improving mitochondrial function and reducing oxidative stress-mediated apoptosis.
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In this comprehensive genome-wide study, we identified and classified 83 Xylanase Inhibitor Protein (XIP) genes in wheat, grouped into five distinct categories, to enhance understanding of wheat's resistance to Fusarium head blight (FHB), a significant fungal threat to global wheat production. Our analysis reveals the unique distribution of XIP genes across wheat chromosomes, particularly at terminal regions, suggesting their role in the evolutionary expansion of the gene family. Several XIP genes lack signal peptides, indicating potential alternative secretion pathways that could be pivotal in plant defense against FHB. The study also uncovers the sequence homology between XIPs and chitinases, hinting at a functional diversification within the XIP gene family. Additionally, the research explores the association of XIP genes with plant immune mechanisms, particularly their linkage with plant hormone signaling pathways like abscisic acid and jasmonic acid. XIP-7A3, in particular, demonstrates a significant increase in expression upon FHB infection, highlighting its potential as a key candidate gene for enhancing wheat's resistance to this disease. This research not only enriches our understanding of the XIP gene family in wheat but also provides a foundation for future investigations into their role in developing FHB-resistant wheat cultivars. The findings offer significant implications for wheat genomics and breeding, contributing to the development of more resilient crops against fungal diseases.
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Resistencia a la Enfermedad , Fusarium , Enfermedades de las Plantas , Proteínas de Plantas , Triticum , Triticum/genética , Triticum/microbiología , Triticum/inmunología , Fusarium/fisiología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/inmunología , Resistencia a la Enfermedad/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Inmunidad de la Planta/genética , Estudio de Asociación del Genoma Completo , Genes de Plantas , Genoma de Planta , FilogeniaRESUMEN
PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.
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Tratamiento Farmacológico de COVID-19 , Mortalidad Hospitalaria , Ritonavir , Humanos , Ritonavir/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , SARS-CoV-2 , Antivirales/uso terapéutico , COVID-19/mortalidad , Hospitalización/estadística & datos numéricos , Resultado del Tratamiento , Quimioterapia Combinada , Estudios RetrospectivosRESUMEN
S-omeprazole and R-rabeprazole are important proton pump inhibitors (PPIs) used for treating peptic disorders. They can be biosynthesized from the corresponding sulfide catalyzed by Baeyer-Villiger monooxygenases (BVMOs). During the development of BVMOs for target sulfoxide preparation, stereoselectivity and overoxidation degree are important factors considered most. In the present study, LnPAMO-Mu15 designed previously and TtPAMO from Thermothelomyces thermophilus showed high (S)- and (R)-configuration stereoselectivity respectively towards thioethers. TtPAMO was found to be capable of oxidating omeprazole sulfide (OPS) and rabeprazole sulfide (RPS) into R-omeprazole and R-rabeprazole respectively. However, the overoxidation issue existed and limited the application of TtPAMO in the biosynthesis of sulfoxides. The structural mechanisms for adverse stereoselectivity between LnPAMO-Mu15 and TtPAMO towards OPS and the overoxidation of OPS by TtPAMO were revealed, based on which, TtPAMO was rationally designed focused on the flexibility of loops near catalytic sites. The variant TtPAMO-S482Y was screened out with lowest overoxidation degree towards OPS and RPS due to the decreased flexibility of catalytic center than TtPAMO. The success in this study not only proved the rationality of the overoxidation mechanism proposed in this study but also provided hints for the development of BVMOs towards thioether substrate for corresponding sulfoxide preparation.
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Coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global public health challenge. This disease causes damage not only to the respiratory system, affecting the normal physiological function of the lungs, but also to other vital organs, such as the heart and testicles. Existing studies have shown that co-expression of angiotensin-converting enzyme 2 and transmembrane serine protease 2 is the main mechanism by which SARS-CoV-2 invades host cells. Angiotensin-converting enzyme 2-expressing cells are widespread in the corpus cavernosum, reproductive tract and testis of men, which has raised concerns. Furthermore, abnormal sex hormone levels and decreased semen parameters were observed in coronavirus disease 2019 patients. This study comprehensively assessed the effects of SARS-CoV-2 infection on the testis, semen parameters, sex hormone levels and erectile function, and discussed possible transmission routes during sexual intercourse and the effect of vaccination on male fertility.
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COVID-19 , Humanos , Masculino , COVID-19/prevención & control , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Peptidil-Dipeptidasa A , Fertilidad , Hormonas Esteroides Gonadales , VacunaciónRESUMEN
Solid-phase microextraction (SPME) coupled with electrospray ionization mass spectrometry (ESI-MS) was developed for rapid and sensitive determination of endogenous androgens. The SPME probe is coated with covalent organic frameworks (COFs) synthesized by reacting 1,3,5-tri(4-aminophenyl)benzene (TPB) with 2,5-dioctyloxybenzaldehyde (C8PDA). This COFs-SPME probe offers several advantages, including enhanced extraction efficiency and stability. The analytical method exhibited wide linearity (0.1-100.0 µg L-1), low limits of detection (0.03-0.07 µg L-1), high enrichment factors (37-154), and satisfactory relative standard deviations (RSDs) for both within one probe (4.0-14.8%) and between different probes (3.4-12.7%). These remarkable performance characteristics highlight the reliability and precision of the COFs-SPME-ESI-MS method. The developed method was successfully applied to detect five kinds of endogenous androgens in female serum samples, indicating that the developed analytical method has great potential for application in preliminary clinical diagnosis.
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Andrógenos , Límite de Detección , Microextracción en Fase Sólida , Espectrometría de Masa por Ionización de Electrospray , Microextracción en Fase Sólida/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Humanos , Andrógenos/sangre , Andrógenos/análisis , Andrógenos/química , Femenino , Estructuras Metalorgánicas/química , Reproducibilidad de los ResultadosRESUMEN
Objectives: Electronic health records (EHRs) have transformed the way modern medicine is practiced, but they remain a major source of documentation burden among physicians. This study aims to use data from Signal, a tool provided by the Epic EHR, to analyze physician metadata in the Montefiore Health System via cluster analysis to assess EHR burden and efficiency. Methods: Data were obtained for a one-month period (July 2020) representing a return to normal operation post-telemedicine implementation. Six metrics from Signal were used to phenotype physicians: time on unscheduled days, pajama time, time outside of 7 AM to 7 PM, turnaround time, proficiency score, and visits closed the same day. k-Means clustering was employed to group physicians, and the clusters were assessed overall and by sex and specialty. Results: Our results demonstrate the partitioning of physicians into a higher-efficiency, lower-time outside of scheduled hours (TOSH) cluster and a lower-efficiency, higher-TOSH cluster even when stratified by sex and specialty. Intra-cluster comparisons showed general homogeneity of physician metrics with the exception of the higher-efficiency, lower-TOSH cluster when stratified by sex. Conclusions: Taken together, the clusters uniquely reflect the EHR efficiency-burden of the Montefiore Health System. Applying k-means clustering to readily available EHR data allows for a scalable, efficient, and adaptable approach of assessing physician EHR burden and efficiency, allowing health systems to examine documentation trends and target wellness interventions.
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Médicos , Telemedicina , Humanos , Registros Electrónicos de Salud , Documentación , Análisis por ConglomeradosRESUMEN
The aim of this study was to explore gestational weight gain (GWG) trajectories and their associations with adverse pregnancy outcomes. A retrospective cohort study including 11,064 women with gestational diabetes mellitus (GDM) was conducted between 2015 and 2019 in China. The latent class trajectory model was used to identify GWG trajectories, and logistic regression was performed to examine odds ratio (OR) of pregnancy outcomes. Three trajectories of GWG were identified in these 11,604 women with GDM. Trajectory 1: 64.02% of women had sustained moderate GWG throughout pregnancy; Trajectory 2: 17.75% of women showed a high initial GWG but followed by a low GWG from the third trimester until delivery; Trajectory 3: 18.23% had low initial GWG but followed by drastic GWG from the second trimester until delivery. Compared with pregnant women with Trajectory 1, women with Trajectory 2 had a higher risk of large for gestational age (adjusted odds ratio [AOR]: 1.29, 95% confidence interval [CI]: 1.12-1.48) but at a lower risk of having hypertensive disorders of pregnancy (AOR: 0.76, 95% CI: 0.57-0.96). Women in Trajectory 3 were more likely to develop small for gestational age (AOR: 2.12, 95% CI: 1.62-2.78), low birthweight (AOR: 1.49, 95% CI: 1.07-2.08), preterm birth (AOR: 1.28, 95% CI: 1.05-1.63), caesarean section (AOR: 1.26, 95% CI: 1.112-1.42) and hypertensive disorders of pregnancy (AOR: 2.24, 95% CI: 1.82-2.76). The association of GWG trajectory with adverse pregnancy outcomes differs across prepregnancy body mass index and GWG categories. Women with a slow initial GWG but followed by drastic GWG had higher risks of adverse pregnancy outcomes. Early clinical recognition of poor GWG trajectory will contribute to early intervention in high-risk groups to minimise adverse outcomes.
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Diabetes Gestacional , Ganancia de Peso Gestacional , Resultado del Embarazo , Humanos , Embarazo , Femenino , Diabetes Gestacional/epidemiología , Estudios Retrospectivos , Adulto , Resultado del Embarazo/epidemiología , China/epidemiología , Estudios de Cohortes , Factores de Riesgo , Trayectoria del Peso Corporal , Recién Nacido , Índice de Masa CorporalRESUMEN
This study aims to observe the efficacy and safety of Bushen Culuan Formula in the treatment of infertility caused by polycystic ovary syndrome(PCOS) and to explore the mechanism using metabolomics. Ninety-four patients with infertility caused by PCOS with the syndrome of kidney deficiency and blood stasis were selected and assigned into treatment and control groups(n=47). The basal body temperature(BBT) was measured, and B-ultrasonography was employed to monitor follicles, ovarian volume, endometrium, ovulation, and pregnancy. The serum levels of sex hormones including follicle-stimulating hormone(FSH), luteinizing hormone(LH), prolactin(PRL), estradiol(E_2), progestin(P), testosterone(T), free testosterone(FT), androstenedione(A2), inhibin B(INHB), and anti-Müllerian hormone(AMH) were measured. The coagulation function, traditional Chinese medicine(TCM) symptom scores, blood and urine routine, liver and kidney functions and other safety indicators were determined. Metabolomics was employed to comparatively analyze the serum metabolites of 26 patients(13 patients in each group) in the clinical study. The results showed that the total response rate and pregnancy rate of the treatment group were higher than those of the control group(P<0.001), suggesting that Bushen Culuan Formula regulated the sex hormones and ovarian function. Specifically, it reduced the levels of LH, T, FT, A2, and INHB(P<0.05 or P<0.01) and the LH/FSH ratio(P<0.05), elevated the level of P(P<0.05), promoted ovulation, increased endothelial thickness, and lowered TCM symptom scores without causing adverse reactions. A total of 24 differential metabolites were screened by metabolomics, and there were correlations between sex hormones and differential metabolites in the PCOS-induced infertility patients with kidney deficiency and blood stasis. In conclusion, Bushen Culuan Formula may regulate hormone levels through lipid and amino acid metabolism.
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Medicamentos Herbarios Chinos , Infertilidad Femenina , Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/fisiopatología , Síndrome del Ovario Poliquístico/complicaciones , Medicamentos Herbarios Chinos/administración & dosificación , Adulto , Infertilidad Femenina/tratamiento farmacológico , Infertilidad Femenina/etiología , Infertilidad Femenina/fisiopatología , Adulto Joven , Embarazo , Hormona Luteinizante/sangreRESUMEN
BACKGROUND: We aimed to identify tumor-associated antigen (TAA) biomarkers through bioinformatic analysis and experimental verification, and to evaluate a panel of autoantibodies against tumor-associated antigens (TAAbs) for the detection of oral cancer (OC). METHODS: GEO and TCGA databases were used to screen significantly up-regulated genes related to OC, and protein-protein interaction (PPI) analysis and Cystoscope software were used to identify key genes. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of autoantibodies in 173 OC patients and 173 normal controls, and binary logistic regression analysis was used to build a diagnostic model. RESULTS: Using bioinformatics, we identified 10 key genes (AURKA, AURKB, CXCL8, CXCL10, COL1A1, FN1, FOXM1, MMP9, SPP1 and UBE2C) that were highly expressed in OC. Three autoantibodies (anti-AURKA, anti-CXCL10, anti-FOXM1) were proven to have diagnostic value for OC in the verification set and the validation set. The combined assessment of these three autoantibodies improved the diagnostic value for OC, with an area under the curve (AUC), sensitivity and specificity of 0.741(95%CI:0.690-0.793),58.4% and 80.4%, respectively. In addition, the combination of these three autoantibodies also had high diagnostic value for oral squamous cell carcinoma (OSCC), with an AUC, sensitivity and specificity of 0.731(95%CI:0.674,0.786), 53.8% and 82.1%, respectively. CONCLUSIONS: Our study revealed that AURKA, CXCL10 and FOXM1 may be potential biomarkers and the panel of three autoantibodies (anti-AURKA, anti-CXCL10 and anti-FOXM1) had good diagnostic value for OC.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/diagnóstico , Área Bajo la Curva , Aurora Quinasa A , AutoanticuerposRESUMEN
OBJECTIVE: To analyze the long-term trends in pollen counts and asthma-related emergency department visits (AREDV) in adult and pediatric populations in the Bronx. METHODS: Daily values of adult and pediatric AREDV were retrospectively obtained from three major Bronx hospitals using ICD-10 codes and pollen counts were obtained from the Armonk station from 2001-2020. Wilcoxon Ranked Sum was applied to compare median values, while Spearman correlation was employed to examine the association between these variables, for both decades and each season. RESULTS: The median value of pediatric AREDV increased by 200% from the 1st to 2nd decade (p < 0.001) and AREDV peak shifted from predominantly the spring season in the 1st decade to the fall and winter seasons in the 2nd decade. Seasonal patterns were consistent over 20 years with summer AREDV lower than all other seasons (9 vs. 17 per day) (p < 0.001). Spring tree pollen peaks were correlated with AREDV peaks (rho = 0.34) (p < 0.001). Tree pollen exceeding 100 grains/m3 corresponded to a median of 19.0 AREDVs while all other tree pollen (0 - 99 grains/m3) corresponded to a median of 15.0 AREDVs (p < 0.001). AREDVs sharply declined in 2020, coinciding with the emergence of COVID-19. CONCLUSIONS: Pollen and AREDVs peak earlier in the spring and are more strongly interconnected, while asthma rates among children are rapidly rising, particularly in the fall and winter. These findings can advise targeted awareness campaigns for better management of asthma related morbidity.
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Asma , COVID-19 , Humanos , Adulto , Niño , Asma/epidemiología , Estaciones del Año , Alérgenos , Estudios Retrospectivos , PolenRESUMEN
Dehydroepiandrosterone (DHEA) is an important neurosteroid hormone to keep human hormonal balance and reproductive health. However, DHEA was always produced with impurities either by chemical or biological method and required high-cost purification before the medical use. To address this issue, a novel chemoenzymatic process was proposed and implemented to produce DHEA. An acetoxylated derivate of 4-androstene-3,17-dione (4-AD) was generated by chemical reaction and converted into DHEA by an enzyme cascade reaction combining a hydrolysis reaction with a reduction reaction. The hydrolysis reaction was catalyzed by a commercial esterase Z03 while the reduction reaction was catalyzed by E. coli cells co-expressing a 3ß-hydroxysteroid dehydrogenase SfSDR and a glucose dehydrogenase BtGDH. After the condition optimization, DHEA was synthesized at a 100 mL scale under 100 mM of substrate loading and purified as white powder with the highest space-time yield (4.80 g/L/h) and purity (99 %) in the biosynthesis of DHEA. The successful attempt in this study provides a new approach for green synthesis of highly purified DHEA in the pharmaceutical industry.
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Deshidroepiandrosterona , Deshidroepiandrosterona/síntesis química , Escherichia coli/metabolismoRESUMEN
Submerged plants and lanthanum-modified bentonite (LMB) have important applications for the remediation of contaminated sediments; however, their combined effect on arsenic (As) removal has not been comprehensively evaluated. In this study, the physicochemical properties and changes in soluble As in sediments treated with LMB, Vallisneria spiralis (V. spiralis), and LMB + V. spiralis were observed at three time points (days 15, 35, and 66), and the changes in microbial and As species in sediments on day 66 were analyzed. LMB + V. spiralis treatment was the most effective for As removal. On day 66, the average concentrations of soluble As at a depth of 0-100 mm decreased by 12.71%, 48.81%, and 59.73% following treatment with LMB, V. spiralis, and LMB + V. spiralis, respectively. Further analysis showed that LMB is more effective at removing As(V) than V. spiralis, while V. spiralis is more effective at removing As(III), and the combination of LMB + V. spiralis is more effective for removing both As(III) and As(V) than individual LMB and V. spiralis treatments. LMB + V. spiralis enhanced the transformation of mobile As to Fe2O3/oxyhydroxide-bound As in sediments and the activity of As-oxidizing microorganisms. LMB promoted the growth of V. spiralis and enhanced the removal of As. This study indicates that this combination is an effective method for removing mobile As from sediments, and could effectively inhibit the release of As from sediments to overlying water.
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Arsénico , Hydrocharitaceae , Bentonita/química , Lantano/química , Sedimentos Geológicos/química , Fósforo/química , Lagos/químicaRESUMEN
Monascus sp. is an important food microbial resource with the production of cholesterol-lowering agent lovastatin and other healthy metabolites. However, the mycotoxin citrinin naturally produced by Monascus sp. and the insufficient productivity of lovastatin limit its large-scale use in food industry. The aim of this paper is to modify a lovastatin-producing strain Monascus pilosus GN-01 through metabolic engineering to obtain a citrinin-free M. pilosus strain with higher yield of lovastatin. The citrinin synthesis regulator gene ctnR was firstly disrupted to obtain GN-02 without citrinin production. Based on that, the lovastatin biosynthesis genes (mokC, mokD, mokE, mokF, mokH, mokI, and LaeA) were, respectively, overexpressed, and pigment-regulatory gene (pigR) was knocked out to improve lovastatin production. The results indicated ctnR inactivation effectively disrupted the citrinin release by M. pilosus GN-01. The overexpression of lovastatin biosynthesis genes and pigR knockout could lead higher contents of lovastatin, of which pigR knockout strain achieved 76.60% increase in the yield of lovastatin compared to GN-02. These studies suggest that such multiplex metabolic pathway engineering in M. pilosus GN-01 is promising for high lovastatin production by a safe strain for application in Monascus-related food. KEY POINTS: ⢠Disruption of the regulator gene ctnR inhibited citrinin production of M. pilosus. ⢠Synchronous overexpression of biosynthesis gene enhanced lovastatin production. ⢠pigR knockout enhanced lovastatin of ΔctnR strain of M. pilosus.
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Purpose: Pen Yan Jing tablets (PYJ), a Chinese patent medicine, has being used for pelvic inflammatory disease (PID) effectively. This study was designed to explore the underlying mechanisms of PYJ for treating PID. Methods: A rat model of PID was established by mixed bacteria liquid plus mechanical damage. After PYJ treatment, the morphology of uteri and extent of pelvic adhesion were observed. The pathological changes were evaluated by hematoxylin-eosin (HE) staining. The protein expressions of CD68, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and cyclooxygenase-2 (COX-2) were quantitated by immunohistochemistry. A cell model of lipopolysaccharide (LPS)-activated RAW 264.7 macrophages was performed. The cell proliferation and NO level were measured by CCK-8 and Griess method, respectively. The tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were detected by ELISA. The protein kinase B (Akt)/nuclear factor kappa-B (NF-κB) pathway-related protein expressions were assayed by western blot or immunofluorescence. Results: PYJ alleviated pelvic adhesion and inflammatory lesions of uteri in PID rats. PYJ down-regulated protein expressions of ICAM-1, VCAM-1, MCP-1, COX-2, p-Akt, p-IκB kinaseα/ß (p-IKKα/ß), p-IκBα, p65, and p-p65 in uteri of PID rats. Moreover, PYJ medicated serum inhibited abnormal cell proliferation, NO release, levels of TNF-α and IL-6, nuclear translocation of p65, and protein expressions of p-Akt, p-p65 and p-IκBα in LPS-activated RAW 264.7 macrophages. Conclusions: Taken together, PYJ may alleviates PID through inhibiting Akt/NF-κB pathway.
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FN-kappa B , Enfermedad Inflamatoria Pélvica , Humanos , Femenino , Ratas , Animales , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Inhibidor NF-kappaB alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedad Inflamatoria Pélvica/tratamiento farmacológico , Lipopolisacáridos/farmacología , Interleucina-6 , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/farmacología , Ciclooxigenasa 2/metabolismoRESUMEN
PURPOSE: To compare residential geography, sex, socioeconomic status (SES), and race/ethnicity of patients screened at Montefiore's Lung Cancer Screening Program with those of patients diagnosed with lung cancer, assessing whether screening efforts are appropriately focused. METHODS: This retrospective cohort study involved patients within a multisite urban medical center undergoing lung cancer screening or diagnosed with lung cancer from January 1, 2015 to December 31, 2019. Inclusion criteria were residence within the Bronx, NY and age between 55 and 80 years. Institutional review board approval was obtained. Data were analyzed using the Wilcoxon two-sample t test and χ2. RESULTS: The cohorts comprised 1568 (50.3%) women and 1551 (49.7%) men (mean age 65.6 ± 6.16). The Southeast Bronx had the most diagnosed lung cancers (29.96%) and screenings (31.22%). Sex did not significantly differ (p = 0.053). Cancer and screening cohorts were from impoverished neighborhoods with mean SES of - 3.11 ± 2.78 and - 3.44 ± 2.80 (p < 0.01). The lower tier SES neighborhoods demonstrated more patients in the screening cohort than cancer cohort (p = 0.01). Both cohorts included a majority of Hispanic patients, although race/ethnicity differed significantly (p = 0.01). Lower SES neighborhoods showed no significant difference in race/ethnicity between cancer and screening cohorts (p = 0.262). CONCLUSION: Though statistically significant differences were found between cohorts, likely due to sample size, few clinically meaningful differences were found, implying our lung cancer screening program was effective in reaching the desired population. Demographics-based programs should be considered in global efforts to screen vulnerable populations.
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Detección Precoz del Cáncer , Neoplasias Pulmonares , Masculino , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Etnicidad , Clase SocialRESUMEN
BACKGROUND: Physical activity promotes health and is particularly important during middle and older age for decreasing morbidity and mortality. We assessed the correlates of changes over time in moderate-to-vigorous physical activity (MVPA) in Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL: mean [SD] age 49.2 y [11.5]) and compared them to a cohort of primarily White adults from the Framingham Heart Study (FHS: mean [SD] 46.9 y [9.2]). METHODS: Between 2008 and 2019, we assessed accelerometry-based MVPA at two time points with an average follow-up of: 7.6 y, SD 1.3 for HCHS/SOL, and 7.8 y, SD 0.7 for FHS. We used multinomial logistic regression to relate socio-demographic and health behaviors with changes in compliance with 2018 US recommendations for MVPA from time 1 to time 2 (remained active or inactive; became active or inactive) across the two cohorts. RESULTS: In HCHS/SOL mean MVPA was 22.6 (SD, 23.8) minutes at time 1 and dropped to 16.7 (19.0) minutes at time 2. In FHS Mean MVPA was 21.7 min (SD, 17.7) at time 1 and dropped to 21.3 min (SD, 19.2) at time 2. Across both cohorts, odds of meeting MVPA guidelines over time were about 6% lower in individuals who had lower quality diets vs. higher, about half in older vs. younger adults, about three times lower in women vs. men, and 9% lower in individuals who had a higher vs. lower BMI at baseline. Cohorts differed in how age, gender, income, education, depressive symptoms, marital status and perception of general health and pain associated with changes in physical activity. High income older Hispanics/Latino adults were more likely to become inactive at the follow-up visit as were HCHS/SOL women who were retired and FHS participants who had lower levels of education and income. Higher depressive symptomology was associated with becoming active only in HCHS/SOL women. Being male and married was associated with becoming inactive in both cohorts. Higher perception of general health and lower perception of pain were associated with remaining active only in FHS adults. CONCLUSIONS: These findings highlight potentially high-risk groups for targeted MVPA intervention.