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BACKGROUND: Osteoarthritis (OA) is a chronic and degenerative joint disease that remains a great challenge in treatment due to the lack of effective therapies. 4-octyl itaconate (4-OI) is a novel and potent modulator of inflammation for the treatment of inflammatory disease. However, the clinical usage of 4-OI is limited due to its poor solubility and low bioavailability. As a promising drug delivery strategy, injectable hydrogels offers an effective approach to address these limitations of 4-OI. OBJECTIVE: The aim of the study was to verify that the composite 4-OI/SA hydrogels could achieve a controlled release of 4-OI and reduce damage to articular cartilage in the group of osteoarthritic rats treated with the system. METHODS: In this study, an injectable composite hydrogel containing sodium alginate (SA) and 4-octyl itaconate (4-OI) has been developed for continuous intra-articular administration in the treatment of OA. RESULTS: After intra-articular injection in arthritic rats, the as-prepared 4-OI/SA hydrogel containing of 62.5 µM 4-OI effectively significantly reduced the expression of TNF-α, IL-1ß, IL-6 and MMP3 in the ankle fluid. Most importantly, the as-prepared 4-OI/SA hydrogel system restored the morphological parameters of the ankle joints close to normal. CONCLUSION: 4-OI/SA hydrogel shows a good anti-inflammatory activity and reverse cartilage disruption, which provide a new strategy for the clinical treatment of OA.
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Herein, we report an organic photoredox-catalyzed hydroazidation of trifluoromethyl alkenes with user-friendly trimethylsilyl azide (TMSN3), enabling a direct access to a broad range of valuable ß-CF3-azides with exclusive selectivity under mild reaction conditions. The synthetic utility of this reaction was demonstrated by the late-stage modification of complex drug derivatives, scale-up of the reaction and diverse further derivatizations of the ß-CF3-azide product.
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Objectives: Preeclampsia/eclampsia (PE), a critical complication during pregnancy, has been suggested to correlate with immune cell phenotypes and levels of circulating inflammatory proteins. Our study aimed to employ a two-sample mendelian randomization (MR) analysis to assess the potential causal effects of immune cell phenotypes and circulating inflammatory proteins on the onset of PE. Methods: We utilized summary-level data from genome-wide association studies (GWAS). This included statistics for 371 immune cell phenotypes from 3,757 individuals in the Sardinian founder population, and data on 91 circulating inflammatory proteins from 14,824 European ancestry participants. Additionally, genetic associations related to PE were extracted from the FinnGen consortium, involving 1,413 cases and 287,137 controls. We applied inverse variance weighting (IVW) and supplementary methods like MR-Egger, weighted median, and weighted mode to comprehensively assess potential causal links. Results: Our analysis revealed significant causal associations of several immune cells type and inflammatory proteins with PE. Out of the immune cell phenotypes analyzed, six immune phenotypes emerged as significant risk factors (p <0.01), mainly include CD4 on activated and secreting CD4 regulatory T cells, CD28 on CD39+ CD4+ T cells, CD127- CD8+ T cell absolute cell (AC) counts, HLA DR on HLA DR+ CD8+ T cell, CD66b on CD66b++ myeloid cells, and HLA DR on dendritic cells. And ten were identified as protective factors (p <0.01). Such as CD45 on CD33br HLA DR+ CD14-, CD33+ HLA DR+ AC, CD33+ HLA DR+ CD14- AC, CD33+ HLA DR+ CD14dim AC, CD27 on CD24+ CD27+ B cell, CD20- CD38- %B cell, IgD- CD24- %B cell CD80 on plasmacytoid DC, CD25 on CD4+ T cell, and CD25 on activated & secreting CD4 regulatory T cell. Furthermore, among the inflammatory proteins studied, five showed a significant association with PE, with three offering protective effects mainly include that C-X-C motif chemokine 1, tumor necrosis factor ligand superfamily member 14, and C-C motif chemokine 19 and two exacerbating PE risk such as STAM-binding domain and Interleukin-6 (p <0.05). Conclusions: Our study highlights the pivotal roles played by diverse immune cell phenotypes and circulating inflammatory proteins in the pathophysiology of PE. These findings illuminate the underlying genetic mechanisms, emphasizing the criticality of immune regulation during pregnancy. Such insights could pave the way for novel intervention strategies in managing PE, potentially enhancing maternal and neonatal health outcomes.
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Estudio de Asociación del Genoma Completo , Preeclampsia , Humanos , Femenino , Preeclampsia/inmunología , Preeclampsia/genética , Preeclampsia/sangre , Embarazo , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Fenotipo , Polimorfismo de Nucleótido Simple , Biomarcadores , Adulto , Inflamación/inmunología , Inflamación/genéticaRESUMEN
Chlamydia trachomatis is the most prevalent bacterial sexually transmitted pathogen worldwide. Since chlamydial infection is largely asymptomatic with the potential for serious complications, a preventative vaccine is likely the most viable long-term answer to this public health threat. Cell-free protein synthesis (CFPS) utilizes the cellular protein manufacturing machinery decoupled from the requirement for maintaining cellular viability, offering the potential for flexible, rapid, and de-centralized production of recombinant protein vaccine antigens. Here, we use CFPS to produce the putative chlamydial type three secretion system (T3SS) needle-tip protein, CT584, for use as a vaccine antigen in mouse models. High-speed atomic force microscopy (HS-AFM) imaging and computer simulations confirm that CFPS-produced CT584 retains a native-like structure prior to immunization. Female mice were primed with CT584 adjuvanted with CpG-1826 intranasally (i.n.) or CpG-1826 + Montanide ISA 720 intramuscularly (i.m.), followed four-weeks later by an i.m. boost before respiratory challenge with 104 inclusion forming units (IFU) of Chlamydia muridarum. Immunization with CT584 generated robust antibody responses but weak cell mediated immunity and failed to protect against i.n. challenge as demonstrated by body weight loss, increased lungs' weights and the presence of high numbers of IFUs in the lungs. While CT584 alone may not be the ideal vaccine candidate, the speed and flexibility with which CFPS can be used to produce other potential chlamydial antigens makes it an attractive technique for antigen production.
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To investigate the flow characteristics in front chamber and rear chamber in pump mode and pump as turbine mode, a 3D computational model of a centrifugal pump was established, including the front and rear chamber. Based on Realizable k-ε turbulence model, numerical calculations of incompressible flow were carried out for internal viscous flow in two operating modes. Further analysis was conducted on the flow stability and hydraulic losses under two modes using energy gradient theory and entropy production theory. The numerical simulation results are within reasonable error compared to the experimental results in pump operation mode, which ensures the reliability of the numerical calculation method. The results indicate that the volumetric efficiency in both two modes is on an upward trend with increasing flow, but the volumetric efficiency of the pump mode is more significantly affected by changes in flow; the distribution patterns of dimensionless circumferential velocity and dimensionless radial velocity in the front and rear chambers under two operating modes are similar, but the distribution pattern of dimensionless radial velocity in the front chamber in turbine mode is significantly different from other operating conditions; flow instability is most likely to occur at the outlet of impeller, and the energy loss in clearance of wear-rings is greater than that in the pump chamber.
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Plants significantly shape root-associated microbiota, making rhizosphere microbes useful environmental indicator organisms for safety assessment. Here, we report the pyrosequencing of the bacterial 16S ribosomal RNA in rhizosphere soil samples collected from transgenic cry1Ab/cry1Ac Bt rice Huahui No. 1 (GM crop) and its parental counterpart, Minghui63. We identified a total of 2579 quantifiable bacterial operational taxonomic units (OTUs). Many treatment-enriched microbial OTUs were identified, including 14 NonGM-enriched OTUs and 10 GM-enriched OTUs. OTUs belonging to the phyla Proteobacteria, Actinobacteria, Acidobacteria, Firmicutes, Nitrospirae, Chlorobi and GN04 were identified as statistically different in abundance between GM and the other two treatments. Compared with the different impacts of different rice varieties on microbiota, the impact of rice planting on microbiota is more obvious. Furthermore, Huahui No. 1 transgenic Bt rice had a greater impact on the rhizosphere bacterial communities than Minghui63. Early developmental stages of the transgenic Bt rice had a significant impact on many Bacillaceae communities. Soil chemical properties were not significantly altered by the presence of transgenic Bt rice. The peak concentration level of Bt protein products was detected during the seedling stage of transgenic Bt rice, which may be an intriguing factor for bacterial diversity variations. Based on these findings, we conclude that transgenic Bt rice has a significant impact on root-associated bacteria. This information may be leveraged in future environmental safety assessments of transgenic Bt rice varieties.
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Chemokines, cytokines, and inflammatory cells mediate the onset and progression of many diseases through the induction of an inflammatory response. LncRNAs have emerged as important regulators of gene expression and signaling pathways. Increasing evidence suggests that lncRNAs are key players in the inflammatory response, making it a potential therapeutic target for various diseases. From the perspective of lncRNAs and inflammatory factors, we summarized the expression level and regulatory mechanisms of lncRNAs in human inflammatory diseases, such as cardiovascular disease, osteoarthritis, sepsis, chronic obstructive pulmonary disease, asthma, acute lung injury, diabetic retinopathy, and Parkinson's disease. We also summarized the functions of lncRNAs in the macrophages polarization and discussed the potential applications of lncRNAs in human inflammatory diseases. Although our understanding of lncRNAs is still in its infancy, these data will provide a theoretical basis for the clinical application of lncRNAs.
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BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.
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The adjoint function of connection number has unique advantages in solving uncertainty problems of water resource complex systems, and has become an important frontier and research hotspot in the uncertainty research of water resource complex problems. However, in the rapid evolution of the adjoint function, some problems greatly limit the application of the adjoint function in the research of water resources. Therefore, based on bibliometric analysis, development, practical application issues, and prospects of the hot directions are analyzed. It is found that the development of the connection number of water resource set pair analysis can be divided into three stages: (1) relatively sluggish development before 2005, (2) a period of rapid advancement in adjoint function research spanning from 2005 to 2017, and (3) a subsequent surge post-2018. The introduction of the adjoint function of connection number promotes the continuous development of set pair analysis of water resources. Set pair potential and partial connection number are the crucial research directions of the adjoint function. Subtractive set pair potential has rapidly developed into a relatively independent and important trajectory. The research on connection entropy is comparatively less, which needs to be further strengthened, while that on adjacent connection number is even less. The adjoint function of set pair potential can be divided into three major categories: division set pair potential, exponential set pair potential, and subtraction set pair potential. The subtraction set pair potential, which retains the original dimension and quantity variation range of the connection number, is widely used in water resources and other fields. Coupled with the partial connection number, a series of new connection number adjoint functions have been developed. The partial connection number can be mainly divided into two categories: total partial connection number, and semi-partial connection number. Among these, the calculation expression and connotation of total partial connection numbers have not yet reached a consensus, accompanied by the slow development of high-order partial connection numbers. Semi-partial connection number can describe the mutual migration movement between different components of the connection number, which develops rapidly. With the limitations and current situation described above, promoting the exploration and application of the adjoint function of connection number in the field of water resources and other fields of complex systems has become the focus of future research.
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Millimeter-wave (mmWave) communication systems leverage the directional beamforming capabilities of antenna arrays equipped at the base stations (BS) to counteract the inherent high propagation path loss characteristic of mmWave channels. In downlink mmWave transmissions, i.e., from the BS to users, distinguishing users within the same beam direction poses a significant challenge. Additionally, digital baseband precoding techniques are limited in their ability to mitigate inter-user interference within identical beam directions, representing a fundamental constraint in mmWave downlink transmissions. This study introduces an innovative analog beamforming-based interference mitigation strategy for downlink transmissions in reconfigurable intelligent surface (RIS)-assisted hybrid analog-digital (HAD) mmWave systems. This is achieved through the joint design of analog beamformers and the corresponding coefficients at both the RIS and the BS. We first present derived closed-form approximation expressions for the achievable rate performance in the proposed scenario and establish a stringent upper bound on this performance in a large number of RIS elements regimes. The exclusive use of analog beamforming in the downlink phase allows our proposed transmission algorithm to function efficiently when equipped with low-resolution analog-to-digital/digital-to-analog converters (A/Ds) at the BS. The energy efficiency of the downlink transmission is evaluated through the deployment of six-bit A/Ds and six-bit pulse-amplitude modulation (PAM) signals across varying numbers of activated RIS elements. Numerical simulation results validate the effectiveness of our proposed algorithms in comparison to various benchmark schemes.
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Increasing radical yields to reduce UV fluence requirement for achieving targeted removal of micropollutants in water would make UV-based advanced oxidation processes (AOPs) less energy demanding in the context of United Nations' Sustainable Development Goals and carbon neutrality. We herein demonstrate that, by switching the UV radiation source from conventional low-pressure UV at 254 nm (UV254) to emerging Far-UVC at 222 nm (UV222), the fluence-based concentration of HO⢠in the UV/peroxydisulfate (UV/PDS) AOP increases by 6.40, 2.89, and 6.00 times in deionized water, tap water, and surface water, respectively, with increases in the fluence-based concentration of SO4â¢- also by 5.06, 5.81, and 55.47 times, respectively. The enhancement to radical generation is confirmed using a kinetic model. The pseudo-first-order degradation rate constants of 16 micropollutants by the UV222/PDS AOP in surface water are predicted to be 1.94-13.71 times higher than those by the UV254/PDS AOP. Among the tested water matrix components, chloride and nitrate decrease SO4â¢- but increase HO⢠concentration in the UV222/PDS AOP. Compared to the UV254/PDS AOP, the UV222/PDS AOP decreases the formation potentials of carbonaceous disinfection byproducts (DBPs) but increases the formation potentials of nitrogenous DBPs.
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Contaminantes Químicos del Agua , Purificación del Agua , Agua , Fotólisis , Contaminantes Químicos del Agua/análisis , Peróxido de Hidrógeno , Oxidación-Reducción , Rayos Ultravioleta , DesinfecciónRESUMEN
BACKGROUND: The prevalence of placenta accreta spectrum, a potentially life-threatening condition, has exhibited a significant global rise in recent decades. Effective screening methods and early identification strategies for placenta accreta spectrum could enable early treatment and improved outcomes. Endometrial thickness plays a crucial role in successful embryo implantation and favorable pregnancy outcomes. Extensive research has been conducted on the impact of endometrial thickness on assisted reproductive technology cycles, specifically in terms of pregnancy rates, live birth rates, and pregnancy loss rates. However, limited knowledge exists regarding the influence of endometrial thickness on placenta accreta spectrum. OBJECTIVE: This study aimed to evaluate the association between preimplantation endometrial thickness and the occurrence of placenta accreta spectrum in women undergoing assisted reproductive technology cycles. STUDY DESIGN: A total of 4637 women who had not undergone previous cesarean delivery and who conceived by in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment and subsequently delivered at the Third Affiliated Hospital of Guangzhou Medical University between January 2008 and December 2020 were included in this study. To explore the relationship between endometrial thickness and placenta accreta spectrum, we used smooth curve fitting, threshold effect, and saturation effect analysis. Multivariate logistic regression analysis was performed to evaluate the independent association between endometrial thickness and placenta accreta spectrum while adjusting for potential confounding factors. Propensity score matching was performed to reduce the influence of bias and unmeasured confounders. Furthermore, we used causal mediation effect analysis to investigate the mediating role of endometrial thickness in the relationship between gravidity and ovarian stimulation protocol and the occurrence of placenta accreta spectrum. RESULTS: Among the 4637 women included in this study, pregnancies with placenta accreta spectrum (159; 3.4%) had significantly thinner endometrial thickness (non-placenta accreta spectrum, 10.08±2.04 mm vs placenta accreta spectrum, 8.88±2.21 mm; P<.001) during the last ultrasound before embryo transfer. By using smooth curve fitting, it was found that changes in endometrial thickness had a significant effect on the incidence of placenta accreta spectrum up to a thickness of 10.9 mm, beyond which the effect plateaued. Then, the endometrial thickness was divided into the following 4 groups: ≤7, >7 to ≤10.9, >10.9 to ≤13, and >13 mm. The absolute rates of placenta accreta spectrum in each group were 11.91%, 3.73%, 1.35%, and 2.54%, respectively. Compared with women with an endometrial thickness from 10.9 to 13 mm, the odds of placenta accreta spectrum increased from an adjusted odds ratio of 2.27 (95% confidence interval, 1.33-3.86) for endometrial thickness from 7 to 10.9 mm to an adjusted odds ratio of 7.15 (95% confidence interval, 3.73-13.71) for endometrial thickness <7 mm after adjusting for potential confounding factors. Placenta previa remained as an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 11.80; 95% confidence interval, 7.65-18.19). Moreover, endometrial thickness <7 mm was still an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 3.91; 95% confidence interval, 1.57-9.73) in the matched cohort after PSM. Causal mediation analysis revealed that approximately 63.9% of the total effect of gravidity and 18.6% of the total effect of ovarian stimulation protocol on placenta accreta spectrum were mediated by endometrial thickness. CONCLUSION: The findings of our study indicate that thin endometrial thickness is an independent risk factor for placenta accreta spectrum in women without previous cesarean delivery undergoing assisted reproductive technology treatment. The clinical significance of this risk factor is slightly lower than that of placenta previa. Furthermore, our results demonstrate that endometrial thickness plays a significant mediating role in the relationship between gravidity or ovarian stimulation protocol and placenta accreta spectrum.
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Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor with a poor prognosis. Fascin actinbundling protein 1 (FSCN1) has been reported to play a crucial role in the development and progression of LSCC; however, the underlying molecular mechanisms remain unknown. Herein, a whole transcriptome microarray analysis was performed to screen for differentially expressed genes (DEGs) in cells in which FSCN1 was knocked down. A total of 462 up and 601 downregulated mRNA transcripts were identified. Functional annotation analysis revealed that these DEGs were involved in multiple biological functions, such as transcriptional regulation, response to radiation, focal adhesion, extracellular matrixreceptor interaction, steroid biosynthesis and others. Through coexpression and proteinprotein interaction analysis, FSCN1 was linked to novel functions, including defense response to virus and steroid biosynthesis. Furthermore, crosstalk analysis with FSCN1interacting proteins revealed seven DEGs, identified as FSCN1interacting partners, in LSCC cells, three of which were selected for further validation. Coimmunoprecipitation validation confirmed that FSCN1 interacted with prostaglandin reductase 1 and 24dehydrocholesterol reductase (DHCR24). Of note, DHCR24 is a key enzyme involved in cholesterol biosynthesis, and its overexpression promotes the proliferation and migration of LSCC cells. These findings suggest that DHCR24 is a novel molecule associated with FSCN1 in LSCC, and that the FSCN1DHCR24 interaction may promote LSCC progression by regulating cholesterol metabolismrelated signaling pathways.
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Carcinoma de Células Escamosas , Proteínas Portadoras , Neoplasias de Cabeza y Cuello , Neoplasias Laríngeas , MicroARNs , Proteínas de Microfilamentos , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Actinas/metabolismo , Neoplasias Laríngeas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Colesterol , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Esteroides , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Línea Celular Tumoral , Proliferación CelularRESUMEN
Using the unsteady Bernoulli equation for the piping system and the angular momentum equation for the rotor, derives here a theoretical model to predict the startup performance of a pump as turbine (PAT). This model is effective for predicting the instantaneous evolution characteristics of the main performance parameters of PAT during startup, and these changings are initially faster and then slowly as a whole. The effect of the rotor moment of inertia and the final stabilized rotational speed of PAT on evolution characteristics of parameters is opposite. The rotational speed, head, hydraulic power, and conversion efficiency show a upward rising trend with the startup time, whereas the flow rate and hydraulic head loss display a downward trend.
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Solidification/stabilization (S/S) is a typical technique to immobilize toxic heavy metals in Municipal solid waste incineration fly ash (MSWI FA). This study utilized blast furnace slag, steel slag, desulfurization gypsum, and phosphoric acid sludge to develop a novel metallurgical slag based cementing material (MSCM). Its S/S effects of MSWI FA and long-term S/S effectiveness under dry-wet circulations (DWC) were evaluated and compared with ordinary Portland cement (OPC). The MSCM-FA block with 25 wt.% MSCM content achieved 28-day compressive strength of 9.38 MPa, indicating its high hydration reactivity. The leaching concentrations of Pb, Zn and Cd were just 51.4, 1895.8 and 36.1 µg/L, respectively, well below the limit standard of Municipal solid wastes in China (GB 16889-2008). After 30 times' DWC, leaching concentrations of Pb, Zn and Cd for MSCM-FA blocks increased up to 130.7, 9107.4 and 156.8 µg/L, respectively, but considerably lower than those for OPC-FA blocks (689, 11,870.6 and 185.2 µg/L, respectively). The XRD and chemical speciation analysis revealed the desorption of Pb, Zn and Cd attached to surface of C-S-H crystalline structure during the DWC. The XPS and SEM-EDS analysis confirmed the formation of Pb-O-Si and Zn-O-Si bonds via isomorphous replacement of C-A-S-H in binder-FA blocks. Ettringite crystalline structure in OPC-FA block was severely destructed during the DWC, resulting in the reduced contents of PbSO4 and CaZn2Si2O7·H2O and the higher leachability of Pb2+ and Zn2+.
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Metales Pesados , Eliminación de Residuos , Ceniza del Carbón/química , Residuos Sólidos/análisis , Material Particulado/química , Cadmio/análisis , Plomo/análisis , Metales Pesados/análisis , Carbono/química , Incineración/métodos , Eliminación de Residuos/métodosRESUMEN
The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.
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Proliferación Celular , Proteínas Hedgehog , Meduloblastoma , Transducción de Señal , Receptor Smoothened , Esteroles , Receptor Smoothened/antagonistas & inhibidores , Receptor Smoothened/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Transducción de Señal/efectos de los fármacos , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Esteroles/química , Esteroles/farmacología , Esteroles/metabolismo , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Colesterol/metabolismoRESUMEN
The Sirtuins family, formally known as the Silent Information Regulator Factors, constitutes a highly conserved group of histone deacetylases. Recent studies have illuminated SIRT6's role in doxorubicin (DOX)-induced oxidative stress and apoptosis within myocardial cells. Nevertheless, the extent of SIRT6's impact on DOX-triggered myocardial cell aging and damage remains uncertain, with the associated mechanisms yet to be fully understood. In our research, we examined the influence of SIRT6 on DOX-induced cardiomyocyte senescence using ß-galactosidase and γ-H2AX staining. Additionally, we gauged the mRNA expression of senescence-associated genes, namely p16, p21, and p53, through Real-time PCR. Employing ELISA assay kits, MDA, and total SOD activity assay kits, we measured inflammatory factors TNF-α, IL-6, and IL-1ß, alongside oxidative stress-related indicators. The results unequivocally indicated that SIRT6 overexpression robustly inhibited DOX-induced cardiomyocyte senescence. Furthermore, we established that SIRT6 overexpression suppressed the inflammatory response and oxidative stress induced by DOX in cardiomyocytes. Conversely, silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury. Our investigations further unveiled that SIRT6 upregulated the expression of genes CD36, CPT1, LCAD, MCAD associated with fatty acid oxidation through its interaction with PPARα, thereby exerting anti-aging effects. In vivo, the overexpression of SIRT6 was observed to restore DOX-induced declines in EF and FS to normal levels in mice. Echocardiography and HE staining revealed the restoration of cardiomyocyte alignment, affording protection against DOX-induced myocardial senescence and injury. The findings from this study suggest that SIRT6 holds significant promise as a therapeutic target for mitigating DOX-induced cardiomyopathy.
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Miocitos Cardíacos , Sirtuinas , Animales , Ratones , Miocitos Cardíacos/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Senescencia Celular , Doxorrubicina/farmacología , Estrés Oxidativo , Sirtuinas/genética , Sirtuinas/metabolismo , ApoptosisRESUMEN
Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anciano , Humanos , Masculino , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Envejecimiento/genética , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , PronósticoRESUMEN
The remediation of heavy metals/metalloids (HMs) co-contaminated soil by solid wastes-based stabilizers (SWBS) has received major concern recently. Based on the literature reported in the latest years (2010-2023), this review systematically summarizes the different types of solid wastes (e.g., steel slag, coal fly ash, red mud, and sewage sludge, etc.) employed to stabilize HMs contaminated soil, and presents results from laboratory and field experiments. Firstly, the suitable solid wastes for soil remediation are reviewed, and the pros and cons are presented. Thereafter, the technical feasibility and economic benefit are evaluated for field application. Moreover, evaluation methods for remediation of different types of HMs-contaminated soil and the effects of SWBS on soil properties are summarized. Finally, due to the large specific surface, porous structure, and high reactivity, the SWBS can effectively stabilize HMs via adsorption, complexation, co/precipitation, ion exchange, electrostatic interaction, redox, and hydration process. Importantly, the environmental implications and long-term effectiveness associated with the utilization of solid wastes are highlighted, which are challenges for practical implementation of soil stabilization using SWBS, because the aging of soil/solid wastes has not been thoroughly investigated. Future attention should focus on modifying the SWBS and establishing an integrated long-term stability evaluation method.
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Algal blooms caused by excessive proliferation of phytoplankton in young reservoirs have been frequently reported, seriously threatening the unstable aquatic ecosystem, water quality safety and public health. Thus, there is an urgent need to investigate the dynamics of phytoplankton in these young reservoirs, and many current studies on phytoplankton in young reservoirs are based on point monitoring information. This study used remote sensing interpretation to invert the chlorophyll-a concentration in 131 images of Zipingpu Reservoir from 2013 to 2021, and analyzed the spatiotemporal characteristics of algal blooms. Partial least squares-structural equation modeling was used to identify the environmental influencing factors of algal blooms. The results showed that the average chlorophyll-a concentration in the reservoir was 4.49 mg/m3, and the frequency of algal blooms was 28%. The maximum area of algal blooms shows a significant increase trend in the interannual (increase by 0.05%/yr in the proportion of water surface area), and the average blooms area shows a weaker increase trend (0.01%/yr). The prone period of algal bloom is from April to August every year. The solar duration and wind speed had significant direct positive effects on the maximum and average algal bloom area, which was the similar effects in different years and months (path coefficient exceeds 0.44). TP also has a significant direct positive effect on the average algal bloom area between different years (path coefficient of 0.30). The suitable meteorological factors level making the bloom-prone period from April to August, the prevailing westerly and southerly winds provide transport for the aggregation of phytoplankton and algal blooms outbreak in the northeastern waters. This study expand the monitoring frequency and spatial information of algal blooms, which provided a reference for young reservoir management and prevention of blooms.