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Objective: Scientific control of wind speed between tobacco leaves can improve quality of tobacco after cured in bulk curing barn. Method: Regarding the light orange color after cured tobacco and high power consumption caused by inaccurate control of the current circulating fan, and different requirements for wind speed during the tobacco curing, this paper designed a variable frequency drive system (VDS) to control the rotation speed of the circulating fan. With the design of anti-interference components, the VDS is integrated with the curing controller. Results: The curing adoption of anti-interference for the VDS device will not affect the normal operation of the tobacco curing controller during tobacco curing. Compared with the traditional circulating fan with high speed and low speed options, the VDS device can accurately control the air speed during the tobacco curing process, and improve the economic characters and internal quality of cured tobacco. This paper is also to provide an alternative method in terms of ventilation and humidity removal for industrial and agricultural production.
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Microglia activation is an early mediator of neuroinflammation and a major contributor to spinal damage and motor dysfunction. This study was designed to investigate the role of small nucleolar RNA host gene 1 (SNHG1) on the apoptosis and inflammatory response of microglial cell BV-2 and its underlying molecular mechanism. The C5 lamina contusion-induced mouse model of spinal cord injury (SCI) was constructed. Mouse microglia BV2 was stimulated by lipopolysaccharide (LPS) to establish the in vitro model of SCI. The quantitative reverse transcription polymerase chain reaction method was used to quantify RNA expression levels. Enzyme-linked immunosorbent assays were used to quantify concentrations of inflammatory cytokines. Protein levels were assessed by western blotting, and apoptosis was assessed by flow cytometry. Dual luciferase reporter gene assay and RNA pull-down assay were conducted to investigate the binding relationships between molecules. Upregulation of SNHG1 and downregulation of miR-195-5p were observed in the spinal cords of SCI mouse model. LPS treatment led to elevation of SNHG1 expression in BV2 cells, as well as accelerated apoptosis and inflammation. Evident mitigation of LPS-induced BV2 cell damage was observed after SNHG1 knockdown. MiR-195-5p was identified as a target of SNHG1. Inhibition of miR-195-5p restored the impact of SNHG1 knockdown on cell damage of LPS-treated BV2 cells. Furthermore, miR-195-5p can target activating transcription factor-6 (ATF6). In summary, SNHG1 knockdown ameliorates LPS-induced microglial apoptosis and inflammatory response via the miR-195-5p/ATF6 axis, providing a novel direction for SCI treatment.
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Apoptosis , Inflamación , Lipopolisacáridos , MicroARNs , Microglía , Traumatismos de la Médula Espinal , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ratones , Inflamación/genética , Inflamación/patología , Inflamación/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Silenciador del Gen , Ratones Endogámicos C57BL , Línea Celular , Modelos Animales de Enfermedad , MasculinoRESUMEN
Pro-inflammatory cytokine production by the retinal pigment epithelium (RPE) is a key etiology in retinal degenerative diseases, yet the underlying mechanisms are not well understood. TMEM97 is a scarcely studied transmembrane protein recently implicated in retinal degeneration. BAH domain coiled coil 1 (BAHCC1) is a newly discovered histone code reader involved in oncogenesis. A role for TMEM97 and BAHCC1 in RPE inflammation was not known. Here we found that they constitute a novel axis regulating pro-inflammatory cytokine expression in RPE cells. Transcriptomic analysis using a TMEM97-/- ARPE19 human cell line and the validation via TMEM97 loss- and gain-of-function revealed a profound role of TMEM97 in promoting the expression of pro-inflammatory cytokines, notably IL1ß and CCL2, and unexpectedly BAHCC1 as well. Moreover, co-immunoprecipitation indicated an association between the TMEM97 and BAHCC1 proteins. While TMEM97 ablation decreased and its overexpression increased NFκB (p50, p52, p65), the master transcription factor for pro-inflammatory cytokines, silencing BAHCC1 down-regulated NFκB and downstream pro-inflammatory cytokines. Furthermore, in an RPE-damage retinal degeneration mouse model, immunofluorescence illustrated down-regulation of IL1ß and CCL2 total proteins and suppression of glial activation in the retina of Tmem97-/- mice compared to Tmem97+/+ mice. Thus, TMEM97 is a novel determinant of pro-inflammatory cytokine expression acting via a previously unknown TMEM97- > BAHCC1- > NFκB cascade. SYNOPSIS: Retinal pigment epithelium (RPE) inflammation can lead to blindness. We identify here a previously uncharacterized cascade that underlies RPE cell production of pro-inflammatory cytokines. Specifically, transmembrane protein TMEM97 positively regulates the recently discovered histone code reader BAHCC1, which in turn enhances pro-inflammatory cytokine expression via the transcription factor NFκB.
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Citocinas , Degeneración Retiniana , Humanos , Ratones , Animales , Citocinas/metabolismo , Degeneración Retiniana/genética , Células Cultivadas , Retina/metabolismo , Inflamación/metabolismo , Epigénesis Genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas/metabolismoRESUMEN
BACKGROUND: Percutaneous kyphoplasty (PKP) or percutaneous short-segment fixation (PSSF) is often used to treat Kummell's disease. However, it is not clear which treatment is better for patients. OBJECTIVE: To retrospectively compare the clinical efficacy of PVP and PSSF for the treatment of Kummell's disease. METHOD: 60 patients were involved in this research and the period of follow-up was at least 2 years. 27 of them were treated with PVP (Group I) and the rest who received PSSF (Group II). The visual analog scale (VAS) and radiographic indexes of each participant had been measured preoperatively as well as 1 week, 3 months, and 2 years postoperatively. Additionally, the Oswestry Disability Index (ODI) scores were assessed at the last time point. RESULTS: Comparing the two groups, no statistical significance was found among all parameters preoperatively. The time of operations and blood loss is less in Group I. At each time point after operation, the imaging indices in Group II are lower (P< 0.05). One week after treatments, the VAS scores are lower in Group I, and similarly, 3 months are the same (P< 0.05), while VAS are similar at the last time point. In the aspect of ODI scores, they are lower in Group II during long-term follow-up. CONCLUSION: For the treatment of Kummell's disease, both PVP and PSSF have been found to be effective. PVP can provide rapid pain relief with a shorter operation time. However, in cases with severe kyphosis deformity, PSSF should be given priority.
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Fracturas por Compresión , Cifoplastia , Fracturas de la Columna Vertebral , Espondilosis , Vertebroplastia , Humanos , Estudios de Seguimiento , Vertebroplastia/efectos adversos , Estudios Retrospectivos , Fracturas de la Columna Vertebral/cirugía , Cifoplastia/métodos , Resultado del Tratamiento , Fracturas por Compresión/cirugíaRESUMEN
Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.
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Antineoplásicos , Carcinoma Hepatocelular , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas c-met , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/química , Antineoplásicos/química , Proliferación CelularRESUMEN
Currently, the calibration of electric energy meters often involves manual meter reading, dismantling inspection, or regular sampling inspection conducted by professionals. To improve work efficiency and verification accuracy, this research integrates machine learning into the scheme of online verification and management of gateway meter flow in the power system. The approach begins by applying the Faster Region Convolutional Neural Network (Faster-RCNN) model and the Single Shot MultiBox Detector (SSD) model to the recognition system for dial readings. Then, the collected measurement data is pre-processed, excluding data collected under light load conditions. Next, an estimation error model and a solution equation for the electricity meter are established based on the pre-processed data. The operation error of the electricity meter is estimated, and the estimation accuracy is verified using the limited memory recursive least squares algorithm (LMRLSA). Furthermore, business assistant decision-making is carried out by combining the remote verification results with the estimation outcomes. The proposed dial reading recognition system is tested using 528 images of meter readings, achieving an accuracy of 98.49%. In addition, the influence of various parameters on the error results of the electricity meter is also explored. The results demonstrate that a memory length ranging from 600 to 1,200 and a line loss error of less than 5% yield the most suitable accuracy for estimating the electricity meter error. Meanwhile, it is advisable to remove measurement data collected under light load to avoid unnecessary checks. The experiments manifest that the proposed algorithm can properly eliminate the influence of old measurement data on the error parameter estimation, thereby enhancing the accuracy of the estimation. The adjustment of the memory length ensures real-time performance in estimating meter errors and enables online monitoring. This research has certain reference significance for achieving the online verification and management of gateway meter flow in the power system.
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The inhibition of miR-192-5p can promote nerve repair in rats with peripheral nerve injury (PNI) but the precise mechanisms underlying this effect remain unclear. Schwann cell (SC) autophagy mediated by autophagy-related gene (ATG) proteins has a key role in PNI but it is uncertain whether miR-192-5p affects the involvement of SC autophagy in PNI. In this study, we investigated the impact of methyltransferase-like protein 3 (METTL3)/miR-192-5p/ATG7 on SC autophagy in a rat PNI model and in an SC oxygen and glucose deprivation model. The results revealed that METTL3 stimulated miR-192-5p maturation via m6A methylation to depress ATG7 and SC autophagy and aggravate PNI. These findings provide a new target and potential basis for the treatment of patients with PNI.
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MicroARNs , Traumatismos de los Nervios Periféricos , Humanos , Animales , Ratas , Metiltransferasas/genética , Autofagia/genética , Células de Schwann , MicroARNs/genéticaRESUMEN
Prostate cancer (PCa) seriously threatens male health, and targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been verified to reduce PCa burden, while the research progress on the DYRK2 inhibitors was relatively slow. In this work, we discovered DYRK2 inhibitor 12 (IC50 = 9681 nM) through virtual screening. Subsequently, we performed systematic structural optimization to obtain 54 (IC50 = 14 nM). Compound 54 exhibited high selectivity among 215 kinases and significantly suppressed the proliferation and metastasis of PCa cells in vitro. Moreover, compound 54 displayed high safety, favorable bioavailability, and potent tumor growth inhibitory activity in vivo, which could be used as a potential candidate in the discovery of novel anti-PCa drugs.
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Neoplasias de la Próstata , Proteínas Serina-Treonina Quinasas , Masculino , Humanos , Proteínas Tirosina Quinasas , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
Objective: YKL-40, previously known as chitinase-3-like protein 1 (CHI3L1), is an inflammation-related glycoprotein that promotes atherosclerosis, but its application and optimal cut-off value as a prognostic biomarker in coronary heart disease (CHD) require more clinical evidence. Thus, this prospective study aimed to evaluate the linkage of serum YKL-40 with disease features, inflammatory cytokines, and major adverse cardiovascular events (MACEs) in CHD patients. Methods: A total of 410 CHD patients were enrolled for serum YKL-40 determination via enzyme-linked immunosorbent assay. Meanwhile, serum YKL-40 levels in 100 healthy controls (HCs) were also quantified. Results: YKL-40 level was higher in CHD patients compared with that in HCs (P < 0.001). YKL-40 was positively linked with hyperlipidemia (P = 0.014), diabetes mellitus (P = 0.001), fasting blood glucose (P = 0.045), C-reactive protein (P < 0.001), the Gensini score (P < 0.001), and stenosis degree (graded by the Gensini score) (P < 0.001) in CHD patients. In addition, an elevated YKL-40 level was associated with increased levels of tumor necrosis factor alpha (P = 0.001), interleukin (IL)-1ß (P = 0.001), IL-6 (P < 0.001), and IL-17A (P = 0.002) in CHD patients. The 1-/2-/3-year cumulative MACE rates of CHD patients were 5.5%, 14.4%, and 25.0%, respectively. Regarding the prognostic capability, YKL-40 ≥100â ng/ml (the median cut-off value) (P = 0.003) and YKL-40 ≥150â ng/ml (the third interquartile cut-off value) (P = 0.021) reflected an elevated accumulating MACE rate, whereas accumulating MACE was not different between CHD patients with YKL-40 ≥80 and <80â ng/ml (the first interquartile cut-off value) (P = 0.083). Conclusion: Serum YKL-40 is positively linked with inflammatory cytokines and the Gensini score, whose high expression cut-off by 100 and 150â ng/ml estimates a higher MACE risk in CHD patients.
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Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.
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Neoplasias de la Mama , Antagonistas del Receptor de Estrógeno , Humanos , Ratones , Animales , Femenino , Receptor alfa de Estrógeno , Receptores de Estrógenos , Cristalografía por Rayos X , Neoplasias de la Mama/tratamiento farmacológico , Células MCF-7 , Antagonistas de EstrógenosRESUMEN
Hematopoietic progenitor kinase 1 (HPK1), a member of mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of Ste20 serine/threonine kinases, is a negative regulator of T-cell receptor (TCR) signaling. Inactivating HPK1 kinase has been reported to be sufficient to elicit antitumor immune response. Therefore, HPK1 has attracted much attention as a promising target for tumor immunotherapy. A few of HPK1 inhibitors have been reported, and none of them have been approved for clinical applications. Hence, more effective HPK1 inhibitors are needed. Herein, a series of structurally novel diaminotriazine carboxamides were rationally designed, synthesized and evaluated for their inhibitory activity against HPK1 kinase. Most of them exhibited potent inhibitory potency against HPK1 kinase. In particular, compound 15b showed more robust HPK1 inhibitory activity than that of 11d developed by Merck in kinase activity assay (IC50 = 3.1 and 8.2 nM, respectively). The significant inhibitory potency against SLP76 phosphorylation in Jurkat T cells further confirmed the efficacy of compound 15b. In human peripheral blood mononuclear cell (PBMC) functional assays, compound 15b more significantly induced the production of interleukin 2 (IL-2) and interferon γ (IFN-γ) relative to 11d. Furthermore, 15b alone or in combination with anti-PD-1 antibodies showed potent in vivo antitumor efficacy in MC38 tumor-bearing mice. Compound 15b represents a promising lead for the development of effective HPK1 small-molecule inhibitors.
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Leucocitos Mononucleares , Transducción de Señal , Animales , Humanos , Ratones , Fosforilación , Células JurkatRESUMEN
Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Receptores ErbB/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Resistencia a Antineoplásicos , Línea Celular TumoralRESUMEN
Nickel-catalyzed amidation of aryl alkynyl acids using tetraalkylthiuram disulfides as the amine source is described, affording a series of aryl alkynyl amides in good to excellent yields under mild conditions. This general methodology provides an alternative pathway for the synthesis of useful aryl alkynyl amides in an operationally simple manner, which shows its practical synthetic value in organic synthesis. The mechanism of this transformation was explored through control experiments and DFT calculations.
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Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.
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Neoplasias de la Próstata , Humanos , Masculino , Solubilidad , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
GRK5 is a member of the G protein-coupled receptor (GPCR) kinase family and is closely associated with heart and nervous system disease. It has been reported that GRK5 is closely related to cerebral nerve function and neurodegenerative diseases. However, the biological function of GRK5 in the brain and the influence of GRK5 deficiency on cognitive dysfunction associated with neurodegenerative diseases are unknown. Here, we reported that mice with reduced GRK5 in the hippocampus exhibit cognitive impairment and some Alzheimer's disease (AD)-related molecular pathologies, such as significant neuronal damage and loss, enhanced tau protein phosphorylation, and increased levels of Aß peptides in the hippocampus. Mechanistically, we observed that GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. GRK5 deficiency elicits microglial morphology changes and proinflammatory-associated gene increases. In addition, transcriptional analysis of hippocampal tissues revealed striking changes in neuroactive ligandâreceptor interactions and TNF signaling in GRK5-deficient mice. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. This finding suggests a possible mechanism by which GRK5 maintains microglial homeostasis, and its loss may induce microglial function deficits and cause some AD-related molecular pathogenesis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Microglía/metabolismo , Ratones Noqueados , Enfermedad de Alzheimer/patología , Hipocampo/metabolismo , Disfunción Cognitiva/metabolismo , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Modelos Animales de EnfermedadRESUMEN
The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R. However, the effect of such modulation on AMD pathology remains underexplored. Here, we evaluated S1R- or S2R-selective modulation in an AMD-related model of Abca4-/-Rdh8-/- mice with a disrupted visual cycle that predisposes RPE and photoreceptors to illumination-induced damage. For S1R modulation, we used (+)-pentazocine, which is a high-affinity S1R-selective drug. For S2R modulation, we chose CM398, a high-affinity and highly S2R-selective ligand with drug-like properties. Abca4-/-Rdh8-/- mice received a single i.p. injection of (+)-pentazocine or CM398 or vehicle 30 min before illumination. Pretreatment with (+)-pentazocine improved electroretinogram a- and b-waves compared to that with vehicle. Consistently, in another AMD-related mouse model induced by tail-vein injected NaIO3, S1R genetic ablation aggravated photoreceptor loss. In Abca4-/-Rdh8-/- mice, pretreatment with CM398 appeared to partially avert illumination-induced photoreceptor loss and autofluorescent granule formation that signals RPE damage, as revealed by optical coherence tomography. Thus, this study using AMD-related models provides evidence of photoreceptor protection afforded by selective modulation of S1R or S2R.
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Degeneración Macular , Degeneración Retiniana , Animales , Ratones , Transportadoras de Casetes de Unión a ATP/metabolismo , Modelos Animales de Enfermedad , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/genética , Degeneración Macular/metabolismo , Pentazocina/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/patología , Degeneración Retiniana/metabolismo , Receptor Sigma-1RESUMEN
The engineering applications and related researches of 3D printing fiber-reinforced geopolymers are becoming more and more extensive. However, compared with traditional mould-casted cement-based materials, the properties of 3D-printed fiber-reinforced geopolymers are significantly different, and their interlayer bonding and anisotropy effects are less studied, so in-depth analysis and summary are needed. Similar to common cement-based materials, the reinforcement fibers for geopolymers include not only traditional fibers, such as steel fibers and carbon fibers, but also synthetic polymer fibers and natural polymer fibers. These fibers have unique properties, most of which have good mechanical properties and bonding properties with geopolymers, as well as excellent crack resistance and enhancement. This paper summarizes and analyzes the effects of traditional fibers, polymer fibers, plant fibers and other reinforcement fibers on the properties of 3D-printed fiber-reinforced geopolymers, especially on the interlayer bonding and anisotropy. The influence of the flow and thixotropic properties of fiber-reinforced fresh geopolymer on the weak bond and anisotropy between layers is summarized and analyzed. At the same time, the influence of fibers on the compressive strength, flexural strength and interlayer binding strength of the hardened geopolymers is investigated. The effect of fibers on the anisotropy of 3D-printed geopolymers and the methods to improve the interlayer binding degree are summarized. The limitations of 3D printing fiber-reinforced geopolymers are pointed out and some suggestions for improvement are put forward. Finally, the research on 3D printing fiber-reinforced geopolymers is summarized. This paper provides a reference for further improving the interlayer bonding strength of 3D-printed fiber-reinforced geopolymers. At the same time, the anisotropy properties of 3D-printed fiber-reinforced geopolymers are used to provide a basis for engineering applications.
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Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.
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COVID-19 , Insulinas , Receptores sigma/metabolismo , Adiposidad , Animales , Dióxido de Carbono/farmacología , Dieta Alta en Grasa , Femenino , Glucosa/farmacología , Insulinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Receptores sigma/genética , Caracteres Sexuales , Receptor Sigma-1RESUMEN
Aberrant smooth muscle cell (SMC) plasticity is etiological to vascular diseases. Cholesterol induces SMC phenotypic transition featuring high LGALS3 (galectin-3) expression. This proatherogenic process is poorly understood for its molecular underpinnings, in particular, the mechanistic role of sterol regulatory-element binding protein-1 (SREBP1), a master regulator of lipid metabolism. Herein we show that cholesterol loading stimulated SREBP1 expression in mouse, rat, and human SMCs. SREBP1 positively regulated LGALS3 expression (and vice versa), whereas Krüppel-like factor-15 (KLF15) acted as a negative regulator. Both bound to the Lgals3 promoter, yet at discrete sites, as revealed by chromatin immunoprecipitation-qPCR and electrophoretic mobility shift assays. SREBP1 and LGALS3 each abated KLF15 protein, and blocking the bromo/extraterminal domain-containing proteins (BETs) family of acetyl-histone readers abolished cholesterol-stimulated SREBP1/LGALS3 protein production. Furthermore, silencing bromodomain protein 2 (BRD2; but not other BETs) reduced SREBP1; endogenous BRD2 co-immunoprecipitated with SREBP1's transcription-active domain, its own promoter DNA, and that of L gals 3. Thus, results identify a previously uncharacterized cholesterol-responsive dyad-SREBP1 and LGALS3, constituting a feedforward circuit that can be blocked by BETs inhibition. This study provides new insights into SMC phenotypic transition and potential interventional targets.
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BACKGROUND: T helper (Th) cells are closely involved in vascular inflammation, endothelial dysfunction, and atherogenesis, which are the hallmarks of aortic dissection (AD). This study aimed to evaluate the clinical value of Th1, Th2, and Th17 cell measurements in Stanford type A AD patients. METHODS: Stanford type A AD patients (N=80) and non-AD patients with chest pain (N = 40) were recruited. Then, Th1, Th2, and Th17 cells in peripheral blood CD4+ T cells from all participants were detected by flow cytometry. The 30-day mortality of Stanford type A AD patients was recorded. RESULTS: Th1 and Th17 cells were higher, while Th2 cells were lower in Stanford type A AD patients compared with non-AD patients (all p < 0.001). Meanwhile, Th1 cells (area under curve (AUC): 0.734, 95% confidence interval (CI): 0.640-0.828), Th2 cells (AUC: 0.841, 95% CI: 0.756-0.925), and Th17 cells (AUC: 0.898, 95% CI: 0.839-0.957) could distinguish Stanford type A patients from non-AD patients. Moreover, Th1 cells (p = 0.037) and Th17 cells (p = 0.001) were positively related to CRP, and Th17 cells (p = 0.039) were also positively associated with D-dimer in Stanford type A AD patients. Furthermore, Th17 cells were elevated in deaths compared with survivors (p = 0.001), also, it could estimate 30-day mortality risk in Stanford type A AD patients with an AUC of 0.741 (95% CI: 0.614-0.867), which was similar to the value of CRP (AUC: 0.771, 95% CI: 0.660-0.882), but lower than the value of D-dimer (AUC: 0.818, 95% CI: 0.722-0.913). CONCLUSION: Th1, Th2, and Th17 cells are dysregulated, but only the Th17 cells relate to CRP, D-dimer, and 30-day mortality risk in Stanford type A AD patients.