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Early brain injury (EBI) is the leading cause of poor prognosis for patients suffering from subarachnoid hemorrhage (SAH), particularly learning and memory deficits in the repair phase. A recent report has involved calcium/calmodulin-dependent protein kinase II (CaMKII) in the pathophysiological process underlying SAH-induced EBI. Alpha-asarone (ASA), a major compound isolated from the Chinese medicinal herb Acorus tatarinowii Schott, was proven to reduce secondary brain injury by decreasing CaMKII over-phosphorylation in rats' model of intracerebral hemorrhage in our previous report. However, the effect of ASA on SAH remains unclear, and the role of CaMKII in both acute and recovery stages of SAH needs further investigation. In this work, we first established a classic SAH rat model by endovascular perforation and intraperitoneally administrated different ASA doses (10, 20, and 40 mg/kg) 2 h after successful modeling. Then, the short- and long-term neurobehavioral performances were blindly evaluated to confirm ASA's efficacy against SAH. Subsequently, we explored ASA's therapeutic mechanism in both acute and recovery stages using histopathological examination, TUNEL staining, flow cytometry, Western-blot, double-immunofluorescence staining, and transmission electron microscopy (TEM) observation. Finally, KN93, a selective CaMKII inhibitor, was applied in oxyhemoglobin-damaged HT22 cells to explore the role of CaMKII in ASA's neuroprotective effect. The results demonstrated that ASA alleviated short- and long-term neurological dysfunction, reduced mortality and seizure rate within 24 h, and prolonged 14-day survival in SAH rats. Histopathological examination showed a reduction of neuronal damage and a restoration of the hippocampal structure after ASA treatment in both acute and recovery phases of SAH. In the acute stage, the Western-blot and flow cytometer analyses showed that ASA restored E/I balance, reduced calcium overload and CaMKII phosphorylation, and inhibited mitochondrion-involved apoptosis, thus preventing neuronal damage and apoptosis underlying EBI post-SAH. In the recovery stage, the TEM observation, double-immunofluorescence staining, and Western-blot analyses indicated that ASA increased the numbers of synapses and enhanced synaptic plasticity in the ipsilateral hippocampi, probably by promoting NR2B/CaMKII interaction and activating subsequent CREB/BDNF/TrkB signaling pathways. Furthermore, KN93 notably reversed ASA's neuroprotective effect on oxyhemoglobin-damaged HT22 cells, confirming CaMKII a potential target for ASA's efficacy against SAH. Our study confirmed for the first time that ASA ameliorated the SAH rats' neurobehavioral deterioration, possibly via modulating CaMKII-involved pathways. These findings provided a promising candidate for the clinical treatment of SAH and shed light on future drug discovery against SAH.
Assuntos
Derivados de Alilbenzenos, Anisóis, Benzenossulfonamidas, Benzilaminas, Lesões Encefálicas, Fármacos Neuroprotetores, Hemorragia Subaracnóidea, Humanos, Ratos, Animais, Ratos Sprague-Dawley, Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina, Fármacos Neuroprotetores/farmacologia, Fármacos Neuroprotetores/uso terapêutico, Hemorragia Subaracnóidea/complicações, Hemorragia Subaracnóidea/tratamento farmacológico, Hemorragia Subaracnóidea/patologia, Cálcio/uso terapêutico, Oxiemoglobinas/uso terapêutico, Lesões Encefálicas/etiologiaRESUMO
PURPOSE: To assess the shade match ability of four varieties of all-ceramic crowns to a neighboring bilayered lithium disilicate crown. MATERIAL AND METHODS: A dentiform was used to fabricate a bilayered lithium disilicate crown on the maxillary right central incisor, following the anatomy and shade of a selected natural tooth. Two crowns (one full-contour, one cutback) were then designed on a prepared maxillary left central incisor, following the contour of the neighboring crown. The designed crowns were used to manufacture monolithic lithium disilicate, bilayered lithium disilicate, bilayered zirconia, and monolithic zirconia crowns, 10 each. An intraoral scanner and a spectrophotometer were used to assess the frequency of matched shades and to calculate the color difference (ΔE) between the two central incisors at the incisal, middle, and cervical thirds. Kruskal-Wallis and two-way ANOVA were used to compare the frequency of matched shades and ΔE values, respectively (α = 0.05). RESULTS: There was no significant (p > 0.05) difference in frequencies of matched shades for each group at the three sites; except bilayered lithium disilicate crowns. Bilayered lithium disilicate crowns had significantly (p < 0.05) higher match frequency than monolithic zirconia at the middle third. The ΔE value was not significantly (p > 0.05) different among the groups at the cervical third. However, monolithic zirconia had significantly (p < 0.05) higher ΔE values than bilayered lithium disilicate and zirconia at the incisal and middle thirds. CONCLUSIONS: Bilayered lithium disilicate and zirconia appeared to most closely match the shade of an existing bilayered lithium disilicate crown.
Assuntos
Cerâmica, Planejamento de Prótese Dentária, Porcelana Dentária, Coroas, Zircônio, Desenho Assistido por ComputadorRESUMO
PURPOSE: This in vitro study evaluated the fracture strength of screw-retained zirconia crowns connected to zirconia (Zr) and titanium (Ti) implants after undergoing a simulation of 5 years of clinical use. MATERIALS AND METHODS: Forty-eight screw-retained zirconia crowns were fabricated and assembled on four implant systems, with 12 in each group: (1) Zr implant (pure ceramic; Straumann AG) (PZr); (2) Zr implant (NobelPearl; Nobel Biocare) (NPZr); (3) Ti-Zr implant (Bone Level Roxolid; Straumann AG) (RSTiZr); (4) Ti implant (Conical Connection PMC; Nobel Biocare) (NRTi). Crowns were luted to their associated abutments using resin cement and then torqued to their assigned implants at the recommended torque value. Specimens were subjected to dynamic loading for 1,200,000 loading cycles. Fracture strength, measured in Newtons (N), was tested under static compression load using a universal testing machine at an angle of 30°. One-way ANOVA and Tukey's multiple comparisons post hoc test were used to compare the mean fracture values between the groups at a significance level of 0.05. RESULTS: The average fracture strengths for the RSTiZr and NRTi groups were 1207 ± 202 and 1073 ± 217 N, respectively, which was significantly (p < 0.0001) higher than the PZr and NPZr groups (712 ± 76 and 571.6 ± 167 N, respectively). However, no significant difference was found between the fracture strength value of RSTiZr and NRTi (p = 0.260) or PZr and NPZr (p = 0.256) groups. CONCLUSIONS: Zirconia crowns connected to Zr implants have the potential to withstand the average physiological occlusal forces which occur in the anterior and premolar regions.
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Implantes Dentários, Porcelana Dentária, Resistência à Flexão, Titânio, Teste de Materiais, Dente Suporte, Falha de Restauração Dentária, Análise do Estresse Dentário, Coroas, ZircônioRESUMO
Chronic pancreatitis (CP) as a progressive inflammatory disorder, remains untreatable. The novel treatment strategy for CP is imperative. We attempted to explore the therapeutic biomarkers for CP. The single-cell sequencing data were retrieved from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in idiopathic CP were identified, followed by function and pathway annotation, and PPI network established. DEGs of interest were verified in human tissue samples. The function of candidate biomarker was determined in the murine model with CP. A total of 208 genes were specially differentially expressed in idiopathic patients. Functional enrichment analysis showed DEGs were mainly enriched in glycogen catabolic process, RNA splicing, and glucagon signaling pathway. A PPI network centered on HDAC1 was constructed. HDAC1 was overexpressed in CP patients. The murine model with CP was induced by repetitive cerulein treatment. Silencing sh-HDAC1 treatment reversed cerulein-induced inflammatory cells accumulation, high expression of TGF-ß1, and collagen 1 in pancreas in vivo. HDAC1 might be served as potential biomarker for CP. The present study provided insights into the molecular mechanism of CP that may be useful in further investigations.
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Perfilação da Expressão Gênica, Pancreatite Crônica, Humanos, Camundongos, Animais, Ceruletídeo/efeitos adversos, Modelos Animais de Doenças, Pancreatite Crônica/genética, Pancreatite Crônica/induzido quimicamente, Biomarcadores, Análise de Dados, Biologia Computacional, Histona Desacetilase 1/genéticaRESUMO
Reservoirs play important roles in the drinking water supply for urban residents, agricultural water provision, and the maintenance of ecosystem health. Satellite optical remote sensing of water quality variables in medium and micro-sized inland waters under oligotrophic and mesotrophic status is challenging in terms of the spatio-temporal resolution, weather conditions and frequent nutrient status changes in reservoirs, etc., especially when quantifying non-optically active components (non-OACs). This study was based on the surface reflectance products of unmanned aerial vehicle (UAV) multispectral images, Sentinel-2B Multispectral instrument (MSI) images and Landsat 7 Enhanced Thematic Mapper Plus (ETM+) by utilizing fuzzy C-means (FCM) clustering algorithm was combined with band combination (BC) model to construct the FCM-BC empirical model, and used mixed density network (MDN), extreme gradient boosting (XGBoost), deep neural network (DNN) and support vector regression (SVR) machine learning (ML) models to invert 12 kinds of optically active components (OACs) and non-OACs. Compared with the unclustered BC (UC) model, the mean coefficient of determination (MR) of the FCM-BC models was improved by at least 46.9%. MDN model showed best accuracy (R2 in the range of 0.60-0.98) and stability (R2 decreased by up to 13.2%). The accuracy of UAV was relatively higher in both empirical methods and machine learning methods. Additionally, the spatio-temporal distribution maps of four water quality variables were mapped based on the MDN model and UAV images, all platforms showed good consistency. An inversion strategy of water quality variables in various monitoring frequencies and weather conditions were proposed finally. The purpose of introducing the UAV platform was to cooperate with the satellite to improve the monitoring response ability of OACs and non-OACs in small and micro-sized oligotrophic and mesotrophic water bodies.
Assuntos
Tecnologia de Sensoriamento Remoto, Qualidade da Água, Ecossistema, Abastecimento de Água, ChinaRESUMO
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the "Cytokine Storm" (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.
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COVID-19, Vacinas, Humanos, Síndrome da Liberação de Citocina/tratamento farmacológico, SARS-CoV-2, Estado Terminal, Citocinas, Antivirais/farmacologia, Antivirais/uso terapêuticoRESUMO
Gelatin and starch are considered as promising sustainable materials for their abundant production and good biodegradability. Efforts have been made to explore their medical application. Herein, scaffolds based on gelatin and starch with a preferred microstructure and antibacterial antioxidant property were fabricated by the emulsion template method. The dialdehyde starch was firstly combined with silver nanoparticles and curcumin to carry out the efficient hybrid antibacterial agent. Then, the gelatin microsphere of appropriate size was prepared by emulsification and gathered by the above agent to obtain gelatin-based scaffolds. The prepared scaffolds showed porous microstructures with high porosity of over 74 % and the preferred pore sizes of â¼65 µm, which is conducive to skin regeneration. Moreover, the scaffolds possessed a good swelling ability of over 640 %, good degradability of over 18 days, excellent blood compatibility, and cell compatibility. The promising antibacterial and antioxidant properties came from the hybrid antibacterial agent were affirmed. As expected, the gelatin-based scaffolds fabricated by the emulsion template method with a preferred microstructure can facilitate more adhered fibroblasts. In summary, gelatin-based scaffolds functionalized by starch-based complex expanded the application of abundant sustainable materials in the biomedical field, especially as antibacterial antioxidant wound dressings.
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Gelatina, Nanopartículas Metálicas, Gelatina/química, Alicerces Teciduais/química, Antioxidantes/farmacologia, Emulsões, Prata/química, Antibacterianos/farmacologia, Cicatrização, Amido/química, PorosidadeRESUMO
Adipose tissue fibrosis has been identified as a novel contributor to the pathomechanism of obesity associated metabolic disorders. Sulforaphane (SFN) has been shown to have an anti-obesity effect. However, the impact of SFN on adipose tissue fibrosis is still not well understood. In this study, obese mice induced by high-fat diets (HFD) were used to examine the effects of SFN on adipose tissue fibrosis. According to the current findings, SFN dramatically enhanced glucose tolerance and decreased body weight in diet-induced-obesity (DIO) mice. Additionally, SFN therapy significantly reduced extracellular matrix (ECM) deposition and altered the expression of genes related to fibrosis. Furthermore, SFN also reduced inflammation and promoted macrophages polarization towards to M2 phenotype in adipose tissue, which protected adipose tissue from fibrosis. Notably, SFN-mediated nuclear factor E2-related factor 2 (Nrf2) activation was crucial in decreasing adipose tissue fibrosis. These results implied that SFN had favorable benefits in adipose tissue fibrosis, which consequently ameliorates obesity-related metabolic problems. Our research provides new treatment strategies for obesity and associated metabolic disorders.
Assuntos
Dieta Hiperlipídica, Isotiocianatos, Doenças Metabólicas, Sulfóxidos, Camundongos, Animais, Dieta Hiperlipídica/efeitos adversos, Tecido Adiposo, Obesidade/tratamento farmacológico, Obesidade/patologia, Fibrose, Macrófagos, Doenças Metabólicas/patologiaRESUMO
Herein, we report a C3 and C1 coupling approach between vinyl 1,3-dithiane derivatives and alkynylsilanes for the construction of highly substituted conjugated dienes. Through the regioselective dual 1,3-sulfur migration process, this method enabled the synthesis of a wide range of highly substituted (E)-1,3-dienes stereoselectively in moderate to high yields, which provided one alternative way to synthesize the corresponding conjugated dienones.
RESUMO
We aimed to determine whether quercetin is capable of improving circadian rhythm and metabolism disorder under vitamin D-deficient condition. Middle-aged mice were randomly divided into four groups, namely, control (CON), vitamin D-deficient diet (VDD), quercetin (Q), and quercetin intervention in vitamin D-deficient diet (VDQ), with a total of 12 weeks' intervention. Mice were sacrificed at zeitgeber time1 (ZT1) and ZT13 time points. At ZT1, circadian locomotor output cycle kaput (CLOCK) protein expression from VDD, Q, and VDQ groups; CRY1 from Q group; and CRY2 from VDD group were significantly lower compared to CON group. The mRNA expression of Sirt1, Bmal1, Clock, Cry1, and Cry2 in VDQ groups, also Bmal1, Clock, and Cry1 from Q group, were significantly decreased compared to CON group. At ZT13, compared to CON group, fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were higher in VDD group; BMAL1 was significantly increased, while CLOCK and CRY1 protein were significantly decreased from VDD group; CLOCK protein from VDQ group was significantly higher compared to CON, VDD, and Q groups, and also, BMAL1 protein expression from VDQ group was elevated compared to CON group. The mRNA expression of Bmal1, Clock, Per2, Cry1, and Cry2 in VDQ groups were significantly increased compared to CON groups. The mRNA expression of Bmal1 from VDQ group was decreased compared to both VDD and Q group. In conclusion, vitamin D-deficient diet resulted in a disordered liver circadian rhythm, and quercetin improved the hepatic circadian desynchronization. Quercetin supplementation might be effective for balancing circadian rhythm under vitamin D-deficient condition.
Assuntos
Relógios Circadianos, Hepatopatias, Camundongos, Animais, Quercetina/farmacologia, Quercetina/uso terapêutico, Fatores de Transcrição ARNTL/genética, Vitamina D/uso terapêutico, Ritmo Circadiano/genética, Proteínas CLOCK/genética, RNA Mensageiro/genética, RNA Mensageiro/metabolismo, DietaRESUMO
Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterised by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumours. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signalling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.
Assuntos
Antineoplásicos, Neoplasias, Humanos, Neoplasias/terapia, Antineoplásicos/farmacologia, Biomarcadores/metabolismo, Transdução de Sinais, Células-Tronco Neoplásicas/metabolismo, Biomarcadores Tumorais/metabolismoRESUMO
Few studies have delved into the effects of heatwaves on sleep duration loss among older adults. Our study examined correlations between heatwave exposure and sleep duration reductions in this demographic. Utilizing data of 7,240 older adults drawn from the China Health and Retirement Longitudinal Study (CHARLS) from 2015 to 2018, we assessed sleep duration differences between the baseline year (2015) and follow-up year (2018). Absolute reductions in sleep duration were defined as differences of ≥ 1, 1.5, or 2 h. Changes in sleep duration were categorized based on cut-offs of 5 and 8 h, including excessive decrease, moderate to short and persistent short sleep duration types. 12 heatwave definitions combining four thresholds (90th, 92.5th, 95th, and 97.5th percentiles of daily minimum temperature) and three durations (≥2, ≥3 and ≥ 4 days) were used. Heatwave exposure was determined by the difference in the number of 12 preceding months' heatwave days or events in 2015 and the number of 12 preceding months' heatwave days or events in 2018. The results showed that increased heatwave events (defined as ≥ P90th percentile & lasting three days) were associated with a higher likelihood of ≥ 1-hour sleep reduction and persistent short sleep duration. An increase in heatwave event (defined as ≥ P95th percentile & lasting three days) was linked to shifts from moderate to short sleep duration. For the association between an absolute reduction in sleep duration and heatwave exposure, while higher thresholds signified greater sleep reduction risks, the effect estimates of longer durations were not uniformly consistent. We observed that air pollution and green space modified the relationship between heatwaves and sleep duration. Females, urban residents, and individuals with chronic diseases were identified as vulnerable populations. This study found that increased heatwave exposure was associated with a higher risk of sleep duration loss in older adults.
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Temperatura Alta, Duração do Sono, Feminino, Humanos, Idoso, Estudos Longitudinais, Fatores de Risco, Raios InfravermelhosRESUMO
BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.
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Imunoterapia, Neoplasias Pulmonares, Humanos, Carcinogênese, Inibidores de Checkpoint Imunológico/uso terapêutico, Análise Multivariada, Mutação, Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
Valine-glutamine (VQ) motif-containing proteins play a crucial role in plant biotic stress responses. Apple Valsa canker, caused by the ascomycete Valsa mali, stands as one of the most severe diseases affecting apple trees. Nonetheless, the underlying resistance mechanism of VQ proteins against this disease has remained largely unexplored. This study reports MdVQ12, a VQ motif-containing protein, as a positive regulator of apple Valsa canker resistance. Genetic transformation experiments demonstrated that MdVQ12 overexpression increased resistance to V. mali, while gene silencing lines exhibited significantly reduced resistance. MdVQ12 interacted with the transcription factor MdWRKY23, which bound to the promoter of the histone deacetylase gene MdHDA19, activating its expression. MdHDA19 enhanced apple resistance to V. mali by participating in the jasmonic acid (JA) and ethylene (ET) signalling pathways. Additionally, MdVQ12 promoted the transcriptional activity of MdWRKY23 towards MdHDA19. Our findings reveal that MdVQ12 enhances apple resistance to V. mali by regulating MdHDA19 expression and thereby regulating the JA and ET signalling pathways, offering potential candidate gene resources for breeding apple Valsa canker-resistant germplasm.
Assuntos
Ascomicetos, Malus, Malus/genética, Malus/metabolismo, Doenças das Plantas/genética, Ascomicetos/genética, Regiões Promotoras GenéticasRESUMO
The energy loss (Eloss) caused by inefficient charge transfer and large energy level offset at the buried interface can easily restrict the performance of p-i-n perovskite solar cells (PVSCs). In this study, the utilization of poly-TPD and P3CT-N as a dual-hole transporting layer (HTLs) was implemented in a sequential manner. This approach aimed to improve the charge transfer efficiency of the HTL and mitigate charge recombination at the interface between the HTL and PVK. The results showed that this strategy also could achieve more suitable energy levels, improve the quality of the perovskite film layer, and ultimately enhance the device's stability. IPVSCs employing the dual-HTLs approach exhibited the highest power conversion efficiency of 19.85%, and the open-circuit voltage increased to 1.09 V from 1.00 V. This study offers a straightforward and efficient approach to boost the device performance by minimizing Eloss and reducing the buried interfacial defects. The findings underscore the potential of employing a dual-HTL strategy as a promising pathway for further advancements in PVSCs.
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Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs' ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum, and transcriptome analyses. The study reveals that aged VSMCs adapt to a relatively inert mechanobiological state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
Assuntos
Actinas, Músculo Liso Vascular, Músculo Liso Vascular/metabolismo, Actinas/metabolismo, Citoesqueleto/metabolismo, Transdução de Sinais, Miócitos de Músculo Liso/metabolismo, Células CultivadasRESUMO
Peripheral blood mononuclear cells (PBMCs) reflect systemic immune response during cancer progression. However, a comprehensive understanding of the composition and function of PBMCs in cancer patients is lacking, and the potential of these features to assist cancer diagnosis is also unclear. Here, the compositional and status differences between cancer patients and healthy donors in PBMCs were investigated by single-cell RNA sequencing (scRNA-seq), involving 262,025 PBMCs from 68 cancer samples and 14 healthy samples. We observed an enhanced activation and differentiation of most immune subsets in cancer patients, along with reduction of naïve T cells, expansion of macrophages, impairment of NK cells and myeloid cells, as well as tumor promotion and immunosuppression. Based on characteristics including differential cell type abundances and/or hub genes identified from weight gene co-expression network analysis (WGCNA) modules of each major cell type, we applied logistic regression to construct cancer diagnosis models. Furthermore, we found that the above models can distinguish cancer patients and healthy donors with high sensitivity. Our study provided new insights into using the features of PBMCs in non-invasive cancer diagnosis.
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Leucócitos Mononucleares, Neoplasias, Humanos, Análise da Expressão Gênica de Célula Única, Neoplasias/diagnóstico, Neoplasias/genética, Diferenciação Celular, Transformação Celular NeoplásicaRESUMO
The neuron reconstruction from raw Optical Microscopy (OM) image stacks is the basis of neuroscience. Manual annotation and semi-automatic neuron tracing algorithms are time-consuming and inefficient. Existing deep learning neuron reconstruction methods, although demonstrating exemplary performance, greatly demand complex rule-based components. Therefore, a crucial challenge is designing an end-to-end neuron reconstruction method that makes the overall framework simpler and model training easier. We propose a Neuron Reconstruction Transformer (NRTR) that, discarding the complex rule-based components, views neuron reconstruction as a direct set-prediction problem. To the best of our knowledge, NRTR is the first image-to-set deep learning model for end-to-end neuron reconstruction. The overall pipeline consists of the CNN backbone, Transformer encoder-decoder, and connectivity construction module. NRTR generates a point set representing neuron morphological characteristics for raw neuron images. The relationships among the points are established through connectivity construction. The point set is saved as a standard SWC file. In experiments using the BigNeuron and VISoR-40 datasets, NRTR achieves excellent neuron reconstruction results for comprehensive benchmarks and outperforms competitive baselines. Results of extensive experiments indicate that NRTR is effective at showing that neuron reconstruction is viewed as a set-prediction problem, which makes end-to-end model training available.
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Encéfalo, Microscopia, Neurônios, Algoritmos, Imageamento Tridimensional/métodos, Processamento de Imagem Assistida por ComputadorRESUMO
Pancreatic cancer remains the common cancer with the worst prognosis because of its late diagnosis and extensive metastasis. This study aimed to investigate the effects of GABRP on pancreatic cancer metastasis and the molecular mechanism. The expression of GABRP was measured using the quantitative real-time PCR and western blot. The biological behaviors of cancer cells were assessed using the cell counting kit-8, Transwell assay, and western blot. The regulation of GABRP on the MEK/ERK pathway was detected by western blot. The results indicated that GABRP was overexpressed in pancreatic cancer tissues and cells. Knockdown of GABRP suppressed cell viability, invasion, migration, and epithelial-mesenchymal transition (EMT), whereas GABRP overexpression facilitated these biological behaviors. Inactivation of the MEK/ERK pathway reversed the effects on cellular processes induced by GABRP. Moreover, silencing of GABRP inhibited tumor growth. In conclusion, GABRP promoted the progression of pancreatic cancer by facilitating cell metastasis and tumor growth via activating the MEK/ERK pathway. The findings suggest that GABRP has the potential to be a therapeutic target for the metastatic pancreatic cancer.
