RESUMO
The nearby radio galaxy M87 offers a unique opportunity to explore the connections between the central supermassive black hole and relativistic jets. Previous studies of the inner region of M87 revealed a wide opening angle for the jet originating near the black hole1-4. The Event Horizon Telescope resolved the central radio source and found an asymmetric ring structure consistent with expectations from general relativity5. With a baseline of 17 years of observations, there was a shift in the jet's transverse position, possibly arising from an 8- to 10-year quasi-periodicity3. However, the origin of this sideways shift remains unclear. Here we report an analysis of radio observations over 22 years that suggests a period of about 11 years for the variation in the position angle of the jet. We infer that we are seeing a spinning black hole that induces the Lense-Thirring precession of a misaligned accretion disk. Similar jet precession may commonly occur in other active galactic nuclei but has been challenging to detect owing to the small magnitude and long period of the variation.
RESUMO
The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.
RESUMO
Plant thermosensors help optimize plant development and architecture for ambient temperatures, and morphogenic adaptation to warm temperatures has been extensively studied in recent years. Phytochrome B (phyB)-mediated thermosensing and the gene regulatory networks governing thermomorphogenic responses are well understood at the molecular level. However, it is unknown how plants manage their responsiveness to fluctuating temperatures in inducing thermomorphogenic behaviors. Here, we demonstrate that SUPPRESSOR OF MAX2 1 (SMAX1), known as a karrikin signaling repressor, enhances the thermosensitivity of hypocotyl morphogenesis in Arabidopsis thaliana. Hypocotyl thermomorphogenesis was largely disrupted in SMAX1-deficient mutants. SMAX1 interacts with phyB to alleviate its suppressive effects on the transcription factor activity of PHYTOCHROME-INTERACTING FACTOR 4 (PIF4), promoting hypocotyl thermomorphogenesis. Interestingly, the SMAX1 protein is slowly destabilized at warm temperatures, preventing hypocotyl overgrowth. Our findings indicate that the thermodynamic control of SMAX1 abundance serves as a molecular gatekeeper for phyB function in thermosensitizing PIF4-mediated hypocotyl morphogenesis.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fitocromo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica de Plantas , Hipocótilo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fitocromo/genética , Fitocromo/metabolismo , Fitocromo B/genética , Fitocromo B/metabolismoRESUMO
Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.
Assuntos
Lisofosfolipídeos , Osteogênese , Receptores de Lisofosfolipídeos , Perda de Dente , Animais , Camundongos , Diferenciação Celular/fisiologia , Lisofosfolipídeos/metabolismo , Osteoblastos/metabolismo , Ligamento Periodontal/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Receptores de Lisofosfolipídeos/metabolismoRESUMO
BACKGROUND: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. METHODS: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). RESULTS: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. CONCLUSIONS: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.
Assuntos
Fibroblastos Associados a Câncer , Nefrite Intersticial , Neoplasias Gástricas , Animais , Humanos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Fibroblastos/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/patologia , Microambiente TumoralRESUMO
Glomerular epithelial protein-1 (Glepp1), a R3 subtype family of receptor-type protein tyrosine phosphatases, plays important role in the activation of Src family kinases and regulates cellular processes such as cell proliferation, differentiation, and apoptosis. In this study, we firstly examined the functional evaluation of Glepp1 in tooth development and morphogenesis. The precise expression level and developmental function of Glepp1 were examined by RT-qPCR, in situ hybridization, and loss and gain of functional study using a range of in vitro organ cultivation methods. Expression of Glepp1 was detected in the developing tooth germs in cap and bell stage of tooth development. Knocking down Glepp1 at E13 for 2 days showed the altered expression levels of tooth development-related signaling molecules, including Bmps, Dspp, Fgf4, Lef1, and Shh. Moreover, transient knock down of Glepp1 revealed alterations in cellular physiology, examined by the localization patterns of Ki67 and E-cadherin. Similarly, knocking down of Glepp1 showed disrupted enamel rod and interrod formation in 3-week renal transplanted teeth. In addition, due to attrition of odontoblastic layers, the expression signals of Dspp and the localization of NESTIN were almost not detected after knock down of Glepp1; however, their expressions were increased after Glepp1 overexpression. Thus, our results suggested that Glepp1 plays modulating roles during odontogenesis by regulating the expression levels of signaling molecules and cellular events to achieve the proper structural formation of hard tissue matrices in mice molar development.
Assuntos
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores , Dente , Animais , Camundongos , Regulação da Expressão Gênica no Desenvolvimento , Morfogênese , Odontogênese , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Transdução de Sinais , Dente/metabolismoRESUMO
BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases. METHODS: We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data. RESULTS: Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells. CONCLUSIONS: Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.
Assuntos
Proliferação de Células , Proteínas Serina-Treonina Quinases , Proteoma , Proteômica , Neoplasias Gástricas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/tratamento farmacológico , Humanos , Linhagem Celular Tumoral , Proteômica/métodos , Proteoma/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Movimento Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina-Proteína Ligases Nedd4/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular , Proteínas Associadas aos MicrotúbulosRESUMO
BACKGROUND: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC. METHODS: Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay. RESULTS: We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model. CONCLUSIONS: This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract.
Assuntos
Fibroblastos Associados a Câncer , Fator de Crescimento do Tecido Conjuntivo , Neoplasias Gástricas , Humanos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Microambiente TumoralRESUMO
Lemna aequinoctialis Welw. is a widely spread species that has diverse physiological and molecular properties. Flower characteristics are important factors in deducing taxonomical status; however, owing to the rarity of flowering observations in Lemna, studying them has been a prolonged challenge. In this study, physiological and morphological analyses were conducted by inducing flowering, and molecular analysis was done based on the two chloroplast DNA loci (matK, atpF-atpH intergeneric spacer) of L. aequinoctialis sensu Landolt (1986) from 70 strains found in 70 localities in Japan, Korea, Thailand, and the US. In total, 752 flowering fronds from 13 strains were observed based on axenic conditions. Two different trends in flower organ development-protogyny and adichogamy-were detected in these strains. Their physiological traits were divided into two groups, showing different morphological features based on frond thickness, root cap, and anther sizes. Molecular analysis showed two lineages corresponding to two physiological groups. These were identified as L. aequinoctialis sensu Beppu et al. (1985) and L. aoukikusa Beppu et Murata based on the description of the nomenclature of L. aoukikusa. These were concluded as independent taxa and can be treated as different species. Furthermore, the distribution of L. aoukikusa is not only limited to Japan.
Assuntos
Araceae , Flores , Filogenia , Araceae/genética , Araceae/fisiologia , Araceae/anatomia & histologia , Araceae/crescimento & desenvolvimento , Flores/anatomia & histologia , Flores/genética , Flores/fisiologia , Flores/crescimento & desenvolvimento , DNA de Cloroplastos/genética , Japão , DNA de Plantas/genéticaRESUMO
BACKGROUND: Although most impacted third molars (ITMs) are extracted in the teens and early 20s, some undergo extractions after their 40s. It is unclear whether the reasons for extraction, the degree of impaction, and complications differ in patients in an older age group compared with a younger age group. PURPOSE: The purpose of this study was to measure the association between age and 1) reason for extraction and 2) postoperative complications. STUDY DESIGN, SETTING, SAMPLE: This was a retrospective cohort study of patients who had undergone surgical extraction of at least one mandibular ITM at a single institution. We excluded 1) age under 20 years, 2) follow-up period of less than 1 week, and 3) tooth extraction under general anesthesia. PREDICTOR VARIABLE: The primary predictor variable was age, classified into 3 groups (20s:20-29; 30s:30-39; over 40s: 40 and greater). MAIN OUTCOME VARIABLE(S): The primary outcome variables were the reason for extraction (prophylactic or symptomatic) and the presence of complications. The secondary outcome variable was type of complication (postoperative infection, dry socket, neurosensory disturbance, presenting pain over 1 month, retained root requiring secondary treatment). COVARIATES: The covariates were sex, laterality of ITM, and difficulty of extraction as measured by the difficulty index, a measure based on depth, orientation, and ramus relationship/space available, with a higher score indicating greater difficulty. ANALYSES: χ2 test was performed to analyze the association of categorical outcome variables and covariates. Level of statistical significance was set at P < .05. RESULTS: Of a total of 831 eligible subjects, there were 555 (66.8%), 159 (19.1%), and 117 (14.1%) in the 20s, 30s, and over 40s age groups, respectively. The percentage of symptomatic extraction of ITM was significantly higher in the over-40 age group compared with the 20s group (92.3 vs 69.4%, (P < .001). Complication rate also significantly differed between over 40s group and the 20s group (7.7 vs 1.8%, P < .001). Difficulty index and indications for ITM extraction were significantly different between groups (P < .001). CONCLUSION AND RELEVANCE: Symptoms, difficulty, and complications related to ITM increase at over 40 years of age. This should be taken into consideration during the joint clinical decision-making process with patients with ITM.
RESUMO
Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors. Amongst formally known anti-coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane-bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1-MMP are all expressed on the surface of RANKL-primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1-MMP. When TACE and MT1-MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti-TACE-mAb inhibited sSema4D release from osteoclast precursors by ~90%. Supernatant collected from osteoclast precursors (OC-sup) suppressed osteoblastogenesis from MC3T3-E1 cells, as measured by alkaline phosphatase activity, but OC-sup harvested from the osteoclast precursors treated with anti-TACE-mAb restored osteoblastogenesis activity in a manner that compensates for diminished sSema4D. Finally, systemic administration of anti-TACE-mAb downregulated the generation of sSema4D in the mouse model of critical-sized bone defect, whereas local injection of recombinant sSema4D to anti-TACE-mAb-treated defect upregulated local osteoblastogenesis. Therefore, a novel pathway is proposed whereby TACE-mediated shedding of Sema4D expressed on the osteoclast precursors generates functionally active sSema4D to suppress osteoblastogenesis.
Assuntos
Osteoclastos , Semaforinas , Animais , Camundongos , Modelos Animais de Doenças , Metaloproteinase 14 da Matriz/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Semaforinas/genética , Semaforinas/metabolismoRESUMO
To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O-GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O-GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage-specific immunostaining results against O-GlcNAc and O-GlcNAc transferase (OGT) in developing tooth germs would suggest that O-GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT-mediated O-GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI-1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI-1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real-time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of ß-catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT-inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT-mediated O-GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis.
Assuntos
N-Acetilglucosaminiltransferases , Dente , Animais , Camundongos , Apoptose/fisiologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Dente/crescimento & desenvolvimento , Dente/metabolismoRESUMO
Mechanically activated factors are important in organogenesis, especially in the formation of secretory organs, such as salivary glands. Piezo-type mechanosensitive ion channel component 1 (Piezo1), although previously studied as a physical modulator of the mechanotransduction, was firstly evaluated on its developmental function in this study. The detailed localization and expression pattern of Piezo1 during mouse submandibular gland (SMG) development were analyzed using immunohistochemistry and RT-qPCR, respectively. The specific expression pattern of Piezo1 was examined in acinar-forming epithelial cells at embryonic day 14 (E14) and E16, which are important developmental stages for acinar cell differentiation. To understand the precise function of Piezo1 in SMG development, siRNA against Piezo1 (siPiezo1) was employed as a loss-of-function approach, during in vitro organ cultivation of SMG at E14 for the designated period. Alterations in the histomorphology and expression patterns of related signaling molecules, including Bmp2, Fgf4, Fgf10, Gli1, Gli3, Ptch1, Shh, and Tgfß-3, were examined in acinar-forming cells after 1 and 2 days of cultivation. Particularly, altered localization patterns of differentiation-related signaling molecules including Aquaporin5, E-cadherin, Vimentin, and cytokeratins would suggest that Piezo1 modulates the early differentiation of acinar cells in SMGs by modulating the Shh signaling pathway.
Assuntos
Mecanotransdução Celular , Glândula Submandibular , Camundongos , Animais , Glândula Submandibular/metabolismo , Glândulas Salivares , Morfogênese/fisiologia , Diferenciação Celular , Canais Iônicos/metabolismoRESUMO
A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor's volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. To this end, we simulated the impact of different fibroblast distributions on treatment outcomes. As a proof of principle, we focused on five types of distribution of fibroblasts characterized by different locations, shapes, and orientations of the fibroblast region with respect to the resistant cells. Our simulation shows that the spatial architecture of fibroblasts modulates tumor progression in both continuous and adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy of a virtual patient with four metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations. Our simulation highlights the importance of undetected metastatic lesions on adaptive therapy outcomes.
Assuntos
Neoplasias , Simulação por Computador , Fibroblastos , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
ABSTRACT: There have been few studies of angiotensin receptor blocker (ARB) dose in myocardial infarction (MI) with preserved left ventricular (LV) systolic function. We evaluated the association of ARB dose with clinical outcomes after MI with preserved LV systolic function. We used MI multicenter registry. Six months after discharge, the ARB dose was indexed to the target ARB doses used in randomized clinical trials and grouped as >0%-25% (n = 2333), >25% of the target dose (n = 1204), and no ARB (n = 1263). The primary outcome was the composite of cardiac death or MI. Univariate analysis showed that mortality of those with any ARB dose was lower than those without ARB therapy. After multivariable adjustment, patients receiving >25% of target dose had a similar risk of cardiac death or MI compared with those receiving ≤25% or no ARB [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.83-1.33; HR 0.94, 95% CI 0.82-1.08, respectively]. Propensity score analysis also demonstrated that patients with >25% dose had no difference in primary endpoint compared with those ≤25% dose or the no ARB group (HR 1.03, 95% CI 0.79-1.33; HR 0.86, 95% CI 0.64-1.14, respectively). The present study demonstrates that patients treated with >25% of target ARB dose do not have better clinical outcomes than those treated with ≤25% of target ARB dose or those with no ARB dose in MI patients with preserved LV systolic function.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Infarto do Miocárdio , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Resultado do Tratamento , Função Ventricular Esquerda , Antagonistas de Receptores de Angiotensina/efeitos adversosRESUMO
To evaluate the protective effect of viral hemorrhagic septicemia virus genotype IVa (VHSV IVa) genome-based single-cycle viruses against VHSV genotype Ia (VHSV Ia) and infectious hematopoietic necrosis virus (IHNV) in rainbow trout, three kinds of single-cycle VHSVs were rescued using reverse genetic technology: i) rVHSV-IaGΔTM-IVaG containing the transmembrane and cytoplasmic region-deleted G protein (GΔTM) of VHSV Ia instead of VHSV IVa full G gene ORF and having VHSV IVa G proteins on the envelope; ii) rVHSV-IaGΔTM-IaG containing VHSV Ia GΔTM instead of VHSV IVa full G gene ORF and having VHSV Ia G proteins on the envelope; iii) rVHSV-IaGΔTM-ihnvGΔTM-IVaG containing not only VHSV Ia GΔTM instead of full G gene but also IHNV GΔTM instead of NV gene and having VHSV IVa G proteins on the envelope. Rainbow trout immunized with rVHSV-IaGΔTM-IaG and rVHSV-IaGΔTM-IVaG showed significantly higher serum antibody titers against both VHSV Ia and VHSV IVa, and showed no mortality against VHSV Ia infection, while fish in the control groups showed 100% mortalities. Fish immunized with rVHSV-IaGΔTM-ihnvGΔTM-IVaG showed significantly higher serum antibody titers against VHSV IVa, VHSV Ia, and IHNV compared to fish in the control group. Immunization with rVHSV-IaGΔTM-ihnvGΔTM-IVaG induced significantly higher protection against not only VHSV Ia but also IHNV. These results suggest that the present single-cycle rVHSV-based system can be used as a platform to produce combined vaccines that can protect fish from multiple pathogenic species. However, the mechanism of the high protection against IHNV despite comparatively low antibody titer remains to be investigated.
Assuntos
Doenças dos Peixes , Septicemia Hemorrágica Viral , Vírus da Necrose Hematopoética Infecciosa , Novirhabdovirus , Oncorhynchus mykiss , Infecções por Rhabdoviridae , Animais , Vírus da Necrose Hematopoética Infecciosa/genética , Imunização , Genótipo , Doenças dos Peixes/prevenção & controleRESUMO
BACKGROUND: This study aimed to examine the association of serum uric acid levels with incident cardiovascular disease and mortality in Korean adults without gout. METHODS: This large longitudinal cohort study included adults aged > 19 years who had serum uric acid levels measured at least once at the National Health Insurance Service Ilsan Hospital from January 1, 2006 to December 31, 2015. Longitudinal data on person-level cardiovascular disease and cardiovascular mortality were linked to the National Health Insurance Service claims database and National Death Index. RESULTS: Among a total of 92,454 study participants with a median follow-up of 4.7 years, 7,670 (8.3%) composite events of cardiovascular disease or cardiovascular mortality were observed. Multivariable Cox proportional-hazards models revealed that each 1 mg/dL increment in uric acid level was associated with a 6% higher risk of composite outcomes. Compared with that for the uric acid level category of 4.0 to < 5.0 mg/dL, adjusted hazard ratios (95% confidence interval) for uric acid level categories of 5.0 to < 6.0, 6.0 to < 7.0, and ≥ 7.0 mg/dL were 1.10 (1.04-1.18), 1.20 (1.11-1.30), and 1.36 (1.25-1.47), respectively. In the secondary analyses for cardiovascular disease or cardiovascular mortality examined separately, a higher uric acid level was similarly associated with a higher risk of each adverse outcome. These associations were generally consistent across clinically relevant subgroups. CONCLUSION: A graded association was noted between serum uric acid levels and cardiovascular risk, suggesting that higher uric acid levels may adversely affect cardiovascular health and survival in individuals without gout.
Assuntos
Doenças Cardiovasculares , Gota , Adulto , Humanos , Estudos Longitudinais , Ácido Úrico , Estudos de CoortesRESUMO
Since October 2021, severe acute hepatitis of unknown etiology in pediatric patients has been observed in many countries around the world. Adenovirus (mainly enteric adenovirus) was detected in more than 50% of the cases. Nationwide surveillance on acute hepatitis of unknown etiology in pediatric patients was started in May 2022 in Korea. Taking into account the severity of the illness and the urgency of the epidemiological situation worldwide, we report a summary of changes in adenovirus epidemiology during the past five years and six months in Korea.
Assuntos
Adenoviridae , Taxa Respiratória , Humanos , Criança , Adenoviridae/genética , República da Coreia/epidemiologiaRESUMO
This work presents a technique for fault detection and identification in centrifugal pumps (CPs) using a novel fault-specific Mann-Whitney test (FSU Test) and K-nearest neighbor (KNN) classification algorithm. Traditional fault indicators, such as the mean, peak, root mean square, and impulse factor, lack sensitivity in detecting incipient faults. Furthermore, for defect identification, supervised models rely on pre-existing knowledge about pump defects for training purposes. To address these concerns, a new centrifugal pump fault indicator (CPFI) that does not rely on previous knowledge is developed based on a novel fault-specific Mann-Whitney test. The new fault indicator is obtained by decomposing the vibration signature (VS) of the centrifugal pump hierarchically into its respective time-frequency representation using the wavelet packet transform (WPT) in the first step. The node containing the fault-specific frequency band is selected, and the Mann-Whitney test statistic is calculated from it. The combination of hierarchical decomposition of the vibration signal for fault-specific frequency band selection and the Mann-Whitney test form the new fault-specific Mann-Whitney test. The test output statistic yields the centrifugal pump fault indicator, which shows sensitivity toward the health condition of the centrifugal pump. This indicator changes according to the working conditions of the centrifugal pump. To further enhance fault detection, a new effect ratio (ER) is introduced. The KNN algorithm is employed to classify the fault type, resulting in promising improvements in fault classification accuracy, particularly under variable operating conditions.
RESUMO
In resistive switching memories or artificial synaptic devices, halide perovskites have attracted attention for their unusual features such as rapid ion migration, adjustable composition, and facile synthesis. Herein, the environmentally friendly and highly air stable CsCu2I3 perovskite films are used as the active layer in the Au/CsCu2I3/ITO/glass artificial synapses. The device shows variable synaptic plasticities such as long-term and short-term synaptic plasticity, paired-pulse facilitation, and spike-timing-dependent plasticity by combining potentiation and depression along the formation of conductive filaments. The performances of the devices are maintained for 160 days under ambient conditions. Additionally, the accuracy evaluation of the CsCu2I3-based artificial synapses performs exceptionally well with the MNIST and Fashion MNIST data sets, demonstrating high learning accuracy in deep neural networks. Using the novel B-site engineered halide perovskite material with extreme air stability, this study paves the way for artificial synaptic devices for next-generation in-memory hardware.