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Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.
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Peptídeo Relacionado com Gene de Calcitonina , Centro Germinativo , Imunidade Humoral , Baço , Animais , Masculino , Camundongos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Gânglios Espinais/metabolismo , Centro Germinativo/imunologia , Camundongos Endogâmicos C57BL , Nociceptores/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais , Baço/inervação , Baço/imunologia , FemininoRESUMO
Polycomb repressive complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of the RNA-PRC2 interaction in human cardiogenesis remains elusive. Here, we found that human-specific heart brake lncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss of JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. In addition, ChIP-seq revealed reduced EED occupancy on 62 overlapped cardiogenic genes in HBL1-/- and JARID2-/- hPSCs, indicating that the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurs, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved 'microRNA-1-JARID2' axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.
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Genoma , Organogênese , Células-Tronco Pluripotentes/metabolismo , Complexo Repressor Polycomb 2/genética , RNA Longo não Codificante/metabolismo , Diferenciação Celular , Cromatina , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Coração/crescimento & desenvolvimento , Histonas/genética , Humanos , MicroRNAsRESUMO
A light-sensitive moiety, e.g., azobenzene, for the light-sensitive liposomal drug carrier has shown advantages as an advanced drug delivery system in site-specific smart therapy due to its reversible photoisomerization characteristics. In this work, a series of 4-position-cholesterol-functionalized azobenzene derivatives with 4'-position substituted pyridine, quinoline, isoquinoline, triethylamine, or ethylenediamine were synthesized, and the relationship between the molecular structure and drug release behaviors was clarified. We found that the charge and electrophilicity of substituents were two important factors (expressed as the characteristic time) that can precisely regulate the isomerization ratio in the liposomal system. There was an approximately linear correlation between the characteristic time of photoisomerization and the fitted first-order constant of photoinduced drug release rate. The photoinduced drug release could be achieved at the desired time and in an appropriate amount by tailoring the substituents at the 4'-position of azobenzene-cholesterol derivatives.
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Cerebral organoids are comprised of diverse cell types found in the developing human brain, and can be leveraged in the identification of critical cell types perturbed by genetic risk variants in common, neuropsychiatric disorders. There is great interest in developing high-throughput technologies to associate genetic variants with cell types. Here, we describe a high-throughput, quantitative approach (oFlowSeq) by utilizing CRISPR-Cas9, FACS sorting, and next-generation sequencing. Using oFlowSeq, we found that deleterious mutations in autism-associated gene KCTD13 resulted in increased proportions of Nestin+ cells and decreased proportions of TRA-1-60+ cells within mosaic cerebral organoids. We further identified that a locus-wide CRISPR-Cas9 survey of another 18 genes in the 16p11.2 locus resulted in most genes with > 2% maximum editing efficiencies for short and long indels, suggesting a high feasibility for an unbiased, locus-wide experiment using oFlowSeq. Our approach presents a novel method to identify genotype-to-cell type imbalances in an unbiased, high-throughput, quantitative manner.
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Sistemas CRISPR-Cas , Edição de Genes , Humanos , Edição de Genes/métodos , Mutação , Organoides , GenótipoRESUMO
Redclaw crayfish (Cherax quadricarinatus) is a large, tropical freshwater crustacean species with considerable potential of commercial production. In recent years, infection with DIV1 in redclaw crayfish is being reported in aquaculture industries, causing high mortality and huge economic losses. However, many characteristics of this virus, including pathogenesis, transmission mechanism, and host immunity, remain largely unknown.MicroRNAs are known to play important roles in numerous biological processes, and many microRNAs are reported to be involved in the regulation of immune responses. In this study, nine-small RNA libraries were constructed using hemocytes of redclaw crayfish to characterize the differentially expressed miRNAs (DE-miRNAs) at 24 and 48 h postinfection (hpi). A total of 14 and 22 DE-miRNAs were identified in response to DIV1 infection at 24 and 48 hpi, respectively. Further, functional annotation of the predicted host target genes using GO and KEGG pathway enrichment analyses indicated that relevant biological processes and signal pathways underwent miRNA-mediated regulation after DIV1 infection. Our results enhanced the understanding of the mechanisms of miRNA-mediated regulation of immune responses under DIV1 infection in crustaceans.
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BACKGROUND: Dog Bone™ button fixation is frequently used to treat acromioclavicular joint (ACJ) dislocation. However, various studies have reported complications after fixation. OBJECTIVE: To investigate the effect of the coracoid bone tunnel location on the treatment of ACJ dislocation through single-tunnel coracoclavicular (CC) ligament fixation with the Dog Bone™ button. METHODS: Six cadaveric shoulders were used. Each specimen was subjected to five testing conditions in the following order: (1) normal ACJ (Gn); (2) acromioclavicular and CC ligaments were removed (G0); (3) CC ligament reconstruction was performed using the Dog Bone™ technique, and the coracoid bone tunnel was at the center of the coracoid base (G1); (4) reconstruction was performed at 5 mm distal from the G1 site, along the axis of the coracoid (G2); (5) reconstruction was performed at 10 mm distal from the G1 site, along the axis of the coracoid (G3). The angles of pronation and supination of the clavicle under the same load (30 N) were measured. Next, a finite element (FE) model was created using computed tomography (CT) images of the normal shoulder. Model 1 (M1), model 2 (M2), and model 3 (M3) correspond to G1, G2, and G3, respectively. A force of 70 N was applied as a vertical upward load to the distal clavicle. Subsequently, the von Mises stress, the strain LE along the FiberWire, and the displacement nephogram of the three models were obtained. RESULTS: After single-tunnel CC ligament fixation using the Dog Bone™ technique, the clavicle in the G2 group (20.50 (19.50, 21.25) °, 20.00 (18.75, 21.25) °) had the best rotational stability. The peak von Mises stress, the strain LE along the FiberWire, and the maximum displacement were smaller in M2 than in M1 and M3. CONCLUSIONS: When the coracoid bone tunnel was located 5 mm anterior to the center of the coracoid base (along the axis of the coracoid), the clavicle showed greater rotational stability.
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Articulação Acromioclavicular , Luxações Articulares , Luxação do Ombro , Articulação Acromioclavicular/diagnóstico por imagem , Articulação Acromioclavicular/cirurgia , Cadáver , Clavícula/cirurgia , Análise de Elementos Finitos , Luxações Articulares/diagnóstico por imagem , Luxações Articulares/cirurgia , Ligamentos Articulares/cirurgia , Ombro , Luxação do Ombro/cirurgia , HumanosRESUMO
Honeycomb (Nidus vespae) is traditional Chinese medicine and can treat rheumatoid arthritis (RA), and protocatechuic acid (PCA) is a bioactive component of honeycomb. This study aimed to investigate whether PCA could reduce the H2O2-induced migration and oxidative stress of RA fibroblast-like synoviocytes (RA-FLSs). H2O2-induced RA-FLSs were used to simulate the in vitro model of RA. The viability, apoptosis, migration, invasion, and oxidative stress of RA-FLSs were detected by Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, wound healing, transwell assays, DCFDA staining, and malonaldehyde and superoxide dismutase enzyme-linked immunosorbent assay kits. The expression of migration and invasion-related proteins and Nrf2/Keap1 signaling pathway-related proteins was analyzed by western blotting. As a result, PCA suppressed the viability, migration, invasion, and oxidative and promoted apoptosis of H2O2-induced RA-FLSs by activating the Nrf2/Keap1 signaling pathway. ML-385, an Nrf2 inhibitor, could enhance the viability, migration, invasion, and oxidative and inhibited apoptosis of H2O2-induced RA-FLSs. In conclusion, PCA reduced H2O2-induced migration and oxidative stress of RA-FLSs by activating the Nrf2-Keap1 signaling pathway.
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Artrite Reumatoide , Sinoviócitos , Humanos , Sinoviócitos/metabolismo , Peróxido de Hidrogênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proliferação de Células , Movimento Celular , Transdução de Sinais , Artrite Reumatoide/metabolismo , Estresse Oxidativo , Fibroblastos/metabolismo , Células CultivadasRESUMO
Photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising non-invasive approaches to cancer treatment. However, the development of multifunctional nanomedicines is necessary to enhance these approaches' effectiveness and safety. In this study, we investigated a polydopamine-based nanoparticle (PDA-ZnPc+ Nps) loaded with the efficient photosensitizer ZnPc(4TAP)12+ (ZnPc+) through in vitro and in vivo experiments to achieve synergistic PDT and PTT. Our results demonstrated that PDA-ZnPc+ Nps exhibited remarkable efficacy due to its ability to generate reactive oxygen species (ROS), induce photothermal effects, and promote apoptosis in cancer cells. Moreover, in both MCF-7 cells and MCF-7 tumor-bearing mice, the combined PDT/PTT treatment with PDA-ZnPc+ Nps led to synergistic effects. Subcellular localization analysis revealed a high accumulation of ZnPc+ in the cytoplasm of cancer cells, resulting in cellular disruption and vacuolation following synergistic PDT/PTT. Furthermore, PDA-ZnPc+ Nps exhibited significant antitumor effects without causing evident systemic damage in vivo, enabling the use of lower doses of photosensitizer and ensuring safer treatment. Our study not only highlights the potential of PDA-ZnPc+ Nps as a dual-functional anticancer agent combining PDA and PTT but also offers a strategy for mitigating the side effects associated with clinical photosensitizers, particularly dark toxicity.
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Nanopartículas , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Terapia Fototérmica , Nanomedicina , Linhagem Celular TumoralRESUMO
AIMS: Idiopathic membranous nephropathy (IMN) is a common cause of adult nephrotic syndrome. Currently, the diagnosis of IMN mainly depends on renal biopsy, which is invasive. What's more, markers already known for the clinical diagnosis of IMN are not sensitive enough. The present study aims to investigate the profiling of urinary exosomal circular RNAs (circRNAs) of IMN, and to look for a potential biomarker for diagnosis of IMN. METHODS: Urine exosomes were collected from patients with IMN and idiopathic nephrotic syndrome (INS), as well as healthy controls (HCs) by ultracentrifuge. A pairwise comparison between 5 IMN and 5 HC was performed by high-throughput sequencing. Enrichment analysis were performed to explore the potential functions of differentially expressed circRNAs in IMN. Among three differentially expressed circRNAs which may be involved in signaling pathways of pathogenesis of IMN and matched conserved mouse circRNAs, hsa_circ_0001250 was selected as the target circRNA after quantitative polymerase chain reaction among 23 IMN, 19 INS and 23HC. Sanger sequencing and RNase R digestion assay were performed to validated the ring-structure and sequence of hsa_circ_0001250. ROC (Receiver Operating Characteristic) curve correlation analysis was used to further validate the potential utility of hsa_circ_0001250 as a diagnostic biomarker of IMN. A circRNA-miRNA-mRNA network was constructed to reflect the relationship between hsa_circ_0001250 and its target miRNAs and mRNAs. RESULTS: 766 up-regulated and 283 down-regulated circRNAs were identified in IMN patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed signaling pathways of pathogenesis of IMN which the different expressed circRNAs may participate in. The ring-structure and the sequence of hsa_circ_0001250 were confirmed, the expression of hsa_circ_0001250 was validated significantly increased in IMN, relevant with high level of proteinuria. A circRNA-miRNA-mRNA network reflected that hsa_circ_0001250 may play a role in the pathogenesis of IMN by target hsa-miR-639 and hsa-miR-4449. CONCLUSION: We revealed the expression and functional profile of differentially expressed urinary exosomal circRNAs of IMN patients. Urinary exosomal hsa_circ_0001250 was tested as a potential biomarker of IMN and a predicted circRNA-miRNA-mRNA network was constructed.
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Glomerulonefrite Membranosa , MicroRNAs , Síndrome Nefrótica , Animais , Camundongos , RNA Circular/genética , MicroRNAs/genética , RNA Mensageiro , Biomarcadores/análiseRESUMO
A ground-based lidar is a powerful tool for studying the vertical structure and optical properties of clouds. A layer detection algorithm is important to determine the presence and spatial position of clouds from vast lidar signals. However, current detection algorithms for ground-based lidar still involve substantial missing and false detections for tenuous layers and layer edges. Here, a joint multiscale cloud layer detection algorithm is proposed. The algorithm can effectively capture the tenuous layers and layer edges by using joint multiscale detection methods based on a trend function and the Bernoulli distribution assumption. Results show that the proposed algorithm detects 10.45% more cloud layers than the official cloud product of Micro Pulse Lidar Network (MPLNET) does. Specifically, 7.93% and 12.57% more cloud layers are detected at daytime and nighttime, respectively. The evaluation based on depolarization properties proves that the additional cloud layers detected by the joint multiscale algorithm are reliable. These additional detected clouds have important implications for cloud climatology and climate change research. The new algorithm remarkably enhances the cloud detection capability of ground-based lidar and potentially be widely used by the community.
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Gut bacteria employ quorum sensing (QS) to coordinate their activities and communicate with one another, this process relies on the production, detection, and response to autoinducers, which are extracellular signaling molecules. In addition to synchronizing behavioral activities within the species, QS plays a crucial role in the gut host-microbiota interaction. In this review, an overview of classical QS systems is presented as well as the interspecies communication mediated by QS, and recent advances in the host-microbiota interaction mediated by QS. A greater knowledge of the communication network of gut microbiota is not only an opportunity and a challenge for developing nutritional and therapeutic strategies against bacterial illnesses, but also a means for improving gut health.
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Unmanned ground vehicles (UGVs) are making more and more progress in many application scenarios in recent years, such as exploring unknown wild terrain, working in precision agriculture and serving in emergency rescue. Due to the complex ground conditions and changeable surroundings of these unstructured environments, it is challenging for these UGVs to obtain robust and accurate state estimations by using sensor fusion odometry without prior perception and optimization for specific scenarios. In this paper, based on an error-state Kalman filter (ESKF) fusion model, we propose a robust lidar-inertial odometry with a novel ground condition perception and optimization algorithm specifically designed for UGVs. The probability distribution gained from the raw inertial measurement unit (IMU) measurements during a certain time period and the state estimation of ESKF were both utilized to evaluate the flatness of ground conditions in real-time; then, by analyzing the relationship between the current ground condition and the accuracy of the state estimation, the tightly coupled lidar-inertial odometry was dynamically optimized further by adjusting the related parameters of the processing algorithm of the lidar points to obtain robust and accurate ego-motion state estimations of UGVs. The method was validated in various types of environments with changeable ground conditions, and the robustness and accuracy are shown through the consistent accurate state estimation in different ground conditions compared with the state-of-art lidar-inertial odometry systems.
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Algoritmos , Percepção , Movimento (Física) , Probabilidade , Fatores de TempoRESUMO
Aggregation is a key process for determining the environmental behavior and impact of a nanoparticle (NP). Since organophosphate esters (OPEs), which are recognized as emerging contaminants, are distributed widely in the natural aquatic environment, they may contribute to interacting with NPs and ultimately influence their transport and fate. Here, we investigated two typical organophosphate esters OPEs on aggregation the Fe2O3 NP in aquatic environments. The results showed that both tri-ethylhexyl phosphate (TEHP) and tris (chloroisopropyl) phosphate (TCPP) improved the colloidal stability of Fe2O3 NP in artificial water and environmental matrices. TEHP exhibited an obvious effect than TCPP on the Zeta potential and aggregation rates of Fe2O3 NP in artificial water. In the presence of electrolyte, 10 mg/L TCPP and TEHP increased the critical coagulation concentration (CCC) by 3.6 times and 17.4 times, respectively. Compared with pore-water, the aggregation rates of Fe2O3 NP in river water were slightly higher than those in pore-water, which can be attributed to the higher DOC in pore-water. We suggested that the high hydrophobicity and molecular weight of OPEs were considered important factors against the aggregation of Fe2O3 NP in water. Greater surface charge and steric hindrance originating from TCPP and TEHP dominated the colloidal stability of Fe2O3 NP.
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Nanopartículas , Poluentes Químicos da Água , Monitoramento Ambiental/métodos , Ésteres , Organofosfatos , Fosfatos , Água , Poluentes Químicos da Água/análiseRESUMO
Human amniotic mesenchymal stem cells (hAMSCs) can be differentiated into Schwann-cell-like cells (SCLCs) in vitro. However, the underlying mechanism of cell differentiation remains unclear. In this study, we explored the phenotype and multipotency of hAMSCs, which were differentiated into SCLCs, and the expression of nerve repair-related Schwann markers, such as S100 calcium binding protein B (S-100), TNF receptor superfamily member 1B (P75), and glial fibrillary acidic protein (GFAP) were observed to be significantly increased. The secreted functional neurotrophic factors, like brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), were determined and also increased with the differentiation time. Moreover, miR-146a-3p, which significantly decreased during the differentiation of hAMSCs into SCLCs, was selected by miRNA-sequence analysis. Further molecular mechanism studies showed that Erb-B2 receptor tyrosine kinase 2 (ERBB2) was an effective target of miR-146a-3p and that miR-146a-3p down-regulated ERBB2 expression by binding to the 3'-UTR of ERBB2. The expression of miR-146a-3p markedly decreased, while the mRNA levels of ERBB2 increased with the differentiation time. The results showed that down-regulating miR-146a-3p could promote SC lineage differentiation and suggested that miR-146a-3p negatively regulated the Schwann-like phenotype differentiation of hAMSCs by targeting ERBB2. The results will be helpful to establish a deeper understanding of the underlying mechanisms and find novel strategies for cell therapy.
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Tecido Adiposo/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Receptor ErbB-2/biossíntese , Células de Schwann/citologia , Células de Schwann/metabolismo , Tecido Adiposo/citologia , Diferenciação Celular/fisiologia , HumanosRESUMO
By analyzing newly collected SARS-CoV-2 genomes and comparing them with our previous study about SARS-CoV-2 single nucleotide variants (SNVs) before June 2020, we found that the SNV clustering had changed remarkably since June 2020. Apart from that the group of SNVs became dominant, which is represented by two nonsynonymous mutations A23403G (S:D614G) and C14408T (ORF1ab:P4715L), a few emerging groups of SNVs were recognized with sharply increased monthly incidence ratios of up to 70% in November 2020. Further investigation revealed sets of SNVs specific to patients' ages and/or gender, or strongly associated with mortality. Our logistic regression model explored features contributing to mortality status, including three critical SNVs, G25088T(S:V1176F), T27484C (ORF7a:L31L), and T25A (upstream of ORF1ab), ages above 40 years old, and the male gender. The protein structure analysis indicated that the emerging subgroups of nonsynonymous SNVs and the mortality-related ones were located on the protein surface area. The clashes in protein structure introduced by these mutations might in turn affect the viral pathogenesis through the alteration of protein conformation, leading to a difference in transmission and virulence. Particularly, we explored the fact that nonsynonymous SNVs tended to occur in intrinsic disordered regions of Spike and ORF1ab to significantly increase hydrophobicity, suggesting a potential role in the change of protein folding related to immune evasion.
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COVID-19/mortalidade , Genoma Viral/genética , Polimorfismo de Nucleotídeo Único/genética , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Poliproteínas/genética , Glicoproteína da Espícula de Coronavírus/genética , Proteínas Virais/genética , Virulência/genética , Adulto JovemRESUMO
BACKGROUND: Laurel wilt caused by Raffaelea lauricola is a lethal vascular disease of North American members of the Lauraceae plant family. This fungus and its primary ambrosia beetle vector Xyleborus glabratus originated from Asia; however, there is no report of laurel wilt causing widespread mortality on native Lauraceae trees in Asia. To gain insight into why R. lauricola is a tree-killing plant pathogen in North America, we generated and compared high quality draft genome assemblies of R. lauricola and its closely related non-pathogenic species R. aguacate. RESULTS: Relative to R. aguacate, the R. lauricola genome uniquely encodes several small-secreted proteins that are associated with virulence in other pathogens and is enriched in secondary metabolite biosynthetic clusters, particularly polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and PKS-NRPS anchored gene clusters. The two species also exhibit significant differences in secreted proteins including CAZymes that are associated with polysaccharide binding including the chitin binding CBM50 (LysM) domain. Transcriptomic comparisons of inoculated redbay trees and in vitro-grown fungal cultures further revealed a number of secreted protein genes, secondary metabolite clusters and alternative sulfur uptake and assimilation pathways that are coordinately up-regulated during infection. CONCLUSIONS: Through these comparative analyses we have identified potential adaptations of R. lauricola that may enable it to colonize and cause disease on susceptible hosts. How these adaptations have interacted with co-evolved hosts in Asia, where little to no disease occurs, and non-co-evolved hosts in North America, where lethal wilt occurs, requires additional functional analysis of genes and pathways.
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Genômica , Transcriptoma , Animais , Ásia , América do Norte , OphiostomatalesRESUMO
PURPOSE: We sought to develop a triage strategy to reduce negative and indeterminate multiparametric magnetic resonance imaging scans in patients at risk for prostate cancer. MATERIALS AND METHODS: In this retrospective study we evaluated 865 patients with no prior prostate cancer diagnosis who underwent prostate multiparametric magnetic resonance imaging between 2009 and 2017. Age, prostate volume, prostate specific antigen and prostate specific antigen density were assessed as predictors of positive multiparametric magnetic resonance imaging, defined as PI-RADS™ (Prostate Imaging Reporting and Data System) version 2/Likert score 4 or greater. The cohort was split into a training cohort of 605 patients and a validation cohort of 260. The optimal threshold to rule out positive multiparametric magnetic resonance imaging was chosen to achieve a negative predictive value greater than 90%. RESULTS: All clinical variables were significant predictors of positive multiparametric magnetic resonance imaging (p <0.05). Prostate specific antigen density outperformed other parameters in diagnostic accuracy and did not significantly differ compared to a multivariate model (AUC=0.74 vs 0.75). At prostate specific antigen density greater than 0.078 ng/ml2 sensitivity, specificity, positive and negative predictive values were 94%, 29%, 22% and 95%, respectively, resulting in 25% fewer scans (64 of 260). In the multivariate model sensitivity, specificity, positive and negative predictive values were 85%, 32%, 22% and 91%, respectively, resulting in 29% fewer scans (75 of 260). Biopsies in men who would not have undergone multiparametric magnetic resonance imaging according to our proposed strategies revealed 2 clinically significant prostate cancers using prostate specific antigen density and 1 using the multivariate model. CONCLUSIONS: In patients at risk for prostate cancer applying a multivariate prediction model or a prostate specific antigen density cutoff of 0.078 ng/ml2 resulted in 25% to 29% fewer multiparametric magnetic resonance imaging scans performed while missing only a minimal number of clinically significant prostate cancers. Further prospective validation is required.
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Calicreínas/sangue , Imageamento por Ressonância Magnética Multiparamétrica/estatística & dados numéricos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Procedimentos Desnecessários/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Carga TumoralRESUMO
BACKGROUND: To investigate the biological relationship, mechanism between perilipin2 and the occurrence, advancement of gastric carcinoma, and explore the mechanism of lipid metabolism disorder leading to gastric neoplasm, and propose that perilipin2 is presumably considered as a potential molecular biomarker of gastric carcinoma. METHODS: RNA-seq was applied to analyze perilipin2 and differentially expressed genes modulated by perilipin2 in neoplastic tissues of both perilipin2 overexpression and knockdown groups in vivo. The mechanism was discovered and confirmed by Rt-qPCR, immunoblotting, immunohistochemistry, staining and microassay, respectively. Cellular function experiments were performed by flow cytometry, CCK8, clonogenic assay, etc. RESULTS: Overexpression and knockdown of perilipin2 augmented the proliferation and apoptosis of gastric carcinoma cell lines SGC7901 and MGC803, respectively. The neoplastic cells with perilipin2-overexpression obtained more conspicuously rapid growth than knockdown group in vivo, and perilipin2 affected the proliferation and apoptosis of gastric carcinoma cells by modulating the related genes:acyl-coa synthetase long-chain family member 3, arachidonate 15-lipoxygenase, microtubule associated protein 1 light chain 3 alpha, pr/set domain 11 and importin 7 that were participated in Ferroptosis pathway. Moreover, RNA-seq indicated perilipin2 was an indispensable gene and protein in the suppression of Ferroptosis caused by abnormal lipometabolism in gastric carcinoma. CONCLUSION: Our study expounded the facilitation of perilipin2 in regulating the proliferation and apoptosis of gastric carcinoma cells by modification in Ferroptosis pathway, and we interpreted that the mechanism of gastric neoplasm caused by obesity, we also discovered that pr/set domain 11 and importin 7 are novel transcription factors relevant to gastric carcinoma. Furthermore, perilipin2 probably serves not only as a diagnostic biomarker, but also a new therapeutic target.
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Biomarcadores Tumorais/genética , Ferroptose/genética , Metabolismo dos Lipídeos/genética , Perilipina-2/metabolismo , Neoplasias Gástricas/patologia , Animais , Apoptose , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Perilipina-2/antagonistas & inibidores , Perilipina-2/genética , RNA-Seq , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Cox proportional hazard model (CPH) is commonly used in clinical research for survival analysis. In quantitative medical imaging (radiomics) studies, CPH plays an important role in feature reduction and modeling. However, the underlying linear assumption of CPH model limits the prognostic performance. In this work, using transfer learning, a convolutional neural network (CNN) based survival model was built and tested on preoperative CT images of resectable Pancreatic Ductal Adenocarcinoma (PDAC) patients. RESULTS: The proposed CNN-based survival model outperformed the traditional CPH-based radiomics approach in terms of concordance index and index of prediction accuracy, providing a better fit for patients' survival patterns. CONCLUSIONS: The proposed CNN-based survival model outperforms CPH-based radiomics pipeline in PDAC prognosis. This approach offers a better fit for survival patterns based on CT images and overcomes the limitations of conventional survival models.
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Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/mortalidade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Humanos , Redes Neurais de Computação , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
Because of the specific characteristics, like high vehicular mobility, unstable topology, and interruption of inter-vehicle wireless communication, it is hard to make a perfect decision on packet forwarding in highly dynamic topology VANETs. Especially in a sparse urban environment, the poor connectivity of nodes will mostly cause problems such as data packet loss and routing redundancy. Therefore, how to choose the best relay node becomes a key challenge in the design of fast and reliable routing protocols. This paper presents real-time effective information traffic routing (RTEIT), which provides an optimal route for forwarding the data packets toward their destination when choosing the relay node. RTEIT introduces a new network parameter named effective information traffic which can estimate the connectivity of nodes by the path that has been successfully created. Moreover, for avoiding unexpected communication interruption, we propose a new formula to evaluate the status of the links via considering the speed, direction, and location information. Finally, the node utility, as the criterion of routing decision, is calculated by effective information traffic and link status. We use the simulator of SUMO and NS-3 platform to evaluate RTEIT, and the results are compared with GPSR MOPR, and MM-GPSR. The evaluation results demonstrate that RTEIT outperforms in terms of packet loss rate, end-to-end delay, and network yield.