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BACKGROUND: Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. METHODS: BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. RESULTS: We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. CONCLUSIONS: Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.
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Ácidos y Sales Biliares , Resina de Colestiramina , Hepatopatías Alcohólicas , Ratones Endogámicos C57BL , Animales , Ratones , Resina de Colestiramina/farmacología , Resina de Colestiramina/uso terapéutico , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/prevención & control , Masculino , Ácidos y Sales Biliares/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Autofagia/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Insect wings are flexible structures that exhibit deformations of complex spatiotemporal patterns. Existing studies on wing deformation underscore the indispensable role of wing deformation in enhancing aerodynamic performance. Here, we investigated forward flight in bluebottle flies, flying semi-freely in a magnetic flight mill; we quantified wing surface deformation using high-speed videography and marker-less surface reconstruction and studied the effects on aerodynamic forces, power and efficiency using computational fluid dynamics. The results showed that flies' wings exhibited substantial camber near the wing root and twisted along the wingspan, as they were coupled effects of deflection primarily about the claval flexion line. Such deflection was more substantial for supination during the upstroke when most thrust was produced. Compared with deformed wings, the undeformed wings generated 59-98% of thrust and 54-87% of thrust efficiency (i.e. ratio of thrust and power). Wing twist moved the aerodynamic centre of pressure proximally and posteriorly, likely improving aerodynamic efficiency.
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Vuelo Animal , Alas de Animales , Animales , Vuelo Animal/fisiología , Alas de Animales/fisiología , Alas de Animales/anatomía & histología , Fenómenos Biomecánicos , Dípteros/fisiología , Modelos BiológicosRESUMEN
OBJECTIVE: Pulse-synchronous tinnitus (PST) has been linked to multiple anatomical variants of the central venous outflow tract (CVOT) including sigmoid sinus (SS) dehiscence and diverticulum. This study investigates flow turbulence, pressure, and wall shear stress along the CVOT and proposes a mechanism that results in SS dehiscence and PST. STUDY DESIGN: Case series. SETTING: Tertiary Academic Center. METHODS: Venous models were reconstructed from computed tomography scans of 3 patients with unilateral PST. Two models for each patient are obtained: a symptomatic and contralateral asymptomatic side. A turbulent model-enabled commercial flow solver was used to simulate the pulsatile blood flow over the cardiac cycle through the models. Fluid flow through the transverse and SS junction was analyzed to observe the velocity, pressure, turbulent kinetic energy (TKE), and shear stress over a simulated cardiac cycle. RESULTS: Fluid flow on the symptomatic side showed increased vorticity in the presence of an SS diverticulum. Higher TKE with periodicity following the cardiac cycle was observed on the symptomatic side, and a sharp increase was observed if SS diverticulum was present. Shear stress was highest near the narrowest segments of the vessel. Pressure was observed to be lower on the symptomatic side at the transverse-SS junction for all 3 patients. CONCLUSION: Computational fluid dynamics modeling of blood flow through the CVOT in PST suggests that low pressure may be the cause of dehiscence, and tinnitus may result from periodic increases in TKE.
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INTRODUCTION: In recent years, the correlation between CD117 antigen and the prognosis of hematological malignancies has been demonstrated. However, there is limited literature on the clinical significance of CD117 antigen in acute promyelocytic leukemia (APL). The aim of this study was to retrospectively analyze the clinical features and prognostic significance of CD117 in APL. METHODS: In this study, we retrospectively investigated the clinicopathological characteristics, outcome, and prognostic impact of negative CD117 expression (CD117-) in 169 APL patients treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) containing regimen. RESULTS: The median follow-up period was 63.0 months. CD117- was detected in 13 APL patients (7.7%). No significant differences were found in baseline characteristics between CD117+ and CD117- subgroups. However, compared to CD117+ APL, the incidence of early death (ED) was significantly higher in CD117- APL (p = 0.023). By multivariate analysis, CD117- was an independent adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) (p = 0.022 and p = 0.014, respectively). CONCLUSIONS: To sum up, CD117- is associated with greater risk of ED and has the statistical power to predict inferior OS and PFS, this marker may be considered to build prognostic scores for risk-adapted therapeutic strategies in APL management.
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Cicadas are heavy fliers well known for their life cycles and sound production; however, their flight capabilities have not been extensively investigated. Here, we show for the first time that cicadas appropriate backward flight for additional maneuverability. We studied this flight mode using computational fluid dynamics (CFD) simulations based on three-dimensional reconstructions of high-speed videos captured in a laboratory. Backward flight was characterized by steep body angles, high angles of attack, and high wing upstroke velocities. Wing motion occurred in an inclined stroke plane that was fixed relative to the body. Likewise, the directions of the half-stroke-averaged aerodynamic forces relative to the body (local frame) were constrained in a narrow range (<20°). Despite the drastic difference of approximately 90° in body posture between backward and forward flight in the global frame, the aerodynamic forces in both flight scenarios were maintained in a similar direction relative to the body. The forces relative to the body were also oriented in a similar direction when observed during climbs and turns, although the body orientation and motions were different. Hence, the steep posture appropriated during backward flight was primarily utilized for reorienting both the stroke plane and aerodynamic force in the global frame. A consequence of this reorientation was the reversal of aerodynamic functions of the half strokes in backward flight when compared to forward flight. The downstroke generated propulsive forces, while the upstroke generated vertical forces. For weight support, the upstroke, which typically generates lesser forces in forward flight, is aerodynamically active in backward flight. A leading-edge vortex (LEV) was observed on the forewings during both half strokes. The LEV's effect, together with the high upstroke velocity, increased the upstroke's force contribution from 10% of the net forces in forward flight to 50% in backward flight. The findings presented in this study have relevance to the design of micro-aerial vehicles (MAVs), as backward flight is an important characteristic for MAV maneuverability or for taking off from vertical surfaces.
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This study aimed to construct an imaging genomics nomogram based on intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) to predict the status of the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene in patients with brain gliomas. We retrospectively analyzed routine MR and IVIM-DWI data from 85 patients with pathologically confirmed brain gliomas from January 2017 to May 2023. The data were divided into a training set (N=61) and a test set (N=24) in a 7:3 ratio. Regions of interest (ROIs) of brain gliomas, including the solid tumor region (rCET), edema region (rE), and necrotic region (rNec), were delineated using 3D-Slicer software and projected onto the D, D*, and f sequences. A total of 1037 features were extracted from each ROI, resulting in 3111 features per patient. Age was incorporated in the calculation of the Radscore, and a clinical-imaging genomics combined model was constructed, from which a nomogram graph was generated. Separate models were built for the D, D*, and f parameters. The AUC value of the D parameter model was 0.97 (95% CI: 0.93-1.00) in the training set and 0.91 (95% CI: 0.79-1.00) in the validation set, which was significantly higher than that of the D* parameter model (0.90, 0.82) and the f parameter model (0.89, 0.91). The imaging genomics nomogram based on IVIM-DWI can effectively predict the ATRX gene status of patients with brain gliomas, with the D parameter showing the highest efficacy.
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Neoplasias Encefálicas , Imagen de Difusión por Resonancia Magnética , Glioma , Mutación , Nomogramas , Proteína Nuclear Ligada al Cromosoma X , Humanos , Glioma/genética , Glioma/diagnóstico por imagen , Glioma/patología , Imagen de Difusión por Resonancia Magnética/métodos , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven , Adolescente , AncianoRESUMEN
This study investigates the interaction of a two-manta-ray school using computational fluid dynamics simulations. The baseline case consists of two in-phase undulating three-dimensional manta models arranged in a stacked configuration. Various vertical stacked and streamwise staggered configurations are studied by altering the locations of the top manta in the upstream and downstream directions. Additionally, phase differences between the two mantas are considered. Simulations are conducted using an in-house developed incompressible flow solver with an immersed boundary method. The results reveal that the follower will significantly benefit from the upstroke vortices (UVs) and downstroke vortices depending on its streamwise separation. We find that placing the top manta 0.5 body length (BL) downstream of the bottom manta optimizes its utilization of UVs from the bottom manta, facilitating the formation of leading-edge vortices (LEVs) on the top manta's pectoral fins during the downstroke. This LEV strengthening mechanism, in turn, generates a forward suction force on the follower that results in a 72% higher cycle-averaged thrust than a solitary swimmer. This benefit harvested from UVs can be further improved by adjusting the phase of the top follower. By applying a phase difference ofπ/3to the top manta, the follower not only benefits from the UVs of the bottom manta but also leverages the auxiliary vortices during the upstroke, leading to stronger tip vortices and a more pronounced forward suction force. The newfound interaction observed in schooling studies offers significant insights that can aid in the development of robot formations inspired by manta rays.
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Hidrodinámica , Natación , Fenómenos BiomecánicosRESUMEN
Metabolic syndrome (MetS) is a worldwide challenge that is closely associated with obesity, nonalcoholic liver disease, insulin resistance, and type 2 diabetes. Boosting nicotinamide adenine dinucleotide (NAD+) presents great potential in preventing MetS. However, the function of nuclear NAD+ in the development of MetS remains poorly understood. In this study, hepatocyte-specific Nmnat1 knockout mice were used to determine a possible link between nuclear NAD+ and high-fat diet (HFD)-induced MetS. We found that Nmnat1 knockout significantly reduced hepatic nuclear NAD+ levels but did not exacerbate HFD-induced obesity and hepatic triglycerides accumulation. Interestingly, loss of Nmnat1 caused insulin resistance. Further analysis revealed that Nmnat1 deletion promoted gluconeogenesis but inhibited glycogen synthesis in the liver. Moreover, Nmnat1 deficiency induced mitochondrial dysfunction by decreasing mitochondrial DNA (mtDNA)-encoded complexes â and â £, suppressing mtDNA replication and mtRNA transcription and reducing mtDNA copy number. In addition, Nmnat1 depletion affected the expression of hepatokines in the liver, particularly downregulating the expression of follistatin. These findings highlight the importance of nuclear NAD+ in maintaining insulin sensitivity and provide insights into the mechanisms underlying HFD-induced insulin resistance.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Nicotinamida-Nucleótido Adenililtransferasa , Animales , Ratones , NAD/metabolismo , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Dieta Alta en Grasa/efectos adversos , Diabetes Mellitus Tipo 2/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Mitocondrias/metabolismo , ADN Mitocondrial/metabolismo , Ratones Endogámicos C57BL , Nicotinamida-Nucleótido Adenililtransferasa/metabolismoRESUMEN
BACKGROUND: The objective of this study was to identify potential biomarkers for predicting response to MSC therapy by pre-MSC treatment plasma proteomic profile in severe COVID-19 in order to optimize treatment choice. METHODS: A total of 58 patients selected from our previous RCT cohort were enrolled in this study. MSC responders (n = 35) were defined as whose resolution of lung consolidation ≥ 51.99% (the median value for resolution of lung consolidation) from pre-MSC to 28 days post-MSC treatment, while non-responders (n = 23) were defined as whose resolution of lung consolidation < 51.99%. Plasma before MSC treatment was detected using data-independent acquisition (DIA) proteomics. Multivariate logistic regression analysis was used to identify pre-MSC treatment plasma proteomic biomarkers that might distinguish between responders and non-responders to MSC therapy. RESULTS: In total, 1101 proteins were identified in plasma. Compared with the non-responders, the responders had three upregulated proteins (CSPG2, CTRB1, and OSCAR) and 10 downregulated proteins (ANXA1, AGRG6, CAPG, DDX55, KV133, LEG10, OXSR1, PICAL, PTGDS, and S100A8) in plasma before MSC treatment. Using logistic regression model, lower levels of DDX55, AGRG6, PICAL, and ANXA1 and higher levels of CTRB1 pre-MSC treatment were predictors of responders to MSC therapy, with AUC of the ROC at 0.910 (95% CI 0.818-1.000) in the training set. In the validation set, AUC of the ROC was 0.767 (95% CI 0.459-1.000). CONCLUSIONS: The responsiveness to MSC therapy appears to depend on baseline level of DDX55, AGRG6, PICAL, CTRB1, and ANXA1. Clinicians should take these factors into consideration when making decision to initiate MSC therapy in patients with severe COVID-19.
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COVID-19 , Trasplante de Células Madre Mesenquimatosas , Humanos , COVID-19/terapia , Proteómica , Biomarcadores/metabolismo , Proteínas Serina-Treonina QuinasasRESUMEN
Background: The hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated. Methods: Intestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity. Results: After alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3γ and α-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced Akkermansia, IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using in vitro cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3. Conclusion: Our study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.
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Antiinfecciosos , Hepatitis Alcohólica , Hepatopatías Alcohólicas , Microbiota , Ratones , Animales , Hepatitis Alcohólica/prevención & control , Simbiosis , Interleucinas , Hepatopatías Alcohólicas/prevención & control , Etanol , Inflamación , Bacterias , Interleucina-22RESUMEN
BACKGROUND: Recent studies have shown that mesenchymal stem cell (MSC) therapy has potential therapeutic effects for patients with end-stage liver diseases. However, a consensus on the efficacy and safety of MSCs has not been reached. METHODS: A systemic literature review was conducted by searching the Cochrane Library and PubMed databases for articles that evaluated the impact of MSC therapy on the outcomes among patients with end-stage liver disease. Various parameters, including pre- and post-treatment model of end-stage liver disease (MELD) score, serum albumin (ALB), total bilirubin (TB), coagulation function, aminotransferase, and survival rate, were evaluated. RESULTS: This meta-analysis included a final total of 13 studies and 854 patients. The results indicated improved liver parameters following MSC therapy at different time points, including in terms of MELD score, TB level, and ALB level, compared with conventional treatment. Furthermore, the MSC treatment increased the overall survival rate among patients with liver cirrhosis and acute-on-chronic liver failure (ACLF). The changes in transaminase level and coagulation function differed between the different therapies at various post-treatment time points, indicating that MSC therapy provided no significant benefits in this regard. The further subgroup analysis stratified by liver background revealed that patients with ACLF benefit more from MSC therapy at most time points with improved liver function, including in terms of MELD score, TB level, and ALB level. In addition, no serious side effects or adverse events were reported following MSC therapy. CONCLUSIONS: The meta-analysis results suggest that MSC therapy is safe and results in improved liver function and survival rates among patients with end-stage liver disease. The subgroup analysis stratified by liver background indicated that patients with ACLF benefit more from MSC therapy than patients with liver cirrhosis at most time points.
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Insuficiencia Hepática Crónica Agudizada , Enfermedad Hepática en Estado Terminal , Células Madre Mesenquimatosas , Humanos , Insuficiencia Hepática Crónica Agudizada/terapia , Médula Ósea , Cirrosis Hepática/terapiaRESUMEN
BACKGROUND: COVID-19 is a global pandemic. Understanding the immune responses in pregnant women recovering from COVID-19 may suggest new therapeutic approaches. METHODS: We performed a cross-sectional study between March 1, 2020, and September 1, 2020. Participants were assigned into the convalescent COVID-19 group if they had a previous COVID-19 infection during pregnancy or the healthy control group. RNA-Seq was performed on human umbilical cord mesenchymal stem cells (hUMSCs) and human amniotic mesenchymal stem cells (hAMSCs). Immunohistochemical staining, cytokine testing, lymphocyte subset analysis, RNA-Seq, and functional analyses were performed on the placental and umbilical cord blood (UCB) and compared between the two groups. RESULTS: A total of 40 pregnant women were enrolled, with 13 in the convalescent group and 27 in the control group. There were 1024, 46, and 32 differentially expressed genes (DEGs) identified in the placental tissue, hUMSCs, and hAMSCs between the convalescent and control groups, respectively. Enrichment analysis showed those DEGs were associated with immune homeostasis, antiviral activity, cell proliferation, and tissue repair. Levels of IL-6, TNF-α, total lymphocyte counts, B lymphocytes, Tregs percentages, and IFN-γ expressing CD4+ and CD8+ T cells were statistically different between two groups (p ≤ 0.05). ACE2 and TMPRSS2 expressed on the placenta were not different between the two groups (p > 0.05). CONCLUSION: Multiple changes in immune responses occurred in the placental tissue, hUMSCs, and hAMSCs after maternal recovery from COVID-19, which might imply their protective roles against COVID-19 infection.
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COVID-19 , Citocinas , Embarazo , Femenino , Humanos , Linfocitos T CD8-positivos , Estudios Transversales , Mujeres Embarazadas , Placenta , ARNRESUMEN
BACKGROUND: The innovative combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated. METHODS: In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA-ATO-containing regimens. RESULTS: Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non-ACA group (p = 0.032). With a median follow-up period of 62.0 months, worse event-free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037). CONCLUSIONS: To sum up, ACA remains the independent prognostic value for EFS, we should build risk-adapted therapeutic strategies in the long-term management of APL when such abnormalities are detected.
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Arsenicales , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Supervivencia sin Progresión , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tretinoina/uso terapéutico , Aberraciones Cromosómicas , Óxidos/uso terapéutico , Arsenicales/uso terapéutico , Resultado del TratamientoRESUMEN
Cytokine release syndrome (CRS) is an acute systemic inflammatory reaction in which hyperactivated immune cells suddenly release a large amount of cytokines, leading to exaggerated inflammatory responses, multiple organ dysfunction, and even death. Although palliative treatment strategies have significantly reduced the overall mortality, novel targeted treatment regimens with superior therapy efficacy are urgently needed. Vascular endothelial cells (ECs) are important target cells of systemic inflammation, and their destruction is considered to be the initiating event underlying many serious complications of CRS. Mesenchymal stem/stromal cells (MSCs) are multipotent cells with self-renewing differentiation capacity and immunomodulatory properties. MSC transplantation can effectively suppress the activation of immune cells, reduce the bulk release of cytokines, and repair damaged tissues and organs. Here, we review the molecular mechanisms underlying CRS-induced vascular endothelial injury and discuss potential treatments using MSCs. Preclinical studies demonstrate that MSC therapy can effectively repair endothelium damage and thus reduce the incidence and severity of ensuing CRS-induced complications. This review highlights the therapeutic role of MSCs in fighting against CRS-induced EC damage, and summarizes the possible therapeutic formulations of MSCs for improved efficacy in future clinical trials.
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Given growing interest in emulating dolphin morphology and kinematics to design high-performance underwater vehicles, the current research effort is dedicated to studying the hydrodynamics of dolphin-like oscillatory kinematics in forward propulsion. A computational fluid dynamics method is used. A realistic three-dimentional surface model of a dolphin is made with swimming kinematics reconstructed from video recording. The oscillation of the dolphin is found to enhance the attachment of the boundary layer to the posterior body, which then leads to body drag reduction. The flapping motion of the flukes is found to generate high thrust forces in both the downstroke and the upstroke, during which vortex rings are shed to produce strong thrust jets. The downstroke jets are found to be on average stronger than the upstroke jet, which then leads to net positive lift production. The flexion of the peduncle and flukes is found to be a crucial feature of dolphin-like swimming kinematics. Dolphin-inspired swimming kinematics were created by varying the flexion angle of the peduncle and flukes, which then resulted in significant performance variation. The thrust benefits and propulsive efficiency benefits are associated with a slight decrease and slight increase of the flexion of the peduncle and flukes, respectively.
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Delfines , Animales , Natación , Fenómenos Biomecánicos , Movimiento (Física) , HidrodinámicaRESUMEN
Gastric cancer tissuederived mesenchymal stem cells (GCMSCs) play a critical role in facilitating gastric cancer metastasis. Recently, circular RNAs (circRNAs) and metabolic reprogramming have been found to be extensively involved in the malignant progression of tumors, including gastric cancer. However, the biological role and potential mechanisms of GCMSCderived circRNAs in metabolic reprogramming remain elusive. Herein, the expression profiles of circRNAs and mRNAs were compared between GCMSCs and bone marrowderived MSCs (BMMSCs) using microarray analysis. circ_0024107 was identified to mediate GCMSCs to promote gastric cancer lymphatic metastasis by inducing fatty acid oxidation (FAO) metabolic reprogramming. Mechanistically, circ_0024107 served as a sponge of miR5572 and miR68555p to elicit the FAO metabolic reprograming of GCMSCs by upregulating carnitine palmitoyltransferase 1A (CPT1A). In addition, GCMSCs promoted metastasis which was dependent on the induction of FAO in gastric cancer cells mediated by circ_0024107. The circ_0024107/miR5572/68555p/CPT1A axis was deregulated in gastric cancer tissues and GCMSCs, and was associated with lymph node metastasis and the prognosis of patients with gastric cancer. Taken together, the findings of the present study suggest the crucial role of FAO metabolic reprogramming mediated by GCMSCderived circ_0024107 in synergistically promoting gastric cancer lymphatic metastasis via miR5572/68555pCPT1A signaling; this suggests that circ_0024107 may be an attractive target for gastric cancer intervention.
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MicroARNs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Metástasis Linfática/genética , ARN Circular/genética , ARN Circular/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ácidos Grasos/genética , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/fisiología , Línea Celular TumoralRESUMEN
OBJECTIVE: To investigate the value of a nomogram based on multiparametric and multiregional MR images to predict Isocitrate Dehydrogenase-1 (IDH1) gene mutations in glioma. DATA AND METHODS: The authors performed a retrospective analysis of 110 MR images of surgically confirmed pathological gliomas; 33 patients with IDH1 gene Mutation (IDH1-M) and 77 patients with Wild-type IDH1 (IDH1-W) were divided into training and validation sets in a 7:3 ratio. The clinical features were statistically analyzed using SPSS and R software. Three glioma regions (rCET, rE, rNEC) were outlined using ITK-SNAP software and projected to four conventional sequences (T1, T2, Flair, T1C) for feature extraction using AI-Kit software. The extracted features were screened using R software. A logistic regression model was established, and a nomogram was generated using the selected clinical features. Eight models were developed based on different sequences and ROIs, and Receiver Operating Characteristic (ROC) curves were used to evaluate the predictive efficacy. Decision curve analysis was performed to assess the clinical usefulness. RESULTS: Age was selected with Radscore to construct the nomogram. The Model 1 AUC values based on four sequences and three ROIs were the highest in these models, at 0.93 and 0.89, respectively. Decision curve analysis indicated that the net benefit of model 1 was higher than that of the other models for most Pt-values. CONCLUSION: A nomogram based on multiparametric and multiregional MR images can predict the mutation status of the IDH1 gene accurately.
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Glioma , Nomogramas , Humanos , Estudios Retrospectivos , Glioma/diagnóstico por imagen , Glioma/genética , Curva ROC , Mutación/genética , Imagen por Resonancia Magnética/métodos , Isocitrato Deshidrogenasa/genéticaRESUMEN
Lysosomal membrane permeabilization (LMP) has emerged as a significant component of cellular signaling pathway by which autophagy or cell death is regulated under many pathological situations including alcohol-associated liver disease (ALD). However, the mechanisms involved in the regulation of LMP in ALD remain obscure. Recently, we demonstrated that lipotoxicity serves as a causal factor to trigger LMP in hepatocytes. We identified that the apoptotic protein BAX (BCL2 associated X, apoptosis regulator) could recruit MLKL (mixed lineage kinase domain-like pseudokinase), a necroptotic executive protein, to lysosomes and induce LMP in various ALD models. Importantly, the pharmacological or genetic inhibition of BAX or MLKL protects hepatocytes from lipotoxicity-induced LMP. Thus, our study reveals a novel molecular mechanism that activation of BAX/MLKL signaling contributes to the pathogenesis of ALD through mediating lipotoxicity-induced LMP.Abbreviations: ALD: alcohol-associated liver disease; BAX: BCL2 associated X; LAMP2: lysosomal associated membrane protein 2; LMP: lysosomal membrane permeabilization; MLKL: mixed lineage kinase domain-like pseudokinase; PA: palmitic acid.
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Tumor microenvironment and metabolic reprogramming are critical for tumor metastasis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely involved in the formation of tumor microenvironment and present oncogenic phenotypes to facilitate lymph node metastasis (LNM) in response to small extracellular vesicles (sEV) released by gastric cancer (GC) cells. However, whether metabolic reprograming mediates transformation of BM-MSCs remains elusive. Herein, we revealed that the capacity of LNM-GC-sEV educating BM-MSCs was positively correlated with the LNM capacity of GC cells themselves. Fatty acid oxidation (FAO) metabolic reprogramming was indispensable for this process. Mechanistically, CD44 was identified as a critical cargo for LNM-GC-sEV enhancing FAO via ERK/PPARγ/CPT1A signaling. ATP was shown to activate STAT3 and NF-κB signaling to induce IL-8 and STC1 secretion by BM-MSCs, thereby in turn facilitating GC cells metastasis and increasing CD44 levels in GC cells and sEV to form a persistent positive feedback loop between GC cells and BM-MSCs. The critical molecules were abnormally expressed in GC tissues, sera and stroma, and correlated with the prognosis and LNM of GC patients. Together, our findings uncover the role of metabolic reprogramming mediated BM-MSCs education by LNM-GC-sEV, which presents a novel insight into the mechanism underlying LNM and provides candidate targets for GC detection and therapy.
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Probiotics and synbiotics supplementation have been shown to play potential roles in animal production. The present study aimed to evaluate the effects of dietary probiotics and synbiotics supplementation to sows during gestation and lactation and to offspring pigs (sow-offspring) on offspring pigs' growth performance and meat quality. Sixty-four healthy Bama mini-pigs were selected and randomly allocated into four groups after mating: the control, antibiotics, probiotics, and synbiotics groups. After weaning, two offspring pigs per litter were selected, and four offspring pigs from two litters were merged into one pen. The offspring pigs were fed a basal diet and the same feed additive according to their corresponding sows, representing the control group (Con group), sow-offspring antibiotics group (S-OA group), sow-offspring probiotics group (S-OP group), and sow-offspring synbiotics group (S-OS group). Eight pigs per group were euthanized and sampled at 65, 95, and 125 d old for further analyses. Our findings showed that probiotics supplementation in sow-offspring diets promoted growth and feed intake of offspring pigs during 95-125 d old. Moreover, sow-offspring diets supplemented with probiotics and synbiotics altered meat quality (meat color, pH45min, pH24h, drip loss, cooking yield, and shear force), plasma UN and AMM levels, and gene expressions associated with muscle-fiber types (MyHCI, MyHCIIa, MyHCIIx, and MyHCIIb) and muscle growth and development (Myf5, Myf6, MyoD, and MyoG). This study provides a theoretical basis for the maternal-offspring integration regulation of meat quality by dietary probiotics and synbiotics supplementation.