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BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.
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Dissecção Aórtica , Músculo Liso Vascular , Animais , Humanos , Camundongos , Dissecção Aórtica/genética , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , FosforilaçãoRESUMO
This study aims to explore the potential mechanism of Biejiajian Pills in the treatment of non-alcoholic steatohepatitis(NASH) based on lipidomics. A mouse model of NASH was induced by high-fat/high cholesterol diet, and the mice of the normal group were fed with a normal diet. The therapeutic efficacy of Biejiajian Pills against NASH was evaluated through biochemical indexes in both of serum and liver, as well as the hepatic histopathology. Lipid metabolites in the liver were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS)-based lipidomics. Then the partial least-squares discriminant analysis, t-test and receiver operating characteristic curve analysis were performed to screen the differential lipid metabolites and the main biomarkers. The proteins and genes involved in the lipid metabolism and inflammatory response were detected by Western blot and qPCR. The results demonstrated that Biejiajian Pills notably lowered the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) in the serum and the levels of triglyceride(TG) and total cholesterol(TC) in the liver tissue. In addition, Biejiajian Pills alleviated the lipid accumulation, hepatocyte ballooning, and liver fibrosis. Lipidomics revealed that Biejiajian Pills regulated the content of 11 biomarkers including phosphatidyl choline(PC), phosphatidyl ethanolamine(PE), sphingomyelin(SM), and ceramide(Cer). The results of Western blot and qPCR demonstrated that Biejiajian Pills regulated the expression of sterol regulatory element-binding protein 1(SREBP1), peroxisome proliferator-activated receptor gamma(PPARγ) and phospho-AMP-activated protein kinase(p-AMPK), and the mRNA level of fatty acid translocase 36 gene(Cd36), Pparγ, cardiolipin synthase 1 gene(Crls1), and phospholipase Cß2 gene(Plcß2). Furthermore, Biejiajian Pills displayed inhibitory effects on phospho-p38 MAPK(p-p38 MAPK) and phospho-ERK1/2(p-ERK1/2) and the mRNA levels of interleukin-6 gene(Il-6), interleukin-1ß gene(Il-1ß) and tumor necrosis factor-α gene(Tnf-α). In conclusion, Biejiajian Pills could alleviate the lipid metabolism disorders and regulate the expression of SREBP1, PPARγ, and p-AMPK and the mRNA levels of pro-inflammatory cytokines.
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Medicamentos de Ervas Chinesas , Metabolismo dos Lipídeos , Lipidômica , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Camundongos , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Humanos , Alanina Transaminase/metabolismo , Alanina Transaminase/genética , Alanina Transaminase/sangue , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/genéticaRESUMO
Background In rheumatoid arthritis (RA), fibroblast-like synoviocyte cells, which are involved in inflammation of the articular cartilage and bone, overexpress fibroblast activation protein (FAP). This is a feature that could be leveraged to improve imaging assessment of disease. Purpose To determine the performance of gallium 68 (68Ga)-labeled FAP inhibitor (FAPI) in assessing joint disease activity of RA and to compare with fluorine 18 (18F) fluorodeoxyglucose (FDG) imaging. Materials and Methods Twenty participants with RA (15 women; mean age, 55 years ± 10 [SD]) were prospectively enrolled from September 2020 to December 2021 and underwent clinical and laboratory assessment of disease activity and dual-tracer PET/CT (68Ga-FAPI and 18F-FDG) imaging. Imaging-derived variables of PET joint count (the number of joints positive for RA at PET) and PET articular index (a sum of the points of the joints using a three-point scale) were correlated to clinical and laboratory variables of disease activity. Results The combined output of both PET/CT techniques helped detect 244 affected joints, all of which showed positive results at 68Ga-FAPI PET/CT. However, fifteen of 244 (6.1%) FAPI-avid joints in six of 20 (30%) participants were not detected at 18F-FDG PET/CT. The maximum standardized uptake value of the most affected joint in each participant was higher in 68Ga-FAPI than in 18F-FDG PET/CT (9.54 ± 4.92 vs 5.85 ± 2.81, respectively; P = .001). The maximum standardized uptake values of the joints at both 68Ga-FAPI and 18F-FDG PET/CT were positively correlated with laboratory evaluation of C-reactive protein levels (r = 0.49 [P = .03] and 0.54 [P = .01], respectively). The PET joint count and PET articular index scores at 68Ga-FAPI PET/CT were also positively correlated with most clinical disease activity variables and radiographic progression of joint damage (P < .05). Conclusion In participants with rheumatoid arthritis who underwent gallium 68 fibroblast activation protein inhibitor PET/CT, the extent of joint involvement correlated with clinical and laboratory variables of disease activity and showed a greater amount and degree of affected joints than at fluorine 18 fluorodeoxyglucose PET/CT. Clinical trial registration no. NCT04514614 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Williams and Ahlman in this issue.
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Artrite Reumatoide , Quinolinas , Humanos , Feminino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Fluordesoxiglucose F18 , Radioisótopos de GálioRESUMO
OBJECTIVES: To explore the survival and risk factors for cancer occurrence after SLE (SLE-CA). METHODS: Patients with cancer diagnosed after SLE in Peking Union Medical College Hospital between January 2006 and September 2017 were recruited and followed. Data regarding medication-related and disease-related factors and survival were collected and compared with matched controls. Logistic regressions were applied to identify risk factors. The Kaplan-Meier method with a log-rank test was performed to evaluate survival. RESULTS: Forty-five SLE-CA patients and 128 controls were included, with the most common cancer site being the female genital system. SLE-CA patients were exposed to a higher cumulative dosage of CYC, with less mucocutaneous and haematologic involvement and higher anti-dsDNA positivity. At the time of cancer diagnosis, SLE-CA patients had lower SLEDAI 2000 (SLEDAI-2K), tended to achieve Definitions of Remission in SLE remission and minimal disease activity, but had higher SLICC/ACR Damage Index. Multivariable analysis identified high dosage of CYC [odds ratio (OR) 1.027, 95% CI 1.008, 1.046; P = 0.005] and low SLEDAI-2K at cancer diagnosis (OR 0.756, 95% CI 0.579, 0.986; P = 0.039) as risk factors. Mucocutaneous (OR 0.330, 95% CI 0.110, 0.991; P = 0.048) and haematologic involvement (OR 0.304, 95% CI 0.103, 0.902; P = 0.032) were negatively associated with cancer occurrence after SLE. The 5- and 10-year survival rates in SLE-CA patients were 95.2% and 92.1%, respectively. No significant difference of survival was observed between SLE-CA patients and controls (P = 0.177). CONCLUSION: High dosage of CYC and disease-related factors (low SLEDAI-2K, less mucocutaneous and haematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.
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Lúpus Eritematoso Sistêmico , Neoplasias , Humanos , Feminino , Modelos Logísticos , Causalidade , Neoplasias/epidemiologia , Neoplasias/etiologia , Fatores de Risco , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
The thermal transport properties of five-fold twinned (5FT) germanium-silicon (Ge-Si) heteronanowires (h-NWs) with varying cross-sectional areas, germanium (Ge) domain ratios and heterostructural patterns are investigated using homogeneous nonequilibrium molecular dynamics (HNEMD) simulations. The results demonstrate a distinctive behavior in the thermal conductivity (κ) of 5FT-NWs, characterized by a "flipped" trend at a critical cross-sectional area. This behavior is attributed to the hydrodynamic phonon flow, arising from the normal three-phonon scattering process in the low-frequency region. In addition, the composition ratio of 5FT-NWs has a significant impact on reducing the κ of 5FT-NWs and suppressing the hydrodynamic effect. Intriguingly, as the homogeneous element domains are separated, stronger phonon hydrodynamic flows are observed in comparison to the adjacent homogeneous element domains. By analyzing various phonon properties, including phonon dispersion, three-phonon scattering rate, and phonon mean free path, critical insights into the origin of the differential κ in different 5FT-NW structures are provided. The findings deepen the understanding of the thermal transport properties of nanomaterials and hold implications for the design and development of nanoelectronics and thermoelectric devices.
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Monoclonal gammopathy (MG) is common in autoimmune diseases (AID), but its progression to hematological neoplasm (HN) and the predictors for the progression are unclear. Patients diagnosed with AID and MG in our hospital from January 2010 to June 2017 were reviewed and followed. Cox proportional hazard regression analysis was applied. Of 160 patients with AID and MG, the most common AID was primary SjÓ§gren's syndrome (37, 23.1%). Thirty-nine (24.4%) patients developed HN during follow-up (median: 3.7 years, IQR: 0.3-5.5 years). The cumulative probability of HN progression was 21.8% at one year and 29.3% at six years after the finding of MG. High levels of monoclonal protein (> 14.35% of total serum protein) (HR 11.71, 95%CI: 5.37-25.54), significant weight loss (HR 6.24, 95%CI: 2.87-13.59), and reduction of other types of immunoglobulins (HR 3.02, 95%CI: 1.40-6.48) are independent risk indicators for HN whose presence warrants vigorous follow-up and monitoring.
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Doenças Autoimunes/complicações , Neoplasias Hematológicas/etiologia , Paraproteinemias/complicações , Adulto , Idoso , Doenças Autoimunes/tratamento farmacológico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/análise , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Atenção Terciária à SaúdeRESUMO
BACKGROUND: The differential diagnosis of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging in clinical practice. We aimed to evaluate the diagnostic accuracy of the IFN-γ/TNF-α FluoroSpot assay for differentiating ATB from LTBI. METHODS: We conducted a pilot study of case-control design, using the FluoroSpot assay to simultaneously detect IFN-γ and TNF-α secretion at the single-cell level. The frequencies of antigen-specific single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells were detected. The optimal cutoffs value of frequencies for differentiating ATB from LTBI were determined according to receiver operating characteristic curve analysis. The sensitivity, specificity, predictive values (PV) and likelihood ratios (LR) of the FluoroSpot assay were calculated. RESULTS: Thirty patients diagnosed microbiologically with ATB, 36 healthcare workers with LTBI and 36 healthy controls were enrolled. After stimulated by ESAT-6 or CFP-10 peptides, the median frequencies of single TNF-α-, total TNF-α-, single IFN-γ-, total IFN-γ- and dual IFN-γ/TNF-α-secreting T cells in ATB patients were all significantly higher than those in LTBI and HC groups (P < 0.01). The frequencies of total IFN-γ-secreting T cells detected by FluoroSpot assay correlated significantly with those of T-SPOT.TB (r = 0.910 for ESAT-6, P < 0.001, r = 0.845 for CFP-10, P < 0.001). After stimulated by ESAT-6 peptides, with total TNF-α-secreting T cells frequencies at a cut off value of 21 iSFCs/250,000 PBMCs, the sensitivity, specificity, PLR, NLR, PPV, NPV of IFN-γ/TNF-α FluoroSpot assay in differentiating ATB from LTBI were 96.7% (95%CI, 82.8-99.9%), 94.3% (95%CI, 80.8-99.3%), 16.92 (95%CI, 4.40-65.08), 0.04 (95%CI, 0.01-0.24), 93.6% (95%CI,78.6-99.2%) and 97.1% (95%CI, 84.7-99.9%), respectively. With the frequencies of total TNF-α- and total IFN-γ-secreting T cells stimulated by ESAT-6 peptides combined, the specificity was increased to 97.1%, and the positive likelihood ratio to 31.5. The combination with CFP-10 might not improve the diagnostic accuracy of the ESAT-6 for differentiating ATB from LTBI. CONCLUSIONS: IFN-γ/TNF-α FluoroSpot assay might have potential to help differentiate ATB from LTBI, but the findings need to be further verified by cross-sectional or prospective cohort studies.
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Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/sangue , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Diagnóstico Diferencial , Humanos , Interferon gama/sangue , Tuberculose Latente/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tuberculose/imunologia , Adulto JovemRESUMO
The construction of heterojunction is considered as a promising approach to designing highly effective visible-light driven photocatalysts. In this research, the AgI/Sb2O3 heterojunction photocatalyst was synthesized by a simple in situ deposition-precipitation procedure, which was supported by XPS results. Among the prepared samples, the 60% AgI/Sb2O3 samples exhibited the best ARG degradation ratio (98.3%) in 1 h under visible light irradiation, while the pure Sb2O3 and AgI exhibited almost none photocatalytic performance. The trapping experiments and EPR proved that the photo-generated ·O2- and ·OH made major contributions to the photocatalytic degradation of ARG by the 60% AgI/Sb2O3 samples. The enhanced photocatalytic performance of AgI/Sb2O3 heterojunction photocatalysts was ascribed to that the e- produced in the CB of AgI would be transferred to the empty CB of Sb2O3, which could effectively promote separation of photo-induced carries. More importantly, the transfer of electrons from AgI to Sb2O3 would be in favor of restraining the reduction of Ag+ to Ag0 resulting in the good stability of heterojunction photocatalysts. The heterojunction photocatalyst provided in this work might be a prospective candidate for decontamination of water.
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Poluentes Ambientais , Catálise , Luz , Estudos Prospectivos , ÁguaAssuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Proteína FUS de Ligação a RNA , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Adulto , Proteínas de Fusão Oncogênica/genética , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Proteína FUS de Ligação a RNA/genética , Idoso , Proteínas RepressorasRESUMO
Objective The aim of this study was to evaluate the diagnostic performance of T-SPOT.TB for tuberculous lymphadenitis. Methods Suspected tuberculous lymphadenitis patients between September 2010 and September 2018 who had both peripheral blood T-SPOT.TB test and lymph node biopsy were retrospectively enrolled in this study. The cutoff value of T-SPOT.TB test for peripheral blood was set as 24 spot forming cell (SFC)/10 6 periphreral blood monocyte cell (PBMC) according to the instruction of testing kits. The gold standard for diagnosis of TBL was the combination of microbiology results, histopathology results and patient's response to anti-TB treatment. Diagnostic efficacy of T-SPOT.TB was evaluated, including sensitivity, specificity, accuracy, predictive values, and likelihood ratio. Results Among 91 patients who met the inclusion criteria, we excluded 8 cases with incomplete clinical information and 6 cases who lost to follow-up. According to the gold standard, there were 37 cases of true TBL (9 confirmed TBL and 28 probable TBL), 30 cases of non-TBL, and 10 cases of clinically indeterminate diagnosis who were excluded from the final analyses. The T-SPOT.TB tests yielded 43 cases of positive response and 24 cases of negative response. The sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) of peripheral blood T-SPOT.TB for diagnosing TBL were 89.2%, 66.7%, 79.1%, 76.7%, 83.3%, 2.68 and 0.16, respectively. The number of SFCs of T-SPOT.TB in TBL patients [432(134-1264)/10 6 PBMCs] was higher than that in non-TBL patients [0 (0-30) /10 6PBMCs] with a significant difference (Z=-5.306, P <0.001).Conclusion T-SPOT.TB is a rapid and simple diagnostic test for TBL with a high sensitivity and negative predictive value.
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Testes de Liberação de Interferon-gama , Tuberculose dos Linfonodos/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/fisiologia , Linfócitos T/imunologia , Tuberculose dos Linfonodos/sangue , Adulto JovemRESUMO
Carbon catabolite repression (CCR) is a highly conserved mechanism that regulates carbon source utilization in Streptomyces. CCR has a negative impact on secondary metabolite fermentation, both in industrial and research settings. In this study, CCR was observed in the daunorubicin (DNR)-producing strain Streptomyces coeruleorubidus DM, which was cultivated in high concentration of carbohydrates. Unexpectedly, DM exhibited a high ability for anthraquinone glucuronidation biotransformation under CCR conditions with a maximum bioconversion rate of 95% achieved at pH 6, 30°C for 24 h. The co-utilization of glucose and sucrose resulted in the highest biotransformation rate compared to other carbon source combinations. Three novel anthraquinone glucuronides were obtained, with purpurin-O-glucuronide showing significantly improved water solubility, antioxidant activity, and antibacterial bioactivity. Comparative transcript analysis revealed that glucose and sucrose utilization were significantly upregulated as DM cultivated under CCR condition, which strongly enhance the biosynthetic pathway of the precursors Uridine diphosphate glucuronic acid (UDPGA). Meanwhile, the carbon metabolic flux has significantly enhanced the fatty acid biosynthesis, the exhaust of acetyl coenzyme A may lead to the complete repression of the biosynthesis of DNR, Additionally, the efflux transporter genes were simultaneously downregulated, which may contribute to the anthraquinones intracellular glucuronidation. Overall, our findings demonstrate that utilizing CCR can be a valuable strategy for enhancing the biotransformation efficiency of anthraquinone O-glucuronides by DM. This approach has the potential to improve the bioavailability and therapeutic potential of these compounds, opening up new possibilities for their pharmaceutical applications.
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CoMnHCF is utilized in aqueous sodium/zinc mixed ion batteries and exhibits a high reversible capacity with good rate and cycle performances. At 0.05 A g-1 current density, the CoMnHCF can deliver a specific capacity for 180.4 mA h g-1, and have 99.3% capacity retention after 300 cycles at 0.3 A g-1. Such high reversible capacity profits from Mn vacancies that generate in situ during the first cycle, which provides more active sites for Zn storage. The de-intercalation of Na+ further elevates this good electrochemical performance. Co atoms in the framework are not only involved in the redox reactions, but help to support the structure, thus achieving better cycle stabilities.
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BACKGROUND: The identification of biomarkers predicting the treatment response of rheumatoid arthritis (RA) is important. [68 Ga]Ga-FAPI-04 showed markedly increased uptake in the joints of patients with RA. The purpose of this study is to investigate whether [68 Ga]Ga-FAPI-04 PET/CT can be a predictor of treatment response in RA. RESULTS: Nineteen patients diagnosed with RA in the prospective cohort study were finally enrolled. Both total synovitis uptake (TSU) and metabolic synovitis volume (MSV) in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT of the responders were significantly higher than those in non-responders according to Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) response criteria at 3-months' follow-up (P < 0.05). The PET joint count (PJC) detected in [68 Ga]Ga-FAPI-04 and [18F]FDG PET/CT were also significantly higher in CDAI responders than non-responders (P = 0.016 and 0.045, respectively). The clinical characteristics of disease activity at baseline did not show significant difference between the responders and non-responders, except CRP (P = 0.035 and 0.033 in CDAI and SDAI response criteria, respectively). The baseline PJCFAPI, TSUFAPI and MSVFAPI > cutoff values in [68 Ga]Ga-FAPI-04 PET/CT successfully discriminated CDAI and SDAI responders and non-responders at 3-months' follow-up. CONCLUSION: [68 Ga]Ga-FAPI-04 uptake at baseline were significantly higher in early responders than those in non-responders. Trial registration ClinicalTrials. NCT04514614. Registered 13 August 2020, https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S000A4PN&selectaction=Edit&uid=U0001JRW&ts=2&cx=-x9t7cp.
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The arcuate nucleus kisspeptin (ARNKISS) neurons represent the GnRH pulse generator that likely drives pulsatile gonadotropin secretion in all mammals. Using an improved GCaMP fiber photometry system enabling long-term continuous recordings, we aimed to establish a definitive profile of ARNKISS neuronal activity across the murine estrous cycle. As noted previously, a substantial reduction in the frequency of ARNKISS neuron synchronization events (SEs) occurs on late proestrus and extends into estrus. The SE amplitude remains constant throughout the cycle. During metestrus, we unexpectedly detected many multipeak SEs where many SEs occurred rapidly, within 160â seconds of each other. By applying a machine learning-based, k-means clustering analysis, we were further able to detect substantial within-stage variability in the patterns of pulse generator activity. Estrous cycle-dependent changes in SE activity occurred around the time of lights on and off. We also find that a mild stressor such as vaginal lavage reduces ARNKISS neuron SE frequency for up to 3â hours. These observations provide a comprehensive account of ARNKISS neuron activity across the estrous cycle, highlight a new pattern of multipeak SE activity, and introduce a new k-means clustering approach for analyzing ARNKISS neuron population behavior.
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Hormônio Liberador de Gonadotropina , Hormônio Luteinizante , Animais , Feminino , Camundongos , Núcleo Arqueado do Hipotálamo/metabolismo , Ciclo Estral/fisiologia , Hormônio Liberador de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Neurônios/metabolismoRESUMO
PURPOSE: In VATS surgery, precise preoperative localization is particularly crucial when dealing with small-diameter pulmonary nodules located deep within the lung parenchyma. The purpose of this study was to compare the efficacy and safety of laser guidance and freehand hook-wire for CT-guided preoperative localization of pulmonary nodules. METHODS: This retrospective study was conducted on 164 patients who received either laser guidance or freehand hook-wire localization prior to Uni-port VATS from September 1st, 2022 to September 30th, 2023 at The First Affiliated Hospital of Soochow University. Patients were divided into laser guidance group and freehand group based on which technology was used. Preoperative localization data from all patients were compiled. The localization success and complication rates associated with the two groups were compared. The risk factors for common complications were analyzed. RESULTS: The average time of the localization duration in the laser guidance group was shorter than the freehand group (p<0.001), and the average CT scan times in the laser guidance group was less than that in the freehand group (p<0.001). The hook-wire was closer to the nodule in the laser guidance group (p<0.001). After the localization of pulmonary nodules, a CT scan showed 14 cases of minor pneumothorax (22.58%) in the laser guidance group and 21 cases (20.59%) in the freehand group, indicating no statistical difference between the two groups (p=0.763). CT scans in the laser guidance group showed pulmonary minor hemorrhage in 8 cases (12.90%) and 6 cases (5.88%) in the freehand group, indicating no statistically significant difference between the two groups (p=0.119). Three patients (4.84%) in the laser guidance group and six patients (5.88%) in the freehand group had hook-wire dislodgement, showing no statistical difference between the two groups (p=0.776). CONCLUSION: The laser guidance localization method possessed a greater precision and less localization duration and CT scan times compared to the freehand method. However, laser guidance group and freehand group do not differ in the appearance of complications such as pulmonary hemorrhage, pneumothorax and hook-wire dislodgement.
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Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Pneumotórax , Nódulo Pulmonar Solitário , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Pneumotórax/cirurgia , Estudos Retrospectivos , Nódulo Pulmonar Solitário/cirurgia , Cirurgia Torácica Vídeoassistida/métodos , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/cirurgia , Tomografia Computadorizada por Raios X/métodos , HemorragiaRESUMO
Natural gas hydrates (NGHs) hold immense potential as a future energy resource and for sustainable applications such as gas capture and storage. Due to the challenging formation conditions, however, their mechanical properties remain poorly understood. Herein, the mechanical characteristics of tetrahydrofuran (THF) hydrates, a proxy for methane hydrates, were investigated at different ice contents, strain rates, and temperatures using uniaxial compressive experiments. The results unveil a distinct behavior in the peak strength of THF hydrates with a varying ice content, strain rate and temperature, exhibiting an increase as the strain rate and temperature decrease, in contrast to the peak strength-strain rate relationship observed in polycrystalline ice. Based on the experimental data, four machine learning (ML) models including extreme gradient boosting (XGboost), multilayer perceptron (MLP), gradient boosting decision tree (GBDT) and decision tree (DT) were developed to predict the peak strength. The XGboost model demonstrates superior predictive performance, emphasizing the significant influence of ice content and temperature on the peak strength of hydrates. Furthermore, molecular dynamics (MD) simulations were employed to gain insights into the dissociation and formation processes of clathrate cages, as well as phase transitions and amorphization occurring at grain boundaries (GBs) involving diverse unconventional clathrate cages, including 51265, 4151062, 4151064, 425861 and 425862, with 425861 and 425862 cages being predominant. This study enhances our understanding of the mechanical properties and deformation mechanisms of hydrates and provides a ML-based predictive framework for estimating the compressive strength of hydrates under diverse coupling conditions. The findings have significant implications for stability assessments of NGHs and the exploitation of NGH resources.
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OBJECTIVE: To investigate the treatment efficacy and safety of baricitinib in patients with refractory Takayasu arteritis (TAK). METHODS: We performed a prospective cohort study in which baricitinib 4 mg daily was prescribed to patients with refractory TAK, combined with oral glucocorticoids (GCs). RESULTS: 10 patients with refractory TAK were enrolled with a median age of 28 (IQR=22-37) years, median disease duration of 50 (IQR=24-65) months. The median dose of GCs was 10 (IQR=8.1-22.5) mg prednisone or equivalence dosage at baseline. At 6 months of baricitinib treatment, 6/10 (60%) patients had an overall treatment response. During an average follow-up of 15.3 (range 4-31) months, 4/10 (40%) patients maintained overall treatment response. 8/10 (80%) patients tapered or maintained the same dose of GCs with no change of the combined classical synthetic disease-modifying antirheumatic drugs. Two patients discontinued GCs at 18 and 24 months and were in continuous remission till the end of the study. One patient withdrew baricitinib due to liver dysfunction. CONCLUSION: Baricitinib 4 mg daily is effective for refractory TAK and is well tolerated.
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Azetidinas , Purinas , Pirazóis , Sulfonamidas , Arterite de Takayasu , Humanos , Lactente , Pré-Escolar , Estudos Prospectivos , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/tratamento farmacológico , Centros de Atenção Terciária , Azetidinas/efeitos adversos , Glucocorticoides/uso terapêuticoRESUMO
Vitamin A (VA) is a micronutrient essential for the physiology of many organisms, but its role in longevity and age-related diseases remains unclear. In this work, we used Caenorhabditis elegans to study the impact of various bioactive compounds on lifespan. We demonstrate that VA extends lifespan and reduces lipofuscin and fat accumulation while increasing resistance to heat and oxidative stress. This resistance can be attributed to high levels of detoxifying enzymes called glutathione S-transferases, induced by the transcription factor skinhead-1 (SKN-1). Notably, VA upregulated the transcript levels of skn-1 or its mammalian ortholog NRF2 in both C. elegans, human cells, and liver tissues of mice. Moreover, the loss-of-function genetic models demonstrated a critical involvement of the SKN-1 pathway in longevity extension by VA. Our study thus provides novel insights into the molecular mechanism of anti-aging and anti-oxidative effects of VA, suggesting that this micronutrient could be used for the prevention and/or treatment of age-related disorders.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Humanos , Camundongos , Caenorhabditis elegans/metabolismo , Longevidade/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Vitamina A/farmacologia , Vitamina A/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Regulação para Cima , Proteínas de Caenorhabditis elegans/metabolismo , Estresse Oxidativo , Mamíferos/metabolismo , Micronutrientes/metabolismo , Micronutrientes/farmacologiaRESUMO
Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.
Assuntos
Artrite Reumatoide , Inibidores de Checkpoint Imunológico , Humanos , Linfócitos T CD8-Positivos/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Líquido Sinovial , Interleucina-1beta/genética , Interleucina-1beta/metabolismoRESUMO
Using molecular dynamics simulations, we investigated the effect of external electric field on ice formation with the present of a substrate surface. It turns out that the electric field can affect the ice formation on substrate surface by altering the dipole orientation of interfacial water molecules (IWs): a crossover from inhibiting to promoting ice formation with the increase of electric field strength. According to the influence of the electric field on ice formation, the electric field strength range of 0.0 V nm-1-7.0 V nm-1can be divided into three regions. In the region I and region III, there are both ice formation on the substrate surface. While, the behavior of IWs in the region I and region III are distinguished, including the arrangements of oxygen atoms and the dipole orientation distribution. In region II, ice formation does not occur in the system within 5 × 200 ns simulations. The IWs show a disorder structure, preventing the ice formation process on substrate. The interfacial water molecular orientation distribution and two-dimensional free energy landscape reveals that the electric field can alter the dipole orientation of the interfacial water and lead a free energy barrier, making the ice formation process harder. Our result demonstrates the external electric field can regulate the behavior of IWs, and further affect the ice formation process. The external electric field act as a crystallization switch of ice formation on substrate, shedding light into the studies on the control of ice crystallization.