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Sepsis-induced acute kidney injury (S-AKI) is highly lethal, and effective drugs for treatment are scarce. Previously, we reported the robust therapeutic efficacy of fibroblastic reticular cells (FRCs) in sepsis. Here, we demonstrate the ability of FRC-derived exosomes (FRC-Exos) to improve C57BL/6 mouse kidney function following cecal ligation and puncture-induced sepsis. In vivo imaging confirmed that FRC-Exos homed to injured kidneys. RNA-Seq analysis of FRC-Exo-treated primary kidney tubular cells (PKTCs) revealed that FRC-Exos influenced PKTC fate in the presence of lipopolysaccharide (LPS). FRC-Exos promoted kinase PINK1-dependent mitophagy and inhibited NLRP3 inflammasome activation in LPS-stimulated PKTCs. To dissect the mechanism underlying the protective role of Exos in S-AKI, we examined the proteins within Exos by mass spectrometry and found that CD5L was the most upregulated protein in FRC-Exos compared to macrophage-derived Exos. Recombinant CD5L treatment in vitro attenuated kidney cell swelling and surface bubble formation after LPS stimulation. FRCs were infected with a CD5L lentivirus to increase CD5L levels in FRC-Exos, which were then modified in vitro with the kidney tubular cell targeting peptide LTH, a peptide that binds to the biomarker protein kidney injury molecule-1 expressed on injured tubule cells, to enhance binding specificity. Compared with an equivalent dose of recombinant CD5L, the modified CD5L-enriched FRC-Exos selectively bound PKTCs, promoted kinase PINK-ubiquitin ligase Parkin-mediated mitophagy, inhibiting pyroptosis and improved kidney function by hindering NLRP3 inflammasome activation, thereby improving the sepsis survival rate. Thus, strategies to modify FRC-Exos could be a new avenue in developing therapeutics against kidney injury.
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Injúria Renal Aguda , Exossomos , Sepse , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Exossomos/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Injúria Renal Aguda/metabolismo , Sepse/complicações , Sepse/metabolismoRESUMO
Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.
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We demonstrate the emergence of nonreciprocal superradiant phase transitions and novel multicriticality in a cavity quantum electrodynamics system, where a two-level atom interacts with two counterpropagating modes of a whispering-gallery-mode microcavity. The cavity rotates at a certain angular velocity and is directionally squeezed by a unidirectional parametric pumping χ^{(2)} nonlinearity. The combination of cavity rotation and directional squeezing leads to nonreciprocal first- and second-order superradiant phase transitions. These transitions do not require ultrastrong atom-field couplings and can be easily controlled by the external pump field. Through a full quantum description of the system Hamiltonian, we identify two types of multicritical points in the phase diagram, both of which exhibit controllable nonreciprocity. These results open a new door for all-optical manipulation of superradiant transitions and multicritical behaviors in light-matter systems, with potential applications in engineering various integrated nonreciprocal quantum devices.
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The key to enhancing water electrolysis efficiency lies in selecting highly efficient catalysts. Currently, high-entropy alloys (HEAs) are utilized in electrocatalysis applications owing to their diverse elemental composition, disordered elemental distribution, and the high solubility of each element, endowing them with excellent catalytic performance. The experiments were conducted using isoatomic FeNiCrMo HEA as a precursor, with a high-activity three-dimensional nanoporous structure rapidly synthesized via electrochemical one-step dealloying in a choline chloride-thiourea (ChCl-TU) deep eutectic solvent (DES). The results indicate that the dealloyed Fe20Co20Ni20Cr20Mo20 HEA mainly consists of two phases: face-centered cubic and σ phases. The imbalance in the distribution of elements in these two phases leads to quite different corrosion speeds with the FCC phase being preferentially corroded. Furthermore, synergistic electron coupling between surface atoms in the three-dimensional nanoporous structure strengthens the behavior of the oxygen evolution reaction (OER). At a current density of 40 mA cm-2, the overpotential after dealloying decreased to 370 mV, demonstrating excellent stability. The technique demonstrated in this work provides a novel approach to improve the catalytic activity of OER.
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A Ru-containing complex shows good catalytic performance toward the hydrogenation of levulinic acid (LA) to γ-valerolactone (GVL) with the assistance of organic base ligands (OBLs) and CO2. Herein, we report the competitive mechanisms for the hydrogenation of LA to GVL, 4-oxopentanal (OT), and 2-methyltetrahydro-2,5-furandiol (MFD) with HCOOH or H2 as the H source catalyzed by RuCl3 in aqueous solution at the M06/def2-TZVP, 6-311++G(d,p) theoretical level. Kinetically, the hydrodehydration of LA to GVL is predominant, with OT and MFD as side products. With HCOOH as the H source, initially, the OBL (triethylamine, pyridine, or triphenylphosphine) is responsible for capturing H+ from HCOOH, leading to HCOO- and [HL]+. Next, the Ru3+ site is in charge of sieving H- from HCOO-, yielding [RuH]2+ hydride and CO2. Alternatively, with H2 as the H source, the OBL stimulates the heterolysis of H-H bond with the aid of Ru3+ active species, producing [RuH]2+ and [HL]+. Toward the [RuH]2+ formation, H2 as the H source exhibits higher activity than HCOOH as the H source in the presence of an OBL. Thereafter, H- in [RuH]2+ gets transferred to the unsaturated C site of ketone carbonyl in LA. Afterwards, the Ru3+ active species is capable of cleaving the C-OH bond in 4-hydroxyvaleric acid, yielding [RuOH]2+ hydroxide and GVL. Subsequently, CO2 promotes Ru-OH bond cleavage in [RuOH]2+, forming HCO3- and regenerating the Ru3+-active species owing to its Lewis acidity. Lastly, between the resultant HCO3- and [HL]+, a neutralization reaction occurs, generating H2O, CO2, and OBLs. Thus, the present study provides insights into the promotive roles of additives such as CO2 and OBLs in Ru-catalyzed hydrogenation.
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For the conversion of fructose/methylglucoside (MG) into both methyl formate (MF) and methyl levulinate (MLev), the C-source of formate [HCOO]- remains unclear at the molecular level. Herein, reaction mechanisms catalyzed by [CH3OH2]+ in a methanol solution were theoretically investigated at the PBE0/6-311++G(d,p) level. For the conversion of fructose into MF and MLev, the formate [HCOO]- comes from the C1-atom of fructose, in which the rate-determining step lies in the reaction of 5-hydroxymethylfurfural (HMF) with CH3OH to yield MF and MLev. The reaction of fructose with CH3OH kinetically tends to generate HMF intermediates rather than yield (MF + MLev). When MG is dissolved in a methanol solution, its O2, O3, and O4 atoms are closer to the first layer of the solvent than O1, O5, and O6 atoms. For the dehydration of MG with methanol into MF and MLev, the formate [HCOO]- stems from the dominant C1- and secondary C3-atoms of MG. Kinetically, MG is ready to yield (MF + MLev), whereas fructose can induce the reaction to remain at the HMF intermediate, inhibiting the further conversion of HMF with CH3OH into MF and MLev. If MG isomerizes into fructose, the reaction will be more preferable for yielding HMF rather than (MF + MLev).
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Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.
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Dislipidemias , Transdução de Sinais , Humanos , Olanzapina/farmacologia , Estudos de Casos e Controles , Estresse do Retículo Endoplasmático , Dislipidemias/induzido quimicamente , Lipídeos , eIF-2 Quinase/metabolismo , ApoptoseRESUMO
The establishment of the Clean Development Mechanism (CDM) has greatly improved China's carbon emission trading system. However, due to the unbalanced development of CDM in China, the effects and mechanism of CDM on reducing pollution and carbon are still unclear. In order to explore the effects and mechanism of CDM on the synergistic effects of pollution mitigation and carbon reduction, we first set up a theoretical analysis framework. Utilizing panel data from 254 prefecture-level cities across China spanning from 2004 to 2021, we employ a synergy degree model of composite system to evaluate the synergistic effects of pollution mitigation and carbon reduction. By treating CDM as a quasi-natural experimental research subject, we construct a multi-period difference-in-difference model to assess the CDM projects' effects. Our findings indicate a positive association between CDM projects and the synergistic effects of pollution mitigation and carbon reduction. Heterogeneity analysis reveals that CDM projects located in the western region, areas with lower levels of economic development, non-resource cities, non-old industrial bases, and projects with Certified Emission Reductions issued exhibit the most pronounced synergistic effects. Specially, dynamic policy effect analysis shows that only non-resource cities and non-old industrial bases exhibit enhanced policy implementation regarding CDM. Mechanism analysis demonstrates that CDM primarily enhances synergistic effects through improved energy efficiency, technological innovation and energy transition. These findings enrich empirical investigations concerning market-driven emission reduction policy in China, shedding light on pivotal pathways for synergistic control of pollution mitigation and carbon reduction and offering valuable policy insights for comprehensive economic and social green transformation in China.
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BACKGROUND: The lack of transparency is a prevalent issue among the current machine-learning (ML) algorithms utilized for predicting mortality risk. Herein, we aimed to improve transparency by utilizing the latest ML explicable technology, SHapley Additive exPlanation (SHAP), to develop a predictive model for critically ill patients. METHODS: We extracted data from the Medical Information Mart for Intensive Care IV database, encompassing all intensive care unit admissions. We employed nine different methods to develop the models. The most accurate model, with the highest area under the receiver operating characteristic curve, was selected as the optimal model. Additionally, we used SHAP to explain the workings of the ML model. RESULTS: The study included 21 395 critically ill patients, with a median age of 68 years (interquartile range, 56-79 years), and most patients were male (56.9%). The cohort was randomly split into a training set (N = 16 046) and a validation set (N = 5349). Among the nine models developed, the Random Forest model had the highest accuracy (87.62%) and the best area under the receiver operating characteristic curve value (0.89). The SHAP summary analysis showed that Glasgow Coma Scale, urine output, and blood urea nitrogen were the top three risk factors for outcome prediction. Furthermore, SHAP dependency analysis and SHAP force analysis were used to interpret the Random Forest model at the factor level and individual level, respectively. CONCLUSION: A transparent ML model for predicting outcomes in critically ill patients using SHAP methodology is feasible and effective. SHAP values significantly improve the explainability of ML models.
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Inteligência Artificial , Estado Terminal , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Estado Terminal/terapia , Unidades de Terapia Intensiva , Algoritmos , Cuidados CríticosRESUMO
Remolding the reactivity of metal active sites is critical to facilitate renewable electricity-powered water electrolysis. Doping heteroatoms, such as Se, into a metal crystal lattice has been considered an effective approach, yet usually suffers from loss of functional heteroatoms during harsh electrocatalytic conditions, thus leading to the gradual inactivation of the catalysts. Here, we report a new heteroatom-containing molecule-enhanced strategy toward sustainable oxygen evolution improvement. An organoselenium ligand, bis(3,5-dimethyl-1H-pyrazol-4-yl)selenide containing robust C-Se-C covalent bonds equipped in the precatalyst of ultrathin metal-organic nanosheets Co-SeMON, is revealed to significantly enhance the catalytic mass activity of the cobalt site by 25 times, as well as extend the catalyst operation time in alkaline conditions by 1 or 2 orders of magnitude compared with these reported metal selenides. A combination of various in situ/ex situ spectroscopic techniques, ab initio molecular dynamics, and density functional theory calculations unveiled the organoselenium intensified mechanism, in which the nonclassical bonding of Se to O-containing intermediates endows adsorption-energy regulation beyond the conventional scaling relationship. Our results showcase the great potential of molecule-enhanced catalysts for highly efficient and economical water oxidation.
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Cobalto , Metais , Adsorção , Oxigênio , ÁguaRESUMO
OBJECTIVES: This observational study was conducted to investigate capillary refill time (CRT) during the early phase of ICU admission in relationship with microvascular flow alteration and outcome in critically ill patients. DESIGN: Prospective, observational, pilot study. SETTING: ICU in a university hospital. PATIENTS: Two hundred eighty-two critically ill adult patients admitted to the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients underwent simultaneous measurements by CRT and sidestream dark field imaging within 24 hours of ICU admission. Other clinical data such as demographic characteristics, hemodynamics, laboratory values, treatment, and physiologic parameters were also included simultaneously. Microcirculatory measurements were performed at 10.2 ± 5.7 hours after ICU admission. Of the 282 included patients, 106 (37.6%) were female, the median (interquartile range) age was 63 years (53-74 yr), and the median Sequential Organ Failure Assessment (SOFA) score was 5 (2-7). The primary finding was the association between CRT and simultaneous the condition of peripheral circulation (microvascular flow index [MFI]: r = -0.4430, p < 0.001; proportion of perfused vessels: r = -0.3708, p < 0.001; heterogeneity index: r = 0.4378, p < 0.001; perfused vessel density: r = -0.1835, p = 0.0020; except total vessel density: p = 0.9641; and De Backer score: p = 0.5202) in critically ill patients. In addition, this relationship was also maintained in subgroups. Microcirculatory flow abnormalities, 28-day mortality, and SOFA score appeared to be more severe for increasing CRT. In a multivariable analysis, prolonged CRT was independently associated with microvascular flow abnormalities (MFI < 2.6; odds ratio [OR], 1.608; 95% CI, 2.1-10.2; p < 0.001). Similarly, multivariable analysis identified CRT as an independent predictor of 28-day mortality (OR, 1.296; 95% CI, 1.078-1.558; p = 0.006). CONCLUSIONS: In our ICU population, a single-spot prolonged CRT was independently associated with abnormal microcirculation and increased mortality.
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Estado Terminal , Soalho Bucal , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Microcirculação/fisiologia , Estudos Prospectivos , Estado Terminal/terapia , Projetos Piloto , Soalho Bucal/irrigação sanguínea , Hemodinâmica/fisiologia , Unidades de Terapia IntensivaRESUMO
BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.
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Doença de Charcot-Marie-Tooth , Neuropatia Hereditária Motora e Sensorial , Humanos , Atrofia Muscular , Diferenciação Celular , Fibras Musculares EsqueléticasRESUMO
The most commonly reported side effect of azithromycin is gastrointestinal (GI) disorders, and the main acid degradation product is 3'-Decladinosyl azithromycin (impurity J). We aimed to compare the GI toxicity of azithromycin and impurity J on zebrafish larvae and investigate the mechanism causing the differential GI toxicity. Results of our study showed that the GI toxicity induced by impurity J was higher than that of azithromycin in zebrafish larvae, and the effects of impurity J on transcription in the digestive system of zebrafish larvae were significantly stronger than those of azithromycin. Additionally, impurity J exerts stronger cytotoxic effects on GES-1 cells than azithromycin. Simultaneously, impurity J significantly increased ghsrb levels in the zebrafish intestinal tract and ghsr levels in human GES-1 cells compared to azithromycin, and ghsr overexpression significantly reduced cell viability, indicating that GI toxicity induced by azithromycin and impurity J may be correlated with ghsr overexpression induced by the two compounds. Meanwhile, molecular docking analysis showed that the highest -CDOCKER interaction energy scores with the zebrafish GHSRb or human GHSR protein might reflect the effect of azithromycin and impurity J on the expression of zebrafish ghsrb or human ghsr. Thus, our results suggest that impurity J has higher GI toxicity than azithromycin due to its greater ability to elevate ghsrb expression in zebrafish intestinal tract.
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Azitromicina , Peixe-Zebra , Animais , Humanos , Azitromicina/toxicidade , Larva , Simulação de Acoplamento Molecular , IntestinosRESUMO
Epithelial ovarian cancer is a malignant tumor of the female reproductive system with insidious symptoms, aggressiveness, risk of metastasis, and high mortality. Carbohydrate antigen 125 (CA125), a standard biomarker for screening epithelial ovarian cancer, can be applied to track cancer progression and treatment response. Here, we constructed an aptamer-based electrochemical biosensor to achieve sensitive detection of CA125. Molybdenum disulfide (MoS2) was used as the stable layered substrate, combined with the irregular branched structure of gold nanoflowers (AuNFs) to provide the sensing interface with a large specific surface area by one-step electrodeposition AuNFs@MoS2. The simplified electrode modification step increased the stability of the electrode while ensuring excellent electrochemical performance and providing many sulfhydryl binding sites. Then, AuNFs@MoS2/CA125 aptamer/MCH sensor was designed for CA125 detection. Based on AuNFs@MoS2 electrode, CA125 aptamer with sulfhydryl as the sensitive layer was fixed on the electrode by gold sulfur bonds. 6-Mercapto-1-hexanol (MCH) was used to block the electrode and reduce the non-specific adsorption. Finally, DPV analysis was applied for CA125 detection with the range of 0.0001 U/mL to 500 U/mL. Our designed aptamer sensor showed reasonable specificity, reproducibility, and stability. Clinical sample testing also proved the consistency of our sensor with the gold standard in negative/positive judgment. This work demonstrated a novel strategy for integrating nanostructures and biocompatibility to build advanced cancer biomarker sensors with promising applications.
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Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Neoplasias Ovarianas , Feminino , Humanos , Molibdênio/química , Limite de Detecção , Nanopartículas Metálicas/química , Carcinoma Epitelial do Ovário , Reprodutibilidade dos Testes , Dissulfetos/química , Aptâmeros de Nucleotídeos/química , Neoplasias Ovarianas/diagnóstico , Carboidratos , Técnicas EletroquímicasRESUMO
BACKGROUND: Primary sclerosing cholangitis (PSC) patients have a risk of developing cholangiocarcinoma (CCA). Establishing predictive models for CCA in PSC is important. METHODS: In a large cohort of 1,459 PSC patients seen at Mayo Clinic (1993-2020), we quantified the impact of clinical/laboratory variables on CCA development using univariate and multivariate Cox models and predicted CCA using statistical and artificial intelligence (AI) approaches. We explored plasma bile acid (BA) levels' predictive power of CCA (subset of 300 patients, BA cohort). RESULTS: Eight significant risk factors (false discovery rate: 20%) were identified with univariate analysis; prolonged inflammatory bowel disease (IBD) was the most important one. IBD duration, PSC duration, and total bilirubin remained significant (p < 0.05) with multivariate analysis. Clinical/laboratory variables predicted CCA with cross-validated C-indexes of 0.68-0.71 at different time points of disease, significantly better compared to commonly used PSC risk scores. Lower chenodeoxycholic acid, higher conjugated fraction of lithocholic acid and hyodeoxycholic acid, and higher ratio of cholic acid to chenodeoxycholic acid were predictive of CCA. BAs predicted CCA with a cross-validated C-index of 0.66 (std: 0.11, BA cohort), similar to clinical/laboratory variables (C-index = 0.64, std: 0.11, BA cohort). Combining BAs with clinical/laboratory variables leads to the best average C-index of 0.67 (std: 0.13, BA cohort). CONCLUSIONS: In a large PSC cohort, we identified clinical and laboratory risk factors for CCA development and demonstrated the first AI based predictive models that performed significantly better than commonly used PSC risk scores. More predictive data modalities are needed for clinical adoption of these models.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Colangite Esclerosante , Humanos , Inteligência Artificial , Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos , Ácido Quenodesoxicólico , Colangiocarcinoma/etiologia , Colangiocarcinoma/patologia , Colangite Esclerosante/complicações , Doenças Inflamatórias Intestinais/complicaçõesRESUMO
In a solution of sorbitol (SBT) and Ga(OTf)3 compounds, the coordination of sorbitol (SBT) to [Ga(OTf)n]3-n (n = 0-3) has been investigated, using both ESI-MS spectra and density functional theory (DFT) calculations at the M06/6-311++g(d,p), aug-cc-pvtz level using a polarized continuum model (PCM-SMD). In sorbitol solution, the most stable conformer of sorbitol includes three intramolecular H-bonds, i.e., O2Hâ¯O4, O4Hâ¯O6, and O5Hâ¯O3. Through ESI-MS spectra, in a tetrahydrofuran solution of both SBT and Ga(OTf)3 compounds, five main species are observed, i.e., [Ga(SBT)]3+, [Ga(OTf)]2+, [Ga(SBT)2]3+, [Ga(OTf)(SBT)]2+, and [Ga(OTf)(SBT)2]2+. Through DFT calculations, in a solution of sorbitol (SBT) and Ga(OTf)3 compounds, the Ga3+ cation tends to form five six-coordination complexes, i.e., [Ga(η2O,O-OTf)3], [Ga(η3O2-O4-SBT)2]3+, [(η2O,O-OTf)Ga(η4O2-O5-SBT)]2+, [(η1O-OTf)(η2O2,O4-SBT)Ga(η3O3-O5-SBT)]2+, and [(η1O-OTf)(η2O,O-OTf)Ga(η3O3-O5-SBT)]+, which are in good agreement with the experimental observation of the ESI-MS spectra. For both [Ga(OTf)n]3-n (n = 1-3) and [Ga(SBT)m]3+ (m = 1, 2) complexes, the negative charge transfer from ligands to the Ga3+-center plays an important role in their stability, because of the strong polarization of the Ga3+ cation. For [Ga(OTf)n(SBT)m]3-n (n = 1, 2; m = 1, 2) complexes, the negative charge transfer from ligands to the Ga3+-center plays an essential role in their stability, accompanied by an electrostatic interaction between the Ga3+-center and ligands and/or spatial inclusion of ligands toward the Ga3+-center.
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Al-containing catalysts, e.g., Al(OTf)3, show good catalytic performance toward the conversion of cellulose to fructose in methanol solution. Here, we report the catalytic isomerization and alcoholysis mechanisms for the conversion of cellobiose to fructose at the PBE0/6-311++G(d,p), aug-cc-pVTZ theoretical level, combining the relevant experimental verifications of electrospray ionization mass spectrometry (ESI-MS), high-performance liquid chromatography (HPLC), and the attenuated total reflection-infrared (ATR-IR) spectra. From the alcoholysis of Al(OTf)3 in methanol solution, the catalytically active species involves both the [CH3OH2]+ Brønsted acid and the [Al(CH3O)(OTf)(CH3OH)4]+ Lewis acid. There are two reaction pathways, i.e., one through glucose (glycosidic bond cleavage followed by isomerization, w-G) and another through cellobiulose (isomerization followed by glycosidic bond cleavage, w-L). The Lewis acid ([Al(CH3O)(OTf)(CH3OH)4]+) is responsible for the aldose-ketose tautomerization, while the Brønsted acid ([CH3OH2]+) is in charge of ring-opening, ring-closure, and glycosidic bond cleavage. For both w-G and w-L, the rate-determining steps are related to the intramolecular [1,2]-H shift between C1-C2 for the aldose-ketose tautomerization catalyzed by the [Al(CH3O)(OTf)(CH3OH)4]+ species. The Lewis acid ([Al(CH3O)(OTf)(CH3OH)4]+) exhibits higher catalytic activity toward the aldose-ketose tautomerization of glycosyl-chain-glucose to glycosyl-chain-fructose than that of chain-glucose to chain-fructose. Besides, the Brønsted acid ([CH3OH2]+) shows higher catalytic activity toward the glycosidic bond cleavage of cellobiulose than that of cellobiose. Kinetically, the w-L pathway is predominant, whereas the w-G pathway is minor. The theoretically proposed mechanism has been experimentally testified. These insights may advance on the novel design of the catalytic system toward the conversion of cellulose to fructose.
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Reactive oxygen species (ROS) mediate lipid peroxidation and produce 4-hydroxynonenal and other related products, which play an important role in the process of cell death, including apoptosis, autophagy, and ferroptosis. Lipid peroxidation of phospholipid bilayers can promote mitochondrial apoptosis, endoplasmic reticulum stress, and other complex molecular signaling pathways to regulate apoptosis. Lipid peroxidation and its products also act at different stages of autophagy, affecting the formation of autophagosomes and the recruitment of downstream proteins. In addition, we discuss the important role of ROS and lipid peroxides in ferroptosis and the regulatory role of nuclear factor erythroid 2-related factor 2 in ferroptosis under a background of oxidation. Finally, from the perspectives of promotion, inhibition, transformation, and common upstream molecules, we summarized the crosstalk among apoptosis, autophagy, and ferroptosis in the context of ROS. Our review discusses the role of ROS and lipid peroxidation in apoptosis, autophagy, and ferroptosis and their possible crosstalk mechanisms, so as to provide new insights and directions for the study of diseases related to pathological cell death. This review also has referential significance for studying the exact mechanism of ferroptosis mediated by lipid peroxidation.
Assuntos
Ferroptose , Espécies Reativas de Oxigênio/metabolismo , Peroxidação de Lipídeos , Apoptose , Morte Celular , AutofagiaRESUMO
The COVID-19 outbreak has become a global emergency since December 2019. Analysis of SARS-CoV-2 sequences can uncover single nucleotide variants (SNVs) and corresponding evolution patterns. The Global Evaluation of SARS-CoV-2/hCoV-19 Sequences (GESS, https://wan-bioinfo.shinyapps.io/GESS/) is a resource to provide comprehensive analysis results based on tens of thousands of high-coverage and high-quality SARS-CoV-2 complete genomes. The database allows user to browse, search and download SNVs at any individual or multiple SARS-CoV-2 genomic positions, or within a chosen genomic region or protein, or in certain country/area of interest. GESS reveals geographical distributions of SNVs around the world and across the states of USA, while exhibiting time-dependent patterns for SNV occurrences which reflect development of SARS-CoV-2 genomes. For each month, the top 100 SNVs that were firstly identified world-widely can be retrieved. GESS also explores SNVs occurring simultaneously with specific SNVs of user's interests. Furthermore, the database can be of great help to calibrate mutation rates and identify conserved genome regions. Taken together, GESS is a powerful resource and tool to monitor SARS-CoV-2 migration and evolution according to featured genomic variations. It provides potential directive information for prevalence prediction, related public health policy making, and vaccine designs.
Assuntos
COVID-19/prevenção & controle , Biologia Computacional/métodos , Bases de Dados Genéticas , Genoma Viral/genética , Genômica/métodos , SARS-CoV-2/genética , Algoritmos , COVID-19/epidemiologia , COVID-19/virologia , Surtos de Doenças , Saúde Global , Humanos , Internet , Taxa de Mutação , Polimorfismo de Nucleotídeo Único , Dinâmica Populacional , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
Lipid droplets (LDs) targeting probes are important for investigating the biological functions of LDs. The interplay between LDs and some other organelles can help to further understand the biological functions of these organelles. However, it is still a challenge to design functional probes that can specifically target LDs and are responsive to some other organelles. Herein, a multifunctional aggregation-induced emission luminogen (AIEgen), namely the TPA-CN, was prepared by the simple aldimine condensation reaction for lipid droplet-specific imaging and tracing. TPA-CN can be sensitively responsive to the acid environment of lysosomes due to the pH-response detachable connector in TPA-CN. With the assistance of this characteristic, it can be concluded from the fluorescence imaging and co-localization analysis results that the internalization of TPA-CN and the targeting of LDs does not involve the lysosome and the lysosomal escape process. At last, the TPA-CN was successfully used for the high-sensitivity imaging of dynamic information of LDs.