RESUMO
The development of new materials and their compositional and microstructural optimization are essential in regard to next-generation technologies such as clean energy and environmental sustainability. However, materials discovery and optimization have been a frustratingly slow process. The Edisonian trial-and-error process is time consuming and resource inefficient, particularly when contrasted with vast materials design spaces1. Whereas traditional combinatorial deposition methods can generate material libraries2,3, these suffer from limited material options and inability to leverage major breakthroughs in nanomaterial synthesis. Here we report a high-throughput combinatorial printing method capable of fabricating materials with compositional gradients at microscale spatial resolution. In situ mixing and printing in the aerosol phase allows instantaneous tuning of the mixing ratio of a broad range of materials on the fly, which is an important feature unobtainable in conventional multimaterials printing using feedstocks in liquid-liquid or solid-solid phases4-6. We demonstrate a variety of high-throughput printing strategies and applications in combinatorial doping, functional grading and chemical reaction, enabling materials exploration of doped chalcogenides and compositionally graded materials with gradient properties. The ability to combine the top-down design freedom of additive manufacturing with bottom-up control over local material compositions promises the development of compositionally complex materials inaccessible via conventional manufacturing approaches.
RESUMO
In the quest for post-CMOS (complementary metal-oxide-semiconductor) technologies, driven by the need for improved efficiency and performance, topologically protected ferromagnetic 'whirls' such as skyrmions1-8 and their anti-particles have shown great promise as solitonic information carriers in racetrack memory-in-logic or neuromorphic devices1,9-11. However, the presence of dipolar fields in ferromagnets, which restricts the formation of ultrasmall topological textures3,6,8,9,12, and the deleterious skyrmion Hall effect, when skyrmions are driven by spin torques9,10,12, have thus far inhibited their practical implementation. Antiferromagnetic analogues, which are predicted to demonstrate relativistic dynamics, fast deflection-free motion and size scaling, have recently become the subject of intense focus9,13-19, but they have yet to be experimentally demonstrated in natural antiferromagnetic systems. Here we realize a family of topological antiferromagnetic spin textures in α-Fe2O3-an Earth-abundant oxide insulator-capped with a platinum overlayer. By exploiting a first-order analogue of the Kibble-Zurek mechanism20,21, we stabilize exotic merons and antimerons (half-skyrmions)8 and their pairs (bimerons)16,22, which can be erased by magnetic fields and regenerated by temperature cycling. These structures have characteristic sizes of the order of 100 nanometres and can be chemically controlled via precise tuning of the exchange and anisotropy, with pathways through which further scaling may be achieved. Driven by current-based spin torques from the heavy-metal overlayer, some of these antiferromagnetic textures could emerge as prime candidates for low-energy antiferromagnetic spintronics at room temperature1,9-11,23.
RESUMO
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid ß-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Metabolismo dos Lipídeos/fisiologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Ácido Palmítico/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Linhagem Celular , Camundongos , Camundongos Knockout , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Oxirredução , Estrutura Secundária de ProteínaRESUMO
Drug resistance is a major barrier in cancer treatment and anticancer drug development. Growing evidence indicates that non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play pivotal roles in cancer progression, therapy, and drug resistance. Furthermore, ncRNAs have been proven to be promising novel therapeutic targets for cancer treatment. Reversing dysregulated ncRNAs by drugs holds significant potential as an effective therapeutic strategy for overcoming drug resistance. Therefore, we developed ncRNADrug, an integrated and comprehensive resource that records manually curated and computationally predicted ncRNAs associated with drug resistance, ncRNAs targeted by drugs, as well as potential drug combinations for the treatment of resistant cancer. Currently, ncRNADrug collects 29 551 experimentally validated entries involving 9195 ncRNAs (2248 miRNAs, 4145 lncRNAs and 2802 circRNAs) associated with the drug resistance of 266 drugs, and 32 969 entries involving 10 480 ncRNAs (4338 miRNAs, 6087 lncRNAs and 55 circRNAs) targeted by 965 drugs. In addition, ncRNADrug also contains associations between ncRNAs and drugs predicted from ncRNA expression profiles by differential expression analysis. Altogether, ncRNADrug surpasses the existing related databases in both data volume and functionality. It will be a useful resource for drug development and cancer treatment. ncRNADrug is available at http://www.jianglab.cn/ncRNADrug.
Assuntos
MicroRNAs , Neoplasias , RNA Longo não Codificante , Humanos , Resistência a Medicamentos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Bases de Dados FactuaisRESUMO
Drug resistance is one of principal limiting factors for cancer treatment. Several mechanisms, especially mutation, have been validated to implicate in drug resistance. In addition, drug resistance is heterogeneous, which makes an urgent need to explore the personalized driver genes of drug resistance. Here, we proposed an approach DRdriver to identify drug resistance driver genes in individual-specific network of resistant patients. First, we identified the differential mutations for each resistant patient. Next, the individual-specific network, which included the genes with differential mutations and their targets, was constructed. Then, the genetic algorithm was utilized to identify the drug resistance driver genes, which regulated the most differentially expressed genes and the least non-differentially expressed genes. In total, we identified 1202 drug resistance driver genes for 8 cancer types and 10 drugs. We also demonstrated that the identified driver genes were mutated more frequently than other genes and tended to be associated with the development of cancer and drug resistance. Based on the mutational signatures of all driver genes and enriched pathways of driver genes in brain lower grade glioma treated by temozolomide, the drug resistance subtypes were identified. Additionally, the subtypes showed great diversity in epithelial-mesenchyme transition, DNA damage repair and tumor mutation burden. In summary, this study developed a method DRdriver for identifying personalized drug resistance driver genes, which provides a framework for unlocking the molecular mechanism and heterogeneity of drug resistance.
Assuntos
Redes Reguladoras de Genes , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Mutação , Oncogenes , Resistência a MedicamentosRESUMO
Pulmonary hypertension (PH) is characterized by vascular remodeling predominantly driven by a phenotypic switching in pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms for this phenotypic alteration remain incompletely understood. Here, we identified that RNA methyltransferase METTL3 is significantly elevated in the lungs of hypoxic PH (HPH) mice and rats, as well as in the pulmonary arteries (PAs) of HPH rats. Targeted deletion of Mettl3 in smooth muscle cells exacerbated hemodynamic consequences of hypoxia-induced PH and accelerated pulmonary vascular remodeling in vivo. Additionally, the absence of METTL3 markedly induced phenotypic switching in PASMCs in vitro. Mechanistically, METTL3 depletion attenuated m6A modification and hindered the processing of pri-miR-143/145, leading to a downregulation of miR-143-3p and miR-145-5p. Inhibition of hnRNPA2B1, an m6A mediator involved in miRNA maturation, similarly resulted in a significant reduction of miR-143-3p and miR-145-5p. We demonstrated that miR-145-5p targets Krüppel-like factor 4 (KLF4) and miR-143-3p targets fascin actin-bundling protein 1 (FSCN1) in PASMCs. The decrease of miR-145-5p subsequently induced an upregulation of KLF4, which in turn suppressed miR-143/145 transcription, establishing a positive feedback circuit between KLF4 and miR-143/145. This regulatory circuit facilitates the persistent suppression of contractile marker genes, thereby sustaining PASMC phenotypic switch. Collectively, hypoxia-induced upregulation of METTL3, along with m6A mediated regulation of miR-143/145, might serve as a protective mechanism against phenotypic switch of PASMCs. Our results highlight a potential therapeutic strategy targeting m6A modified miR-143/145-KLF4 loop in the treatment of PH.
Assuntos
Adenosina , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Metiltransferases , MicroRNAs , Miócitos de Músculo Liso , Artéria Pulmonar , Fator 4 Semelhante a Kruppel/metabolismo , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Artéria Pulmonar/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Miócitos de Músculo Liso/metabolismo , Camundongos , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferases/metabolismo , Metiltransferases/genética , Ratos , Fenótipo , Masculino , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Músculo Liso Vascular/metabolismo , Camundongos Endogâmicos C57BL , Remodelação Vascular/genética , Ratos Sprague-Dawley , HumanosRESUMO
Interfaces play a critical thermodynamic role in the existence of multilayer systems. Due to their utility in bridging energetic and compositional differences between distinct species, the formation of interfaces inherently creates internal strain in the bulk due to the reorganization needed to accommodate such a change. We report the effect of scaling interfacial stress by deposition of different adlayers on a host thin metal film. Intrinsic property differences between host and deposited metal atoms result in varying degree of composition and energy gradient within the interface. Interfacial stress can increase defects in the host leading to (i) energy dissipation and reorganization to minimize surface energy, and (ii) increased material strength. We infer that dissipation of interfacial stress induces defect migration, hence bulk and surface atomic reconstruction as captured by the surface roughness and grain size reduction coupled with a concomitant increase in material strength.
RESUMO
BACKGROUND: Normobaric hyperoxia (NBO) has neuroprotective effects in acute ischemic stroke. Thus, we aimed to identify the optimal NBO treatment duration combined with endovascular treatment. METHODS: This is a single-center, randomized controlled, open-label, blinded-end point dose-escalation clinical trial. Patients with acute ischemic stroke who had an indication for endovascular treatment at Tianjin Huanhu Hospital were randomly assigned to 4 groups (1:1 ratio) based on NBO therapy duration: (1) control group (1 L/min oxygen for 4 hours); (2) NBO-2h group (10 L/min for 2 hours); (3) NBO-4h group (10 L/min for 4 hours); and (4) NBO-6h group (10 L/min for 6 hours). The primary outcome was cerebral infarction volume at 72 hours after randomization using an intention-to-treat analysis model. The primary safety outcome was the 90-day mortality rate. RESULTS: Between June 2022 and September 2023, 100 patients were randomly assigned to the following groups: control group (n=25), NBO-2h group (n=25), NBO-4h group (n=25), and NBO-6h group (n=25). The 72-hour cerebral infarct volumes were 39.4±34.3 mL, 30.6±30.1 mL, 19.7±15.4 mL, and 22.6±22.4 mL, respectively (P=0.013). The NBO-4h and NBO-6h groups both showed statistically significant differences (adjusted P values: 0.011 and 0.027, respectively) compared with the control group. Compared with the control group, both the NBO-4h and NBO-6h groups showed significant differences (P<0.05) in the National Institutes of Health Stroke Scale scores at 24 hours, 72 hours, and 7 days, as well as in the change of the National Institutes of Health Stroke Scale scores from baseline to 24 hours. Additionally, there were no significant differences among the 4 groups in terms of 90-day mortality rate, symptomatic intracranial hemorrhage, early neurological deterioration, or severe adverse events. CONCLUSIONS: The effectiveness of NBO therapy was associated with oxygen administration duration. Among patients with acute ischemic stroke who underwent endovascular treatment, NBO therapy for 4 and 6 hours was found to be more effective. Larger-scale multicenter studies are needed to validate these findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05404373.
Assuntos
Procedimentos Endovasculares , AVC Isquêmico , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Procedimentos Endovasculares/métodos , Idoso , AVC Isquêmico/terapia , Hiperóxia , Resultado do Tratamento , Terapia Combinada , Oxigenoterapia/métodosRESUMO
BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.
Assuntos
Adenosina , Adipogenia , Homólogo AlkB 5 da RNA Desmetilase , Galinhas , Fosfatidilcolina-Esterol O-Aciltransferase , Estabilidade de RNA , Animais , Adipogenia/genética , Galinhas/genética , Galinhas/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Feminino , Adenosina/análogos & derivados , Adenosina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , MetilaçãoRESUMO
Endometriosis is defined as an oestrogen-dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single-cell RNA sequencing (scRNA-seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis-promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T-cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis.
Assuntos
Linfócitos T CD8-Positivos , Endometriose , Fator de Transcrição STAT1 , Células Estromais , Endometriose/imunologia , Endometriose/patologia , Endometriose/metabolismo , Feminino , Linfócitos T CD8-Positivos/imunologia , Humanos , Animais , Camundongos , Células Estromais/imunologia , Células Estromais/metabolismo , Fator de Transcrição STAT1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Endométrio/imunologia , Endométrio/patologia , Modelos Animais de Doenças , Transdução de Sinais , Camundongos Nus , Adulto , Proteína Quinase CDC2/metabolismo , Técnicas de Cocultura , Citocinas/metabolismoRESUMO
Selective synthesis of chiral bridged (hetero)bicyclic scaffolds via asymmetric C-H activation constitutes substantial challenges due to the multiple reactivities of strained bicyclic structures. Herein, we develop the domino transformations through an unprecedented cobalt-catalyzed enantioselective C-H activation/nucleophilic [3 + 2] annulation with symmetrical bicyclic alkenes. The methods offer straightforward access to a wide range of chiral molecules bearing [2.2.1]-bridged bicyclic cores with four and five consecutive stereocenters in a single step. Two elaborate salicyloxazoline (Salox) ligands were synthesized based on the rational design and mechanistic understanding. The well-defined chiral pockets generated from asymmetric coordination around the trivalent cobalt catalyst direct the orientation of bicyclic alkenes, leading to excellent enantioselectivity.
RESUMO
BACKGROUND: Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear. METHODS: We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson's correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins. RESULTS: Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro. CONCLUSIONS: This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.
Assuntos
Endometriose , Fibrose , Proteômica , Ubiquitinação , Feminino , Humanos , Endometriose/metabolismo , Endometriose/patologia , Endometriose/genética , Ontologia Genética , Multiômica , Proteoma/metabolismoRESUMO
Double line self-focusing characteristics of elliptical Airyprime beams (EAPBs) with different elliptical vertical-axis factor ß are investigated by varying the main ring radius r0. Overly large or small r0 results in the inhomogeneous distribution of light intensity at one linear focus of the double line self-focusing. Only when r0 is appropriate and ß is within a certain range, can double uniform line self-focusing happen to the EAPB. Moreover, the self-focusing ability of the second line self-focusing is weaken than that of the first line self-focusing. Under the premise of our selected values of beam parameters, the EAPB can achieve double uniform line self-focusing when r0 = 0.3 mm and ß = 0.58â¼0.71. The focal length of the first line self-focusing, the lengths of double linear focus, and the self-focusing abilities of the double uniform line self-focusing can be regulated by varying ß within the range of 0.58â¼0.71. If ß is smaller than 0.58 or larger than 0.71, it will lead to nonuniform line self-focusing. An explanation of the physical mechanism behind the double uniform line self-focusing of the EAPB is proposed. Finally, the experimental measurements of the line self-focusing of the EAPB confirm the validity of the above conclusions. This research provides a new solution on how to generate double uniform line self-focusing and new insights into the practical application of elliptical self-focusing beams.
RESUMO
The reported autofocusing ability of a ring Airyprime beam array reaches up to 8632.40, while the strongest autofocusing ability of a circular Airyprime beam (CAPB) is only 1822.49. How can the autofocusing ability of a single beam reach the autofocusing ability of a beam array? To achieve this goal, a circularly transformed Airyprime beam (CTAPB) is introduced by following two steps. First, a circular equation transformation on the two transverse coordinates in the electric field expression of a propagating Airyprime beam is performed. Then, the electric field expression of a propagating Airyprime beam is integrated over the angle. The intensity profile of a CTAPB on the initial plane changes significantly with varying the primary ring radius r0. With increasing r0, therefore, the autofocusing ability of a CTAPB undergoes a process of first increasing and then decreasing, while the focal length always increases. A CTAPB exhibits more powerful autofocusing ability than a CAPB. The maximum autofocusing ability of a CTAPB can reach up to 8634.76, which is 4.74 times that of a CAPB, while the corresponding focal length is 95.11% of a CAPB. A CTAPB on the initial plane can be approximately characterized by a ring Airyprime beam array with sufficient number of Airyprime beams. Due to the better symmetry, a CTAPB has a slightly stronger autofocusing ability than a ring Airyprime beam array and almost the same focal length as a ring Airyprime beam array. The CTAPB is also experimentally generated, and the experimental results indicate that the CTAPB has powerful autofocusing ability. As a replacement of a CAPB and a ring Airyprime beam array, this introduced CTAPB can be applied to the scenes which involve abruptly autofocusing effect.
RESUMO
With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.
Assuntos
Lipogênese , Fígado , Camundongos Endogâmicos C57BL , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Espécies Reativas de Oxigênio , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Nanopartículas/química , Lipogênese/efeitos dos fármacos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Receptores Notch/metabolismo , Receptores Notch/antagonistas & inibidores , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Bilirrubina , Polietilenoglicóis/química , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , DibenzazepinasRESUMO
OBJECTIVES: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). MATERIALS AND METHODS: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. RESULTS: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. KâM survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). CONCLUSION: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. CLINICAL RELEVANCE STATEMENT: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. KEY POINTS: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments.
RESUMO
INTRODUCTION: ARDS (acute respiratory distress syndrome) is the most severe form of acute hypoxic respiratory failure. Most studies related to ARDS have excluded patients with hematologic diseases, let alone allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Numerous patients experiencing severe hypoxic respiratory failure do not meet the Berlin definition due to the limitations of diagnosis and treatment. A new definition of ARDS, remove some diagnosis restrictions, was proposed in 2023. Based on the 2023 new definition of ARDS, we investigated the clinical features of ARDS in allo-HSCT recipients and reported risk factors for in-hospital mortality in allo-HSCT recipients defined by the Berlin definition and the new definition of ARDS respectively. METHODS: From Jan 2016 to Dec 2020, 135 allo-HSCT recipients identified with the new definition and 87 identified with the Berlin definition at three teaching hospitals were retrospectively included in this study. Variables (demographic information, characteristics of hematologic disease and ARDS episode, laboratory tests and SOFA score) with P < 0.05 in univariate logistic regression analysis were included in multivariate stepwise logistic regression analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. RESULTS: Under the new definition, SOFA score (OR = 1.351, 95% CI: 1.146-1.593, P < 0.01) were found as an independent risk factor for in-hospital mortality in ARDS after allo-HSCT, while SpO2/FiO2 (OR = 0.984, 95% CI: 0.972-0.996, P < 0.01) was a protective factor. The infusion of peripheral-derived stem cells was found to be a protective factor against in-hospital mortality in post-transplantation ARDS compared with the infusion of bone marrow-derived stem cells (OR = 0.726, 95% CI: 0.164-3.221, P = 0.04). Under the Berlin definition, PaO2/FiO2 (OR = 0.977, 95% CI: 0.961-0.993, P = 0.01, lactate (OR = 7.337, 95% CI: 1.313-40.989, P < 0.01) and AST (OR = 1.165, 95% CI: 1.072-1.265, P < 0.01) were independently associated with in-hospital mortality. CONCLUSION: These prognostic risk factors we found in allo-HSCT recipients may contribute to closer monitoring and ARDS prevention strategies. These findings require confirmation in prospective, large sample size studies.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mortalidade Hospitalar , Síndrome do Desconforto Respiratório , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Estudos Retrospectivos , Feminino , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Pessoa de Meia-Idade , Fatores de Risco , Adulto , Transplante Homólogo/efeitos adversos , Idoso , Modelos Logísticos , Adulto JovemRESUMO
BACKGROUND: The TRIANGLE operation benefits patients with pancreatic cancer; however, the Heidelberg triangle, where the operation occurs, contains vessels that can impact safety, especially in laparoscopic pancreaticoduodenectomy (LPD) with the TRIANGLE operation. This study aimed to identify Heidelberg triangle vessel types and their implications in pancreaticoduodenectomy (PD). METHODS: Retrospective collection of radiographic data was performed from January 2017 to April 2023. Three-dimensional (3D) CT reconstructions were performed on patients. Vascular types in the Heidelberg triangle were classified based on named vessels crossing its interior. The impact of these types on surgical outcomes and complications in PD with the TRIANGLE operation was assessed. RESULTS: Preoperative CT reconstruction was conducted on 184 pancreatic surgery patients. The findings revealed 99 patients (53.8%) with the type I Heidelberg triangle, lacking named vessels crossing the interior. Type II (n = 85, 46.2%), with named vessels crossing the interior, was identified. Among reconstructed patients who underwent PD with the TRIANGLE operation (n = 103), they were categorized as type I (n = 57) or type II (n = 46). The results showed that LPD patients with type II had significantly higher median intraoperative blood loss (300 mL vs. 200 mL, P = 0.030) and mean examined lymph nodes (17.2 ± 7.6 vs. 13.4 ± 5.2, P = 0.019) compared to those with type I. No significant differences were found in operative time or postoperative complications. CONCLUSION: The presence of named vessels crossing the interior of the Heidelberg triangle was associated with increased intraoperative bleeding during LPD combined with the TRIANGLE operation. Therefore, targeted preoperative planning is required before the operation, thus improving the safety of the TRIANGLE operation in minimally invasive surgery.
Assuntos
Laparoscopia , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/métodos , Estudos Retrospectivos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/complicações , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Tempo de InternaçãoRESUMO
Extreme drought weather has occurred frequently in recent years, resulting in serious yield loss in tea plantations. The study of drought in tea plantations is becoming more and more intensive, but there are fewer studies on drought-resistant measures applied in actual production. Therefore, in this study, we investigated the effect of exogenous tea polyphenols on the drought resistance of tea plant by pouring 100 mg·L-1 of exogenous tea polyphenols into the root under drought. The exogenous tea polyphenols were able to promote the closure of stomata and reduce water loss from leaves under drought stress. Drought-induced malondialdehyde (MDA) accumulation in tea leaves and roots was also significantly reduced by exogenous tea polyphenols. Combined transcriptomic and metabolomic analyses showed that exogenous tea polyphenols regulated the abnormal responses of photosynthetic and energy metabolism in leaves under drought conditions and alleviated sphingolipid metabolism, arginine metabolism, and glutathione metabolism in the root system, which enhanced the drought resistance of tea seedlings. Exogenous tea polyphenols induced jasmonic acid-isoleucine (JA-ILE) accumulation in the root system, and the jasmonic acid-isoleucine synthetase gene (TEA028623), jasmonic acid ZIM structural domain proteins (JAMs) synthesis genes (novel.22237, TEA001821), and the transcription factor MYC2 (TEA014288, TEA005840) were significantly up-regulated. Meanwhile, the flavonoid metabolic flow was significantly altered in the root; for example, the content of EGCG, ECG, and EGC was significantly increased. Thus, exogenous tea polyphenols enhance the drought resistance of tea plants through multiple pathways.
Assuntos
Camellia sinensis , Ciclopentanos , Resistência à Seca , Oxilipinas , Isoleucina , Polifenóis/farmacologia , Camellia sinensis/genética , Flavonoides , CháRESUMO
Transition metal-catalyzed enantioselective C-H carbonylation with carbon monoxide, an essential and easily available C1 feedstock, remains challenging. Here, we disclosed an unprecedented enantioselective C-H carbonylation catalyzed by inexpensive and readily available cobalt(II) salt. The reactions proceed efficiently through desymmetrization, kinetic resolution, and parallel kinetic resolution, affording a broad range of chiral isoindolinones in good yields with excellent enantioselectivities (up to 92 % yield and 99 % ee). The synthetic potential of this method was demonstrated by asymmetric synthesis of biological active compounds, such as (S)-PD172938 and (S)-Pazinaclone. The resulting chiral isoindolinones also serve as chiral ligands in cobalt-catalyzed enantioselective C-H annulation with alkynes to construct phosphorus stereocenter.