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1.
Int J Biol Macromol ; 277(Pt 3): 134423, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39097045

RESUMO

The synergistic interaction gels (SIGs) can be created by blending konjac glucomannan (KGM) and κ-carrageenan, and have been applied to modify and improve the rheological and texture properties of food system. However, the assembly behaviors between them are still unclear. This work revealed that the presence of KGM promoted phase transition of nearby κ-carrageenan molecules probably by contributing to entropy increment. Subsequently, the rest of κ-carrageenan transformed into helical structure, assembled into a series of laterally arranged trigonal units and formed a three-dimensional network. In KGM/κ-carrageenan SIGs, the size of high density domains (Ξ) in aggregates and the distance of these high density domains (ξ) were narrowed firstly and then enlarged as increasing of KGM content. These nano-scale structure features were responsible for the relative higher gel strength for KGM/κ-carrageenan SIGs with proportion ratios of 1:9 (K1C9) and 3:7 (K3C7). This study serves to facilitate the design and production of SIGs with the requisite performance characteristics.

3.
J Transl Med ; 22(1): 743, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39107765

RESUMO

BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.


Assuntos
Insuficiência Cardíaca , Modelos de Riscos Proporcionais , Humanos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Feminino , Masculino , Idoso , Reprodutibilidade dos Testes , Prognóstico , Análise de Sobrevida , Pessoa de Meia-Idade , Curva ROC , Algoritmos , Área Sob a Curva , Bases de Dados Factuais , Aprendizado Profundo , Índice de Gravidade de Doença
4.
Sci Data ; 11(1): 866, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39127825

RESUMO

Anthocidaris crassispina is a very popular edible sea urchin distributed along the coast of the South China Sea. In this study, we performed whole-genome sequencing and generated a chromosome-level assembly of this species. The total length of the genomic contig sequence was 891.02 Mb, and contig N50 was 808.15 kb when Hifiasm was used for assembly. The Hi-C library was constructed and sequenced, yielding approximately 68.61 Gb of data. After Hi-C assembly, approximately 886.72 Mb of sequence was able to be mapped onto 21 chromosomes, accounting for 99.52% of the total genome length. Among the sequences located on the chromosomes, those for which the order and direction could be determined accounted for approximately 826.82 Mb, or 93.24% of the total length. These results provide valuable resources for further study of A. crassispina at the genetic level.


Assuntos
Anotação de Sequência Molecular , Ouriços-do-Mar , Animais , Ouriços-do-Mar/genética , Genoma , Sequenciamento Completo do Genoma , Cromossomos , China
5.
J Am Chem Soc ; 146(32): 22335-22347, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39092859

RESUMO

Searching for high energy-density electrode materials for sodium ion batteries has revealed Na-deficient intercalation compounds with lattice oxygen redox as promising high-capacity cathodes. However, anionic redox reactions commonly encountered poor electrochemical reversibility and unfavorable structural transformations during dynamic (de)sodiation processes. To address this issue, we employed lithium orbital hybridization chemistry to create Na-O-Li configuration in a prototype P2-layered Na43/60Li1/20Mg7/60Cu1/6Mn2/3O2 (P2-NaLMCM') cathode material. That Li+ ions, having low electronegativity, reside in the transition metal slabs serves to stimulate unhybridized O 2p orbitals to facilitate the stable capacity contribution of oxygen redox at high state of charge. The prismatic-type structure evolving to an intergrowth structure of the Z phase at high charging state could be simultaneously alleviated by reducing the electrostatic repulsion of O-O layers. As a consequence, P2-NaLMCM' delivers a high specific capacity of 183.8 mAh g-1 at 0.05 C and good cycling stability with a capacity retention of 80.2% over 200 cycles within the voltage range of 2.0-4.5 V. Our findings provide new insights into both tailoring oxygen redox chemistry and stabilizing dynamic structural evolution for high-energy battery cathode materials.

6.
Angew Chem Int Ed Engl ; : e202413600, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39136072

RESUMO

Achieving high energy density has always been the goal of lithium-ion batteries (LIBs). SiOx has emerged as a compelling candidate for use as a negative electrode material due to its remarkable capacity. However, the huge volume expansion and the unstable electrode interface during (de)lithiation, hinder its further development. Herein, we report a facile strategy for the synthesis of surface fluorinated SiOx (SiOx@vG-F), and investigate their influences on battery performance. Systematic experiments investigations indicate that the reaction between Li+ and fluorine groups promotes the in-situ formation of stable LiF-rich solid electrolyte interface (SEI) on the surface of SiOx@vG-F anode, which effectively suppresses the pulverization of microsized SiOx particles during the charge and discharge cycle. As a result, the SiOx@vG-F enabled a higher capacity retention of 86.4% over 200 cycles at 1.0 C in the SiOx@vG-F||LiNi0.8Co0.1Mn0.1O2 full cell. This approach will provide insights for the advancement of alternative electrode materials in diverse energy conversion and storage systems.

7.
J Neurointerv Surg ; 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39122255

RESUMO

BACKGROUND: This study investigates the efficacy and safety of bridging intravenous thrombolysis (IVT) before endovascular therapy (EVT) compared with EVT alone in patients with large infarction core. METHODS: We conducted a comprehensive search of PubMed, EMBASE, and the Cochrane Library from January 2015 to June 2024. Included studies involved patients with acute ischemic stroke with an Alberta Stroke Program Early CT Score of ≤5 or an ischemic core volume of ≥50 mL. Studies were required to provide either 90-day modified Rankin Scale (mRS) score, reperfusion, symptomatic intracranial hemorrhage (sICH), or 90-day mortality. RESULTS: Nine observational studies with 2641 patients were analyzed. The IVT+EVT group had a higher rate of 90-day functional independence (mRS 0-2; OR 1.56, 95% CI 1.31 to 1.87; adjusted OR (aOR) 1.43, 95% CI 1.21 to 1.68) and 90-day functional outcome (mRS 0-3; OR 1.34, 95% CI 1.11 to 1.62; aOR 1.18, 95% CI 1.02 to 1.37) compared with EVT alone. There was no significant difference in successful reperfusion (OR 1.01, 95% CI 0.62 to 1.64; aOR 1.07, 95% CI 0.74 to 1.54) and 90-day mortality (OR 0.86, 95% CI 0.73 to 1.02; aOR 0.89, 95% CI 0.77 to 1.04) between the two groups. Moreover, patients who received IVT+EVT had a higher rate of sICH (OR 1.30, 95% CI 1.03 to 1.64; aOR 2.21, 95% CI 1.22 to 4.01). CONCLUSIONS: In patients with large infarction core, bridging IVT before EVT is associated with favorable functional outcomes compared with EVT, even though bridging therapy entails a higher risk of sICH. Further trials are needed to confirm these findings.

8.
Sci Rep ; 14(1): 17792, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090212

RESUMO

Hypertension is a disease associated with epigenetic aging. However, the pathogenic mechanism underlying this relationship remains unclear. We aimed to characterize the shared genetic architecture of hypertension and epigenetic aging, and identify novel risk loci. Leveraging genome-wide association studies (GWAS) summary statistics of hypertension (129,909 cases and 354,689 controls) and four epigenetic clocks (N = 34,710), we investigated genetic architectures and genetic overlap using bivariate casual mixture model and conditional/conjunctional false discovery rate methods. Functional gene-sets pathway analyses were performed by functional mapping and gene annotation (FUMA) protocol. Hypertension was polygenic with 2.8 K trait-influencing genetic variants. We observed cross-trait genetic enrichment and genetic overlap between hypertension and all four measures of epigenetic aging. Further, we identified 32 distinct genomic loci jointly associated with hypertension and epigenetic aging. Notably, rs1849209 was shared between hypertension and three epigenetic clocks (HannumAge, IEAA, and PhenoAge). The shared loci exhibited a combination of concordant and discordant allelic effects. Functional gene-set analyses revealed significant enrichment in biological pathways related to sensory perception of smell and nervous system processes. We observed genetic overlaps with mixed effect directions between hypertension and all four epigenetic aging measures, and identified 32 shared distinct loci with mixed effect directions, 25 of which were novel for hypertension. Shared genes enriched in biological pathways related to olfaction.


Assuntos
Envelhecimento , Epigênese Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipertensão , Humanos , Hipertensão/genética , Envelhecimento/genética , Polimorfismo de Nucleotídeo Único , Herança Multifatorial/genética , Loci Gênicos , Locos de Características Quantitativas
9.
Oncol Lett ; 28(4): 468, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39119236

RESUMO

8p11 myeloproliferative syndrome (EMS) is a rare and aggressive hematological malignancy, characterized by myeloproliferative neoplasms, and associated with eosinophilia and T- or B-cell lineage lymphoblastic lymphoma. The pathogenesis is defined by the presence of chromosomal translocations associated with the fibroblast growth factor-1 (FGFR1) gene, located in the 8p11-12.1 chromosomal locus. At present, only ~100 cases have been reported globally. At least 15 partner genes have been identified, including the most common, the zinc finger MYM-type containing 2 (ZNF198)-FGFR1 fusion gene formed by t(8;13)(p11;q12). Different fusion genes determine the clinical manifestations and prognosis of the disease. Patients with EMS with t(8;13)(p11;q12) commonly present with lymphadenopathy and T-lymphoblastic lymphoma, which usually converts to acute myeloid leukemia (AML) with the progression of the disease. The present study describes the case of an elderly female patient with EMS with t(8;13)(p11;q12), presenting with myeloid/lymphoid syndrome (myeloproliferative neoplasms and T lymphoblastic lymphoma). The patient received the CHOPE regimen combined with tyrosine kinase inhibitor (dasatin) treatment and obtained short-term complete remission. However, 6 months later, the disease progressed from EMS to AML and the patient died due to ineffective induction therapy. The present study also reviews the relevant literature about this unusual entity to enhance the understanding of EMS.

10.
Spectrochim Acta A Mol Biomol Spectrosc ; 323: 124899, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-39094269

RESUMO

As a type of biosurfactant, rhamnolipids (RLs) are multifunctional skin-care ingredients, and the molecular interaction of RLs with silk fibroin (SF) is a more complicated process than has long been believed. The interaction and functional properties of them, and their potential as fungicidal agents for agricultural products and as organic preservatives for cosmetics were assessed in this paper. The SF addition makes the RLs aggregation easier through the complexes formation, which decreases the applied concentration of surfactant. The results of spectroscopic analyses and molecular docking suggest that hydrogen bonding and van der Waals forces are significant contributed to the binding mechanism between the two substances. The addition of SF notably enhances the foaming capacity and stability of RLs. The certain antibacterial and antifungal properties of RLs are basically not affected by the SF addition, even the SF-RLS system demonstrates an unobvious synergistic inhibitory impact on Glomerella cingulate (GC). The results offer a theoretical framework for the utilization of RLs as natural fungicides and preservatives in presence of nutritional components, considering the properties of RLs as nontoxic, biodegradable, environmentally friendly, and good compatibility.

11.
Int J Biometeorol ; 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39105775

RESUMO

Long time series of vegetation monitoring can be carried out by remote sensing data, the level of urban greening is objectively described, and the spatial characteristics of plant pollen are indirectly understood. Pollen is the main allergen in patients with seasonal allergic rhinitis. Meteorological factors affect the release and diffusion of pollen. Therefore, studying of the complex relationship between meteorological factors and allergic rhinitis is essential for effective prevention and treatment of the disease. In this study, we leverage remote sensing data for a comprehensive decade-long analysis of urban greening in Tianjin, which exhibits an annual increase in vegetative cover of 0.51 per annum, focusing on its impact on allergic rhinitis through changes in pollen distribution. Utilizing high-resolution imagery, we quantify changes in urban Fractional Vegetation Coverage (FVC) and its correlation with pollen types and allergic rhinitis cases. Our analysis reveals a significant correlation between FVC trends and pollen concentrations, with a surprising value of 0.71, highlighting the influence of urban greenery on allergenic pollen levels. We establish a robust connection between the seasonal patterns of pollen outbreaks and allergic rhinitis consultations, with a noticeable increase in consultations during high pollen seasons. our findings indicate a higher allergenic potential of herbaceous compared to woody vegetation. This nuanced understanding underscores the importance of pollen sensitivity, alongside concentration, in driving allergic rhinitis incidents. Utilizing a Generalized Linear Model, significant features influencing the number of visits for allergic rhinitis (P < 0.05) were identified. Both GLM and LSTM models were employed to forecast the visitation volumes for rhinitis during the spring and summer-autumn of 2022. Upon validation, it was found that the R² values between the simulated and actual values for both GLM and LSTM models surpassed the 95% confidence threshold. Moreover, the R² values for the summer-autumn seasons (GLM: 0.56, LSTM: 0.72) were higher than those for spring (GLM: 0.22, LSTM: 0.47). Comparing the errors between the simulated and actual values of GLM and LSTM models, LSTM exhibited higher simulation precision in both spring and summer-autumn seasons, demonstrating superior simulation performance. Overall, our study pioneers the integration of remote sensing with meteorological and health data for allergic rhinitis forecasting. This integrative approach provides valuable insights for public health planning, particularly in urban settings, and lays the groundwork for advanced, location-specific allergenic pollen forecasting and mitigation strategies.

12.
Heliyon ; 10(15): e35507, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39166026

RESUMO

Optical paths in telescopes frequently incorporate silver mirrors for high sensitivity. Unfortunately, silver mirrors without protective coatings are susceptible to sulfurization and oxidation, compromising their quality. Even with protective layers, insufficient adhesion between the coating and the silver film can lead to peeling, exposing the silver to external environments and affecting its quality. This study aimed to identify dielectric materials with superior adhesion to silver, rendering them ideal choices for silver coating applications. By electron gun evaporation, different dielectric layers were deposited on the top and bottom of the silver film under a substrate temperature below 150 °C. These coatings were composed of materials with desired refractive indices, including aluminum oxide (Al2O3), aluminum-doped silicon, magnesium fluoride (MgF2), and other dielectrics. Following the deposition, a tape adhesion test was conducted to evaluate the bond strength of the samples. X-ray photoelectron spectroscopy (XPS) analysis was carried out to investigate the interaction between silver and its neighboring layers. The results revealed that Al2O3 and MgF2 exhibited exceptional adhesion to silver. Moreover, these multilayer coatings can effectively enhance the reflectance of silver in the visible (VIS) wavelength ranges.

13.
Dalton Trans ; 53(32): 13409-13415, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39087922

RESUMO

Two Ni-added poly(polyoxometalate)s built of Keggin-type {Ni6PW9} and Anderson-type NiW6O24 units via WO4/Sb2O bridges and Ni-O-W linkages, Na4H8[Ni(enMe)2][(Sb2O)2(NiW6O24)-{Ni12O2(OH)4(enMe)4(H2O)3(WO4)2(B-α-PW9O34)2}2]·39H2O (1) and H9[Ni(en)2(H2O)][Ni0.5(en)2(H2O)][Ni-(enMe)2(H2O)][(Sb2O)2(NiW6O24){Ni12O2(OH)4(en)2(enMe)2(H2O)3(WO4)2}-{Ni12O2(OH)4(en)4(H2O)3(WO4)2}(B-α-PW9O34)4]·45H2O (2), have been hydrothermally synthesized and characterized, in which the {Ni12(WO4)2(PW9)2} subunit was obtained by the synergistic directing effect of 2 lacunary PW9O34 (PW9) fragments and further linked by a central Anderson-type (Sb2O)2(NiW6O24) bridge. Both compounds represent the first example of Ni-added polyoxometalates (POMs) simultaneously based on Keggin-type and Anderson-type POM components. Photocatalytic studies revealed that 2 can work as an efficient heterogeneous catalyst towards a light-driven H2 evolution reaction, achieving a hydrogen evolution rate of as high as 19 214 µmol g-1 h-1 (TON = 1500), which is superior to most of the reported POM-based heterogeneous catalysts.

14.
Alzheimers Dement ; 2024 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-39129223

RESUMO

INTRODUCTION: The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability. METHODS: Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. RESULTS: Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets. DISCUSSION: Our study contributes to the current body of evidence on the genetic etiology of ADRD. HIGHLIGHTS: Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.

15.
ACS Appl Mater Interfaces ; 16(32): 41855-41868, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39093305

RESUMO

Inflammation caused by a bacterial infection and the subsequent dysregulation of the host immune-inflammatory response are detrimental to periodontal regeneration. Herein, we present an infection-sensitive scaffold prepared by layer-by-layer assembly of Feraheme-like superparamagnetic iron oxide nanoparticles (SPIONs) on the surface of a three-dimensional-printed polylactic-co-glycolic acid (PLGA) scaffold. The SPION/PLGA scaffold is magnetic, hydrophilic, and bacterial-adhesion resistant. As indicated by gene expression profiling and confirmed by quantitative real-time reverse transcription polymerase chain reaction and flow cytometry analysis, the SPION/PLGA scaffold facilitates macrophage polarization toward the regenerative M2 phenotype by upregulating IL-10, which is the molecular target of repair promotion, and inhibits macrophage polarization toward the proinflammatory M1 phenotype by downregulating NLRP3, which is the molecular target of anti-inflammation. As a result, macrophages modulated by the SPS promote osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs) in vitro. In a rat periodontal defect model, the SPION/PLGA scaffold increased IL-10 secretion and decreased NLRP3 and IL-1ß secretion with Porphyromonas gingivalis infection, achieving superior periodontal regeneration than the PLGA scaffold alone. Therefore, this antibacterial SPION/PLGA scaffold has anti-inflammatory and bacterial antiadhesion properties to fight infection and promote periodontal regeneration by immunomodulation. These findings provide an important strategy for developing engineered scaffolds to treat periodontal defects.


Assuntos
Antibacterianos , Macrófagos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Porphyromonas gingivalis , Alicerces Teciduais , Animais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Ratos , Porphyromonas gingivalis/efeitos dos fármacos , Alicerces Teciduais/química , Ratos Sprague-Dawley , Nanopartículas Magnéticas de Óxido de Ferro/química , Masculino , Regeneração/efeitos dos fármacos , Fenótipo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Camundongos
16.
J Nanobiotechnology ; 22(1): 477, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39135044

RESUMO

The secondary injury is more serious after traumatic brain injury (TBI) compared with primary injury. Release of excessive reactive oxygen species (ROS) and Ca2+ influx at the damaged site trigger the secondary injury. Herein, a neutrophil-like cell membrane-functionalized nanoparticle was developed to prevent ROS-associated secondary injury. NCM@MP was composed of three parts: (1) Differentiated neutrophil-like cell membrane (NCM) was synthesized, with inflammation-responsive ability to achieve effective targeting and to increase the retention time of Mn3O4 and nimodipine (MP) in deep injury brain tissue via C-X-C chemokine receptor type 4, integrin beta 1 and macrophage antigen-1. (2) Nimodipine was used to inhibit Ca2+ influx, eliminating the ROS at source. (3) Mn3O4 further eradicated the existing ROS. In addition, NCM@MP also exhibited desirable properties for T1 enhanced imaging and low toxicity which may serve as promising multifunctional nanoplatforms for precise therapies. In our study, NCM@MP obviously alleviated oxidative stress response, reduced neuroinflammation, protected blood-brain barrier integrity, relieved brain edema, promoted the regeneration of neurons, and improved the cognition of TBI mice. This study provides a promising TBI management to relieve the secondary spread of damage.


Assuntos
Lesões Encefálicas Traumáticas , Cálcio , Nanopartículas , Neutrófilos , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Camundongos , Nanopartículas/química , Cálcio/metabolismo , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Masculino , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos Endogâmicos C57BL
17.
J Med Chem ; 67(14): 11712-11731, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38996382

RESUMO

Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.


Assuntos
Ferroptose , Sequestradores de Radicais Livres , AVC Isquêmico , Ferroptose/efeitos dos fármacos , Animais , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/síntese química , AVC Isquêmico/tratamento farmacológico , Humanos , Camundongos , Relação Estrutura-Atividade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/síntese química , Descoberta de Drogas , Masculino , Estrutura Molecular , Camundongos Endogâmicos C57BL
18.
Nat Commun ; 15(1): 5982, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013902

RESUMO

The Mn4CaO5(6) cluster in photosystem II catalyzes water splitting through the Si state cycle (i = 0-4). Molecular O2 is formed and the natural catalyst is reset during the final S3 → (S4) → S0 transition. Only recently experimental breakthroughs have emerged for this transition but without explicit information on the S0-state reconstitution, thus the progression after O2 release remains elusive. In this report, our molecular dynamics simulations combined with density functional calculations suggest a likely missing link for closing the cycle, i.e., restoring the first catalytic state. Specifically, the formation of closed-cubane intermediates with all hexa-coordinate Mn is observed, which would undergo proton release, water dissociation, and ligand transfer to produce the open-cubane structure of the S0 state. Thereby, we theoretically identify the previously unknown structural isomerism in the S0 state that acts as the origin of the proposed structural flexibility prevailing in the cycle, which may be functionally important for nature's water oxidation catalysis.

19.
CNS Neurosci Ther ; 30(7): e14857, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39014454

RESUMO

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.


Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Demência , Progressão da Doença , Proteínas tau , Humanos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Prognóstico , Demência/diagnóstico , Demência/sangue , Demência/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/sangue , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Idoso de 80 Anos ou mais
20.
Biomed Opt Express ; 15(7): 4044-4064, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39022550

RESUMO

We demonstrate a method that reduces the noise caused by multi-scattering (MS) photons in an in vivo optical coherence tomography image. This method combines a specially designed image acquisition (i.e., optical coherence tomography scan) scheme and subsequent complex signal processing. For the acquisition, multiple cross-sectional images (frames) are sequentially acquired while the depth position of the focus is altered for each frame by an electrically tunable lens. In the signal processing, the frames are numerically defocus-corrected, and complex averaged. Because of the inconsistency in the MS-photon trajectories among the different electrically tunable lens-induced defocus, this averaging reduces the MS signal. Unlike the previously demonstrated volume-wise multi-focus averaging method, our approach requires the sample to remain stable for only a brief period, approximately 70 ms, thus making it compatible with in vivo imaging. This method was validated using a scattering phantom and in vivo unanesthetized small fish samples, and was found to reduce MS noise even for unanesthetized in vivo measurement.

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