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1.
Genes Dev ; 33(3-4): 221-235, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30692206

RESUMEN

Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52-null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability.


Asunto(s)
Proteína Recombinante y Reparadora de ADN Rad52/metabolismo , Recombinasas/metabolismo , Homeostasis del Telómero/genética , Línea Celular Tumoral , Roturas del ADN de Doble Cadena , Técnicas de Inactivación de Genes , Inestabilidad Genómica/genética , Células HEK293 , Células HeLa , Humanos , Interfase , Proteína Recombinante y Reparadora de ADN Rad52/genética , Recombinasas/genética
2.
Nat Methods ; 20(8): 1244-1255, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37460718

RESUMEN

A fundamental interest in developmental neuroscience lies in the ability to map the complete single-cell lineages within the brain. To this end, we developed a CRISPR editing-based lineage-specific tracing (CREST) method for clonal tracing in Cre mice. We then used two complementary strategies based on CREST to map single-cell lineages in developing mouse ventral midbrain (vMB). By applying snapshotting CREST (snapCREST), we constructed a spatiotemporal lineage landscape of developing vMB and identified six progenitor archetypes that could represent the principal clonal fates of individual vMB progenitors and three distinct clonal lineages in the floor plate that specified glutamatergic, dopaminergic or both neurons. We further created pandaCREST (progenitor and derivative associating CREST) to associate the transcriptomes of progenitor cells in vivo with their differentiation potentials. We identified multiple origins of dopaminergic neurons and demonstrated that a transcriptome-defined progenitor type comprises heterogeneous progenitors, each with distinct clonal fates and molecular signatures. Therefore, the CREST method and strategies allow comprehensive single-cell lineage analysis that could offer new insights into the molecular programs underlying neural specification.


Asunto(s)
Encéfalo , Células Madre , Ratones , Animales , Linaje de la Célula , Diferenciación Celular/fisiología , Neuronas Dopaminérgicas
3.
Neuroimage ; 290: 120578, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38499051

RESUMEN

Face perception is a complex process that involves highly specialized procedures and mechanisms. Investigating into face perception can help us better understand how the brain processes fine-grained, multidimensional information. This research aimed to delve deeply into how different dimensions of facial information are represented in specific brain regions or through inter-regional connections via an implicit face recognition task. To capture the representation of various facial information in the brain, we employed support vector machine decoding, functional connectivity, and model-based representational similarity analysis on fMRI data, resulting in the identification of three crucial findings. Firstly, despite the implicit nature of the task, emotions were still represented in the brain, contrasting with all other facial information. Secondly, the connection between the medial amygdala and the parahippocampal gyrus was found to be essential for the representation of facial emotion in implicit tasks. Thirdly, in implicit tasks, arousal representation occurred in the parahippocampal gyrus, while valence depended on the connection between the primary visual cortex and the parahippocampal gyrus. In conclusion, these findings dissociate the neural mechanisms of emotional valence and arousal, revealing the precise spatial patterns of multidimensional information processing in faces.


Asunto(s)
Emociones , Imagen por Resonancia Magnética , Humanos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Giro Parahipocampal/diagnóstico por imagen , Expresión Facial
4.
Small ; : e2404815, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39105462

RESUMEN

The strong anti-inflammatory effect of methylprednisolone (MP) is a necessary treatment for various severe cases including acute spinal cord injury (SCI). However, concerns have been raised regarding adverse effects from MP, which also severely limits its clinical application. Natural polyphenols, due to their rich phenolic hydroxyl chemical properties, can form dynamic structures without additional modification, achieving targeted enrichment and drug release at the disease lesion, making them a highly promising carrier. Considering the clinical application challenges of MP, a natural polyphenolic platform is employed for targeted and efficient delivery of MP, reducing its systemic side effects. Both in vitro and SCI models demonstrated polyphenols have multiple advantages as carriers for delivering MP: (1) Achieved maximum enrichment at the injured site in 2 h post-administration, which met the desires of early treatment for diseases; (2) Traceless release of MP; (3) Reducing its side effects; (4) Endowed treatment system with new antioxidative properties, which is also an aspect that needs to be addressed for diseases treatment. This study highlighted a promising prospect of the robust delivery system based on natural polyphenols can successfully overcome the barrier of MP treatment, providing the possibility for its widespread clinical application.

5.
Small ; : e2401731, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38682736

RESUMEN

Natural polyphenolic compounds play a vital role in nature and are widely utilized as building blocks in the fabrication of emerging functional nanomaterials. Although diverse fabrication methodologies are developed in recent years, the challenges of purification, uncontrollable reaction processes and additional additives persist. Herein, a modular and facile methodology is reported toward the fabrication of natural polyphenolic nanoparticles. By utilizing low frequency ultrasound (40 kHz), the assembly of various natural polyphenolic building blocks is successfully induced, allowing for precise control over the particle formation process. The resulting natural polyphenolic nanoparticles possessed excellent in vitro antioxidative abilities and in vivo therapeutic effects in typical oxidative stress models including wound healing and acute kidney injury. This study opens new avenues for the fabrication of functional materials from naturally occurring building blocks, offering promising prospects for future advancements in this field.

6.
Blood ; 140(12): 1431-1447, 2022 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-35443019

RESUMEN

Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.


Asunto(s)
Enfermedad Injerto contra Huésped , Animales , Trasplante de Médula Ósea/efectos adversos , Células Dendríticas , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismo , Péptido Intestinal Vasoactivo/metabolismo
7.
Cardiovasc Diabetol ; 23(1): 123, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38581039

RESUMEN

BACKGROUND: Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS: We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS: Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION: Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.


Asunto(s)
Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Microbioma Gastrointestinal , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Fusobacterium nucleatum/fisiología , Enfermedad de la Arteria Coronaria/etiología
8.
Biomacromolecules ; 25(4): 2563-2573, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38485470

RESUMEN

In the current years, polydopamine nanoparticles (PDA NPs) have been extensively investigated as an eumelanin mimic. However, unlike natural eumelanin, PDA NPs contain no 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-derived units and may be limited in certain intrinsic properties; superior eumelanin-like nanomaterials are still actively being sought. Levodopa (l-DOPA) is a natural eumelanin precursor and expected to convert into DHICA and further remain within the final product through covalent or physical interactions. Herein, poly(levodopa) nanoparticles [P(l-DOPA) NPs] were synthesized with the assistance of zinc oxide as a supplement to synthetic eumelanin. This study found that P(l-DOPA) NPs had ∼90% DHICA-derived subunits on their surface and exhibited superior antioxidant activity compared to PDA NPs due to their looser polymeric microstructure. Benefitting from a stronger ROS scavenging ability, P(l-DOPA) NPs outperformed PDA NPs in treating cellular oxidative stress and acute inflammation. This research opens up new possibilities for the development and application of novel melanin-like materials.


Asunto(s)
Levodopa , Melaninas , Humanos , Melaninas/química , Antioxidantes , Inflamación/tratamiento farmacológico
9.
Biomacromolecules ; 25(4): 2607-2620, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38530873

RESUMEN

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.


Asunto(s)
Nanopartículas , Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Humanos , Riluzol/farmacología , Riluzol/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Traumatismos de la Médula Espinal/tratamiento farmacológico , Ácido Glutámico , Inflamación/tratamiento farmacológico , Médula Espinal
10.
Biomacromolecules ; 25(2): 1133-1143, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38226558

RESUMEN

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.


Asunto(s)
Nanopartículas Multifuncionales , Nanopartículas , Sepsis , Humanos , Lipopolisacáridos/toxicidad , Peróxido de Hidrógeno , Polimixina B/farmacología , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Especies Reactivas de Oxígeno/metabolismo
11.
Artículo en Inglés | MEDLINE | ID: mdl-38453435

RESUMEN

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

12.
Nature ; 557(7705): 424-428, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29743678

RESUMEN

Triticum urartu (diploid, AA) is the progenitor of the A subgenome of tetraploid (Triticum turgidum, AABB) and hexaploid (Triticum aestivum, AABBDD) wheat1,2. Genomic studies of T. urartu have been useful for investigating the structure, function and evolution of polyploid wheat genomes. Here we report the generation of a high-quality genome sequence of T. urartu by combining bacterial artificial chromosome (BAC)-by-BAC sequencing, single molecule real-time whole-genome shotgun sequencing 3 , linked reads and optical mapping4,5. We assembled seven chromosome-scale pseudomolecules and identified protein-coding genes, and we suggest a model for the evolution of T. urartu chromosomes. Comparative analyses with genomes of other grasses showed gene loss and amplification in the numbers of transposable elements in the T. urartu genome. Population genomics analysis of 147 T. urartu accessions from across the Fertile Crescent showed clustering of three groups, with differences in altitude and biostress, such as powdery mildew disease. The T. urartu genome assembly provides a valuable resource for studying genetic variation in wheat and related grasses, and promises to facilitate the discovery of genes that could be useful for wheat improvement.


Asunto(s)
Evolución Molecular , Genoma de Planta/genética , Filogenia , Triticum/clasificación , Triticum/genética , Altitud , Cromosomas Artificiales Bacterianos/genética , Cromosomas de las Plantas/genética , Elementos Transponibles de ADN/genética , Variación Genética , Mapeo Geográfico , Anotación de Secuencia Molecular , Enfermedades de las Plantas/microbiología , Análisis de Secuencia de ADN , Sintenía/genética
13.
Ann Vasc Surg ; 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39096958

RESUMEN

BACKGROUND: Chronic limb-threatening ischemia (CLTI) represents the severest manifestation of peripheral artery disease. Malnutrition is closely associated with poor clinical outcomes in patients with chronic diseases. The Controlling Nutritional Status (CONUT) score is a tool to evaluate the systemic inflammation and nutritional status. This study aimed to investigate the association of baseline CONUT score with mortality in patients with CLTI following endovascular revascularization. METHODS: A single-center retrospective analysis of patients with CLTI undergoing endovascular revascularization between January 2015 and December 2022 was performed. Preoperative nutritional status was evaluated using CONUT score, which was calculated using the serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration. A CONUT score ≥5 indicates moderate or severe malnutrition. The Kaplan-Meier and multivariate Cox proportional hazards regression were used for survival analysis and to evaluate the risk factors associated with mortality. RESULTS: Among 232 enrolled patients, 20.7% of patients had moderate or severe malnutrition defined by the CONUT score. During a median follow-up of 2.1 (interquartile ranges, 1.0-3.5) years, 87 (37.5%) patients died. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 63.7%. The high CONUT (≥5) group had significantly worse 3-year overall survival (42.0% versus 68.8%, P=0.004) and limb salvage (73.3% versus 84.1%, P=0.005) rates than the low CONUT (<5) group. Multivariate analysis showed that high CONUT score was significantly associated with increased risk for mortality in patients with CLTI after endovascular revascularization (hazard ratio, 1.687; 95% confidence interval, 1.031-2.759; P=0.037). CONCLUSION: The present study indicated that moderate or severe malnutrition defined by the CONUT score was significantly associated with increased mortality in patients with CLTI following endovascular revascularization. Future study is required to evaluate the efficacy of nutritional intervention in these patients.

14.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-34921116

RESUMEN

Crystallization is a fundamental natural phenomenon and the ubiquitous physical process in materials science for the design of new materials. So far, experimental observations of the structural dynamics in crystallization have been mostly restricted to slow dynamics. We present here an exclusive way to explore the dynamics of crystallization in highly controlled conditions (i.e., in the absence of impurities acting as seeds of the crystallites) as it occurs in vacuum. We have measured the early formation stage of solid Xe nanoparticles nucleated in an expanding supercooled Xe jet by means of an X-ray diffraction experiment with 10-fs X-ray free-electron laser (XFEL) pulses. We found that the structure of Xe nanoparticles is not pure face-centered cubic (fcc), the expected stable phase, but a mixture of fcc and randomly stacked hexagonal close-packed (rhcp) structures. Furthermore, we identified the instantaneous coexistence of the comparably sized fcc and rhcp domains in single Xe nanoparticles. The observations are explained by the scenario of structural aging, in which the nanoparticles initially crystallize in the highly stacking-disordered rhcp phase and the structure later forms the stable fcc phase. The results are reminiscent of analogous observations in hard-sphere systems, indicating the universal role of the stacking-disordered phase in nucleation.

15.
Pestic Biochem Physiol ; 199: 105795, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38458689

RESUMEN

Fusarium head blight in wheat is caused by Fusarium graminearum, resulting in significant yield losses and grain contamination with deoxynivalenol (DON), which poses a potential threat to animal health. Cyclobutrifluram, a newly developed succinate dehydrogenase inhibitor, has shown excellent inhibition of Fusarium spp. However, the resistance risk of F. graminearum to cyclobutrifluram and the molecular mechanism of resistance have not been determined. In this study, we established the average EC50 of a range of F. graminearum isolates to cyclobutrifluram to be 0.0110 µg/mL. Six cyclobutrifluram-resistant mutants were obtained using fungicide adaptation. All mutants exhibited impaired fitness relative to their parental isolates. This was evident from measurements of mycelial growth, conidiation, conidial germination, virulence, and DON production. Interestingly, cyclobutrifluram did not seem to affect the DON production of either the sensitive isolates or the resistant mutants. Furthermore, a positive cross-resistance was observed between cyclobutrifluram and pydiflumetofen. These findings suggest that F. graminearum carries a moderate to high risk of developing resistance to cyclobutrifluram. Additionally, point mutations H248Y in FgSdhB and A73V in FgSdhC1 of F. graminearum were observed in the cyclobutrifluram-resistant mutants. Finally, an overexpression transformation assay and molecular docking indicated that FgSdhBH248Y or FgSdhC1A73V could confer resistance of F. graminearum to cyclobutrifluram.


Asunto(s)
Fungicidas Industriales , Fusarium , Fungicidas Industriales/farmacología , Simulación del Acoplamiento Molecular , Micelio , Enfermedades de las Plantas
16.
Pestic Biochem Physiol ; 199: 105786, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38458686

RESUMEN

Ipconazole is a broad-spectrum triazole fungicide that is highly effective against Fusarium pseudograminearum. However, its risk of developing resistance and mechanism are not well understood in F. pseudograminearum. Here, the sensitivities of 101 F. pseudograminearum isolates to ipconazole were investigated, and the average EC50 value was 0.1072 µg/mL. Seven mutants resistant to ipconazole were obtained by fungicide adaption, with all but one showing reduced fitness relative to the parental isolates. Cross-resistance was found between ipconazole and mefentrifluconazole and tebuconazole, but none between ipconazole and pydiflumetofen, carbendazim, fludioxonil, or phenamacril. In summary, these findings suggest that there is a low risk of F. pseudograminearum developing resistance to ipconazole. Additionally, a point mutation, G464S, was seen in FpCYP51B and overexpression of FpCYP51A, FpCYP51B and FpCYP51C was observed in ipconazole-resistant mutants. Assays, including transformation and molecular docking, indicated that G464S conferred ipconazole resistance in F. pseudograminearum.


Asunto(s)
Fungicidas Industriales , Fusarium , Farmacorresistencia Fúngica/genética , Fungicidas Industriales/farmacología , Simulación del Acoplamiento Molecular , Fusarium/genética , Desmetilación , Enfermedades de las Plantas
17.
Sensors (Basel) ; 24(6)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38543998

RESUMEN

To solve the problems of high computational cost and the long time required by the simulation and calculation of aeroengines' exhaust systems, a method of predicting the characteristics of infrared radiation based on the hybrid kernel extreme learning machine (HKELM) optimized by the improved dung beetle optimizer (IDBO) was proposed. Firstly, the Levy flight strategy and variable spiral strategy were introduced to improve the optimization performance of the dung beetle optimizer (DBO) algorithm. Secondly, the superiority of IDBO algorithm was verified by using 23 benchmark functions. In addition, the Wilcoxon signed-rank test was applied to evaluate the experimental results, which proved the superiority of the IDBO algorithm over other current prominent metaheuristic algorithms. Finally, the hyperparameters of HKELM were optimized by the IDBO algorithm, and the IDBO-HKELM model was applied to the prediction of characteristics of infrared radiation of a typical axisymmetric nozzle. The results showed that the RMSE and MAE of the IDBO-HKELM model were 20.64 and 8.83, respectively, which verified the high accuracy and feasibility of the proposed method for predictions of aeroengines' infrared radiation characteristics.

18.
Molecules ; 29(3)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38338427

RESUMEN

Peptide-based biomimetic underwater adhesives are emerging candidates for understanding the adhesion mechanism of natural proteins secreted by sessile organisms. However, there is a grand challenge in the functional recapitulation of the on-site interfacial spreading, adhesion and spontaneous solidification of native proteins in water using peptide adhesives without applied compressing pressure. Here, a solvent-exchange strategy was utilized to exert the underwater injection, on-site spreading, adhesion and sequential solidification of a series of peptide/polyoxometalate coacervates. The coacervates were first prepared in a mixed solution of water and organic solvents by rationally suppressing the non-covalent interactions. After switching to a water environment, the solvent exchange between bulk water and the organic solvent embedded in the matrix of the peptide/polyoxometalate coacervates recovered the hydrophobic effect by increasing the dielectric constant, resulting in a phase transition from soft coacervates to hard solid with enhanced bulk cohesion and thus compelling underwater adhesive performance. The key to this approach is the introduction of suitable organic solvents, which facilitate the control of the intermolecular interactions and the cross-linking density of the peptide/polyoxometalate adhesives in the course of solidification under the water line. The solvent-exchange method displays fascinating universality and compatibility with different peptide segments.

19.
J Am Chem Soc ; 145(28): 15538-15546, 2023 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-37413790

RESUMEN

Metallacarboranes have attracted significant attention due to their unique properties. Considerable efforts have been made on the reactions around the metal centers or the metal ion itself, while transformations of functional groups of the metallacarboranes have been much less explored. We presented here the formation of imidazolium-functionalized nickelacarboranes (2), their subsequent conversion to nickelacarborane-supported N-heterocyclic carbenoids (NHCs, 3), and the reactivities of 3 toward Au(PPh3)Cl and Se powder, which resulted in the formation of bis-gold carbene complexes (4) and NHC selenium adducts (5). Cyclic voltammetry of 4 shows two reversible peaks, corresponding to the interconversion transformations NiII ↔ NiIII and NiIII ↔ NiIV. Theoretical calculations demonstrated relatively high-lying lone-pair orbitals, weak B-H···H-C interactions between the BH units and the methyl group, and weak B-H···π interactions between the BH groups and the vacant p-orbital of the carbene.

20.
Clin Exp Immunol ; 213(1): 114-124, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-36840628

RESUMEN

(IL)-17A, the effective factor of Th17 cells, acts an important pathological role in the pathogenesis of psoriasis. Notch1/hairy and split 1 (Hes1) and PI3K/AKT signaling pathways are interpenetrated and involved in Th17 cell differentiation and IL-17A production. In this present study, we used imiquimod (IMQ)-induced mouse psoriatic skin inflammation to explore the possible mechanism of Notch1/Hes1-PTEN/AKT/IL-17A feedback loop in psoriasis by employing AKT inhibitor LY294002 as an intervention with the methods of flow cytometry analysis, reverse transcription-quantitative polymerase chain reaction, western blot, co-immunoprecipitation, and immunofluorescence. First, LY294002 inhibition can obviously alleviate the mouse psoriatic skin inflammation both in skin structural and histopathological characteristics, which is similar to the changes found in IL-17A antibody-treated mice. Additionally, the interaction between Notch1 intracellular domain (NICD1) and nuclear factor kappa B (NF-κB) activator 1 (Act1) was demonstrated. LY294002 interruption resulted in consistent changes in expression levels of key signaling molecules both in Notch1/Hes1 and PI3K/AKT signaling pathways in a time-dependent manner. Moreover, chloroquine (CQ) can partly reverse the inhibitory effects of LY294002 on the Notch1/Hes1-PTEN/AKT/IL-17A feedback loop by affecting Notch1 ubiquitination and lysosomal degradation. The present study showed that LY294002 can exert the inhibitory effect on Notch1/Hes1-PTEN/AKT/IL-17A feedback loop to regulate Th17 cell differentiation and IL-17A function in the process of psoriasis, which provides a new possible therapeutic strategy for psoriasis.


Asunto(s)
Interleucina-17 , Psoriasis , Ratones , Animales , Interleucina-17/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Retroalimentación , Fosfatidilinositol 3-Quinasas/metabolismo , Piel/metabolismo , Psoriasis/metabolismo , Inflamación/metabolismo , Modelos Animales de Enfermedad , Factor de Transcripción HES-1/metabolismo
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