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1.
Int J Biol Sci ; 20(7): 2686-2697, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725852

RESUMO

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Breast cancer stem cells (BCSCs) are believed to play a crucial role in the carcinogenesis, therapy resistance, and metastasis of TNBC. It is well known that inflammation promotes stemness. Several studies have identified breast cancer-associated gene 2 (BCA2) as a potential risk factor for breast cancer incidence and prognosis. However, whether and how BCA2 promotes BCSCs has not been elucidated. Here, we demonstrated that BCA2 specifically promotes lipopolysaccharide (LPS)-induced BCSCs through LPS induced SOX9 expression. BCA2 enhances the interaction between myeloid differentiation primary response protein 88 (MyD88) and Toll-like receptor 4 (TLR4) and inhibits the interaction of MyD88 with deubiquitinase OTUD4 in the LPS-mediated NF-κB signaling pathway. And SOX9, an NF-κB target gene, mediates BCA2's pro-stemness function in TNBC. Our findings provide new insights into the molecular mechanisms by which BCA2 promotes breast cancer and potential therapeutic targets for the treatment of breast cancer.


Assuntos
Lipopolissacarídeos , Células-Tronco Neoplásicas , Fatores de Transcrição SOX9 , Humanos , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/genética , Feminino , Lipopolissacarídeos/farmacologia , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Regulação para Cima , Transdução de Sinais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Regulação Neoplásica da Expressão Gênica
2.
Nat Biomed Eng ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693431

RESUMO

Bispecific T-cell engagers (BiTEs) bring together tumour cells and cytotoxic T cells by binding to specific cell-surface tumour antigens and T-cell receptors, and have been clinically successful for the treatment of B-cell malignancies. Here we show that a BiTE-sialidase fusion protein enhances the susceptibility of solid tumours to BiTE-mediated cytolysis of tumour cells via targeted desialylation-that is, the removal of terminal sialic acid residues on glycans-at the BiTE-induced T-cell-tumour-cell interface. In xenograft and syngeneic mouse models of leukaemia and of melanoma and breast cancer, and compared with the parental BiTE molecules, targeted desialylation via the BiTE-sialidase fusion proteins enhanced the formation of immunological synapses, T-cell activation and T-cell-mediated tumour-cell cytolysis in the presence of the target antigen. The targeted desialylation of tumour cells may enhance the potency of therapies relying on T-cell engagers.

3.
Mol Phylogenet Evol ; 196: 108072, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38615706

RESUMO

While the diversity of species formation is broadly acknowledged, significant debate exists regarding the universal nature of hybrid species formation. Through an 18-year comprehensive study of all Populus species on the Qinghai-Tibet Plateau, 23 previously recorded species and 8 new species were identified. Based on morphological characteristics, these can be classified into three groups: species in section Leucoides, species with large leaves, and species with small leaves in section Tacamahaca. By conducting whole-genome re-sequencing of 150 genotypes from these 31 species, 2.28 million single nucleotide polymorphisms (SNPs) were identified. Phylogenetic analysis utilizing these SNPs not only revealed a highly intricate evolutionary network within the large-leaf species of section Tacamahaca but also confirmed that a new species, P. curviserrata, naturally hybridized with P. cathayana, P. szechuanica, and P. ciliata, resulting in 11 hybrid species. These findings indicate the widespread occurrence of hybrid species formation within this genus, with hybridization serving as a key evolutionary mechanism for Populus on the plateau. A novel hypothesis, "Hybrid Species Exterminating Their Ancestral Species (HSEAS)," is introduced to explain the mechanisms of hybrid species formation at three different scales: the entire plateau, the southeastern mountain region, and individual river valleys.


Assuntos
Especiação Genética , Hibridização Genética , Filogenia , Polimorfismo de Nucleotídeo Único , Populus , Populus/genética , Populus/classificação , Tibet
4.
Free Radic Biol Med ; 219: 163-179, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38615890

RESUMO

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is one of the liver illnesses that may be affected by mitophagy, which is the selective removal of damaged mitochondria. RNF31, an E3 ubiquitin ligase, is carcinogenic in many malignancies. However, the influence of RNF31 on mitochondrial homeostasis and NAFLD development remains unknown. METHODS: Oleic-palmitic acid treated hepatocytes and high-fat diet (HFD)-fed mice were established to observe the effect of RNF31 on hepatocyte mitophagy and steatosis. Mitophagy processes were comprehensively assessed by mt-Keima fluorescence imaging, while global changes in hepatic gene expression were measured by RNA-seq. RESULTS: The present study discovered a reduction in RNF31 expression in lipotoxic hepatocytes with mitochondrial dysfunction. The observed decrease in RNF31 expression was associated with reduced mitochondrial membrane potential, disturbed mitophagy, and increased steatosis. Additionally, the findings indicated that RNF31 is a pivotal factor in the initiation of mitophagy and the facilitation of mitochondrial homeostasis, resulting in a decrease in steatosis in lipotoxic hepatocytes. Mechanistically, RNF31 enhanced p53 ubiquitination and subsequent proteasomal degradation. Down-regulation of p53 led to increased expression of the mitophagy receptor protein BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), thereby promoting mitophagy in hepatocytes. Furthermore, it was demonstrated that the transportation of RNF31 via small extracellular vesicles derived from mesenchymal stem cells (referred to as sEV) had a substantial influence on reducing hepatic steatosis and restoring liver function in HFD-fed mice. CONCLUSIONS: The findings highlight RNF31's essential role in the regulation of mitochondrial homeostasis in hepatocytes, emphasizing its potential as a therapeutic target for NAFLD.


Assuntos
Dieta Hiperlipídica , Hepatócitos , Proteínas de Membrana , Mitofagia , Hepatopatia Gordurosa não Alcoólica , Proteína Supressora de Tumor p53 , Ubiquitina-Proteína Ligases , Animais , Mitofagia/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Humanos , Dieta Hiperlipídica/efeitos adversos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Ubiquitinação , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Masculino , Camundongos Endogâmicos C57BL , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/genética
5.
Int Immunopharmacol ; 132: 111999, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38581994

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.


Assuntos
Fibrose Pulmonar Idiopática , Imunossupressores , Camundongos Endogâmicos C57BL , Monócitos , Tacrolimo , Tacrolimo/uso terapêutico , Tacrolimo/farmacologia , Animais , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/patologia , Camundongos , Imunossupressores/uso terapêutico , Imunossupressores/farmacologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Imunidade Inata/efeitos dos fármacos , Indóis/uso terapêutico , Indóis/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Progressão da Doença , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Células Cultivadas , Masculino , Citocinas/metabolismo , Miofibroblastos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças
6.
J Bone Miner Res ; 39(3): 326-340, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38477820

RESUMO

Proteasome activator subunit 3 (PA28γ) is a member of the proteasome activator family, which mainly regulates the degradation and stability of proteins. Studies have shown that it plays crucial roles in lipid formation, stemness maintenance, and blood vessel formation. However, few studies have clarified the association between PA28γ and bone diseases. Herein, we identified PA28γ as a previously unknown regulator of bone homeostasis that coordinates bone formation and lipid accumulation. PA28γ-knockout mice presented with the characteristics of low bone mass and accumulation of lipids. Suppressed expression of PA28γ restrained the osteogenic differentiation and enhanced the adipogenic differentiation of bone marrow stromal cells (BMSCs). Overexpression of PA28γ promoted osteogenic differentiation and inhibited adipogenic differentiation of BMSCs. Mechanistically, PA28γ interacted with Wnt5α, and the two interactors appeared to be positively correlated. PA28γ mainly activated the downstream Wnt/ß-catenin signaling pathway, which affects BMSCs differentiation homeostasis. Deletion of Wnt5α significantly delayed the promotion of osteogenic differentiation and partially alleviated the inhibitory effect of adipogenic differentiation of BMSCs in the PA28γ-overexpressing group. Furthermore, we demonstrated that PA28γ-knockout mice had an inhibited rate of bone healing in a drill-hole femoral bone defect model in vivo. Therefore, our results confirm the effects of PA28γ on bone formation and bone defect repair, indicating that PA28γ mainly interacts with Wnt5α to activate the Wnt/ß-catenin signaling pathway regulating BMSCs differentiation homeostasis. Our results reveal the function of PA28γ in bone diseases and provide a new theoretical basis for expanding the treatment of bone diseases.


Assuntos
Autoantígenos , Doenças Ósseas , Células-Tronco Mesenquimais , Camundongos , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/farmacologia , Osteogênese , beta Catenina/metabolismo , Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Via de Sinalização Wnt/fisiologia , Doenças Ósseas/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas , Camundongos Knockout , Lipídeos
7.
J Hazard Mater ; 469: 133760, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38522206

RESUMO

This study aimed to assess the global spatiotemporal variations of trihalomethanes (THMs) in drinking water, evaluate their cancer and non-cancer risks, and THM-attributable bladder cancer burden. THM concentrations in drinking water around fifty years on a global scale were integrated. Health risks were assessed using Monte Carlo simulations and attributable bladder cancer burden was estimated by comparative risk assessment methodology. The results showed that global mean THM concentrations in drinking water significantly decreased from 78.37 µg/L (1973-1983) to 51.99 µg/L (1984-2004) and to 21.90 µg/L (after 2004). The lifestage-integrative cancer risk and hazard index of THMs through all exposure pathways were acceptable with the average level of 6.45 × 10-5 and 7.63 × 10-2, respectively. The global attributable disability adjusted of life years (DALYs) and the age-standardized DALYs rate (ASDR) dropped by 16% and 56% from 1990-1994 to 2015-2019, respectively. A big decline in the attributable ASDR was observed in the United Kingdom (62%) and the United States (27%), while China experienced a nearly 3-fold increase due to the expanded water supply coverage and increased life expectancy. However, China also benefited from the spread of chlorination, which helped reduce nearly 90% of unsafe-water-caused mortality from 1998 to 2018.


Assuntos
Água Potável , Neoplasias da Bexiga Urinária , Poluentes Químicos da Água , Humanos , Trialometanos/toxicidade , Trialometanos/análise , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia , Efeitos Psicossociais da Doença , Medição de Risco , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise
8.
Cell Chem Biol ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38508196

RESUMO

Immunology was one of the first biological fields to embrace chemical approaches. The development of new chemical approaches and techniques has provided immunologists with an impressive arsenal of tools to address challenges once considered insurmountable. This review focuses on advances at the interface of chemistry and immunobiology over the past two decades that have not only opened new avenues in basic immunological research, but also revolutionized drug development for the treatment of cancer and autoimmune diseases. These include chemical approaches to understand and manipulate antigen presentation and the T cell priming process, to facilitate immune cell trafficking and regulate immune cell functions, and therapeutic applications of chemical approaches to disease control and treatment.

9.
Genes (Basel) ; 15(3)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38540322

RESUMO

Lindera aggregata is a species of the Lauraceae family, which has important medicinal, economic and ornamental values. In this study, we sequenced, assembled and annotated the chloroplast genome of L. aggregata and reannotated and corrected eight unverified annotations in the same genus. The chloroplast genomes taxa from Lindera and from different genera of Lauraceae were compared and analyzed, and their phylogenetic relationship and divergence time were speculated. All the 36 chloroplast genomes had typical quadripartite structures that ranged from 150,749 to 154,736 bp in total length. These genomes encoded 111-112 unique genes, including 78-79 protein-coding genes, 29-30 tRNA and 4 rRNA. Furthermore, there were 78-97 SSRs loci in these genomes, in which mononucleotide repeats were the most abundant; there were 24-49 interspersed repeats, and forward repeat types were the most frequent. The codon bias patterns of all species tended to use codons ending with A or U. Five and six highly variable regions were identified within genus and between genera, respectively, and three common regions (ycf1, ndhF-rpl32 and rpl32-trnL) were identified, which can be used as important DNA markers for phylogeny and species identification. According to the evaluation of the Ka/Ks ratio, most of the genes were under purifying selection, and only 10 genes were under positive selection. Finally, through the construction of the evolutionary tree of 39 chloroplast genomes, the phylogenetic relationship of Lauraceae was clarified and the evolutionary relationship of Lindera was revealed. The species of genus Lindera experienced rapid adaptive radiation from Miocene to Pleistocene. The results provided valuable insights for the study of chloroplast genomes in the Lauraceae family, especially in the genus Lindera.


Assuntos
Genoma de Cloroplastos , Lindera , Filogenia , Lindera/genética , Genoma de Cloroplastos/genética , Evolução Biológica , Marcadores Genéticos
10.
ACS Nano ; 18(11): 8125-8142, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38451090

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.


Assuntos
Cartilagem Articular , Células-Tronco Mesenquimais , Osteoartrite , Sinovite , Camundongos , Animais , Condrogênese , Nanomedicina , Osteoartrite/tratamento farmacológico , Diferenciação Celular , Inflamação/metabolismo , Sinovite/metabolismo , RNA Mensageiro/metabolismo
11.
Sci Prog ; 107(1): 368504241236345, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38490169

RESUMO

The accurate identification of dynamic change of limb length discrepancy (LLD) in non-clinical settings is of great significance for monitoring gait function change in people's everyday lives. How to search for advanced techniques to measure LLD changes in non-clinical settings has always been a challenging endeavor in recent related research. In this study, we have proposed a novel approach to accurately measure the dynamic change of LLD outdoors by using deep learning and wearable sensors. The basic idea is that the measurement of dynamic change of LLD was considered as a multiple gait classification task based on LLD change that is clearly associated with its gait pattern. A hybrid deep learning model of convolutional neural network and long short-term memory (CNN-LSTM) was developed to precisely classify LLD gait patterns by discovering the most representative spatial-temporal LLD dynamic change features. Twenty-three healthy subjects were recruited to simulate four levels of LLD by wearing a shoe lift with different heights. The Delsys TrignoTM system was implemented to simultaneously acquire gait data from six sensors positioned on the hip, knee and ankle joint of two lower limbs respectively. The experimental results showed that the developed CNN-LSTM model could reach a higher accuracy of 93.24% and F1-score of 93.48% to classify four different LLD gait patterns when compared with CNN, LSTM, and CNN-gated recurrent unit(CNN-GRU), and gain better recall and precision (more than 92%) to detect each LLD gait pattern accurately. Our model could achieve excellent learning ability to discover the most representative LLD dynamic change features for classifying LLD gait patterns accurately. Our technical solution would help not only to accurately measure LLD dynamic change in non-clinical settings, but also to potentially find out lower limb joints with more abnormal compensatory change caused by LLD.


Assuntos
Aprendizado Profundo , Dispositivos Eletrônicos Vestíveis , Humanos , Desigualdade de Membros Inferiores/diagnóstico , Desigualdade de Membros Inferiores/etiologia , Marcha , Articulação do Joelho
12.
J Pharm Pharmacol ; 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38530642

RESUMO

OBJECTIVES: Several studies have shown that propofol administration during surgery effectively attenuates remifentanil-induced hyperalgesia (RIH). Ciprofol, a novel intravenous sedative agent analogous to propofol, has not yet been proven efficacious in alleviating RIH. The present study aimed to investigate the effect of ciprofol on RIH and the possible mechanisms involved. METHODS: The RIH model was established by an infusion of remifentanil (1 µg·kg-1·min-1) 60 min in rats with incisional pain. Ciprofol (0.1, 0.25, and 0.4 mg·kg-1·min-1) was simultaneously infused to evaluate its effect on RIH. The antinociception of ciprofol was verified by measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). γ-aminobutyric acid type A receptor α2 subunit (α2GABAAR), N-methyl-d-aspartate receptor NR2B subunit (NR2B), calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and phosphorylated CaMKIIα (P-CaMKIIα) in the spinal cord and hippocampus of rats were assessed by western blotting and immunohistochemistry. KEY FINDINGS: The results showed that ciprofol dose-dependently increased PWMT and PWTL values in RIH rats. Moreover, ciprofol upregulated α2GABAAR and downregulated NR2B and P-CaMKIIα in the rat spinal cord and hippocampus. CONCLUSIONS: Ciprofol alleviates RIH effectively, and the anti-hyperalgesic mechanisms may involve increasing α2GABAAR levels and decreasing NR2B and P-CaMKIIα levels in the spinal cord and hippocampus.

13.
Plants (Basel) ; 13(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38337963

RESUMO

Improving fruit size or weight, firmness, and shelf life is a major target for horticultural crop breeding. It is associated with the depolymerization and rearrangement of cell components, including pectin, hemicellulose, cellulose, and other structural (glyco)proteins. Expansins are structural proteins to loosen plant cell wall polysaccharides in a pH-dependent manner and play pivotal roles in the process of fruit development, ripening, and softening. Rubus chingii Hu, a unique Chinese red raspberry, is a prestigious pharmaceutical and nutraceutical dual-function food with great economic value. Thirty-three RchEXPs were predicted by genome-wide identification in this study, containing twenty-seven α-expansins (EXPAs), three ß-expansins (EXPBs), one expansin-like A (EXPLA), and two expansin-like B (EXPLBs). Subsequently, molecular characteristics, gene structure and motif compositions, phylogenetic relationships, chromosomal location, collinearity, and regulatory elements were further profiled. Furthermore, transcriptome sequencing (RNA-seq) and real-time quantitative PCR assays of fruits from different developmental stages and lineages showed that the group of RchEXPA5, RchEXPA7, and RchEXPA15 were synergistically involved in fruit expanding and ripening, while another group of RchEXPA6 and RchEXPA26 might be essential for fruit ripening and softening. They were regulated by both abscisic acid and ethylene and were collinear with phylogenetic relationships in the same group. Our new findings laid the molecular foundation for improving the fruit texture and shelf life of R. chingii medicinal and edible fruit.

14.
Adv Sci (Weinh) ; 11(13): e2306792, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38288517

RESUMO

This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation's unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation.


Assuntos
Líquidos Iônicos , Distrofia Muscular de Duchenne , Animais , Camundongos , Códon sem Sentido/genética , Camundongos Endogâmicos mdx , Líquidos Iônicos/uso terapêutico , Aminoácidos , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo
15.
Small ; : e2311180, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38174602

RESUMO

The practical application of the room-temperature sodium-sulfur (RT Na-S) batteries is currently limited by low reversible capacity and serious capacity decay due to the sluggish reaction kinetics and shuttle effect. It is necessary to design a suitable sulfur host integrated with electrocatalysts to realize effective chemisorption and catalysis of sodium polysulfides (NaPSs). Herein, under the guidance of theoretical calculation, the Mott-Schottky heterojunction with a built-in electric field composed of iron (Fe) and iron disulfide (FeS2 ) components anchored on a porous carbon matrix (Fe/FeS2 -PC) is designed and prepared. The enhanced chemisorption effect of Fe, the fast electrocatalytic effect of FeS2 , and the fast transfer effect of the built-in electric field within the Fe/FeS2 heterojunction in the cathode of RT Na-S batteries work together to effectively improve the electrochemical performance. As a result, the Fe/FeS2 -PC@S cathode exhibits high reversible capacity (815 mAh g-1 after 150 cycles at 0.2 A g-1 ) and excellent stability (516 mAh g-1 after 600 cycles at 5 A g-1 , with only 0.07% decay per cycle). The design of the Fe/FeS2 heterojunction electrocatalyst provides a new strategy for the development of highly stable RT Na-S batteries.

16.
Sci Total Environ ; 912: 169222, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38081430

RESUMO

Prenatal exposure to rare earth elements (REEs) may contribute to adverse birth outcomes in previous studies. Cord blood vitamin D has been suggested to modify or mediate the effects of environmental exposures. However, none has investigated these roles of cord blood vitamin D in the associations of prenatal exposure to REEs with fetal growth. Maternal trimester-specific urinary concentrations of 13 REEs, cord blood total 25-hydroxyvitamin D at delivery, and birth weight (BW)-for-gestational age (GA) were determined in 710 mother-newborn pairs from Wuhan, China. Higher maternal average urinary concentrations of europium (Eu), gadolinium (Gd), dysprosium (Dy), holmium (Ho), erbium (Er), and ytterbium (Yb) across three trimesters, either individually or jointly, were significantly associated with lower BW-for-GA Z-scores and higher odds of small for gestational age (SGA) [ß = -0.092; 95 % confidence interval (CI): -0.149, -0.035 for BW-for-GA Z-scores, and odds ratio = 1.60; 95 % CI: 1.14, 2.24 for SGA involved in each unit increase in weighted quantile sum index of REEs mixture]. When stratified by cord blood vitamin D levels, the associations mentioned above persisted in participants with relatively low vitamin D levels (<13.94 µg/L, the first tertile of distribution), but not among those with relatively high levels (≥13.94 µg/L) (all p-values for interaction < 0.05). The mediation analyses taking account of exposure-mediator interaction showed that the relationships between REEs (as individual and mixture) exposure and lower BW-for-GA were partly mediated through decreasing cord blood vitamin D levels. The proportions mediated by cord blood vitamin D levels were 24.48 % for BW-for-GA Z-scores and 29.05 % for SGA corresponding to the REEs mixture exposure. Conclusively, our study revealed that prenatal exposures to Eu, Gd, Dy, Ho, Er, and Yb were related to fetal growth restriction. Cord blood vitamin D might alleviate toxic effects of these REEs and its reduction might partly mediate REE-induced fetal growth restriction.


Assuntos
Metais Terras Raras , Efeitos Tardios da Exposição Pré-Natal , Recém-Nascido , Gravidez , Feminino , Humanos , Peso ao Nascer , Idade Gestacional , Retardo do Crescimento Fetal , Sangue Fetal/química , Vitamina D , Metais Terras Raras/análise
17.
Adv Mater ; 36(7): e2306772, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37661841

RESUMO

The vector characteristics of light and the vectorial transformations during its transmission lay a foundation for polarized photodetection of objects, which broadens the applications of related detectors in complex environments. With the breakthrough of low-dimensional materials (LDMs) in optics and electronics over the past few years, the combination of these novel LDMs and traditional working modes is expected to bring new development opportunities in this field. Here, the state-of-the-art progress of LDMs, as polarization-sensitive components in polarized photodetection and even the imaging, is the main focus, with emphasis on the relationship between traditional working principle of polarized photodetectors (PPs) and photoresponse mechanisms of LDMs. Particularly, from the view of constitutive equations, the existing works are reorganized, reclassified, and reviewed. Perspectives on the opportunities and challenges are also discussed. It is hoped that this work can provide a more general overview in the use of LDMs in this field, sorting out the way of related devices for "more than Moore" or even the "beyond Moore" research.

18.
Mol Phylogenet Evol ; 190: 107966, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37981264

RESUMO

Although numerous studies have been conducted on hybrid speciation, our understanding of this process remains limited. Through an 18-year systematic investigation of all taxa of Populus on the Qinghai-Tibet Plateau, we discovered three new taxa with clear characteristics of sect. Leucoides. Further evidence was gathered from morphology, whole-genome bioinformatics, biogeography, and breeding to demonstrate synthetically that they all originated from distant hybridization between sect. Leucoides and sect. Tacamahaca. P. gonggaensis originated from the hybridization of P. lasiocarpa with P. cathayana, P. butuoensis from the hybridization of P. wilsonii with P. szechuanica, and P. dafengensis from the hybridization of P. lasiocarpa with P. szechuanica. Due to heterosis, the three hybrid taxa possess greater ecological adaptability than their ancestral species. We propose a hybrid speciation process model that incorporates orthogonal, reverse, and backcrossing events. This model can adequately explain some crucial evolutionary concerns, such as the nuclear-cytoplasmic conflict on phylogeny and the extinction of ancestral species within the distribution range of hybrid species.


Assuntos
Populus , Filogenia , Populus/genética , Evolução Biológica , Hibridização Genética , Hibridização de Ácido Nucleico
19.
Int J Biol Macromol ; 255: 128108, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37979769

RESUMO

Forest trees face many abiotic stressors during their lifetime, including drought, heavy metals, high salinity, and chills, affecting their quality and yield. The RING-type ubiquitin ligase E3 is an invaluable component of the ubiquitin-proteasome system (UPS) and participates in plant growth and environmental interactions. Interestingly, only a few studies have explored the RING ZINC FINGER PROTEIN (RZFP) gene family. This study identified eight PtrRZFPs genes in the Populus genome, and their molecular features were analyzed. Gene structure analysis revealed that all PtrRZFPs genes contained >10 introns. Evolutionarily, the RZFPs were separated into four categories, and segmental replication events facilitated their amplification. Notably, many stress-related elements have been identified in the promoters of PtrRZFPs using Cis-acting element analysis. Moreover, some PtrRZFPs were significantly induced by drought and sorbitol, revealing their potential roles in regulating stress responses. Particularly, overexpression of the PtrRZFP1 gene in poplars conferred excellent drought tolerance; however, PtrRZFP1 knockdown plants were drought-sensitive. We identified the potential upstream transcription factors of PtrRZFPs and revealed the possible biological functions of RZFP1/4/7 in resisting osmotic and salt stress, laying the foundation for subsequent biological function studies and providing genetic resources for genetic engineering breeding for drought resistance in forest trees. This study offers crucial information for the further exploration of the functions of RZFPs in poplars.


Assuntos
Proteínas de Plantas , Populus , Proteínas de Plantas/química , Populus/genética , Populus/metabolismo , Zinco/metabolismo , Melhoramento Vegetal , Íntrons , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genética , Secas , Filogenia
20.
J Virol Methods ; 323: 114841, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37939857

RESUMO

Tomato brown rugose fruit virus (ToBRFV) is an emerging tobamovirus that has become a great concern to tomato production industry. Due to the lack of resistant cultivars, precise detection of ToBRFV is essential to prevent the spread of ToBRFV. In this study, we produced highly sensitive and specific monoclonal antibodies against ToBRFV and established dot-enzyme-linked immunosorbent assay (dot-ELISA) and colloidal gold immunochromatographic strip (CGICS)-based methods for ToBRFV detection. These two methods could specifically detect ToBRFV without cross-reaction with seven tested tobamoviruses and three frequently occurring tomato-infecting viruses. Sensitivity analysis showed that the limit of detection of the established dot-ELISA and CGICS methods reached up to 1:6400 and 1:10,000 (w/v, g/mL) dilution of ToBRFV-infected tomato tissue, respectively. Further analyses using field-collected tomato foliar and fruit samples showed that the results obtained by dot-ELISA and CGICS were consistent with those obtained by reverse transcription polymerase chain reaction. The established methods here allow for specific, sensitive, and robust detection of ToBRFV, and will be helpful for precise monitoring and early warning of ToBRFV.


Assuntos
Solanum lycopersicum , Tobamovirus , Anticorpos Monoclonais , Coloide de Ouro , Frutas , Doenças das Plantas , Ensaio de Imunoadsorção Enzimática/métodos
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