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The paraneoplastic Ma antigen (PNMA) proteins are associated with cancer-induced paraneoplastic syndromes that present with an autoimmune response and neurological symptoms. Why PNMA proteins are associated with this severe autoimmune disease is unclear. PNMA genes are predominantly expressed in the central nervous system and are ectopically expressed in some tumors. We show that PNMA2, which has been co-opted from a Ty3 retrotransposon, encodes a protein that is released from cells as non-enveloped virus-like capsids. Recombinant PNMA2 capsids injected into mice induce autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, whereas a capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic disease show similar preferential binding to spike capsid epitopes. PNMA2 capsid-injected mice develop learning and memory deficits. These observations suggest that PNMA2 capsids act as an extracellular antigen, capable of generating an autoimmune response that results in neurological deficits.
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Antígenos de Neoplasias , Neoplasias , Proteínas do Tecido Nervoso , Síndromes Paraneoplásicas do Sistema Nervoso , Animais , Humanos , Camundongos , Autoanticorpos , Capsídeo/metabolismo , Epitopos , Neoplasias/complicações , Síndromes Paraneoplásicas do Sistema Nervoso/metabolismo , Síndromes Paraneoplásicas do Sistema Nervoso/patologia , Antígenos de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
In mice and humans, sleep quantity is governed by genetic factors and exhibits age-dependent variation1-3. However, the core molecular pathways and effector mechanisms that regulate sleep duration in mammals remain unclear. Here, we characterize a major signalling pathway for the transcriptional regulation of sleep in mice using adeno-associated virus-mediated somatic genetics analysis4. Chimeric knockout of LKB1 kinase-an activator of AMPK-related protein kinase SIK35-7-in adult mouse brain markedly reduces the amount and delta power-a measure of sleep depth-of non-rapid eye movement sleep (NREMS). Downstream of the LKB1-SIK3 pathway, gain or loss-of-function of the histone deacetylases HDAC4 and HDAC5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Moreover, phosphorylation of HDAC4 and HDAC5 is associated with increased sleep need, and HDAC4 specifically regulates NREMS amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signalling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate the power of somatic genetics in mouse sleep research.
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Transdução de Sinais , Duração do Sono , Transcrição Gênica , Animais , Camundongos , Regulação da Expressão Gênica , Fosforilação , Transdução de Sinais/fisiologia , Sono de Ondas Lentas/genética , Perfilação da Expressão GênicaRESUMO
SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.
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COVID-19 , Senescência Celular , Células Gigantes , Insuficiência Cardíaca , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/virologia , Animais , Células Gigantes/virologia , Células Gigantes/metabolismo , Células Gigantes/patologia , COVID-19/metabolismo , COVID-19/complicações , COVID-19/virologia , COVID-19/patologia , Humanos , Glicoproteína da Espícula de Coronavírus/metabolismo , Camundongos , Vesículas Extracelulares/metabolismoRESUMO
The imbalance between endogenous and exogenous healing is the fundamental reason for the poor tendon healing. In this study, a Janus patch was developed to promote endogenous healing and inhibit exogenous healing, leading to improved tendon repair. The upper layer of the patch is a poly(dl-lactide-co-glycolide)/polycaprolactone (PLGA/PCL) nanomembrane (PMCP-NM) modified with poly(2-methylacryloxyethyl phosphocholine) (PMPC), which created a lubricated and antifouling surface, preventing cell invasion and mechanical activation. The lower layer is a PLGA/PCL fiber membrane loaded with fibrin (Fb) (Fb-NM), serving as a temporary chemotactic scaffold to regulate the regenerative microenvironment. In vitro, the Janus patch effectively reduced 92.41% cell adhesion and 79.89% motion friction. In vivo, the patch inhibited tendon adhesion through the TGF-ß/Smad signaling pathway and promoted tendon maturation. This Janus patch is expected to provide a practical basis and theoretical guidance for high-quality soft tissue repair.
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Tendões , Cicatrização , Tendões/fisiologia , Adesão CelularRESUMO
Sulfur reduction reaction (SRR) facilitates up to 16 electrons, which endows lithium-sulfur (Li-S) batteries with a high energy density that is twice that of typical Li-ion batteries. However, its sluggish reaction kinetics render batteries with only a low capacity and cycling life, thus remaining the main challenge to practical Li-S batteries, which require efficient electrocatalysts of balanced atom utilization and site-specific requirements toward highly efficient SRR, calling for an in-depth understanding of the atomic structural sensitivity for the catalytic active sites. Herein, we manipulated the number of Fe atoms in iron assemblies, ranging from single Fe atom to diatomic and triatomic Fe atom groupings, all embedded within a carbon matrix. This led to the revelation of a "volcano peak" correlation between SRR catalytic activity and the count of Fe atoms at the active sites. Utilizing operando X-ray absorption and X-ray diffraction spectroscopies, we observed that polysulfide adsorption-desorption and electrochemical conversion kinetics varied up and down with the incremental addition of even a single iron atom to the catalyst's metal center. Our results demonstrate that the metal center with exactly two iron atoms represents the optimal configuration, maximizing atom utility and adeptly handling the conversion of varied intermediate sulfur species, rendering the Li-S battery with a high areal capacity of 23.8 mAh cm-2 at a high sulfur loading of 21.8 mg cm-2. Our results illuminate the pivotal balance between atom utilization and site-specific requirements for optimal electrocatalytic performance in SRR and diverse electrocatalytic reactions.
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The detection of multiple single nucleotide polymorphisms (SNPs) of circulating tumor DNA (ctDNA) is still a great challenge. In this study, we designed enzyme-assisted nucleic acid strand displacement amplification combined with high-performance liquid chromatography (HPLC) for the simultaneous detection of three ctDNA SNPs. First, the trace ctDNA could be hybridized to the specially designed template strand, which initiated the strand displacement nucleic acid amplification process under the synergistic action of DNA polymerase and restriction endonuclease. Then, the targets would be replaced with G-quadruplex fluorescent probes with different tail lengths. Finally, the HPLC-fluorescence assay enabled the separation and quantification of multiple signals. Notably, this method can simultaneously detect both the wild type (WT) and mutant type (MT) of multiple ctDNA SNPs. Within a linear range of 0.1 fM-0.1 nM, the detection limits of BRAF V600E-WT, EGFR T790M-WT, and KRAS 134A-WT and BRAF V600E-MT, EGFR T790M-MT, and KRAS 134A-MT were 29, 31, and 11 aM and 22, 29, and 33 aM, respectively. By using this method, the mutation rates of multiple ctDNA SNPs in blood samples from patients with lung or breast cancer can be obtained in a simple way, providing a convenient and highly sensitive analytical assay for the early screening and monitoring of lung cancer.
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DNA Tumoral Circulante , Neoplasias Pulmonares , Humanos , DNA Tumoral Circulante/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Receptores ErbB/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases , Cromatografia LíquidaRESUMO
Micro/nano-robots are powerful tools for biomedical applications and are applied in disease diagnosis, tumor imaging, drug delivery, and targeted therapy. Among the various types of micro-robots, cell-based micro-robots exhibit unique properties because of their different cell sources. In combination with various actuation methods, particularly externally propelled methods, cell-based microrobots have enormous potential for biomedical applications. This review introduces recent progress and applications of cell-based micro/nano-robots. Different actuation methods for micro/nano-robots are summarized, and cell-based micro-robots with different cell templates are introduced. Furthermore, the review focuses on the combination of cell-based micro/nano-robots with precise control using different external fields. Potential challenges, further prospects, and clinical translations are also discussed.
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Nanotecnologia , Neoplasias , Humanos , Nanotecnologia/métodos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMO
Aerobically autoxidized self-charging concept has drawn significant attraction due to its promising chemical charge features without external power supply. Particularly, heteroatom-doped carbon materials with abundant oxidizable sites and good conductivity are expected to be ideal cathode materials. However, there is no well-defined aerobically autoxidized self-charging concept based on heteroatom-doped carbon materials, significantly hindering the design of related carbon cathodes. An aerobically autoxidized self-chargeable concept derived from synergistic effect of pyrrolic nitrogen and catechol configuration in carbon cathode using model single pyrrolic nitrogen and oxygen (N-5, O) co-doped carbon and O-enriched carbon is proposed. First, self-charging of N-5, O co-doped carbon cathode can be achieved by aerobic oxidation of pyrrolic nitrogen and catechol to oxidized pyrrolic nitrogen and ortho-quinone configurations, respectively. Second, introducing a single pyrrolic nitrogen configuration enhanced acidic wettability of N-5, O co-doped carbon facilitating air self-charge/galvanic discharge involving proton removal/introduction. Third, synergistic effect of pyrrolic nitrogen and hydroxyl species with the strong electron-donating ability to conjugated carbon-based backbone endows N-5, O co-doped carbon with a higher highest occupied molecular orbital (HOMO) energy level more susceptible to oxidation charging. The assembled Cu/Carbon batteries can drive a timer after every air-charging run. This promising aerobically autoxidized self-charging concept can inspire exploring high-efficiency self-charging devices.
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People living with HIV (PLWH) are particularly vulnerable to SARS-CoV-2. This multicentre prospective cohort study evaluated the long-term immunogenicity and safety of a third homologous dose of Sinovac CoronaVac in PLWH in China. A total of 228 PLWH and 127 HIV-negative controls were finally included and followed up for 6 months. Fewer participants reported mild or moderate adverse reactions, and no serious adverse events were observed. The median levels of neutralizing antibodies (nAbs) and immunoglobulin G against the receptor-binding domain of the spike protein (S-IgG) in PLWH (655.92 IU/mL, IQR: 175.76-1663.55; 206.83 IU/mL, IQR: 85.20-397.82) were comparable to those in control group (1067.16 IU/mL, IQR: 239.85-1670.83; 261.70 IU/mL, IQR: 77.13-400.75), and reached their peak at 4 weeks, exhibiting a delayed peak pattern compared to the 2-week peak in control group. After then, the immune titres gradually decreased over time, but most participants still maintained positive seroconversion at the 6-month mark. Multivariable generalized estimating equation analysis indicated that CD4+T cell count, HIV viral load, and antiretroviral therapy (ART) were independent factors strongly associated with immune response (each p < 0.05). We suggested that PLWH should maintain well-controlled HIV status through ART and receive timely administration of the second booster dose for optimal protection.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , Vacinas de Produtos Inativados , Humanos , Estudos Prospectivos , China , Contagem de Linfócito CD4 , Imunogenicidade da VacinaRESUMO
KEY MESSAGE: The gene BrABCG26 responsible for male sterility of Chinese cabbage was confirmed by two allelic mutants. Male-sterile lines are an important way of heterosis utilization in Chinese cabbage. In this study, two allelic male-sterile mutants msm3-1 and msm3-2 were obtained from a Chinese cabbage double haploid (DH) line 'FT' by using EMS-mutagenesis. Compared to the wild-type 'FT,' the stamens of mutants were completely degenerated and had no pollen, and other characters had no obvious differences. Cytological observation revealed that the failure of vacuolation of the mononuclear microspore, accompanied by abnormal tapetal degradation, resulted in anther abortion in mutants. Genetic analysis showed that a recessive gene controlled the mutant trait. MutMap combined with kompetitive allele specific PCR genotyping analyses showed that BraA01g038270.3C, encoding a transporter ABCG26 that played a vital role in pollen wall formation, was the candidate gene for msm3-1, named BrABCG26. Compared with wild-type 'FT,' the mutations existed on the second exon (C to T) and the sixth exon (C to T) of BrABCG26 gene in mutants msm3-1 and msm3-2, leading to the loss-of-function truncated protein, which verified the BrABCG26 function in stamen development. Subcellular localization and expression pattern analysis indicated that BrABCG26 was localized in the nucleus and was expressed in all organs, with the highest expression in flower buds. Compared to the wild-type 'FT,' the expressions of BrABCG26 were significantly reduced in flower buds and anthers of mutants. Promoter activity analysis showed that a strong GUS signal was detected in flower buds. These results indicated that BrABCG26 is responsible for the male sterility of msm3 mutants in Chinese cabbage.
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Brassica rapa , Brassica , Infertilidade das Plantas , Transportadores de Cassetes de Ligação de ATP/genética , Brassica/genética , Brassica rapa/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas , Mutação , Infertilidade das Plantas/genética , Proteínas de Plantas/genéticaRESUMO
10-Hydroxycamptothecin (HCPT) is a widely used clinical anticancer drug but has a significant side effect profile. Melatonin has a beneficial impact on the chemotherapy of different cancer cells and reproductive processes, but the effect and underlying molecular mechanism of melatonin's involvement in the HCPT-induced side effects in cells, especially in the testicular cells, are poorly understood. In this study, we found that melatonin therapy significantly restored HCPT-induced testicular cell damage and did not affect the antitumor effect of HCPT. Further analysis found that melatonin therapy suppressed HCPT-induced DNA damage associated with ataxia-telangiectasia mutated- and Rad3-related and CHK1 phosphorylation levels in the testis. Changes in apoptosis-associated protein levels (Bax, Bcl-2, p53, and Cleaved caspase-3) and in reactive oxygen species-associated proteins (Nrf2 and Keap1) and index (malondialdehyde and glutathione) suggested that melatonin treatment relieved HCPT-induced cell apoptosis and oxidative damage, respectively. Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.
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Apoptose , Camptotecina , Melatonina , Estresse Oxidativo , Transdução de Sinais , Testículo , Animais , Masculino , Camundongos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Camptotecina/farmacologia , Camptotecina/análogos & derivados , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Melatonina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismoRESUMO
In recent years, the continuous development of magnetic nanostructures (MNSs) has tremendously promoted both fundamental scientific research and technological applications. Different from the bulk magnet, the systematic engineering on MNSs has brought a great breakthrough in some emerging fields such as the construction of MNSs, the magnetism exploration of multidimensional MNSs, and their potential translational applications. In this review, we give a detailed description of the synthetic strategies of MNSs based on the fundamental features and application potential of MNSs and discuss the recent progress of MNSs in the fields of nanomedicines, advanced nanobiotechnology, catalysis, and electromagnetic wave adsorption (EMWA), aiming to provide guidance for fabrication strategies of MNSs toward diverse applications.
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Nanoestruturas , Adsorção , Catálise , Fenômenos Magnéticos , Nanomedicina , Nanoestruturas/químicaRESUMO
BACKGROUND: Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases requiring prioritized research. Previous studies have provided insights into the classification and geographic characteristics of LASV lineages. However, the factor of the distribution and evolution characteristics and phylodynamics of the virus was still limited. METHODS: To enhance comprehensive understanding of LASV, we employed phylogenetic analysis, reassortment and recombination detection, and variation evaluation utilizing publicly available viral genome sequences. RESULTS: The results showed the estimated the root of time of the most recent common ancestor (TMRCA) for large (L) segment was approximately 634 (95% HPD: [385879]), whereas the TMRCA for small (S) segment was around 1224 (95% HPD: [10301401]). LASV primarily spread from east to west in West Africa through two routes, and in route 2, the virus independently spread to surrounding countries through Liberia, resulting in a wider spread of LASV. From 1969 to 2018, the effective population size experienced two significant increased, indicating the enhanced genetic diversity of LASV. We also found the evolution rate of L segment was faster than S segment, further results showed zinc-binding protein had the fastest evolution rate. Reassortment events were detected in multiple lineages including sub-lineage IIg, while recombination events were observed within lineage V. Significant amino acid changes in the glycoprotein precursor of LASV were identified, demonstrating sequence diversity among lineages in LASV. CONCLUSION: This study comprehensively elucidated the transmission and evolution of LASV in West Africa, providing detailed insights into reassortment events, recombination events, and amino acid variations.
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Febre Lassa , Vírus Lassa , Humanos , Vírus Lassa/genética , Filogenia , Febre Lassa/epidemiologia , Aminoácidos , LibériaRESUMO
The application of nanoscale scaffolds has become a promising strategy in vaccine design, with protein-based nanoparticles offering desirable avenues for the biocompatible and efficient delivery of antigens. Here, we presented a novel endogenous capsid-forming protein, activated-regulated cytoskeleton-associated protein (ARC), which could be engineered through the plug-and-play strategy (SpyCatcher3/SpyTag3) for multivalent display of antigens. Combined with the self-assembly capacity and flexible modularity of ARC, ARC-based vaccines elicited robust immune responses against Mpox or SARS-CoV-2, comparable to those induced by ferritin-based vaccines. Additionally, ARC-based nanoparticles functioned as immunostimulants, efficiently stimulating dendritic cells and facilitating germinal center responses. Even without adjuvants, ARC-based vaccines generated protective immune responses in a lethal challenge model. Hence, this study showed the feasibility of ARC as a novel protein-based nanocarrier for multivalent surface display of pathogenic antigens and demonstrated the potential of exploiting recombinant mammalian retrovirus-like protein as a delivery vehicle for bioactive molecules.
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Proteínas do Capsídeo , Nanopartículas , Nanovacinas , Animais , Feminino , Humanos , Camundongos , Proteínas do Capsídeo/química , Proteínas do Capsídeo/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/química , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Células Dendríticas/imunologia , Camundongos Endogâmicos BALB C , Nanopartículas/química , Proteínas do Tecido NervosoRESUMO
PURPOSE: To compare the biomechanical effects of augmenting Bankart repair (BR) with either remplissage or dynamic anterior stabilization (DAS) in the treatment of anterior shoulder instability with on-track or off-track bipolar bone loss. METHODS: Eight fresh-frozen cadaveric shoulders were tested at 60° of glenohumeral abduction in the intact, injury, and repair conditions. Injury conditions included 15% glenoid bone loss with an on-track or off-track Hill-Sachs lesion as previously recommended. Repair conditions included isolated BR, BR with remplissage, and BR with DAS (long head of biceps transfer). The glenohumeral stability was assessed by measuring the anterior translation under 0, 10, 20, 30, 40, 50 N load and maximum load without causing instability at mid-range (60°) and end-range (90°) external rotation (ER). Maximum range of motion (ROM) was measured by applying a 2.2-N·m torque in passive ER and internal rotation. RESULTS: Isolated BR failed to restore native glenohumeral stability in both on-track and off-track bipolar bone loss models. Both remplissage and DAS significantly decreased the anterior instability in the bipolar bone loss models, showing better restoration than the isolated BR. In the on-track lesions, DAS successfully restored native glenohumeral stability and mobility, whereas remplissage significantly decreased anterior translation without load (-2.12 ± 1.07 mm at 90° ER, P = .003; -1.98 ± 1.23 mm at 60° ER, P = .015). In the off-track lesions, remplissage restored native glenohumeral stability but led to significant ROM limitation (-8.6° ± 2.3° for internal rotation, P < .001; -13.9° ± 6.2° for ER, P = .003), whereas DAS failed to restore native stability at 90° ER regarding the increased anterior translation under 50 N (4.10 ± 1.53 mm, P < .001) and decreased maximum load (-13.8 ± 9.2 N, P = .021). CONCLUSIONS: At time-zero, both remplissage and DAS significantly reduced residual anterior instability compared with isolated BR in the bipolar bone loss models and restored the native glenohumeral stability under most translational loads. However, remplissage could decrease the anterior translation without load for on-track lesions and may restrict ROM for off-track lesions, whereas DAS failed to restore native stability under high translational loads for off-track lesions. CLINICAL RELEVANCE: DAS could be recommended to treat on-track bipolar bone loss with less biomechanical adverse effects, whereas remplissage might be the preferred procedure to address off-track bipolar bone loss for better stability.
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Cadáver , Instabilidade Articular , Articulação do Ombro , Humanos , Instabilidade Articular/cirurgia , Instabilidade Articular/fisiopatologia , Fenômenos Biomecânicos , Articulação do Ombro/fisiopatologia , Articulação do Ombro/cirurgia , Pessoa de Meia-Idade , Masculino , Amplitude de Movimento Articular , Feminino , Idoso , Lesões de Bankart/cirurgiaRESUMO
The emergence of natural products has provided extremely valuable references for the treatment of various diseases. Cucurbitacin B, a tetracyclic triterpenoid compound isolated from cucurbitaceae and other plants, is the most abundant member of the cucurbitin family and exhibits a wide range of biological activities, including anti-inflammatory, anti-cancer, and even agricultural applications. Due to its high toxicity and narrow therapeutic window, structural modification and dosage form development are necessary to address these issues with cucurbitacin B. This paper reviews recent research progress in the pharmacological action, structural modification, and application of cucurbitacin B. This review aims to enhance understanding of advancements in this field and provide constructive suggestions for further research on cucurbitacin B.
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Triterpenos , Triterpenos/química , Triterpenos/farmacologia , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Animais , Cucurbitaceae/química , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologiaRESUMO
Designing and synthesizing multifunctional hybrid copper halides with near ultraviolet (NUV) light-excited high-energy emission (<500â nm) remains challenging. Here, a pair of broadband-excited high-energy emitting isomers, namely, α-/ß-(MePh3P)2CuI3 (MePh3P=methyltriphenylphosphonium), were synthesized. α-(MePh3P)2CuI3 with blue emission peaking at 475â nm is firstly discovered wherein its structure contains regular [CuI3]2- triangles and crystallizes in centrosymmetric space group P21/c. While ß-(MePh3P)2CuI3 featuring distorted [CuI3]2- planar triangles shows inversion symmetry breaking and crystallizes in the noncentrosymmetric space group P21, which exhibits cyan emission peaking at 495â nm with prominent near-unity photoluminescence quantum yield and the excitation band ranging from 200 to 450â nm. Intriguingly, ß-(MePh3P)2CuI3 exhibits phase-matchable second-harmonic generation response of 0.54×KDP and a suitable birefringence of 0.06@1064â nm. Furthermore, ß-(MePh3P)2CuI3 also can be excited by X-ray radioluminescence with a high scintillation light yield of 16193 photon/MeV and an ultra-low detection limit of 47.97 nGy/s, which is only 0.87 % of the standard medical diagnosis (5.5â µGy/s). This work not only promotes the development of solid-state lighting, laser frequency conversion and X-ray imaging, but also provides a reference for constructing multifunctional hybrid metal halides.
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OBJECTIVES: To investigate the endoscopic ultrasonography (EUS) features of benign esophageal stenosis in children. METHODS: A retrospective analysis was conducted on the medical data of the children who were diagnosed with benign esophageal stenosis from February 2019 to February 2022. The clinical manifestations, EUS findings, and treatment outcome were analyzed to summarize the EUS features of benign esophageal stenosis in children. RESULTS: A total of 42 children with benign esophageal stenosis were included. Among these children, 19 (45%) had anastomotic stenosis after surgery for esophageal atresia, with unclear echogenic boundary of the esophageal walls and uneven thicknesses of the surrounding wall on EUS, and had 0-12 sessions of endoscopic treatment (average 2.1 sessions); 5 children (12%) had corrosive esophageal stenosis and 1 child (2%) had physical esophageal stenosis, with unclear stratification of the esophageal walls on EUS, and they had 2-9 sessions of endoscopic treatment (average 5.3 sessions); 1 child (2%) had patchy irregular hypoechoic areas of the esophageal walls on EUS and was diagnosed with tracheobronchial remnants with reference to pathology; 16 children (38%) had unexplained esophageal stenosis and unclear stratification of the esophageal walls on EUS, among whom 6 received endoscopic treatment. During follow-up, 95% (40/42) of the children had significant alleviation of the symptoms such as vomiting and dysphagia. CONCLUSIONS: For benign esophageal stenosis in children, EUS can help to evaluate the degree of esophageal wall involvement in esophageal stenosis lesions, possible etiologies, and the relationship between the esophagus and the lesion and provide an important basis for selecting treatment modality and avoiding complications, thereby helping to optimize the treatment regimen.
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Transtornos de Deglutição , Estenose Esofágica , Criança , Humanos , Estenose Esofágica/diagnóstico por imagem , Estenose Esofágica/etiologia , Estenose Esofágica/terapia , Endossonografia , Estudos RetrospectivosRESUMO
Classical forward and reverse mouse genetics require germline mutations and, thus, are unwieldy to study sleep functions of essential genes or redundant pathways. It is also time-consuming to conduct electroencephalogram/electromyogram-based mouse sleep screening owing to labor-intensive surgeries and genetic crosses. Here, we describe a highly accurate SleepV (video) system and adeno-associated virus (AAV)-based adult brain chimeric (ABC)-expression/knockout (KO) platform for somatic genetics analysis of sleep in adult male or female mice. A pilot ABC screen identifies CREB and CRTC1, of which constitutive or inducible expression significantly reduces quantity and/or quality of non-rapid eye movement sleep. Whereas ABC-KO of exon 13 of Sik3 by AAV-Cre injection in Sik3-E13flox/flox adult mice phenocopies Sleepy (Sik3Slp/+) mice, ABC-CRISPR of Slp/Sik3 reverses hypersomnia of Sleepy mice, indicating a direct role of SLP/SIK3 kinase in sleep regulation. Multiplex ABC-CRISPR of both orexin/hypocretin receptors causes narcolepsy episodes, enabling one-step analysis of redundant genes in adult mice. Therefore, this somatic genetics approach should facilitate high-throughput analysis of sleep regulatory genes, especially for essential or redundant genes, in adult mice by skipping mouse development and minimizing genetic crosses.SIGNIFICANCE STATEMENTThe molecular mechanisms of mammalian sleep regulation remain unclear. Classical germline mouse genetics are unwieldy to study sleep functions of essential genes or redundant pathways. The EEG/EMG-based mouse sleep screening is time-consuming owing to labor-intensive surgeries and lengthy genetic crosses. To overcome these "bottlenecks", we developed a highly accurate video-based sleep analysis system and adeno-associated virus-mediated ABC-expression/knockout platform for somatic genetics analysis of sleep in adult mice. These methodologies facilitate rapid identification of sleep regulatory genes, but also efficient mechanistic studies of the molecular pathways of sleep regulation in mice.
RESUMO
Oomycetes are diploid eukaryotic microorganisms that seriously threaten sustainable crop production. MicroRNAs (miRNAs) and corresponding natural antisense transcripts (NATs) are important regulators of multiple biological processes. However, little is known about their roles in plant immunity against oomycete pathogens. In this study, we report the identification and functional characterization of miR398b and its cis-NAT, the core-2/I-branching beta-1,6-N-acetylglucosaminyltransferase gene (AtC2GnT), in plant immunity. Gain- and loss-of-function assays revealed that miR398b mediates Arabidopsis thaliana susceptibility to Phytophthora parasitica by targeting Cu/Zn-Superoxidase Dismutase1 (CSD1) and CSD2, leading to suppressed expression of CSD1 and CSD2 and decreased plant disease resistance. We further showed that AtC2GnT transcripts could inhibit the miR398b-CSDs module via inhibition of pri-miR398b expression, leading to elevated plant resistance to P. parasitica. Furthermore, quantitative reverse transcription PCR, RNA ligase-mediated 5'-amplification of cDNA ends (RLM-5' RACE), and transient expression assays indicated that miR398b suppresses the expression of AtC2GnT. We generated AtC2GnT-silenced A. thaliana plants by CRISPR/Cas9 or RNA interference methods, and the Nicotiana benthamiana NbC2GnT-silenced plants by virus-induced gene silencing. Pathogenicity assays showed that the C2GnT-silenced plants were more susceptible, while AtC2GnT-overexpressing plants exhibited elevated resistance to P. parasitica. AtC2GnT encodes a Golgi-localized protein, and transient expression of AtC2GnT enhanced N. benthamiana resistance to Phytophthora pathogens. Taken together, our results revealed a positive role of AtC2GnT and a negative regulatory loop formed by miR398b and AtC2GnT in regulating plant resistance to P. parasitica.