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1.
Adv Sci (Weinh) ; : e2400819, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38837628

RESUMO

Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet-induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination-proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.

2.
Nat Med ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839897

RESUMO

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

3.
Am J Cancer Res ; 14(5): 2626-2642, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38859854

RESUMO

Immunotherapy, in the shape of immune checkpoint inhibitors (ICIs), has completely changed the treatment of cancer. However, the increasing expense of treatment and the frequency of immune-related side effects, which are frequently associated with combination antibody therapies and Fc fragment of antibody, have limited the patient's ability to benefit from these treatments. Herein, we presented the therapeutic effects of the plasmid-encoded PD-1 and CTLA-4 scFvs (single-chain variable fragment) for melanoma via an optimized intramuscular gene delivery system. After a single injection, the plasmid-encoded ICI scFv in mouse sera continued to be above 150 ng/mL for 3 weeks and reached peak amounts of 600 ng/mL. Intramuscular delivery of plasmid encoding PD-1 and CTLA-4 scFvs significantly changed the tumor microenvironment, delayed tumor growth, and prolonged survival in melanoma-bearing mice. Furthermore, no significant toxicity was observed, suggesting that this approach could improve the biosafety of ICIs combination therapy. Overall, the expression of ICI scFvs in vivo using intramuscular plasmid delivery could potentially develop into a reliable, affordable, and safe immunotherapy technique, expanding the range of antibody-based gene therapy systems that are available.

4.
Transl Psychiatry ; 14(1): 251, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858375

RESUMO

This research aimed to devise and assess a mobile game therapy software for children with Attention-Deficit/Hyperactivity Disorder (ADHD), as well as evaluating its suitability and effectiveness in improving the cognitive ability of typically developing children. The study encompassed 55 children diagnosed with ADHD and 55 neurotypical children. Initial assessments involved ADHD-related scales, computerized tests for information processing, and physiological-psychological evaluations. After a 4-week home-based game intervention, participants underwent re-evaluation using baseline measures and provided feedback on treatment satisfaction. Considering the small proportion of study participants who dropped out, data was analyzed using both the Intention-to-Treat (ITT) analysis and the Per-protocol (PP) analysis. The trial was registered at ClinicalTrials.gov (NCT06181747). In ITT analysis, post-intervention analysis using linear mixed models indicated that the ADHD group improved significantly more than the neurotypical group particularly in Continuous Performance Test (CPT) accuracy (B = -23.92, p < 0.001) and reaction time (B = 86.08, p < 0.01), along with enhancements in anti-saccade (B = -10.65, p < 0.05) and delayed-saccade tasks (B = 0.34, p < 0.05). A reduction in parent-rated SNAP-IV scores was also observed (B = 0.43, p < 0.01). In PP analysis, paired-sample t-tests suggested that the ADHD group had significant changes pre- and post-intervention, in terms of CPT Accuracy (t = -7.62, p < 0.01), Anti-saccade task Correct Rate (t = -3.90, p < 0.01) and SNAP-IV scores (t = -4,64, p < 0.01). However, no significant changes post-intervention were observed in the neurotypical group. Survey feedback highlighted a strong interest in the games across both groups, though ADHD participants found the game more challenging. Parents of ADHD children reported perceived benefits and a willingness to continue the game therapy, unlike the neurotypical group's parents. The findings advocated for the integration of serious video games as a complementary tool in ADHD treatment strategies, demonstrating the potential to augment attentional abilities and alleviate clinical symptoms. However, a randomized controlled trial (RCT) is needed to further verify its efficacy.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estudos de Viabilidade , Jogos de Vídeo , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Masculino , Feminino , Aplicativos Móveis , Resultado do Tratamento
5.
Genome Med ; 16(1): 77, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840170

RESUMO

BACKGROUND: Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS: Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS: Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS: This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.


Assuntos
Neoplasias Colorretais , Metilação de DNA , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/genética , Feminino , Masculino , Pessoa de Meia-Idade , Epigênese Genética , Idoso , Ilhas de CpG , Metagenômica/métodos , Metagenoma , Microbiota/genética , Fezes/microbiologia , RNA Ribossômico 16S/genética
6.
iScience ; 27(6): 109796, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38832016

RESUMO

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

7.
Sci Data ; 11(1): 592, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844753

RESUMO

The 'Red Fuji' apple (Malus domestica), is one of the most important and popular economic crops worldwide in the fruit industry. Using PacBio HiFi long reads and Hi-C reads, we assembled a high-quality haplotype-resolved genome of 'Red Fuji', with sizes of 668.7 and 668.8 Mb, and N50 sizes of 34.1 and 31.4 Mb. About 97.2% of sequences were anchored in 34 chromosomes. We annotated both haploid genomes, identifying a total of 95,439 protein-coding genes in the two haplotype genomes, with 98% functional annotation. The haplotype-resolved genome of 'Red Fuji' apple stands as a precise benchmark for an array of analyses, such as comparative genomics, transcriptomics, and allelic expression studies. This comprehensive resource is paramount in unraveling variations in allelic expression, advancing quality improvements, and refining breeding efforts.


Assuntos
Genoma de Planta , Haplótipos , Malus , Malus/genética
8.
Int Immunopharmacol ; 137: 112355, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38851158

RESUMO

One major obstacle in the treatment of cancer is the presence of proteins resistant to cancer therapy, which can impede the effectiveness of traditional approaches such as radiation and chemotherapy. This resistance can lead to disease progression and cause treatment failure. Extensive research is currently focused on studying these proteins to create tailored treatments that can circumvent resistance mechanisms. CLU (Clusterin), a chaperone protein, has gained notoriety for its role in promoting resistance to a wide range of cancer treatments, including chemotherapy, radiation therapy, and targeted therapy. The protein has also been discovered to have a role in regulating the immunosuppressive environment within tumors. Its ability to influence oncogenic signaling and inhibit cell death bolster cancer cells resistant against treatments, which poses a significant challenge in the field of oncology. Researchers are actively investigating to the mechanisms by which CLU exerts its resistance-promoting effects, with the ultimate goal of developing strategies to circumvent its impact and enhance the effectiveness of cancer therapies. By exploring CLU's impact on cancer, resistance mechanisms, tumor microenvironment (TME), and therapeutic strategies, this review aims to contribute to the ongoing efforts to improve cancer treatment outcomes.

9.
Artigo em Inglês | MEDLINE | ID: mdl-38822723

RESUMO

OBJECTIVE: Previous studies have indicated that there is an association between cervical cerclage and type of suture material. However, it is still unclear which suture material can provide the greatest benefit to patients who have undergone cerclage. This study investigated the effect of two different suture materials (Mersilene tape vs braided suture) used for transvaginal cervical cerclage placement on maternal outcomes of women with cervical insufficiency. METHODS: In this retrospective case-control study, 170 women who underwent history-, ultrasound-, or physical examination-indicated transvaginal cervical cerclage were categorized according to suture materials used for cerclage: a total of 96 received Mersilene tape and 74 received braided suture. Study participants received a transvaginal cervical cerclage before 28 weeks and were followed up until delivery to assess pregnancy and neonatal outcomes. The primary outcome was gestational age at delivery. Secondary outcomes included preterm premature rupture of membranes (PPROM), premature rupture of membranes (PROM), chorioamnionitis, neonatal survival rate, and neonatal morbidity. RESULTS: Out of 170 eligible women, 74 (43.5%) received braided suture while 96 (56.5%) received Mersilene tape. Baseline characteristics were similar between the two groups. The group that received braided suture had a lower incidence of gestational age at delivery <37 weeks (29.2% vs 54.2%, P = 0.046), PPROM (9.5% vs 21.9%, P = 0.029) and PROM (17.6% vs 32.3%, P = 0.028) compared to the group that received Mersilene tape. However, there were no significant differences between the two groups in average gestational age at delivery, the rate of gestational age at delivery <24, <28, <32, and < 34 weeks, chorioamnionitis, and neonatal survival rate, as well as neonatal morbidity. CONCLUSION: Compared to Mersilene tape, the utilization of braided suture has been significantly associated with a reduction in the incidence of gestational age at delivery <37 weeks, as well as a decreased risk of PPROM and PROM. However, the use of braided sutures did not result in discernible differences in the rates of chorioamnionitis or adverse neonatal outcomes.

10.
Hortic Res ; 11(6): uhae100, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38863996

RESUMO

Horticultural crops comprising fruit, vegetable, ornamental, beverage, medicinal and aromatic plants play essential roles in food security and human health, as well as landscaping. With the advances of sequencing technologies, genomes for hundreds of horticultural crops have been deciphered in recent years, providing a basis for understanding gene functions and regulatory networks and for the improvement of horticultural crops. However, these valuable genomic data are scattered in warehouses with various complex searching and displaying strategies, which increases learning and usage costs and makes comparative and functional genomic analyses across different horticultural crops very challenging. To this end, we have developed a lightweight universal search engine, HortGenome Search Engine (HSE; http://hort.moilab.net), which allows for the querying of genes, functional annotations, protein domains, homologs, and other gene-related functional information of more than 500 horticultural crops. In addition, four commonly used tools, including 'BLAST', 'Batch Query', 'Enrichment analysis', and 'Synteny Viewer' have been developed for efficient mining and analysis of these genomic data.

11.
J Affect Disord ; 361: 277-284, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38844166

RESUMO

BACKGROUND: The short-term adverse effects of ambient fine particulate matter (PM2.5) and ozone (O3) on anxiety disorders (ADs) remained inconclusive. METHODS: We applied an individual-level time-stratified case-crossover study, which including 126,112 outpatient visits for ADs during 2019-2021 in Guangdong province, China, to investigate the association of short-term exposure to PM2.5 and O3 with outpatient visits for ADs, and estimate excess outpatient visits in South China. Daily residential air pollutant exposure assessments were performed by extracting grid data (spatial resolution: 1 km × 1 km) from validated datasets. We employed the conditional logistic regression model to quantify the associations and excess outpatient visits. RESULTS: The results of the single-pollutant models showed that each 10 µg/m3 increase of PM2.5 and O3 exposures was significantly associated with a 3.14 % (95 % confidence interval: 2.47 %, 3.81 %) and 0.88 % (0.49 %, 1.26 %) increase in odds of outpatient visits for ADs, respectively. These associations remained robust in 2-pollutant models. The proportion of outpatient visits attributable to PM2.5 and O3 exposures was up to 7.20 % and 8.93 %, respectively. Older adults appeared to be more susceptible to PM2.5 exposure, especially in cool season, and subjects with recurrent outpatient visits were more susceptible to O3 exposure. LIMITATION: As our study subjects were from one single hospital in China, it should be cautious when generalizing our findings to other regions. CONCLUSION: Short-term exposure to ambient PM2.5 and O3 was significantly associated with a higher odds of outpatient visits for ADs, which can contribute to considerable excess outpatient visits.

12.
Inflammation ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884700

RESUMO

Acute pancreatitis (AP) is one of the most common gastrointestinal emergencies, often resulting in self-digestion, edema, hemorrhage, and even necrosis of pancreatic tissue. When AP progresses to severe acute pancreatitis (SAP), it often causes multi-organ damage, leading to a high mortality rate. However, the molecular mechanisms underlying SAP-mediated organ damage remain unclear. This study aims to systematically mine SAP data from public databases and combine experimental validation to identify key molecules involved in multi-organ damage caused by SAP. Retrieve transcriptomic data of mice pancreatic tissue for AP, lung and liver tissue for SAP, and corresponding normal tissue from the Gene Expression Omnibus (GEO) database. Conduct gene differential analysis using Limma and DEseq2 methods. Perform enrichment analysis using the clusterProfiler package in R software. Score immune cells and immune status in various organs using single-sample gene set enrichment analysis (ssGSEA). Evaluate mRNA expression levels of core genes using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Validate serum amylase, TNF-α, IL-1ß, and IL-6 levels in peripheral blood using enzyme-linked immunosorbent assay (ELISA), and detect the formation of neutrophil extracellular traps (NETs) in mice pancreatic, liver, and lung tissues using immunofluorescence. Differential analysis reveals that 46 genes exhibit expression dysregulation in mice pancreatic tissue for AP, liver and lung tissue for SAP, as well as peripheral blood in humans. Functional enrichment analysis indicates that these genes are primarily associated with neutrophil-related biological processes. ROC curve analysis indicates that 12 neutrophil-related genes have diagnostic potential for SAP. Immune infiltration analysis reveals high neutrophil infiltration in various organs affected by SAP. Single-cell sequencing analysis shows that these genes are predominantly expressed in neutrophils and macrophages. FPR1, ITGAM, and C5AR1 are identified as key genes involved in the formation of NETs and activation of neutrophils. qPCR and IHC results demonstrate upregulation of FPR1, ITGAM, and C5AR1 expression in pancreatic, liver, and lung tissues of mice with SAP. Immunofluorescence staining shows increased levels of neutrophils and NETs in SAP mice. Inhibition of NETs formation can alleviate the severity of SAP as well as the levels of inflammation in the liver and lung tissues. This study identified key genes involved in the formation of NETs, namely FPR1, ITGAM, and C5AR1, which are upregulated during multi-organ damage in SAP. Inhibition of NETs release effectively reduces the systemic inflammatory response and liver-lung damage in SAP. This research provides new therapeutic targets for the multi-organ damage associated with SAP.

13.
J Transl Med ; 22(1): 578, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890658

RESUMO

BACKGROUND: IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease. METHODS: To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes. RESULTS: In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15-2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09-2.91]; GALSS: HR = 1.66[1.09-2.54]; UCSF: HR = 1.33[1.00-1.77]; UPENN HR = 1.29[1.04-1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience. CONCLUSIONS: Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Isocitrato Desidrogenase , Imageamento por Ressonância Magnética , RNA Mensageiro , Humanos , Análise por Conglomerados , Glioblastoma/genética , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Glioblastoma/terapia , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Isocitrato Desidrogenase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Mutação/genética , Reprodutibilidade dos Testes , Estudos de Coortes , Resultado do Tratamento , Multiômica
14.
Plants (Basel) ; 13(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38891285

RESUMO

Soils play a dominant role in supporting the survival and growth of crops and they are also extremely important for human health and food safety. At present, the contamination of soil by heavy metals remains a globally concerning environmental issue that needs to be resolved. In the environment, iron plaque, naturally occurring on the root surface of wetland plants, is found to be equipped with an excellent ability at blocking the migration of heavy metals from soils to plants, which can be further developed as an environmentally friendly strategy for soil remediation to ensure food security. Because of its large surface-to-volume porous structure, iron plaque exhibits high binding affinity to heavy metals. Moreover, iron plaque can be seen as a reservoir to store nutrients to support the growth of plants. In this review, the formation process of iron plaque, the ecological role that iron plaque plays in the environment and the interaction between iron plaque, plants and microbes, are summarized.

15.
Dev Sci ; : e13540, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898660

RESUMO

Three preregistered studies examined whether 5-year-old children cheat consistently or remain honest across multiple math tests. We observed high consistency in both honesty and cheating. All children who cheated on the first test continued cheating on subsequent tests, with shorter cheating latencies over time. In contrast, 77% of initially honest children maintained honesty despite repeated failure to complete the tests successfully. A brief integrity intervention helped initially honest children remain honest but failed to dissuade initially cheating children from cheating. These findings demonstrate that cheating emerges early and persists strongly in young children, underscoring the importance of early prevention efforts. They also suggest that bolstering honesty from the start may be more effective than attempting to remedy cheating after it has occurred. RESEARCH HIGHLIGHTS: Our research examines whether 5-year-old children, once they have started cheating, will continue to do so consistently. We also investigate whether 5-year-old children who are initially honest will continue to be honest subsequently. We discovered high consistency in both honesty and cheating among 5-year-old children. Almost all the children who initially cheated continued this behavior, while those who were honest stayed honest. A brief integrity-boosting intervention successfully helped 5-year-old children maintain their honesty. However, the same intervention failed to deter cheaters from cheating again. These findings underscore the importance of implementing integrity intervention as early as possible, potentially before children have had their first experience of cheating.

16.
Opt Express ; 32(9): 15269-15279, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38859182

RESUMO

Telescopes play an essential important role in the fields of astronomical observation, emergency rescue, etc. The traditional telescopes achieve zoom function through the mechanical movement of the solid lenses, usually requiring refocusing after magnification adjustment. Therefore, the traditional telescopes lack adaptability, port-ability and real-time capability. In this paper, a continuous optical zoom telescopic system based on liquid lenses is proposed. The main components of the system consist of an objective lens, an eyepiece, and a zoom group composed of six pieces of liquid lenses. By adjusting the external voltages on the liquid lenses, the zoom telescopic system can achieve continuous optical zoom from ∼1.0× to ∼4.0× operating with an angular resolution from 28.648" to 19.098", and the magnification switching time is ∼50ms. The optical structure of the zoom telescopic system with excellent performance is given, and its feasibility is demonstrated by simulations and experiments. The proposed system with fast response, portability and high adaptability is expected to be applied to astronomical observation, emergency rescue and so on.

17.
Plant Commun ; : 100999, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38853433

RESUMO

Grain weight, a key determinant of yield in rice (Oryza sativa L.), is governed primarily by genetic factors, whereas grain chalkiness, a detriment to grain quality, is intertwined with environmental factors such as mineral nutrients. Nitrogen (N) is recognized for its impact on grain chalkiness, yet the underlying molecular mechanisms remain elusive. This study revealed the pivotal role of rice NODULE INCEPTION-LIKE PROTEIN 3 (OsNLP3) in simultaneously regulating grain weight and grain chalkiness. Our investigation showed that the loss of OsNLP3 leads to a reduction in both grain weight and dimension, in contrast to the enhancement observed with OsNLP3 overexpression. OsNLP3 directly suppresses the expression of OsCEP6.1 and OsNF-YA8, which were identified as negative regulators associated with grain weight. Consequently, two novel regulatory modules, OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8, were identified as key players in grain weight regulation. Notably, the OsNLP3-OsNF-YA8 module not only augments grain weight but also mitigates grain chalkiness in response to N. This research clarifies the molecular mechanisms orchestrating grain weight through the OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8 modules, underscoring the pivotal role of the OsNLP3-OsNF-YA8 module in alleviating grain chalkiness. These findings offer potential targets for concurrently enhancing rice yield and quality.

18.
Adv Mater ; : e2401667, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38843541

RESUMO

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, this work develops a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers. The microneedles are engineered through an ice-templated method to generate the grooved structure for sufficient T-cell loading. In addition, with the surface modification of chemokine CCL22, the MNs could not only directly deliver tumor-specific T cells into solid tumors through physical penetration, but also specifically divert Treg cells from the tumor microenvironment to the surface of the microneedles via a cytokine concentration gradient, leading to an increase in the ratio of Teff cells/Treg cells in a mouse melanoma model. Consequently, this local delivery strategy of both T cell receptor T cells and chimeric antigen receptor T cells via the CCL22-modified grooved microneedles as a local niche could significantly enhance the antitumor efficacy and reduce the on-target off-tumor toxicity of ACT.

19.
bioRxiv ; 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38826376

RESUMO

SARS-CoV-2 variants derived from the immune evasive JN.1 are on the rise worldwide. Here, we investigated JN.1-derived subvariants SLip, FLiRT, and KP.2 for their ability to be neutralized by antibodies in bivalent-vaccinated human sera, XBB.1.5 monovalent-vaccinated hamster sera, sera from people infected during the BA.2.86/JN.1 wave, and class III monoclonal antibody (Mab) S309. We found that compared to parental JN.1, SLip and KP.2, and especially FLiRT, exhibit increased resistance to COVID-19 bivalent-vaccinated human sera and BA.2.86/JN.1-wave convalescent sera. Interestingly, antibodies in XBB.1.5 monovalent vaccinated hamster sera robustly neutralized FLiRT and KP.2 but had reduced efficiency for SLip. These JN.1 subvariants were resistant to neutralization by Mab S309. In addition, we investigated aspects of spike protein biology including infectivity, cell-cell fusion and processing, and found that these subvariants, especially SLip, had a decreased infectivity and membrane fusion relative to JN.1, correlating with decreased spike processing. Homology modeling revealed that L455S and F456L mutations in SLip reduced local hydrophobicity in the spike and hence its binding to ACE2. In contrast, the additional R346T mutation in FLiRT and KP.2 strengthened conformational support of the receptor-binding motif, thus counteracting the effects of L455S and F456L. These three mutations, alongside D339H, which is present in all JN.1 sublineages, alter the epitopes targeted by therapeutic Mabs, including class I and class III S309, explaining their reduced sensitivity to neutralization by sera and S309. Together, our findings provide insight into neutralization resistance of newly emerged JN.1 subvariants and suggest that future vaccine formulations should consider JN.1 spike as immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection.

20.
Paediatr Drugs ; 2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38880837

RESUMO

Bacterial infection is one of the major causes of neonatal morbidity and mortality worldwide. Finding rapid and reliable methods for early recognition and diagnosis of bacterial infections and early individualization of antibacterial drug administration are essential to eradicate these infections and prevent serious complications. However, this is often difficult to perform due to non-specific clinical presentations, low accuracy of current diagnostic methods, and limited knowledge of neonatal pharmacokinetics. Although neonatal medicine has been relatively late to embrace the benefits of machine learning (ML), there have been some initial applications of ML for the early prediction of neonatal sepsis and individualization of antibiotics. This article provides a brief introduction to ML and discusses the current state of the art in diagnosing and treating neonatal bacterial infections, gaps, potential uses of ML, and future directions to address the limitations of current studies. Neonatal bacterial infections involve a combination of physiologic development, disease expression, and treatment response outcomes. To address this complex relationship, future models could consider appropriate ML algorithms to capture time series features while integrating influences from the host, microbes, and drugs to optimize antimicrobial drug use in neonates. All models require prospective clinical trials to validate their clinical utility before clinical use.

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