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Increasing planting density has been adopted as an effective means to increase maize (Zea mays) yield. Competition for light from neighbors can trigger plant shade avoidance syndrome, which includes accelerated flowering. However, the regulatory networks of maize inflorescence development in response to high-density planting remain poorly understood. In this study, we showed that shade-mimicking treatments cause precocious development of the tassels and ears. Comparative transcriptome profiling analyses revealed the enrichment of phytohormone-related genes and transcriptional regulators among the genes co-regulated by developmental progression and simulated shade. Network analysis showed that three homologous Squamosa promoter binding protein (SBP)-like (SPL) transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), individually exhibited connectivity to over 2,400 genes across the V3-to-V9 stages of tassel development. In addition, we showed that the ub2 ub3 double mutant and tsh4 single mutant were almost insensitive to simulated shade treatments. Moreover, we demonstrated that UB2/UB3/TSH4 could directly regulate the expression of Barren inflorescence2 (BIF2) and Zea mays teosinte branched1/cycloidea/proliferating cell factor30 (ZmTCP30). Furthermore, we functionally verified a role of ZmTCP30 in regulating tassel branching and ear development. Our results reveal a UB2/UB3/TSH4-anchored transcriptional regulatory network of maize inflorescence development and provide valuable targets for breeding shade-tolerant maize cultivars.
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Inflorescência , Zea mays , Inflorescência/genética , Inflorescência/metabolismo , Zea mays/metabolismo , Redes Reguladoras de Genes , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Brassinosteroids (BRs) are a class of steroid phytohormones that control various aspects of plant growth and development. Several transcriptional factors (TFs) have been suggested to play roles in BR signaling. However, their possible relationship remains largely unknown. Here, we identified a rice mutant dwarf and low-tillering 2 (dlt2) with altered plant architecture, increased grain width, and reduced BR sensitivity. DLT2 encodes a GIBBERELLIN INSENSITIVE (GAI)-REPRESSOR OF GAI (RGA)-SCARECROW (GRAS) TF that is mainly localized in the nucleus and has weak transcriptional activity. Our further genetic and biochemical analyses indicate that DLT2 interacts with two BR-signaling-related TFs, DLT and BRASSINAZOLE-RESISTANT 1, and probably modulates their transcriptional activity. These findings imply that DLT2 is implicated in a potentially transcriptional complex that mediates BR signaling and rice development and suggests that DLT2 could be a potential target for improving rice architecture and grain morphology. This work also sheds light on the role of rice GRAS members in regulating numerous developmental processes.
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Brassinosteroides , Oryza , Proteínas de Plantas/metabolismo , Transdução de Sinais/genética , Grão Comestível/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Early-onset Schizophrenia (EOS) is a profoundly progressive psychiatric disorder characterized by both positive and negative symptoms, whose pathogenesis is influenced by genes, environment and brain structure development. In this study, the MIND (Morphometric Inverse Divergence) network was employed to explore the relationship between morphological similarity and specific transcriptional expression patterns in EOS patients. This study involved a cohort of 187 participants aged between 7 and 17 years, consisting of 97 EOS patients and 90 healthy controls (HC). Multiple morphological features were used to construct the MIND network for all participants. Furthermore, we explored the associations between MIND network and brain-wide gene expression in EOS patients through partial least squares (PLS) regression, shared genetic predispositions with other psychiatric disorders, functional enrichment of PLS weighted genes, as well as transcriptional signature assessment of cell types, cortical layers, and developmental stages. The MIND showed similarity differences in the orbitofrontal cortex, pericalcarine cortex, lingual gyrus, and multiple networks in EOS patients compared to HC. Moreover, our exploration revealed a significant overlap of PLS2 weighted genes linking to EOS-related MIND differences and the dysregulated genes reported in other psychiatric diseases. Interestingly, genes correlated with MIND changes (PLS2-) exhibited a significant enrichment not only in metabolism-related pathways, but also in specific astrocytes, cortical layers (specifically layer I and III), and posterior developmental stages (late infancy to young adulthood stages). However, PLS2+ genes were primarily enriched in synapses signaling-related pathways and early developmental stages (from early-mid fetal to neonatal early infancy) but not in special cell types or layers. These findings provide a novel perspective on the intricate relationship between macroscopic morphometric structural abnormalities and microscopic transcriptional patterns during the onset and progression of EOS.
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Esquizofrenia , Recém-Nascido , Humanos , Adulto Jovem , Adulto , Criança , Adolescente , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Imageamento por Ressonância Magnética , Encéfalo , Córtex Pré-Frontal , Lobo OccipitalRESUMO
Starch accumulation is key for the maturity of rice pollen grains; however, the regulatory mechanism underlying this process remains unknown. Here, we have isolated a male-sterile rice mutant, abnormal pollen 1 (ap1), which produces nonviable pollen grains with defective starch accumulation. Functional analysis revealed that AP1 encodes an active L-type lectin receptor-like kinase (L-LecRLK). AP1 is localized to the plasma membrane and its transcript is highly accumulated in pollen during the starch synthesis phase. RNA-seq and phosphoproteomic analysis revealed that the expression/phosphorylation levels of numerous genes/proteins involved in starch and sucrose metabolism pathway were significantly altered in the mutant pollen, including a known rice UDP-glucose pyrophosphorylase (OsUGP2). We further found that AP1 physically interacts with OsUGP2 to elevate its enzymatic activity, likely through targeted phosphorylation. These findings revealed a novel role of L-LecRLK in controlling pollen maturity via modulating sucrose and starch metabolism.
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Oryza/genética , Proteínas de Plantas/genética , Pólen/genética , Amido/genética , Regulação da Expressão Gênica de Plantas/genética , Lectinas/genética , Proteínas Mutantes/genética , Oryza/crescimento & desenvolvimento , Fosfotransferases/genética , Proteínas de Plantas/isolamento & purificação , Pólen/crescimento & desenvolvimento , Receptores Mitogênicos/genética , Amido/metabolismoRESUMO
Grain size and weight determine rice yield. Although numerous genes and pathways involved in regulating grain size have been identified, our knowledge of post-transcriptional control of grain size remains elusive. In this study, we characterize a rice mutant, decreased grain width and weight 1 (dgw1), which produces small grains. We show that DGW1 encodes a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family protein and preferentially expresses in developing panicles, positively regulating grain size by promoting cell expansion in spikelet hulls. Overexpression of DGW1 increases grain weight and grain numbers, leading to a significant rise in rice grain yield. We further demonstrate that DGW1 functions in grain size regulation by directly binding to the mRNA of Grain Width 6 (GW6), a critical grain size regulator in rice. Overexpression of GW6 restored the grain size phenotype of DGW1-knockout plants. DGW1 interacts with two oligouridylate binding proteins (OsUBP1a and OsUBP1b), which also bind the GW6 mRNA. In addition, the second RRM domain of DGW1 is indispensable for its mediated protein-RNA and protein-protein interactions. In summary, our findings identify a new regulatory module of DGW1-GW6 that regulates rice grain size and weight, providing important insights into the function of hnRNP-like proteins in the regulation of grain size.
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Oryza , Proteínas de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , RNA Mensageiro/genética , Regulação da Expressão Gênica de Plantas/genética , Grão Comestível/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Oryza/genética , Oryza/metabolismoRESUMO
Maize silk is a specialized type of stigma, covered with numerous papillae for pollen grain capture. However, the developmental process of stigmatic papillae and the underlying regulatory mechanisms have remained largely unknown. Here, we combined the cytological, genetic and molecular studies to demonstrate that three homologous genes ZmSPL10, ZmSPL14 and ZmSPL26 play a central role in promoting stigmatic papilla formation in maize. We show that their triple knockout mutants are nearly complete lack of stigmatic papilla, resulting in a severe reduction in kernel setting. Cellular examination reveals that stigmatic papilla is developed from a precursor cell, which is the smaller daughter cell resulting from asymmetric cell division of a silk epidermal cell. In situ hybridization shows that ZmSPL10, ZmSPL14 and their target genes SPI1, ZmPIN1b, ZmARF28 and ZmWOX3A are preferentially expressed in the precursor cells of stigmatic papillae. Moreover, ZmSPL10, ZmSPL14 and ZmSPL26 directly bind to the promoters of SPI1, ZmPIN1b, ZmARF28 and ZmWOX3A and promote their expression. Further, Zmwox3a knockout mutants display severe defects in stigmatic papilla formation and reduced seed setting. Collectively, our results demonstrate that ZmSPL10, ZmSPL14 and ZmSPL26 act together to promote stigmatic papilla development through regulating auxin signaling and ZmWOX3A expression.
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Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos , Proteínas de Plantas , Transdução de Sinais , Zea mays , Zea mays/genética , Zea mays/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Mutação/genética , Flores/genética , Flores/crescimento & desenvolvimento , Regiões Promotoras Genéticas/genética , Genes de Plantas , Ligação Proteica , FenótipoRESUMO
BACKGROUND: Cervical cancer is a common cancer that seriously affects women's health globally. The key roles of long non-coding RNAs (lncRNAs) in the onset and development of cervical cancer have attracted much attention. Our study aims to uncover the roles of lncRNA EBLN3P and miR-29c-3p and the mechanisms by which EBLN3P and miR-29c-3p regulate malignancy in cervical cancer. METHODS: Tumor and adjacent normal tissues were collected from cervical cancer patients, and the expression of EBLN3P and miR-29c-3p were analyzed via RT-qPCR. The capacities of proliferation, migration, and invasion were assessed using CCK-8, wound healing and transwell assays. The interaction among EBLN3P, miR-29c-3p and TAF15 was determined by luciferase, RNA immunoprecipitation and RNA pull-down assays, respectively. A subcutaneous tumor xenograft mouse model was established to evaluate the functional role of EBLN3P in vivo. RESULTS: The interaction and reciprocal negative regulation between EBLN3P and miR-29c-3p were uncovered in cervical cancer cells. Likewise, EBLN3P and miR-29c-3p expression patterns in tumor tissues presented a negative association. EBLN3P knockdown weakened cell proliferation, migration and invasion, but these effects were abrogated by miR-29c-3p depletion. Mechanistically, ALKBH5 might impaired EBLN3P stability to reduce its expression. EBLN3P functioned as a competing endogenous RNA (ceRNA) for miR-29c-3p to relieve its suppression of RCC2. Besides, EBLN3P enhanced RCC2 mRNA stability via interacting with TAF15. Furthermore, silencing of EBLN3P repressed the tumor growth in mice. CONCLUSION: Altogether, lncRNA EBLN3P positively regulates RCC2 expression via competitively binding to miR-29c-3p and interacting with TAF15, thereby boosting proliferation, migration, and invasion of cervical cancer cells.
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BACKGROUND: Patients with Parkinson's disease (PD) respond to deep brain stimulation (DBS) variably. However, how brain substrates restrict DBS outcomes remains unclear. OBJECTIVE: In this article, we aim to identify prognostic brain signatures for explaining the response variability. METHODS: We retrospectively investigated a cohort of patients with PD (n = 141) between 2017 and 2022, and defined DBS outcomes as the improvement ratio of clinical motor scores. We used a deviation index to quantify individual perturbations on a reference structural covariance network acquired with preoperative T1-weighted magnetic resonance imaging. The neurobiological perturbations of patients were represented as z scored indices based on the chronological perturbations measured on a group of normal aging adults. RESULTS: After applying stringent statistical tests (z > 2.5) and correcting for false discoveries (P < 0.01), we found that accelerated deviations mainly affected the prefrontal cortex, motor strip, limbic system, and cerebellum in PD. Particularly, a negative network within the accelerated deviations, expressed as "more preoperative deviations, less postoperative improvements," could predict DBS outcomes (mean absolute error = 0.09, R2 = 0.15). Moreover, a fusion of personal brain predictors and medical responses significantly improved traditional evaluations of DBS outcomes. Notably, the most important brain predictor, a pathway connecting the cognitive unit (prefrontal cortex) and motor control unit (cerebellum and motor strip), partially mediates DBS outcomes with the age at surgery. CONCLUSIONS: Our findings suggest that individual structural perturbations on the cognitive motor control circuit are critical for modulating DBS outcomes. Interventions toward the circuit have the potential for additional clinical improvements. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Generalized anxiety disorder (GAD) is a common anxiety disorder experiencing psychological and somatic symptoms. Here, we explored the link between the individual variation in functional connectome and anxiety symptoms, especially psychological and somatic dimensions, which remains unknown. In a sample of 118 GAD patients and matched 85 healthy controls (HCs), we used multivariate distance-based matrix regression to examine the relationship between resting-state functional connectivity (FC) and the severity of anxiety. We identified multiple hub regions belonging to salience network (SN) and default mode network (DMN) where dysconnectivity associated with anxiety symptoms (P < 0.05, false discovery rate [FDR]-corrected). Follow-up analyses revealed that patient's psychological anxiety was dominated by the hyper-connectivity within DMN, whereas the somatic anxiety could be modulated by hyper-connectivity within SN and DMN. Moreover, hypo-connectivity between SN and DMN were related to both anxiety dimensions. Furthermore, GAD patients showed significant network-level FC changes compared with HCs (P < 0.01, FDR-corrected). Finally, we found the connectivity of DMN could predict the individual psychological symptom in an independent GAD sample. Together, our work emphasizes the potential dissociable roles of SN and DMN in the pathophysiology of GAD's anxiety symptoms, which may be crucial in providing a promising neuroimaging biomarker for novel personalized treatment strategies.
Assuntos
Conectoma , Humanos , Conectoma/métodos , Rede de Modo Padrão , Imageamento por Ressonância Magnética/métodos , Transtornos de Ansiedade/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.
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Autonomous underwater gliders (AUGs) are effective platforms for oceanic research and environmental monitoring. However, complex underwater environments with uncertainties could pose the risk of vehicle loss during their missions. It is therefore essential to conduct risk prediction to assist decision making for safer operations. The main limitation of current studies for AUGs is the lack of a tailored method for risk analysis considering both dynamic environments and potential functional failures of the vehicle. Hence, this study proposed a copula-based approach for evaluating the risk of AUG loss in dynamic underwater environments. The developed copula Bayesian network (CBN) integrated copula functions into a traditional Bayesian belief network (BBN), aiming to handle nonlinear dependencies among environmental variables and inherent technical failures. Specifically, potential risk factors with causal effects were captured using the BBN. A Gaussian copula was then employed to measure correlated dependencies among identified risk factors. Furthermore, the dependence analysis and CBN inference were performed to assess the risk level of vehicle loss given various environmental observations. The effectiveness of the proposed method was demonstrated in a case study, which considered deploying a Slocum G1 Glider in a real water region. Risk mitigation measures were provided based on key findings. This study potentially contributes a tailored tool of risk prediction for AUGs in dynamic environments, which can enhance the safety performance of AUGs and assist in risk mitigation for decision makers.
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BACKGROUND: Effective teaching methods are needed to improve students' abilities in hand-eye coordination and understanding of cardiac anatomy in echocardiography education. Simulation devices have emerged as innovative teaching tools and exhibited distinctive advantages due to their ability to provide vivid and visual learning experiences. This study aimed to investigate the effect of simulation of sectional human anatomy using ultrasound on students' learning outcomes and satisfaction in echocardiography education. METHODS: The study included 18 first-year clinical medical students with no prior echocardiography training. After randomization, they underwent a pre-test to assess basic knowledge. Following this, the students were divided into two groups: traditional teaching (traditional group) and simulation of sectional human anatomy using ultrasound (digital group). Each group received 60 min of instruction. Post-tests were assigned to students at two different time points: immediately after the lecture, and one week later (referred to as post-tests 1, and 2). In addition, anonymous questionnaires were distributed to students after class to investigate their satisfaction with teaching. RESULTS: Both groups showed significant improvement in their scores on post-test 1 compared to pre-test (traditional group: from 33.1 ± 8.8 to 48.1 ± 13.1, P = 0.034 vs. digital group: from 35.0 ± 6.7 to 58.0 ± 13.2, P = 0.008). However, there were no significant differences between the two groups in several post-test comparisons. Student satisfaction ratings revealed that the digital group experienced significantly greater satisfaction in areas such as subject interest, teaching style, course alignment, and interaction compared to the traditional group. Additionally, 80% of the digital group strongly endorsed the use of simulation of sectional human anatomy using ultrasound for echocardiography teaching, highlighting its effectiveness. CONCLUSIONS: Simulation of sectional human anatomy using ultrasound may improve students' understanding of echocardiography and satisfaction with the course. Our study provides evidence supporting the use of simulation teaching devices in medical education. Further research is needed to explore the long-term impact of this teaching method on students' learning outcomes and its integration into the medical curriculum. TRIAL REGISTRATION: http://www.chictr.org.cn (registration number: ChiCTR2300074015, 27/07/2023).
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Ecocardiografia , Educação de Graduação em Medicina , Avaliação Educacional , Satisfação Pessoal , Estudantes de Medicina , Humanos , Projetos Piloto , Feminino , Masculino , Educação de Graduação em Medicina/métodos , Adulto Jovem , Treinamento por Simulação , Anatomia/educação , CurrículoRESUMO
Nucleotide-binding and leucine-rich repeat receptors (NLRs) are the most important and largest class of immune receptors in plants. The Pi36 gene encodes a canonical CC-NBS-LRR protein that confers resistance to rice blast fungal infections. Here, we show that the CC domain of Pi36 plays a role in cell death induction. Furthermore, self-association is required for the CC domain-mediated cell death, and the self-association ability is correlated with the cell death level. In addition, the NB-ARC domain may suppress the activity of the CC domain through intramolecular interaction. The mutations D440G next to the RNBS-D motif and D503V in the MHD motif autoactivated Pi36, but the mutation K212 in the P-loop motif inhibited this autoactivation, indicating that nucleotide binding of the NB-ARC domain is essential for Pi36 activation. We also found that the LRR domain is required for D503V- and D440G-mediated Pi36 autoactivation. Interestingly, several mutations in the CC domain compromised the CC domain-mediated cell death without affecting the D440G- or D503V-mediated Pi36 autoactivation. The autoactivate Pi36 variants exhibited stronger self-associations than the inactive variants. Taken together, we speculated that the CC domain of Pi36 executes cell death activities, whereas the NB-ARC domain suppressed CC-mediated cell death via intermolecular interaction. The NB-ARC domain releases its suppression of the CC domain and strengthens the self-association of Pi36 to support the CC domain, possibly through nucleotide exchange.
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Proteínas NLR , Oryza , Proteínas de Plantas , Oryza/metabolismo , Oryza/genética , Oryza/imunologia , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/química , Proteínas NLR/metabolismo , Proteínas NLR/genética , Proteínas NLR/química , Morte Celular , Mutação , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Doenças das Plantas/imunologia , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Domínios Proteicos , Resistência à Doença/genética , Imunidade Vegetal/genéticaRESUMO
Thanks to progress in the development of three-dimensional (3D) culture technologies, human central nervous system (CNS) development and diseases have been gradually deciphered by using organoids derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Selforganized neural organoids (NOs) have been used to mimic morphogenesis and functions of specific organs in vitro. Many NOs have been reproduced in vitro, such as those mimicking the human brain, retina, and spinal cord. However, NOs fail to capitulate to the maturation and complexity of in vivo neural tissues. The persistent issues with current NO cultivation protocols are inadequate oxygen supply and nutrient diffusion due to the absence of vascular networks. In vivo, the developing CNS is interpenetrated by vasculature that not only supplies oxygen and nutrients but also provides a structural template for neuronal growth. To address these deficiencies, recent studies have begun to couple NO culture with bioengineering techniques and methodologies, including genetic engineering, coculture, multidifferentiation, microfluidics and 3D bioprinting, and transplantation, which might promote NO maturation and create more functional NOs. These cutting-edge methods could generate an ever more reliable NO model in vitro for deciphering the codes of human CNS development, disease progression, and translational application. In this review, we will summarize recent technological advances in culture strategies to generate vascularized NOs (vNOs), with a special focus on cerebral- and retinal-organoid models.
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Células-Tronco Pluripotentes Induzidas , Organoides , Humanos , OxigênioRESUMO
Pollen development includes a series of biological events that require precise gene regulation. Although several transcription factors (TFs) have been shown to play roles in maintaining pollen fertility, the major regulatory networks underlying tapetum development and pollen wall formation are largely unknown. Herein, we report that ABERRANT MICROSPORE DEVELOPMENT1 (AMD1), a protein annotated previously as unknown protein, is required for tapetum development and pollen exine patterning in rice (Oryza sativa L.). AMD1 encodes a grass-specific protein exhibiting transactivation activity in the nucleus and is spatiotemporally expressed in the tapetum and microspores during pollen development. Further biochemical assays indicate that AMD1 directly activates the transcription of DEFECTIVE POLLEN WALL (DPW) and POLYKETIDE SYNTHASE2 (OsPKS2), which are both implicated in sporopollenin biosynthesis during exine formation. Additionally, AMD1 directly interacts with TAPETUM DEGENERATION RETARDATION (TDR), a key TF involved in the regulation of tapetum degradation and exine formation. Taken together, we demonstrate that AMD1 is an important regulatory component involved in the TDR-mediated regulatory pathway to regulate sporopollenin biosynthesis, tapetum degradation, and exine formation for pollen development. Our work provides insights into the regulatory network of rice sexual reproduction and a useful target for genetic engineering of new male-sterile lines for hybrid rice breeding.
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Oryza , Policetídeos , Biopolímeros , Carotenoides , Fertilidade , Regulação da Expressão Gênica de Plantas , Oryza/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poaceae/metabolismo , Pólen/metabolismo , Policetídeos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: This study aimed to investigate the neuroanatomical subtypes among early-onset schizophrenia (EOS) patients by exploring the association between structural alterations and molecular mechanisms using a combined analysis of morphometric similarity network (MSN) changes and specific transcriptional expression patterns. METHODS: We recruited 206 subjects aged 7 to 17 years, including 100 EOS patients and 106 healthy controls (HC). Heterogeneity through discriminant analysis (HYDRA) was used to identify the EOS subtypes within the MSN strength. The differences in morphometric similarity between each EOS subtype and HC were compared. Furthermore, we examined the link between morphometric changes and brain-wide gene expression in different EOS subtypes using partial least squares regression (PLS) weight mapping, evaluated genetic commonalities with psychiatric disorders, identified functional enrichments of PLS-weighted genes, and assessed cellular transcriptional signatures. RESULTS: Two distinct MSN-based EOS subtypes were identified, each exhibiting different abnormal MSN strength and cognitive functions compared to HC. The PLS1 score mapping demonstrated anterior-posterior gradients of gene expression in EOS1, whereas inverse distributions were observed in EOS2 cohorts. Genetic commonalities were identified in autistic disorder and adult schizophrenia with EOS1 and inflammatory bowel diseases with EOS2 cohorts. The EOS1 PLS1- genes (Z < -5) were significantly enriched in synaptic signaling-related functions, whereas EOS2 demonstrated enrichments in virtual infection-related pathways. Furthermore, the majority of observed associations with EOS1-specific MSN strength differences contributed to specific transcriptional changes in astrocytes and neurons. CONCLUSIONS: The findings of this study provide a comprehensive analysis of neuroanatomical subtypes in EOS, shedding light on the intricate relationships between macrostructural and molecular aspects of the EOS disease.
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Esquizofrenia , Adulto , Humanos , Esquizofrenia/genética , Encéfalo , Cognição , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: AD16 is a Class 1.1 new drug candidate for Alzheimer's disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults. METHODS: Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed. RESULTS: Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred. CONCLUSIONS: The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD. TRIAL REGISTRATION: ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.
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Doença de Alzheimer , Adulto , Humanos , Doença de Alzheimer/tratamento farmacológico , Estudos Cross-Over , Doenças Neuroinflamatórias , Jejum , Método Duplo-Cego , Relação Dose-Resposta a Droga , Área Sob a Curva , Administração OralRESUMO
Flowering time is a key agronomic trait determining environmental adaptation and yield potential of crops. The regulatory mechanisms of flowering in maize still remain rudimentary. In this study, we combine expressional, genetic, and molecular studies to identify two homologous SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors ZmSPL13 and ZmSPL29 as positive regulators of juvenile-to-adult vegetative transition and floral transition in maize. We show that both ZmSPL13 and ZmSPL29 are preferentially expressed in leaf phloem, vegetative and reproductive meristem. We show that vegetative phase change and flowering time are moderately delayed in the Zmspl13 and Zmspl29 single knockout mutants and more significantly delayed in the Zmspl13/29 double mutants. Consistently, the ZmSPL29 overexpression plants display precocious vegetative phase transition and floral transition, thus early flowering. We demonstrate that ZmSPL13 and ZmSPL29 directly upregulate the expression of ZmMIR172C and ZCN8 in the leaf, and of ZMM3 and ZMM4 in the shoot apical meristem, to induce juvenile-to-adult vegetative transition and floral transition. These findings establish a consecutive signaling cascade of the maize aging pathway by linking the miR156-SPL and the miR172-Gl15 regulatory modules and provide new targets for genetic improvement of flowering time in maize cultivars.
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Flores , Proteínas de Plantas , Proteínas de Plantas/metabolismo , Flores/fisiologia , Zea mays/genética , Zea mays/metabolismo , Folhas de Planta/metabolismo , Meristema/genética , Meristema/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
The pollen wall is important for protecting the male gametophyte and for fertilization. The lipid components of the pollen wall are mainly synthesized and transported from the sporophytic tapetum. Although several factors related to lipid biosynthesis have been characterized, the molecular mechanisms underlying lipid biosynthesis during pollen development in rice (Oryza sativa L.) remain elusive. Here, we showed that mutation in the SWOLLEN TAPETUM AND STERILITY 1 (STS1) gene causes delayed tapetum degradation and aborted pollen wall formation in rice. STS1 encodes an endoplasmic reticulum (ER)-localized protein that contains domain of unknown function (DUF) 726 and exhibits lipase activity. Lipidomic and transcriptomic analyses showed that STS1 is involved in anther lipid homeostasis. Moreover, STS1 interacts with Polyketide Synthase 2 (OsPKS2) and Acyl-CoA Synthetase 12 (OsACOS12), two enzymes crucial in lipidic sporopollenin biosynthesis in pollen wall formation, suggesting a potentially lipidic metabolon for sporopollenin biosynthesis in rice. Collectively, our results indicate that STS1 is an important factor for lipid biosynthesis in reproduction, providing a target for the artificial control of male fertility in hybrid rice breeding and insight into the function of DUF726-containing protein in plants.
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Infertilidade , Oryza , Flores , Regulação da Expressão Gênica de Plantas , Infertilidade/metabolismo , Lipídeos , Oryza/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , PólenRESUMO
Ubiquitin-specific proteases (UBPs) process deubiquitination in eukaryotic organisms and are widely involved in plant development and responses to environmental stress. However, their role in cell death and plant immunity remains largely unknown. Here, we identified a rice lesion mimic mutant (LMM) and cloned its causative gene, LMM22. Both dysfunction and overexpression of LMM22 gave rise to the hypersensitive response-like cell death, reactive oxygen species bursts, and activated defence responses. LMM22 encodes an active UBP that is localised to the endoplasmic reticulum (ER) and displays a constitutive expression pattern in rice. LMM22 interacts with SPOTTED LEAF 35 (SPL35), a coupling of ubiquitin conjugation to ER degradation domain-containing protein that is known to participate in ubiquitination and the regulation of cell death and disease response in rice. Additional analyses suggest that LMM22 can positively regulate and stabilise the abundance of SPL35 protein likely through its deubiquitination activity. These data therefore improve our understanding of the function of UBP in rice innate immune responses by demonstrating that LMM22 functions as a critical regulator of SPL35 in cell death and disease resistance.