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The major antioxidant L-ascorbic acid (AsA) plays important roles in plant growth, development, and stress responses. However, the importance of AsA concentration and the regulation of AsA metabolism in plant reproduction remain unclear. In Arabidopsis (Arabidopsis thaliana) anthers, the tapetum monolayer undergoes cell differentiation to support pollen development. Here, we report that a transcription factor, DEFECTIVE IN TAPETAL DEVELOPMENT AND FUNCTION 1 (TDF1), inhibits tapetal cell division leading to cell differentiation. We identified SKEWED5-SIMILAR 18 (SKS18) as a downstream target of TDF1. Enzymatic assays showed that SKS18, annotated as a multicopper oxidase-like protein, has ascorbate oxidase activity, leading to AsA oxidation. We also show that VITAMIN C DEFECTIVE1 (VTC1), an AsA biosynthetic enzyme, is negatively controlled by TDF1 to maintain proper AsA contents. Consistently, either knockout of SKS18 or VTC1 overexpression raised AsA concentrations, resulting in extra tapetal cells, while SKS18 overexpression in tdf1 or the vtc1-3 tdf1 double mutant mitigated their defective tapetum. We observed that high AsA concentrations caused lower accumulation of reactive oxygen species (ROS) in tapetal cells. Overexpression of ROS scavenging genes in tapetum restored excess cell divisions. Thus, our findings demonstrate that TDF1-regulated AsA balances cell division and cell differentiation in the tapetum through governing ROS homeostasis.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ácido Ascórbico , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , División Celular , Diferenciación Celular/genética , Homeostasis , Regulación de la Expresión Génica de las PlantasRESUMEN
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and recent epidemiological studies suggested type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of AF. Zinc finger and BTB (broad-complex, tram-track and bric-a-brac) domain containing 16 (Zbtb16) serve as transcriptional factors to regulate many biological processes. However, the potential effects of Zbtb16 in AF under T2DM condition remain unclear. Here, we reported that db/db mice displayed higher AF vulnerability and Zbtb16 was identified as the most significantly enriched gene by RNA sequencing (RNA-seq) analysis in atrium. In addition, thioredoxin interacting protein (Txnip) was distinguished as the key downstream gene of Zbtb16 by Cleavage Under Targets and Tagmentation (CUT&Tag) assay. Mechanistically, increased Txnip combined with thioredoxin 2 (Trx2) in mitochondrion induced excess reactive oxygen species (ROS) release, calcium/calmodulin-dependent protein kinase II (CaMKII) overactivation, and spontaneous Ca2+ waves (SCWs) occurrence, which could be inhibited through atrial-specific knockdown (KD) of Zbtb16 or Txnip by adeno-associated virus 9 (AAV9) or Mito-TEMPO treatment. High glucose (HG)-treated HL-1 cells were used to mimic the setting of diabetic in vitro. Zbtb16-Txnip-Trx2 signaling-induced excess ROS release and CaMKII activation were also verified in HL-1 cells under HG condition. Furthermore, atrial-specific Zbtb16 or Txnip-KD reduced incidence and duration of AF in db/db mice. Altogether, we demonstrated that interrupting Zbtb16-Txnip-Trx2 signaling in atrium could decrease AF susceptibility via reducing ROS release and CaMKII activation in the setting of T2DM.
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Fibrilación Atrial , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animales , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteínas Portadoras/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Especies Reactivas de Oxígeno , Tiorredoxinas/genéticaRESUMEN
INTRODUCTION: The histological transformation (HT) of follicular lymphoma (FL) is a crucial biological event. The study aimed to evaluate the incidence, clinicial characteristics, prognosis and impact of HT time on survival of FL transforming to diffuse large B-cell lymphoma in population-based large-scale cohorts. METHODS: A retrospective cohort study of FL with HT was performed in the Surveillance, Epidemiology, and End Results database. The Hematological Malignancy Research Network FL cohort and Aristotle study FL cohort were used to assess the external validity. RESULTS: Among 44,127 FL cases from the Surveillance, Epidemiology, and End Results database, 1311 cases were pathology-proven recorded to transform to diffuse large B-cell lymphoma. The cumulative rates of HT at 5, 10, and 15 years after FL diagnosis were estimated to be 1.19%, 2.93%, and 5.01%, respectively. Significantly worse overall survival and cancer-specific survival were exhibited in patients with HT than those without HT. Early HT (transformation of FL within 48 months after FL diagnosis [TOD48]) was an independent predictor for adverse overall survival of HT patients, regardless of treatment modalities before transformation. The adverse prognostic effect of TOD48 was validated in the Hematological Malignancy Research Network cohort and Aristotle study cohort. Older age (>75 years) and B symptoms within FL at diagnosis were the independent risk factors of TOD48. Furthermore, a novel prognostic model combining TOD48 with Follicular Lymphoma International Prognostic Index (TOD48-FLIPI) was constructed and validated for risk stratification. CONCLUSION: TOD48 was a risk indicator of HT, and the novel prognostic model "TOD48-FLIPI" for HT patients was proposed.
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Far-red absorbing allophycocyanins (APC), identified in cyanobacteria capable of FRL photoacclimation (FaRLiP) and low-light photoacclimation (LoLiP), absorb far-red light, functioning in energy transfer as light-harvesting proteins. We report an optimized method to obtain high purity far-red absorbing allophycocyanin B, AP-B2, of Chroococcidiopsis thermalis sp. PCC7203 by synthesis in Escherichia coli and an improved purification protocol. The crystal structure of the trimer, (PCB-ApcD5/PCB-ApcB2)3, has been resolved to 2.8 Å. The main difference to conventional APCs absorbing in the 650-670 nm range is a largely flat chromophore with the co-planarity extending, in particular, from rings BCD to ring A. This effectively extends the conjugation system of PCB and contributes to the super-red-shifted absorption of the α-subunit (λmax = 697 nm). On complexation with the ß-subunit, it is even further red-shifted (λmax, absorption = 707 nm, λmax, emission = 721 nm). The relevance of ring A for this shift is supported by mutagenesis data. A variant of the α-subunit, I123M, has been generated that shows an intense FR-band already in the absence of the ß-subunit, a possible model is discussed. Two additional mechanisms are known to red-shift the chromophore spectrum: lactam-lactim tautomerism and deprotonation of the chromophore that both mechanisms appear inconsistent with our data, leaving this question unresolved.
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BACKGROUND: The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient outcomes, MM remains incurable. Recent studies have highlighted the crucial role of the chemokine network in MM's pathological mechanism. Gaining a better understanding of this network and creating an overview of chemokines in MM could aid in identifying potential biomarkers and developing new therapeutic strategies and targets. PURPOSE: To summarize the complicated role of chemokines in MM, discuss their potential as biomarkers, and introduce several treatments based on chemokines. METHODS: Pubmed, Web of Science, ICTRP, and Clinical Trials were searched for articles and research related to chemokines. Publications published within the last 5 years are selected. RESULTS: Malignant cells can utilize chemokines, including CCL2, CCL3, CCL5, CXCL7, CXCL8, CXCL12, and CXCL13 to evade apoptosis triggered by immune cells or medication, escape from bone marrow and escalate bone lesions. Other chemokines, including CXCL4, CCL19, and CXCL10, may aid in recruiting immune cells, increasing their cytotoxicity against cancer cells, and inducing apoptosis of malignant cells. CONCLUSION: Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.
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Compuestos Heterocíclicos , Mieloma Múltiple , Humanos , Movilización de Célula Madre Hematopoyética , Quimiocinas , Transducción de Señal , BiomarcadoresRESUMEN
The initiation and progression of atherosclerotic plaque caused by abnormal lipid metabolism is one of the main causes of atherosclerosis (AS). Lipid droplet accumulation has become a novel research pointcut for AS treatment in recent years. In AS patients, miR-135b level was up-regulated relative to the normal cases, which showed negative correlations with the levels of Semaphorin 3A (SEMA3A) and circZNF609, separately. The U937-derived macrophages were cultured with ox-LDL to establish AS models in vitro. After that, the lipid accumulation, inflammation, mitochondrial dysfunction and cell death were evaluated by ORO, ELISA, RT-qPCR, western blot, JC-1 and FCM assays respectively. Transfection of the circZNF609 expression vector notably declined lipid accumulation, attenuated inflammation, reduced mitochondrial dysfunction and inhibited cell death in ox-LDL-stimulated cells. The direct binding of miR-135b to circZNF609 in vitro was confirmed using RIP assay, and SEMA3A expression was up-regulated by circZNF609 overexpression. After manipulating the endogenous expressions of circZNF609, miR-135b and SEMA3A, the above damages in ox-LDL-stimulated cells were rescued by inhibition of miR-135b expression and overexpression of circZNF609 or SEMA3A. Besides, the AS mice model was built to demonstrate the excessive lipid accumulation, increasing inflammation and cell death in AS pathogenesis according to the results of HE staining, ELISA and IHC assays, while these damages were reversed after overexpression of circZNF609 or SEMA3A. In AS models, overexpressed circZNF609 prevents the AS progression through depleting miR-135b expression and subsequent up-regulation of SEMA3A expression to overwhelm lipid accumulation, mitochondrial dysfunction and cell death.
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BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.
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Mieloma Múltiple , Sistema de Registros , Mieloma Múltiple/epidemiología , Mieloma Múltiple/terapia , Mieloma Múltiple/diagnóstico , Humanos , Sistema de Registros/estadística & datos numéricos , Asia/epidemiología , Masculino , Femenino , Taiwán/epidemiología , Malasia/epidemiología , Singapur/epidemiología , Persona de Mediana Edad , República de Corea/epidemiología , Estudios ProspectivosRESUMEN
To address the solid waste challenges associated with coal gasification fine ash, this study conducted a low-temperature alkali fusion de-ashing treatment to transform coal gasification fine ash into mineral-carbon adsorbent. The preparation process was simplified without grinding, carbonization and high-temperature (500-800 °C) activation treatment. The results demonstrate a positive linear correlation between the ash removal rate of the samples (measured during the preparation process, i.e., low-temperature alkaline fusion treatment of coal gasification fine ash) and their maximum equilibrium adsorption capacity for methylene blue. For the samples with an ash removal rate of 95.71 %, which exhibit a maximum adsorption capacity of 161.36 mg/g for methylene blue. The adsorption behavior of methylene blue on mineral-carbon adsorbent was a monolayer adsorption on the surface of homogeneous medium, involving both physical and chemical adsorption. The main adsorb rate-controlling steps for the samples with ash removal rates of 27.91-59.33 % and 95.71 % were the intra particle diffusion process and the liquid film diffusion process, respectively. The adsorption mechanism of methylene blue on the surface of mineral-carbon adsorbent involved electrostatic attraction and hydrogen bonding. The aforementioned results demonstrated the potential of coal gasification fine ash as an adsorbent material, providing new options for promoting the resource utilization and high-value applications of coal gasification fine ash.
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Ceniza del Carbón , Contaminantes Químicos del Agua , Temperatura , Adsorción , Carbono , Azul de Metileno , Carbón Mineral , Minerales , CinéticaRESUMEN
BACKGROUND: This study aimed to assess the knowledge, attitudes and practices among medical workers toward outpatient diabetes information platform. METHODS: This web-based cross-sectional study was conducted between May 2023 and June 2023 at the First Hospital of Zhangjiakou, China. A self-designed questionnaire was developed to collect demographic information of medical workers, and assess their knowledge, attitudes and practices toward outpatient diabetes information platform. RESULTS: A total of 685 questionnaires were collected. Among the participants, 603 (88.03%) were female, 432 (63.07%) work in a tertiary hospital, 548 (80.00%) have a bachelor degree, 270 (39.42%) of them work in the department of internal medicine and 315 (45.99%) of them received previous training on outpatient diabetes information platform. The mean knowledge, attitudes and practices scores were 4.32 ± 1.27 (possible range: 0-6), 56.76 ± 5.72 (possible range: 14-70), and 32.22 ± 8.42 (possible range: 9-45), respectively. 350 (51.09%) of them have sufficient knowledge, 168 (24.53%) have positive attitudes and 395 (57.66%) have active practices. Pearson correlation analysis showed that knowledge was positively correlated with attitudes (r = 0.397, P < 0.001), and attitudes were positively correlated with practices (r = 0.306, P < 0.001). Multivariate analysis showed that primary hospital (OR = 0.32, 95% CI: 0.14-0.71, P = 0.005), secondary hospital (OR = 0.48, 95% CI: 0.32-0.72, P < 0.001), doctor (OR = 2.44, 95% CI: 1.39-4.28, P = 0.002) were independently associated with sufficient knowledge. Knowledge (OR = 1.49, 95% CI: 1.29-1.73, P < 0.001), community hospital staff (OR = 0.21, 95% CI: 0.05-0.88, P = 0.032) were independently associated with positive attitudes. Attitudes (OR = 1.13, 95% CI: 1.09-1.17, P < 0.001), junior college (OR = 1.72, 95% CI: 1.07-2.77, P = 0.026) were independently associated with active practices. The structural equation model demonstrated that knowledge had a direct effect on attitudes (path coefficient = 0.521, P < 0.001), and attitudes had a direct effect on practices (path coefficient = 0.542, P < 0.001). Moreover, the type of hospital had a direct effect on knowledge (path coefficient = 0.085, P < 0.001). Additionally, previous training on the outpatient diabetes platform had direct effects on attitudes (path coefficient = 0.191, P < 0.001) and practices (path coefficient = 0.184, P < 0.001). CONCLUSION: These findings revealed that medical workers have insufficient knowledge, positive attitudes and inactive practices toward the outpatient diabetes information platform. Comprehensive training programs are needed to improve medical staff's practices in this area.
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Diabetes Mellitus , Pacientes Ambulatorios , Humanos , Femenino , Masculino , Estudios Transversales , Conocimientos, Actitudes y Práctica en Salud , Encuestas y Cuestionarios , Centros de Atención Terciaria , Personal de HospitalRESUMEN
BACKGROUND: An increasing rate of encephalopathy associated with coronavirus disease 2019 (COVID-19) has been observed among children. However, the literature on neuroimaging data in children with COVID-19 is limited. OBJECTIVE: To analyze brain magnetic resonance imaging (MRI) of pediatric COVID-19 patients with neurological complications. MATERIALS AND METHODS: This multicenter retrospective observational study analyzed clinical (n=102, 100%) and neuroimaging (n=93, 91.2%) data of 102 children with COVID-19 infections and comorbid acute neurological symptoms. These children were hospitalized at five pediatric intensive care units (PICUs) in China between December 1, 2022, and January 31, 2023. RESULTS: All patients were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as detected via reverse transcriptase polymerase chain reaction. About 75.7% of the children were infected with the Omicron variant BF.7 strain. Brain MRI was performed 1-12 days following the onset of neurological symptoms, which revealed acute neuroimaging findings in 74.2% (69/93) of cases, including evidence of acute necrotizing encephalopathy (33/69, 47.8%), encephalitis (31/69, 44.9%), reversible splenial lesion syndrome (3/69, 4.3%), reversible posterior leukoencephalopathy (1/69, 1.4%), and hippocampal atrophy (1/69, 1.4%). CONCLUSIONS: Overall, these data highlighted five neuroimaging patterns associated with the outbreak of the SARS-CoV-2 Omicron variant, with acute necrotizing encephalopathy being the most common of these neuroimaging findings. Rarely, the brain MRI of these pediatric COVID-19 patients also demonstrate hippocampal atrophy.
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COVID-19 , Imagen por Resonancia Magnética , SARS-CoV-2 , Humanos , Estudios Retrospectivos , COVID-19/diagnóstico por imagen , COVID-19/complicaciones , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Niño , Preescolar , Lactante , Adolescente , Encefalopatías/diagnóstico por imagen , China , Neuroimagen/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/etiologíaRESUMEN
BACKGROUND AND AIMS: There is no evidence on the longitudinal and causal associations between multiple pesticides and the incidence of type 2 diabetes mellitus (T2DM) in the Chinese rural population, and whether physical activity (PA) modified these associations remains unclear. Here, we aimed to investigate the longitudinal and causal associations between pesticides mixture and T2DM, and determine whether PA modified these associations. METHODS: A total of 925 subjects with normal glucose and 925 subjects with impaired fasting glucose (IFG) were enrolled in this case-cohort study. A total of 51 targeted pesticides were quantified at baseline. Logistic regression, quantile g-computation, and Bayesian kernel machine regression (BKMR) were used to assess the individual and combined effects of pesticides on IFG and T2DM. Mendelian randomization (MR) analysis was employed to obtain the causal association between pesticides and T2DM. RESULTS: After 3-year follow-up, one-unit increment in ln-isofenphos, ln-malathion, and ln-deltamethrin were associated with an increase conversion of IFG to T2DM (FDR-P<0.05). One quartile increment in organochlorine pesticides (OCPs), organophosphorus pesticides (OPs), herbicides and pyrethroids mixtures were related to a higher incidence of T2DM among IFG patients (P<0.05). The BKMR results showed a positive trend between exposure to pesticides mixture and T2DM. The MR analysis indicated a positive association between exposure to pesticides and T2DM risk (P<0.05). No any significant association was found between pesticides and IFG. In addition, compared to subjects with high levels of PA, those with low levels of PA were related to increased risk of T2DM with the increased levels of pesticides among IFG patients. CONCLUSIONS: Individual and combined exposure to pesticides increased the incidence of T2DM among IFG patients. MR analysis further supported the causal association of pesticides exposure with T2DM risk. Our study furtherly indicated that high levels of PA attenuated the diabetogenic effect of pesticides exposure.
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Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS.
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Sarcoma Histiocítico , Linfoma Folicular , Humanos , Femenino , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/terapia , Linfoma Folicular/patología , Persona de Mediana Edad , Sarcoma Histiocítico/tratamiento farmacológico , Sarcoma Histiocítico/patología , Sarcoma Histiocítico/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inducción de RemisiónRESUMEN
In this study, S-doped graphitic carbon nitride (S-C3N4) was prepared using the high-temperature polymerization method, and then S-C3N4/AgCdS heterojunction photocatalyst was obtained using the chemical deposition method through loading Ag-doped CdS nanoparticles (AgCdS NPs) on the surface of S-C3N4. Experimental results show that the AgCdS NPs were evenly dispersed on the surface of S-C3N4, indicating that a good heterojunction structure was formed. Compared to S-C3N4, CdS, AgCdS and S-C3N4/CdS, the photocatalytic performance of S-C3N4/AgCdS has been significantly improved, and exhibits excellent photocatalytic degradation performance of Rhodamine B and methyl orange. The doping of Ag in collaboration with the construction of a Z-scheme heterojunction system promoted the effective separation and transport of the photogenerated carriers in S-C3N4/AgCdS, significantly accelerated its photocatalytic reaction process, and thus improved its photocatalytic performance.
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Wheat culms, comprising four to six internodes, are critically involved in determining plant height and lodging resistance, essential factors for field performance and regional adaptability. This study revealed the regulatory function of miR319 in common wheat plant height. Repression of tae-miR319 through short tandem target mimics (STTM) caused an increased plant height, while overexpression (OE) of tae-miR319 had the opposite effect. Overexpressing a miR319-resistant target gene TaPCF8 (rTaPCF8), increased plant height. TaPCF8 acted as a transcription repressor of downstream genes TaIAAs, which interact physically with TaSPL14. The significant differences of indole-3-acetic acid (IAA) contents indicate the involvement of auxin pathway in miR319-mediated plant height regulation. Finally, we identified two TaPCF8 haplotypes in global wheat collections. TaPCF8-5A-Hap2, as per association and evolution examinations, was subjected to strong substantial selection throughout wheat breeding. This haplotype, associated with shorter plant height, aligns with global breeding requirements. Consequently, in high-yield wheat breeding, we proposed a potential molecular marker for marker-assisted selection (MAS). Our findings offer fresh perspectives into the molecular mechanisms that underlie the miR319-TaPCF8 module's regulation of plant height by orchestrating auxin signaling and biosynthesis in wheat.
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IDEAL PLANT ARCHITECTURE1 (IPA1) is a pivotal gene controlling plant architecture and grain yield. However, little is known about the effects of Triticum aestivum SQUAMOSA PROMOTER-BINDING-LIKE 14 (TaSPL14), an IPA1 ortholog in wheat, on balancing yield traits and its regulatory mechanism in wheat (T. aestivum L.). Here, we determined that the T. aestivum GRAIN WIDTH2 (TaGW2)-TaSPL14 module influences the balance between tiller number and grain weight in wheat. Overexpression of TaSPL14 resulted in a reduced tiller number and increased grain weight, whereas its knockout had the opposite effect, indicating that TaSPL14 negatively regulates tillering while positively regulating grain weight. We further identified TaGW2 as a novel interacting protein of TaSPL14 and confirmed its ability to mediate the ubiquitination and degradation of TaSPL14. Based on our genetic evidence, TaGW2 acts as a positive regulator of tiller number, in addition to its known role as a negative regulator of grain weight, which is opposite to TaSPL14. Moreover, combinations of TaSPL14-7A and TaGW2-6A haplotypes exhibit significantly additive effects on tiller number and grain weight in wheat breeding. Our findings provide insight into how the TaGW2-TaSPL14 module regulates the trade-off between tiller number and grain weight and its potential application in improving wheat yield.
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Intelligent manufacturing technologies, including databases, mathematical modeling, and information systems have played a significant role in process control, production management, and supply chain management in traditional Chinese medicine(TCM) industry. However, their ability to process and utilize unstructured data, such as research and development reports, batch production records, quality inspection records, and supplier documents, is relatively weak. For text, images, language, and other unstructured data, generative artificial intelligence(AI) technology has shown strong potential for development in extracting information, extracting knowledge, semantic retrieval, and content generation. Generative AI is expected to provide a feasible set of tools for the utilization of unstructured data resources in the TCM industry. Based on years of research and industrial application experience in TCM intelligent manufacturing technology, this study reviewed the current situation of intelligent manufacturing in TCM and the utilization of unstructured data, analyzed the application value of generative AI in the TCM manufacturing process and supply chain, summarized four typical application scenarios, including intelligent pharmaceutical knowledge base/knowledge graph, intelligent on-the-job trai-ning, intelligent production quality control, and intelligent supply chain. Furthermore, this study also explained the data collection and processing, business process design, application potential, and value of each scenario based on industry demands. Finally, based on the integration of generative AI and TCM industrial models, the study proposed a preliminary concept of a smart industrial brain for TCM, aiming to provide a reference for the application of AI technology in the field of TCM manufacturing.
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Inteligencia Artificial , Medicamentos Herbarios Chinos , Medicina Tradicional China , Medicamentos Herbarios Chinos/química , Control de Calidad , HumanosRESUMEN
Multiple myeloma (MM) is an incurable plasma cell malignancy with the hallmark of immunodeficiency, including dysfunction of T cells, NK cells, and APCs. Dysfunctional APCs have been reported to play a key role in promoting MM progression. However, the molecular mechanisms remain elusive. Here, single-cell transcriptome analysis of dendritic cells (DC) and monocytes from 10 MM patients and three healthy volunteers was performed. Both DCs and monocytes were divided into five distinct clusters, respectively. Among them, monocyte-derived DCs (mono-DC) were shown to develop from intermediate monocytes (IM) via trajectory analysis. Functional analysis showed that, compared with healthy controls, conventional DC2 (cDC2), mono-DC, and IM of MM patients exhibited impaired antigen processing and presentation capacity. Moreover, reduced regulon activity of interferon regulatory factor 1 (IRF1) was found in cDC2, mono-DC and IM of MM patients according to single-cell regulatory network inference and clustering (SCENIC) analysis, while the downstream mechanisms were distinct. Specifically in MM patients, cathepsin S (CTSS) was markedly downregulated in cDC2, major histocompatibility complex (MHC) class II transactivator (CIITA) was significantly decreased in IM, in addition both CTSS and CIITA were downregulated in mono-DC based on differentially expressed genes analysis. In vitro study validated that knockdown of Irf1 downregulated Ctss and Ciita respectively in mouse DC cell line DC2.4 and mouse monocyte/macrophage cell line RAW264.7, which ultimately inhibited proliferation of CD4+ T cells after being cocultured with DC2.4 or RAW264.7 cells. This current study unveils the distinct mechanisms of cDC2, IM, and mono-DC function impairment in MM, offering new insight into the pathogenesis of immunodeficiency.
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Monocitos , Mieloma Múltiple , Ratones , Animales , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Antígenos , Presentación de Antígeno , Células Dendríticas , Antígenos de Histocompatibilidad Clase II , Diferenciación CelularRESUMEN
BACKGROUND: Founder parents play extremely important roles in wheat breeding. Studies into the genetic basis of founder parents and the transmission rules of favorable alleles are of great significance in improving agronomically important traits in wheat. RESULTS: Here, a total of 366 founder parents, widely grown cultivars, and derivatives of four representative founder parents were genotyped based on efficient kompetitive allele-specific PCR (KASP) markers in 87 agronomically important genes controlling yield, quality, adaptability, and stress resistance. Genetic composition analysis of founder parents and widely grown cultivars showed a consistently high frequency of favorable alleles for yield-related genes. This analysis further showed that other alleles favorable for resistance, strong gluten, dwarf size, and early heading date were also subject to selective pressure over time. By comparing the transmission of alleles from four representative founder parents to their derivatives during different breeding periods, it was found that the genetic composition of the representative founder parents was optimized as breeding progressed over time, with the number and types of favorable alleles carried gradually increasing and becoming enriched. There are still a large number of favorable alleles in wheat founder parents that have not been fully utilized in breeding selection. Eighty-seven agronomically important genes were used to construct an enrichment map that shows favorable alleles of four founder parents, providing an important theoretical foundation for future identification of candidate wheat founder parents. CONCLUSIONS: These results reveal the genetic basis of founder parents and allele transmission for 87 agronomically important genes and shed light on breeding strategies for the next generation of elite founder parents in wheat.
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Pan , Triticum , Alelos , Triticum/genética , Fitomejoramiento , GenotipoRESUMEN
BACKGROUND: Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets. METHODS: First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. RESULTS: We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. CONCLUSIONS: Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.
Asunto(s)
Mieloma Múltiple , Proteoma , Humanos , Proteoma/genética , Estudio de Asociación del Genoma Completo , Mieloma Múltiple/genética , Teorema de Bayes , Factores de Riesgo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 4/genéticaRESUMEN
Temperature measurements with high spatial resolution and accuracy can provide crucial data for understanding the changing process of microregion. Non-contact ratiometric fluorescence thermometers have received widespread attention for their sensitivity and interference resistibility. However, polymer and organic dye thermometers with such ratiometric fluorescence are very rare, and their applicability and processability are limited. In this study, novel tridurylboron compounds PPB1, PPB2, and PPB3 are designed and synthesized. They exhibit significant temperature responsive ratiometric fluorescence when dispersed in thermoplastic polyurethane elastomers (TPU). With a self-referencing feature and protection of TPU solid polymer, such fluorescence thermometers possess strong interference resistibility. From -10° to 60 °C, the fluorescence peak of PPB1-TPU system redshifted by 41 nm, the fluorescence color changes from blue to green. For the fluorescence ratiometric temperature measurement procedure, the absolute sensitivity is 14.5% °C-1 (40 °C) and relative sensitivity is 6.3% °C-1 (35 °C), which is much higher than reported solid polymer fluorescence thermometers. The temperature-responsive ranges can be adjusted by altering the types of polymer substrate and the number of the substituents. Such tridurylboron-TPU polymer fluorescence thermometers can be applied in aqueous environment and processed into devices of various shapes and sizes, demonstrating great potential for application.