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Homomeric dimerization of metabotropic glutamate receptors (mGlus) is essential for the modulation of their functions and represents a promising avenue for the development of novel therapeutic approaches to address central nervous system diseases. Yet, the scarcity of detailed molecular and energetic data on mGlu2 impedes our in-depth comprehension of their activation process. Here, we employ computational simulation methods to elucidate the activation process and key events associated with the mGlu2, including a detailed analysis of its conformational transitions, the binding of agonists, Gi protein coupling, and the guanosine diphosphate (GDP) release. Our results demonstrate that the activation of mGlu2 is a stepwise process and several energy barriers need to be overcome. Moreover, we also identify the rate-determining step of the mGlu2's transition from the agonist-bound state to its active state. From the perspective of free-energy analysis, we find that the conformational dynamics of mGlu2's subunit follow coupled rather than discrete, independent actions. Asymmetric dimerization is critical for receptor activation. Our calculation results are consistent with the observation of cross-linking and fluorescent-labeled blot experiments, thus illustrating the reliability of our calculations. Besides, we also identify potential key residues in the Gi protein binding position on mGlu2, mGlu2 dimer's TM6-TM6 interface, and Gi α5 helix by the change of energy barriers after mutation. The implications of our findings could lead to a more comprehensive grasp of class C G protein-coupled receptor activation.
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Receptores de Glutamato Metabotrópico , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/química , Humanos , Multimerización de Proteína , Simulación de Dinámica Molecular , Conformación Proteica , Unión ProteicaRESUMEN
Molecular generative models have exhibited promising capabilities in designing molecules from scratch with high binding affinities in a predetermined protein pocket, offering potential synergies with traditional structural-based drug design strategy. However, the generative processes of such models are random and the atomic interaction information between ligand and protein are ignored. On the other hand, the ligand has high propensity to bind with residues called hotspots. Hotspot residues contribute to the majority of the binding free energies and have been recognized as appealing targets for designed molecules. In this work, we develop an interaction prompt guided diffusion model, InterDiff to deal with the challenges. Four kinds of atomic interactions are involved in our model and represented as learnable vector embeddings. These embeddings serve as conditions for individual residue to guide the molecular generative process. Comprehensive in silico experiments evince that our model could generate molecules with desired ligand-protein interactions in a guidable way. Furthermore, we validate InterDiff on two realistic protein-based therapeutic agents. Results show that InterDiff could generate molecules with better or similar binding mode compared to known targeted drugs.
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Proteínas , Proteínas/química , Proteínas/metabolismo , Ligandos , Unión Proteica , Diseño de Fármacos , Modelos Moleculares , Algoritmos , Sitios de Unión , Simulación por ComputadorRESUMEN
Over-expression (OE) lines for the ER-tethered NAC transcription factor ANAC017 displayed de-repression of gun marker genes when grown on lincomycin (lin). RNA-seq revealed that ANAC017OE2 plants constitutively expressed greater than 40% of the genes induced in wild-type with lin treatment, including plastid encoded genes ycf1.2 and the gene cluster ndhH-ndhA-ndhI-ndhG-ndhE-psaC-ndhD, documented as direct RNA targets of GUN1. Genes encoding components involved in organelle translation were enriched in constitutively expressed genes in ANAC017OE2. ANAC017OE resulted in constitutive location in the nucleus and significant constitutive binding of ANAC017 was detected by ChIP-Seq to target genes. ANAC017OE2 lines maintained the ability to green on lin, were more ABA sensitive, did not show photo-oxidative damage after exposure of de-etiolated seedlings to continuous light and the transcriptome response to lin were as much as 80% unique compared to gun1-1. Both double mutants, gun1-1:ANAC017OE and bzip60:ANAC017OE (but not single bzip60), have a gun molecular gene expression pattern and result in variegated and green plants, suggesting that ANAC017OE may act through an independent pathway compared to gun1. Over-expression of ANAC013 or rcd1 did not produce a GUN phenotype or green plants on lin. Thus, constitutive ANAC017OE2 establishes an alternative transcriptional program that likely acts through a number of pathways, that is, maintains plastid gene expression, and induction of a variety of transcription factors involved in reactive oxygen species metabolism, priming plants for lin tolerance to give a gun phenotype.
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As sessile organisms, plants need to respond to rapid changes in numerous environmental factors, mainly diurnal changes of light, temperature, and humidity. Maize is the world's most grown crop, and as a C4 plant it exhibits high photosynthesis capacity, reaching the highest rate of net photosynthesis at midday; that is, there is no "midday depression." Revealing the physiological responses to diurnal changes and underlying mechanisms will be of great significance for guiding maize improvement efforts. In this study, we collected maize leaf samples and analyzed the proteome and phosphoproteome at nine time points during a single day/night cycle, quantifying 7424 proteins and 5361 phosphosites. The new phosphosites identified in our study increased the total maize phosphoproteome coverage by 8.5%. Kinase-substrate network analysis indicated that 997 potential substrates were phosphorylated by 20 activated kinases. Through analysis of proteins with significant changes in abundance and phosphorylation, we found that the response to a heat stimulus involves a change in the abundance of numerous proteins. By contrast, the high light at noon and rapidly changing light conditions induced changes in the phosphorylation level of proteins involved in processes such as chloroplast movement, photosynthesis, and C4 pathways. Phosphorylation is involved in regulating the activity of large number of enzymes; for example, phosphorylation of S55 significantly enhanced the activity of maize phosphoenolpyruvate carboxykinase1 (ZmPEPCK1). Overall, the database of dynamic protein abundance and phosphorylation we have generated provides a resource for the improvement of C4 crop plants.
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Plantas , Zea mays , Zea mays/metabolismo , Plantas/metabolismo , Fosforilación , Proteínas de Plantas/metabolismo , Fosfoproteínas/metabolismo , Hojas de la Planta/metabolismo , FotosíntesisRESUMEN
The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID-19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike-angiotensin-converting enzyme-2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse-grained model. Our study extended beyond the receptor-binding domain (RBD) of spike trimer through comprehensive modeling of the full-length spike trimer rather than just the RBD. Our free-energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full-length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Mutación , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/química , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , COVID-19/virología , COVID-19/transmisión , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/química , Simulación de Dinámica Molecular , Termodinámica , Modelos MolecularesRESUMEN
The dysfunction and defects of ion channels are associated with many human diseases, especially for loss-of-function mutations in ion channels such as cystic fibrosis transmembrane conductance regulator mutations in cystic fibrosis. Understanding ion channels is of great current importance for both medical and fundamental purposes. Such an understanding should include the ability to predict mutational effects and describe functional and mechanistic effects. In this work, we introduce an approach to predict mutational effects based on kinetic information (including reaction barriers and transition state locations) obtained by studying the working mechanism of target proteins. Specifically, we take the Ca2+-activated chloride channel TMEM16A as an example and utilize the computational biology model to predict the mutational effects of key residues. Encouragingly, we verified our predictions through electrophysiological experiments, demonstrating a 94% prediction accuracy regarding mutational directions. The mutational strength assessed by Pearson's correlation coefficient is -0.80 between our calculations and the experimental results. These findings suggest that the proposed methodology is reliable and can provide valuable guidance for revealing functional mechanisms and identifying key residues of the TMEM16A channel. The proposed approach can be extended to a broad scope of biophysical systems.
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Canales de Cloruro , Cloruros , Humanos , Cloruros/metabolismo , Anoctamina-1/genética , Anoctamina-1/metabolismo , Canales de Cloruro/genética , Canales de Cloruro/química , Canales de Cloruro/metabolismo , Mutación , Transducción de Señal , Calcio/metabolismoRESUMEN
For grain crops such as rice (Oryza sativa), grain size substantially affects yield. The histone acetyltransferase GRAIN WEIGHT 6a (GW6a) determines grain size and yield in rice. However, the gene regulatory network underlying GW6a-mediated regulation of grain size has remained elusive. In this study, we show that GW6a interacts with HOMOLOG OF DA1 ON RICE CHROMOSOME 3 (HDR3), a ubiquitin-interacting motif-containing ubiquitin receptor. Transgenic rice plants overexpressing HDR3 produced larger grains, whereas HDR3 knockout lines produce smaller grains compared to the control. Cytological data suggest that HDR3 modulates grain size in a similar manner to GW6a, by altering cell proliferation in spikelet hulls. Mechanistically, HDR3 physically interacts with and stabilizes GW6a in an ubiquitin-dependent manner, delaying protein degradation by the 26S proteasome. The delay in GW6a degradation results in dramatic enhancement of the local acetylation of H3 and H4 histones. Furthermore, RNA sequencing analysis and chromatin immunoprecipitation assays reveal that HDR3 and GW6a bind to the promoters of and modulate a common set of downstream genes. In addition, genetic analysis demonstrates that HDR3 functions in the same genetic pathway as GW6a to regulate the grain size. Therefore, we identified the grain size regulatory module HDR3-GW6a as a potential target for crop yield improvement.
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Grano Comestible/crecimiento & desarrollo , Oryza/genética , Proteínas de Plantas/genética , Grano Comestible/genética , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Oryza/enzimología , Oryza/crecimiento & desarrollo , Proteínas de Plantas/metabolismoRESUMEN
Background: Mitral valve repair (MVr) is an effective treatment for degenerative mitral regurgitation (DMR).And the outcomes and repair rates for posterior leaflet prolapse (PLP), anterior leaflet prolapse (ALP), and bileaflet prolapse (BLP) vary. This study aimed to compare the outcomes of mitral valve repair for patients with PLP, ALP, and BLP. Methods: From 2010 to 2019, 1192 patients with degenerative mitral valve regurgitation underwent surgery at our hospital. And 1069 patients were identified. The average age of all patients was (54.74 ± 12.17) years old for all patients. 273 patients (25.5%) had ALP, 148 patients (13.8%) had BLP, and 648 patients (60.6%) had PLP. All patients were followed up for an average duration of 5.1 years. We compared the outcomes of patients with ALP, PLP, and BLP. Results: Patients with ALP were the youngest of the 3 groups and had the highest prevalence of atrial fibrillation. Patients with PLP had the highest prevalence of hypertension, whereas patients with BLP and ALP had larger left ventricular end-diastolic and left ventricular end-systolic diameters. ALP and BLP repairs had a longer cardiopulmonary bypass and aortic cross-clamp time.10 patients dead in-hospital, 5 patients had PLP, 3 had ALP, and 2 had BLP. The 10-year survival cumulative incidences of reoperation among ALP, BLP, and PLP repairs were not significantly different. ALP repair still had higher cumulative incidences of recurrent mitral regurgitation (MR) compared to PLP. Conclusions: The rates of long-term survival and freedom from reoperation were not significantly different among patients with ALP, BLP, and PLP. ALP repair has higher cumulative incidences of recurrent MR compared to PLP.
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Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The existence of cancer stem cells (CSC) causes tumor relapses, metastasis, and resistance to conventional therapy. Alternative splicing has been shown to affect physiological and pathological processes. Accumulating evidence has confirmed that targeting alternative splicing could be an effective strategy to treat CRC. Currently, the role of alternative splicing in the regulation of CSC properties in CRC has not been elucidated. Here, we show that RBM17 displays oncogenic roles in CRC cells. RBM17 enhances cell proliferation and reduces chemotherapeutic-induced apoptosis in CRC cells. Besides, RBM17 increases CD133 positive and ALDEFLUOR positive populations and promotes sphere formation in CRC cells. In mechanism studies, we found that FOXM1 is critical for RBM17 enhanced CSC properties. Moreover, FOXM1 alternative splicing is essential for RBM17 enhanced CSC properties in CRC cells. Additionally, RBM17 enhances CSC characteristics by controlling FOXM1 expression to promote Sox2 expression. Furthermore, AKT1 works as an upstream kinase to control RBM17-mediated FOXM1 alternative splicing and enhancement of CSC properties in CRC cells. Our study reveals that AKT1-RBM17-FOXM1-Sox2 axis could be a potential target for modulating alternative splicing to reduce CSC properties in CRC cells.
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Neoplasias Colorrectales , Humanos , Empalme Alternativo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Empalme de ARN/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
BACKGROUND: Cannabis use is associated with higher intravenous anesthetic administration. Similar data regarding inhalational anesthetics are limited. With rising cannabis use prevalence, understanding any potential relationship with inhalational anesthetic dosing is crucial. We compared average intraoperative isoflurane/sevoflurane minimum alveolar concentration equivalents between older adults with and without cannabis use. METHODS: The electronic health records of 22,476 surgical patients ≥65 years old at the University of Florida Health System between 2018-2020 were reviewed. The primary exposure was cannabis use within 60 days of surgery, determined via i) a previously published natural language processing algorithm applied to unstructured notes and ii) structured data, including International Classification of Disease codes for cannabis use disorders and poisoning by cannabis, laboratory cannabinoids screening results, and RxNorm codes. The primary outcome was the intraoperative time-weighted average of isoflurane/sevoflurane minimum alveolar concentration equivalents at one-minute resolution. No a priori minimally clinically important difference was established. Patients demonstrating cannabis use were matched 4:1 to non-cannabis use controls using a propensity score. RESULTS: Among 5,118 meeting inclusion criteria, 1,340 patients (268 cannabis users and 1,072 nonusers) remained after propensity score matching. The median and interquartile range (IQR) age was 69 (67, 73) years; 872 (65.0%) were male, and 1,143 (85.3%) were non-Hispanic White. The median (IQR) anesthesia duration was 175 (118, 268) minutes. After matching, all baseline characteristics were well-balanced by exposure. Cannabis users had statistically significantly higher average minimum alveolar concentrations than nonusers [mean±SD: 0.58±0.23 versus 0.54±0.22, respectively; mean difference=0.04; 95% confidence limits, 0.01 to 0.06; p=0.020]. CONCLUSION: Cannabis use was associated with administering statistically significantly higher inhalational anesthetic minimum alveolar concentration equivalents in older adults, but the clinical significance of this difference is unclear. These data do not support the hypothesis that cannabis users require clinically meaningfully higher inhalational anesthetics doses.
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MicroRNAs (miRNAs) are noncoding RNAs with 18-26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA-target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update's critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3' untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.
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Regiones no Traducidas 3' , Bases de Datos de Ácidos Nucleicos , Redes Reguladoras de Genes , MicroARNs/genética , Neoplasias/genética , ARN no Traducido/genética , Animales , Sitios de Unión , Biomarcadores/metabolismo , Minería de Datos/estadística & datos numéricos , Exosomas/química , Exosomas/metabolismo , Regulación de la Expresión Génica , Humanos , Internet , Ratones , MicroARNs/clasificación , MicroARNs/metabolismo , Anotación de Secuencia Molecular , Neoplasias/metabolismo , Neoplasias/patología , Polimorfismo de Nucleótido Simple , ARN no Traducido/clasificación , ARN no Traducido/metabolismo , Células Tumorales Cultivadas , Interfaz Usuario-ComputadorRESUMEN
One third of the western population suffers from nonalcoholic fatty liver disease (NAFLD), which may ultimately develop into hepatocellular carcinoma (HCC). The molecular event(s) that triggers the disease are not clear. Current understanding, known as the multiple hits model, suggests that NAFLD is a result of diverse events at several tissues (e.g., liver, adipose tissues, and intestine) combined with changes in metabolism and microbiome. In contrast to this prevailing concept, we report that fatty liver could be triggered by a single mutated protein expressed only in the liver. We established a transgenic system that allows temporally controlled activation of the MAP kinase p38α in a tissue-specific manner by induced expression of intrinsically active p38α allele. Here we checked the effect of exclusive activation in the liver. Unexpectedly, induction of p38α alone was sufficient to cause macrovesicular fatty liver. Animals did not become overweight, showing that fatty liver can be imposed solely by a genetic modification in liver per se and can be separated from obesity. Active p38α-induced fatty liver is associated with up-regulation of MUC13, CIDEA, PPARγ, ATF3, and c-jun mRNAs, which are up-regulated in human HCC. Shutting off expression of the p38α mutant resulted in reversal of symptoms. The findings suggest that p38α plays a direct causative role in fatty liver diseases and perhaps in other chronic inflammatory diseases. As p38α activity was induced by point mutations, it could be considered a proto-inflammatory gene (proto-inflammagene).
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Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/metabolismo , Mutación con Ganancia de Función , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Variable renewable energy (VRE) is the most promising form of primary generation under a carbon neutrality target due to its environmental benefits, incentive policy, and technological progress. However, the increasing proportion of VRE generation, such as solar and wind power, has sharply increased integration cost and reduced power grid stability. This study uses portfolio theory to investigate China's optimal power generation portfolio by 2050 considering flexibility constraint and system cost, including technical and integration costs. The results demonstrate that non-fossil-fuel power generation technologies have cost and emission reduction advantages over fossil-fuel-based technologies. VRE generation technologies must be developed in synergy with other forms of power generation when considering flexibility requirement and integration cost. A complete phase-out of fossil-fuel power generation technologies in China appears unlikely in the study period. Gas-fired and coal-fired power generation are the pillar forms of power generation to meet future flexibility needs.
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Carbono , Combustibles Fósiles , Carbono/análisis , Carbón Mineral , Viento , China , Dióxido de Carbono/análisis , Centrales EléctricasRESUMEN
OBJECTIVE: To evaluate the long-term outcomes of degenerative mitral valve (MV) repair. METHODS: This study analysed 1,069 patients who underwent MV repair due to degenerative MV disease at Beijing Anzhen Hospital from January 2010 to December 2019. All patients were clinically followed until December 2019, with an average follow-up period of 4.7 years. Perioperative complications, 30-day mortality, long-term outcomes, and risk factors of all-cause death and recurrent mitral regurgitation (MR) were summarised. RESULTS: Ten patients died in the hospital and 33 died during the follow-up period. Recurrent MR occurred in 113 patients. Fourteen patients underwent re-operation. Rates of long-term survival, absence of recurrent MR, and no re-operation were 94.0% (91.6%-96.6%), 81.2% (77.3%-85.3%), and 98.2% (97.2%-99.3%), respectively. The risk factors for long-term all-cause death included age and an ejection fraction (EF) <60%. The risk factors for recurrent MR included age, female sex, E-wave velocity, anterior prolapse, residual 1+MR postoperatively, and lower body mass index. CONCLUSIONS: Mitral valve repair is an effective treatment for degenerative MV disease that, in an experienced heart centre, can be performed with low mortality, recurrence, and re-operation rates. Advanced age and an EF <60% were risk factors for long-term all-cause death. Age, female sex, residual 1+MR postoperatively, lower body mass index, higher peak E-wave velocity, and anterior prolapse were risk factors for recurrent MR.
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Procedimientos Quirúrgicos Cardíacos , Insuficiencia de la Válvula Mitral , Humanos , Femenino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/cirugía , Resultado del Tratamiento , Prolapso , Estudios RetrospectivosRESUMEN
BACKGROUND: Gamma-aminobutyric acid (GABA) is an important neurotransmitter in the human body, with several negative emotions reported as being associated with GABA dysregulation. This study investigates the safety and modulatory effects of GABA-enriched milk, fermented by Streptococcus thermophilus GA8 and Lacticasebacillus rhamnosus HAO9, on the gut microbiota and neurotransmitter profiles in mice. RESULTS: Through rigorous culturing and fermentation processes, we achieved consistent GABA production in milk, with concentrations reaching 4.6 and 8.5 g L-1 for GA8-fermented and co-fermented milk, respectively, after 48 h. Using SPF male C57BL/6J mice, we administered either mono-culture or combined-culture milk treatments and monitored physiological impacts. The treatments did not affect mouse body weight but induced significant changes in gut microbiota composition. Beta diversity analysis revealed distinct microbial profiles between treatment groups, highlighting fermentation-specific microbial shifts, such as an increase in Verrucomicrobia for the GA8 group and a modulation in Saccharibacteria_genera_incertae_sedis for the GA8 + HAO9 group. Serum neurotransmitter levels were elevated in both treatment groups, with significant increases in l-glutamine, l-tryptophan and, notably, serotonin hydrochloride in the GA8 + HAO9 group. Correlation analysis identified a positive association between specific bacterial genera and neurotransmitter levels, suggesting a probiotic effect on neuroactive substances. CONCLUSION: These findings suggest that fermented milk has potential as a probiotic supplement for mood improvement and stress relief, highlighting its role in modulating the gut-brain axis. © 2024 Society of Chemical Industry.
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In this study, peptide-based self-assembled nanosheets with a thickness of approximately 1â nm were prepared using a hierarchical covalent physical fabrication strategy. The covalent alternating polymerization of helical peptide E3 with an azobenzene (AZO) structure yielded copolymers CoP(E3-AZO), which physically self-assembled into ultrathin nanosheets in an unanticipated two-dimensional horizontal monolayer arrangement. This special monolayer arrangement enabled the thickness of the nanosheets to be equal to the cross-sectional diameter of a single linear copolymer, which is a rare phenomenon. Molecular dynamics simulations suggested that the synergistic effect of multiple molecular interactions drives the self-assembly of CoP(E3-AZO) into nanosheets and that various methods, including phototreatment, pH adjustment, the addition of additives, and introduction of cosolvents, can alter the molecular interactions and modulate the self-assembly of CoP(E3-AZO), yielding diverse nanostructures. Remarkably, the ultrathin nanosheets selectively inhibited cancer cells at certain concentrations.
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Nanoestructuras , Péptidos , Nanoestructuras/química , Péptidos/química , Humanos , Simulación de Dinámica Molecular , Compuestos Azo/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Leaves are the primary photosynthetic organs, providing essential substances for tree growth. It is important to obtain an anatomical understanding and regulatory network analysis of leaf development. Here, we studied leaf development in Populus Nanlin895 along a development gradient from the newly emerged leaf from the shoot apex to the sixth leaf (L1 to L6) using anatomical observations and RNA-seq analysis. It indicated that mesophyll cells possess obvious vascular, palisade, and spongy tissue with distinct intercellular spaces after L3. Additionally, vacuoles fuse while epidermal cells expand to form pavement cells. RNA-seq analysis indicated that genes highly expressed in L1 and L2 were related to cell division and differentiation, while those highly expressed in L3 were enriched in photosynthesis. Therefore, we selected L1 and L3 to integrate ATAC-seq and RNA-seq and identified 735 differentially expressed genes (DEGs) with changes in chromatin accessibility regions within their promoters, of which 87 were transcription factors (TFs), such as ABI3VP1, AP-EREBP, MYB, NAC, and GRF. Motif enrichment analysis revealed potential regulatory functions for the DEGs through upstream TFs including TCP, bZIP, HD-ZIP, Dof, BBR-BPC, and MYB. Overall, our research provides a potential molecular foundation for regulatory network exploration in leaf development during photosynthesis establishment.
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MAIN CONCLUSION: OsTST1 affects yield and development and mediates sugar transportation of plants from source to sink in rice, which influences the accumulation of intermediate metabolites from tricarboxylic acid cycle indirectly. Tonoplast sugar transporters (TSTs) are essential for vacuolar sugar accumulation in plants. Carbohydrate transport across tonoplasts maintains the metabolic balance in plant cells, and carbohydrate distribution is crucial to plant growth and productivity. Large plant vacuoles store high concentrations of sugars to meet plant requirements for energy and other biological processes. The abundance of sugar transporter affects crop biomass and reproductive growth. However, it remains unclear whether the rice (Oryza sativa L.) sugar transport protein OsTST1 affects yield and development. In this study, we found that OsTST1 knockout mutants generated via CRISPR/Cas9 exhibited slower development, smaller seeds, and lower yield than wild type (WT) rice plants. Notably, plants overexpressing OsTST1 showed the opposite effects. Changes in rice leaves at 14 days after germination (DAG) and at 10 days after flowering (DAF) suggested that OsTST1 affected the accumulation of intermediate metabolites from the glycolytic pathway and the tricarboxylic acid (TCA) cycle. The modification of the sugar transport between cytosol and vacuole mediated by OsTST1 induces deregulation of several genes including transcription factors (TFs). In summary, no matter the location of sucrose and sink is, these preliminary results revealed that OsTST1 was important for sugar transport from source to sink tissues, thus affecting plant growth and development.
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Oryza , Proteínas de Plantas , Transporte Biológico , Carbohidratos , Oryza/genética , Oryza/metabolismo , Azúcares , Vacuolas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
The optical angular memory effect (AME) is a basic feature of turbid media and defines the correlation of speckles when the incident light is tilted. AME based imaging through solid scattering media such as ground glass and biomedical tissue has been recently developed. However, in the case of liquid media such as turbid water or blood, the speckle pattern exhibits dynamic time-varying characteristics, which introduces several challenges. The AME of the thick volume dynamic media is particularly different from the layer scatterers. In practice, there are more parameters, e.g., scattering particle size, shape, density, or even the illuminating beam aperture that can influence the AME range. Experimental demonstration of AME phenomenon in liquid dynamic media and confirm the distinctions will contribution to complete the AME theory. In this paper, a dual-polarization speckle detection setup was developed to characterize the AME of dynamic turbid media, where two orthogonal polarized beams were employed for simultaneous detection by a single CCD. The AME of turbid water, milk and blood were measured. The influence of thickness, concentration, particle size and shape, and beam diameter were analyzed. The AME increasement of upon the decrease of beam diameter was tested and verified. The results demonstrate the feasibility of this method for investigating the AME phenomenon and provide guidance for AME based imaging through scattering media.
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The mortality rate of clear cell renal cell carcinoma (ccRCC) remains high. Immunohistochemical staining, Western blotting and real-time quantitative polymerase chain reaction were employed to evaluate ADAM (a disintegrin and metalloproteinase) metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) levels in ccRCC tissues and paired normal tissues, and all tissues were obtained from clinical samples of 46 cases of ccRCC patients. Moreover, we analyzed the role ADAMTS16 in the progression of ccRCC using Cell Counting Kit-8 assay and flow cytometry. ADAMTS16 levels in ccRCC tissues were markedly low, relative to normal tissues, and ADAMTS16 level closely correlated with tumor stage, lymph node metastasis as well as pathological grade. Patients with elevated ADAMTS16 expressions have a more favorable survival outcome, relative to patients with low expression of ADAMTS16. In vitro study showed ADAMTS16 expression markedly decreased in ccRCC cells and acted as a tumor suppressor compared with the normal cells. The expression of ADAMTS16 is down-regulated in ccRCC tissues, relative to normal tissues, and it may inhibit the malignancies of ccRCC. Such inhibitory effect may be ascribed to the involvement of AKT/mammalian target of rapamycin signaling. Hence, the present study of ADAMTS16 will provide new insight into the underlying biological mechanisms of ccRCC.