RESUMO

Hydrogels can improve the delivery of mesenchymal stromal cells (MSCs) by providing crucial biophysical cues that mimic the extracellular matrix. The differentiation of MSCs is dependent on biophysical cues like stiffness and viscoelasticity, yet conventional hydrogels cannot be dynamically altered after fabrication and implantation to actively direct differentiation. We developed a composite hydrogel, consisting of type I collagen and phase-shift emulsion, where osteogenic differentiation of MSCs can be non-invasively modulated using ultrasound. When exposed to ultrasound, the emulsion within the hydrogel was non-thermally vaporized into bubbles, which locally compacted and stiffened the collagen matrix surrounding each bubble. Bubble growth and matrix compaction were correlated, with collagen regions proximal (i.e., ≤ ∼60 µm) to the bubble displaying a 2.5-fold increase in Young's modulus compared to distal regions (i.e., > ∼60 µm). The viability and proliferation of MSCs, which were encapsulated within the composite hydrogel, were not impacted by bubble formation. In vitro and in vivo studies revealed encapsulated MSCs exhibited significantly elevated levels of RUNX2 and osteocalcin, markers of osteogenic differentiation, in collagen regions proximal to the bubble compared to distal regions. Additionally, alkaline phosphatase activity and calcium deposition were enhanced adjacent to the bubble. An opposite trend was observed for CD90, a marker of MSC stemness. Following subcutaneous implantation, bubbles persisted in the hydrogels for two weeks, which led to localized collagen alignment and increases in nuclear asymmetry. These results are a significant step toward controlling the 3D differentiation of MSCs in a non-invasive and on-demand manner.

RESUMO

Pampus argenteus demonstrates a preference for Rhopilema esculentum as prey, yet the ramifications of consuming supplemental medusa on fish microbiota and metabolism remain elusive. To elucidate these effects, 300 juvenile fish were divided into two groups: control group (C, given commercial food only) and supplemental medusa (SM) group (given supplemental medusa + commercial feed). After 15 days, fish in the SM group exhibited a significant increase in fatness, the amylase activity in the intestine significantly increased, and the intestinal microvilli were arranged more neatly. The comprehensive approach involving 16S rRNA amplicon sequencing and metabolomics was employed, leading to the identification of five genera within the SM group, namely Lactococcus, Cohaesibacter, Maritalea, Sulfitobacter, and Carnobacterium. Functional prediction analysis of the microbiota indicated that the consumption of supplemental medusa facilitated processes such as glycolysis/gluconeogenesis and amino acid absorption. Metabolomics analysis revealed significant enrichment of 85 differential metabolites, most of them belonging to fatty acids and conjugates. These differential metabolites primarily participated in processes such as amino acid metabolism, fatty acid synthesis, and disease. Notably, the consumption of medusa resulted in a significant reduction in nine lysophospholipids associated with cardiovascular disease and inflammation. Pearson's correlation coefficient analysis revealed associations between specific microorganisms and metabolites, indicating that Cobetia, Weissella, and Macrococcus exhibited an increased abundance in the SM group, positively correlating with apocynin, 12-Hete, and delta 9-THC-d3. The indicator bacteria Psychrobacter reduced in the SM group, exhibiting a negative correlation with cystathionine (a compound involved in glutathione synthesis). Overall, the supplementation of medusa may confer a beneficial effect on the immunity of the fish. This study contributes to the theoretical framework for fish feed development.

RESUMO

BACKGROUND: Vascular endothelial dysfunction is the initial factor involved in cardiovascular injury in patients with diabetes. Retinoic acid is involved in improving vascular complications in patients with diabetes, but its protective mechanism is still unclear. This study aimed to evaluate the effect and mechanism of All-Trans Retinoic Acid (ATRA) on endothelial dysfunction induced by diabetes. METHODS: In the present study, streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were observed, and the effects of ATRA on HG-induced endothelial dysfunction and ferroptosis were evaluated. RESULTS: ATRA treatment improved impaired vasorelaxation in diabetic aortas in an endothelium-dependent manner, and this effect was accompanied by an increase in the NO concentration and eNOS expression. Ferroptosis, characterized by lipid peroxidation and iron overload induced by HG, was improved by ATRA administration, and a ferroptosis inhibitor (ferrostatin-1, Fer-1) improved endothelial function to a similar extent as ATRA. In addition, the inactivation of phosphoinositol-3-kinase (PI3K)/protein kinases B (AKT) and Yes-Associated Protein (YAP) nuclear localization induced by HG were reversed by ATRA administration. Vascular ring relaxation experiments showed that PI3K/AKT activation and YAP inhibition had similar effects on ferroptosis and endothelial function. However, the vasodilative effect of retinoic acid was affected by PI3K/AKT inhibition, and the inhibitory effects of ATRA on ferroptosis and the improvement of endothelial function were dependent on the retinoic acid receptor. CONCLUSION: ATRA could improve vascular endothelial dysfunction by inhibiting PI3K/AKT/YAP-mediated ferroptosis induced by HG, which provides a new idea for the treatment of vascular lesions in diabetes.

RESUMO

The internalization of nanoparticles is of great significance for their biological applications. Clathrin-mediated endocytosis (CME) is one of the main endocytic pathways. However, there is still a lack of a fundamental understanding regarding the internalization of multiple nanoparticles via CME. Therefore, in this study, we conducted computational investigations to uncover detailed molecular mechanisms and kinetic pathways for differently shaped nanoparticles in the presence of clathrin. Particular focus is given to understanding the CME of multiple-nanoparticle systems. We found that unlike receptor-mediated endocytosis, multiple nanoparticles did not get cooperatively wrapped by the membrane but tended to undergo independent endocytosis in the presence of clathrin. To further investigate the endocytosis mechanism, we studied the effects of clathrins, nanoparticle shape, nanoparticle size, nanoparticle arrangement, and membrane surface tension. The self-assembly of clathrin prefers independent endocytosis for multiple nanoparticles. Besides, the cooperative behavior is weak with increasing nanoparticle-shape anisotropy. However, when the membrane tension is reduced, the endocytosis pathway for multiple nanoparticles is cooperative endocytosis. Moreover, we found that the self-assembly of clathrins reduces the critical size of nanoparticles to undergo cooperative wrapping by the cell membrane. Our results provide valuable insights into the molecular mechanisms of multiple nanoparticles through CME and offer useful guidance for the design of nanoparticles as drug/gene delivery carriers.

RESUMO

Light is a vital environmental signal that regulates the expression of plastid genes. Plastids are crucial organelles that respond to light, but the effects of light on plastid RNA processing following transcription remain unclear. In this study, we systematically examined the influence of light exposure on plastid RNA processing, focusing on RNA splicing and RNA editing. We demonstrated that light promotes the splicing of transcripts from the plastid genes rps12, ndhA, atpF, petB, and rpl2. Additionally, light increased the editing rate of the accD transcript at nucleotide 794 (accD-794) and the ndhF transcript at nucleotide 290 (ndhF-290), while decreasing the editing rate of the clpP transcript at nucleotide 559 (clpP-559). We have identified key regulators of signaling pathways, such as CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1), ELONGATED HYPOCOTYL 5 (HY5), and PHYTOCHROME-INTERACTING FACTORs (PIFs), as important players in the regulation of plastid RNA splicing and editing. Notably, COP1 was required for GENOMES UNCOUPLED1 (GUN1)-dependent repression of clpP-559 editing in the light. We showed that HY5 and PIF1 bind to the promoters of nuclear genes encoding plastid-localized RNA processing factors in a light-dependent manner. This study provides insight into the mechanisms underlying light-mediated post-transcriptional regulation of plastid gene expression.

RESUMO

Perturb-Seq combines CRISPR (clustered regularly interspaced short palindromic repeats)-based genetic screens with single-cell RNA sequencing readouts for high-content phenotypic screens. Despite the rapid accumulation of Perturb-Seq datasets, there remains a lack of a user-friendly platform for their efficient reuse. Here, we developed PerturbDB (http://research.gzsys.org.cn/perturbdb), a platform to help users unveil gene functions using Perturb-Seq datasets. PerturbDB hosts 66 Perturb-Seq datasets, which encompass 4 518 521 single-cell transcriptomes derived from the knockdown of 10 194 genes across 19 different cell lines. All datasets were uniformly processed using the Mixscape algorithm. Genes were clustered by their perturbed transcriptomic phenotypes derived from Perturb-Seq data, resulting in 421 gene clusters, 157 of which were stable across different cellular contexts. Through integrating chemically perturbed transcriptomes with Perturb-Seq data, we identified 552 potential inhibitors targeting 1409 genes, including an mammalian target of rapamycin (mTOR) signaling inhibitor, retinol, which was experimentally verified. Moreover, we developed a 'Cancer' module to facilitate the understanding of the regulatory role of genes in cancer using Perturb-Seq data. An interactive web interface has also been developed, enabling users to visualize, analyze and download all the comprehensive datasets available in PerturbDB. PerturbDB will greatly drive gene functional studies and enhance our understanding of the regulatory roles of genes in diseases such as cancer.

RESUMO

This study develops an observational model to assess kidney function recovery and xenogeneic immune responses in kidney xenotransplants, focusing on gene editing and immunosuppression. Two brain-dead patients undergo single kidney xenotransplantation, with kidneys donated by minipigs genetically modified to include triple-gene knockouts (GGTA1, ß4GalNT2, CMAH) and human gene transfers (hCD55 or hCD55/hTBM). Renal xenograft functions are fully restored; however, immunosuppression without CD40-CD154 pathway blockade is ineffective in preventing acute rejection by day 12. This rejection manifests as both T cell-mediated rejection and antibody-mediated rejection (AMR), confirmed by natural killer (NK) cell and macrophage infiltration in sequential xenograft biopsies. Despite donor pigs being pathogen free before transplantation, xenografts and recipient organs test positive for porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) by the end of the observation period, indicating reactivation and contributing to significant immunopathological changes. This study underscores the critical need for extended clinical observation and comprehensive evaluation using deceased human models to advance xenograft success.

RESUMO

Although immune checkpoint inhibitors (ICIs) have been a revelation for treating several cancers, an unmet need remains to broaden ICI therapeutic scope and increase their response rates in clinical trials. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell activation and has previously been identified as a promising target for immunotherapy. Herein, we report the discovery of a series of HPK1 inhibitors with novel 1(2H)-phthalazinone and 1(2H)-isoquinolinone scaffolds. Among them, compound 24 demonstrated potent in vitro activity (HPK1 IC50 value of 10.4 nM) and cellular activity (pSLP76 EC50 = 41 nM & IL-2 EC50 = 108 nM). Compound 24 exhibited favorable mouse and rat pharmacokinetic profiles with reasonable oral exposure. Compound 24 showed potent in vivo anti-tumor activity in a CT26 syngeneic tumor model with 95 % tumor growth inhibition in combination with anti-PD-1.

RESUMO

OBJECTIVE: To assess the cardioprotective effect and impact of Qishen Granules (QSG) on different ischemic areas of the myocardium in heart failure (HF) rats by evaluating its metabolic pattern, substrate utilization, and mechanistic modulation. METHODS: In vivo, echocardiography and histology were used to assess rat cardiac function; positron emission tomography was performed to assess the abundance of glucose metabolism in the ischemic border and remote areas of the heart; fatty acid metabolism and ATP production levels were assessed by hematologic and biochemical analyses. The above experiments evaluated the cardioprotective effect of QSG on left anterior descending ligation-induced HF in rats and the mode of energy metabolism modulation. In vitro, a hypoxia-induced H9C2 model was established, mitochondrial damage was evaluated by flow cytometry, and nuclear translocation of hypoxia-inducible factor-1 α (HIF-1 α) was observed by immunofluorescence to assess the mechanism of energy metabolism regulation by QSG in hypoxic and normoxia conditions. RESULTS: QSG regulated the pattern of glucose and fatty acid metabolism in the border and remote areas of the heart via the HIF-1 α pathway, and improved cardiac function in HF rats. Specifically, QSG promoted HIF-1 α expression and entry into the nucleus at high levels of hypoxia (P<0.05), thereby promoting increased compensatory glucose metabolism; while reducing nuclear accumulation of HIF-1 α at relatively low levels of hypoxia (P<0.05), promoting the increased lipid metabolism. CONCLUSIONS: QSG regulates the protein stability of HIF-1 α, thereby coordinating energy supply balance between the ischemic border and remote areas of the myocardium. This alleviates the energy metabolism disorder caused by ischemic injury.

RESUMO

Background: The increasing prevalence of child and adolescent overweight and obesity (CAOAO) in Beijing poses significant health and economic challenges. This study assesses the potential health and economic outcomes of implementing specific interventions to address CAOAO in Beijing. Methods: A deterministic Markov cohort model was used to estimate the impact of five interventions from 2025 to 2115: restrictions on unhealthy food marketing to children, mandatory front of package labeling (FOPL), family-based nutrition and exercise education, school-based nutritional health education, and nutritional counseling in primary healthcare. The model evaluated societal costs, healthcare savings, wages, and economic productivity in adulthood, calculating the return on investment (ROI) for each intervention and their combined effect. Result: Without intervention, Beijing is projected to experience a loss of 13.4 million disability-adjusted life years (DALYs) due to CAOAO. The health and economic impact of childhood obesity in Beijing is projected to be CNY 14.6 trillion (USD 2.1 trillion), or a lifetime loss of CNY 6.8 million (USD 0.96 million) per affected child, exceeding the sum of Beijing's GDP from 2021 to 2023. Restrictions on unhealthy food marketing to children and nutrition counseling in primary healthcare are projected to yield the highest returns, with benefits accruing within one year of implementation. Owing to the substantial upfront costs, including personnel, materials, and training, school-based and family-based interventions require a longer time horizon to realize significant health and economic benefits. Conclusions: Effective management of CAOAO in Beijing demands a multifaceted approach. The combination of restrictions on unhealthy food marketing to children, mandatory front of package labeling, nutrition counseling in primary healthcare, school-based intervention, and family-based intervention presents the most substantial health and economic returns. This comprehensive strategy aligns with global best practices and addresses the unique challenges faced by Beijing in combating childhood obesity.

Assuntos

RESUMO

6:2 Chlorinated polyfluorinated ether sulfonate, commonly known as F-53B, is widely used as a mist suppressant in various industries and is frequently detected in the environment. Despite its prevalent presence, the adverse effects of F-53B are not well understood and require future investigation. This study utilized zebrafish embryos and adults to examine the toxic effects of F-53B. Our findings revealed that F-53B impaired gill structure and increased erythrocyte numbers in adult zebrafish. Notably, F-53B demonstrated a higher sensitivity for inducing mortality (LC50 at 96 h) in adult zebrafish compared to embryos. Additionally, F-53B disrupted the expression of critical steroidogenic genes and hindered sex hormone production, which negatively affecting egg production. In conclusion, this study underscores the detrimental impact of F-53B on gill structure and reproductive toxicity in zebrafish, providing valuable insights into its overall toxicity.

Assuntos

RESUMO

Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.

RESUMO

In this study, wettability behavior and the interaction between the K492M alloy and an Al2O3 shell were investigated at 1430 °C for 2~5 min. The microstructural characterization of the alloy-shell interface was carried out by optical microscopy (OM) and scanning electron microscopy (SEM). The results indicated that the interaction could cause a sand adhesion phenomenon affecting the alloy, and the attached products were Al2O3 particles. In addition, the wetting angles of the alloys located on the shell were 125.2°, 109.4°, 97.0°, and 95.0°, respectively, as the contact time was increased from 2 to 5 min. Apparently, the wettability of the alloy in relation to the shell had a relationship with the contact time, where a longer contact time was beneficial to the permeation of the alloy into the shell and the interaction between the two components. No significant chemical products could be detected in the interaction layer, indicating that only the occurrence of the physical dissolution of the shell took place in the alloy melt.

RESUMO

Chrysanthemum indicum L. capitulum is an enriched source of flavonoids with broad-ranging biological activities, mainly due to their anti-inflammatory, anti-cancer, immune regulation, anti-microbial activity, hepatoprotective, and neuroprotective effects. The O-methylation of various secondary metabolites has previously been demonstrated to be mainly catalyzed by S-adenosyl-L-methionine-dependent O-methyltransferase (OMT) proteins encoded by the OMT gene family. However, limited comprehensive study was published on the OMT gene family, especially the CCoAOMT subfamily, involved in the O-methylation of flavonoids in Chrysanthemum. Here, we analyzed the spatiotemporal expression patterns of C. indicum OMT genes in leaf and flower at different developmental stages. Transcriptome sequencing and qRT-PCR analysis showed that COMTs were mainly highly expressed in capitulum, especially in full bloom, while CCoAOMTs were mainly highly expressed in leaves. Correlation analysis of OMT gene expression and flavonoids accumulation revealed that four OMTs (CHR00029120, CHR00029783, CHR00077404, and CHR00078333) were putatively involved in most methylated flavonoids biosynthesis in the capitulum. Furthermore, we identified a true CCoAOMT enzyme, CiCCoAOMT1, and found that it catalyzed O-methylation of quercetin and luteolin at the 3'-OH position. In summary, this work provides an important theoretical basis for further research on the biological functions of OMTs in C. indicum.

Assuntos

RESUMO

Plants absorb light energy for photosynthesis via photosystem complexes in their chloroplasts. However, excess light can damage the photosystems and decrease photosynthetic output, thereby inhibiting plant growth and development. Plants have developed a series of light acclimation strategies that allow them to withstand high light. In the first line of defense against excess light, leaves and chloroplasts move away from the light and the plant accumulates compounds that filter and reflect the light. In the second line of defense, known as photoprotection, plants dissipate excess light energy through non-photochemical quenching, cyclic electron transport, photorespiration, and scavenging of excess reactive oxygen species. In the third line of defense, which occurs after photodamage, plants initiate a cycle of photosystem (mainly photosystem II) repair. In addition to being the site of photosynthesis, chloroplasts sense stress, especially light stress, and transduce the stress signal to the nucleus, where it modulates the expression of genes involved in the stress response. In this review, we discuss current progress in our understanding of the strategies and mechanisms employed by plants to withstand high light at the whole-plant, cellular, physiological, and molecular levels across the three lines of defense.

RESUMO

Smart materials enabling emission intensity or wavelength tuning by light stimulus attract attention in numerous cutting-edge fields. However, due to the generally dense molecular stacking against photoresponsivity in solid states, especially in crystals, developing rapidly phototunable solid-state luminescent systems remains challenging. Herein, we propose a new luminophore that serves as both a photoresponsive unit and a luminescent group, while possessing enhanced conformational freedom to provide a solution. Namely, photoexcitation-induced molecular conformational change of an ionized persulfurated arene based on weak intermolecular aliphatic C-H···π interaction was employed. On these basis, rapidly enhanced phosphorescence upon irradiation can be observed in a series of phase states, like solution state, crystal, and amorphous state, especially with a high photoresponsive rate of 0.033 s-1 in crystal state that is superior to the relevant reported cases. Moreover, a rapidly phototunable afterglow effect is achieved by extending this molecule into some polymer-based doping systems, endowing the system with unique dynamic imaging and fast photopatterning capabilities. Such a single-luminophore molecular engineering and the underlying mechanism have implications for building different condensed functional materials, principally for those with stimuli responses in solid states.

RESUMO

Accurate assessment of material and energy exchange between land and atmosphere is essential for water resources management and sustainable development of agriculture. To understand the characteristics of energy distribution and the dynamic change process of water and heat fluxes within the maize farmland ecosystem in the old course of Yellow River and their response to meteorological factors, we utilized the eddy covariance measurements and the full-element automatic weather station to continuously observe energy fluxes and conventional meteorological elements of summer maize farmland in the old course of Yellow River during 2019-2020. We analyzed the variation of energy fluxes and the effects of environmental factors, such as temperature, precipitation, and wind speed. Additionally, we calculated the energy closure rate and the proportion of energy distribution during the growth stage. The results showed that the peaks of net radiation, sensible heat flux, and latent heat flux occurred between 11:00 and 14:00, and the peak of soil heat flux occurred between 14:00 and 15:00. In terms of energy distribution, energy consumption of summer maize farmland during the whole growth period was dominated by latent heat flux and sensible heat flux. Energy was mainly consumed by sensible heat flux at sowing-emergence stage, accounting for 37.1% of net radiation, respectively. Energy in the rest of growth stages was dominated by latent heat flux. The energy closure rate during the whole growth period was better, with a coefficient of determination of 0.83, and the closure rate was higher in day and lower at night. Precipitation affected latent heat flux and sensible heat flux, and latent heat flux was more sensitive to precipitation. The increase of latent heat flux after rainfall was lower in late growth stage than in early growth stage. During the whole growth period of summer maize, solar radiation was the most significant meteorological factor affecting both sensible heat flux and latent heat flux, followed by vapor pressure deficit. The contribution of temperature and vapor pressure deficit to latent heat flux was significantly higher than sensible heat flux, while the relative contribution of wind speed, relative humidity, and solar radiation to latent heat flux was lower than sensible heat flux. Leaf area index and fractional vegetation cover had a significant positive correlation with latent heat flux and a significant negative correlation with sensible heat flux. Our results could deepen the understanding of water and heat transfer law of summer maize farmland in the old course of Yellow River, providing a theoretical basis for efficient water use of crops.

Assuntos

Assuntos