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Conductive metal-organic frameworks (cMOFs) manifest great potential in modern electrical devices due to their porous nature and the ability to conduct charges in a regular network. cMOFs applied in electrical devices normally hybridize with other materials, especially a substrate. Therefore, the precise control of the interface between cMOF and a substrate is particularly crucial. However, the unexplored interface chemistry of cMOFs makes the controlled synthesis and advanced characterization of high-quality thin films, particularly challenging. Herein, we report the development of a simplified synthesis method to grow "face-on" and "edge-on" cMOF nanofilms on substrates, and the establishment of operando characterization methodology using atomic force microscopy and X-ray, thereby demonstrating the relationship between the soft structure of surface-mounted oriented networks and their characteristic conductive functions. As a result, crystallinity of cMOF nanofilms with a thickness down to a few nanometers is obtained, the possible growth mechanisms are proposed, and the interesting anisotropic softness-dependent conducting properties (over 2 orders of magnitude change) of the cMOF are also illustrated.
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BACKGROUND: Sex-related differences in colorectal (CRC) incidence and mortality are well-documented. However, the impact of sex on metabolic pathways that drive cancer growth is not well understood. High expression of asparagine synthetase (ASNS) is associated with inferior survival for female CRC patients only. Here, we used a CRISPR/Cas9 technology to generate HCT116 ASNS-/- and HCT 116 ASNS+/+ cancer cell lines. We examine the effects of ASNS deletion on tumor growth and the subsequent rewiring of metabolic pathways in male and female Rag2/IL2RG mice. RESULTS: ASNS loss reduces cancer burden in male and female tumor-bearing mice (40% reduction, q < 0.05), triggers metabolic reprogramming including gluconeogenesis, but confers a survival improvement (30 days median survival, q < 0.05) in female tumor-bearing mice alone. Transcriptomic analyses revealed upregulation of G-protein coupled estrogen receptor (GPER1) in tumors from male and female mice with HCT116 ASNS-/- xenograft. Estradiol activates GPER1 in vitro in the presence of ASNS and suppresses tumor growth. CONCLUSIONS: Our study indicates that inferior survival for female CRC patients with high ASNS may be due to metabolic reprogramming that sustains tumor growth. These findings have translational relevance as ASNS/GPER1 signaling could be a future therapeutic target to improve the survival of female CRC patients.
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Aspartato-Amônia Ligase , Animais , Humanos , Feminino , Masculino , Camundongos , Aspartato-Amônia Ligase/genética , Aspartato-Amônia Ligase/metabolismo , Células HCT116 , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Proliferação de Células/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Xenoenxertos , Fatores Sexuais , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-AmidaRESUMO
While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/ß-catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL-mediated oncogenic ß-catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic ß-catenin, and reducing its cytoplasmic levels in a GSK3ß- and ß-TrCP-independent manner, indicating that NEURL-ß-catenin interactions can lead to a disruption of the canonical Wnt/ß-catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/ß-catenin signalling.
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Neoplasias do Colo , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Via de Sinalização Wnt , Neoplasias do Colo/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Contendo Repetições de beta-Transducina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Linhagem Celular TumoralRESUMO
Neutrophil extracellular traps (NETs) are web-like structures composed of cytoplasmic contents, DNA chromatin and various granular proteins released by neutrophils in response to viruses, bacteria, immune complexes and cytokines. Studies have shown that NETs can promote the occurrence, development and metastasis of tumors. In this paper, the mechanism underlying the formation and degradation of NETs and the malignant biological behaviors of NETs, such as the promotion of tumor cell proliferation, epithelial mesenchymal transition, extracellular matrix remodeling, angiogenesis, immune evasion and tumor-related thrombosis, are described in detail. NETs are being increasingly studied as therapeutic targets for tumors. We have summarized strategies for targeting NETs or interfering with NET-cancer cell interactions and explored the potential application value of NETs as biomarkers in cancer diagnosis and treatment, as well as the relationship between NETs and therapeutic resistance.
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Resistencia a Medicamentos Antineoplásicos , Armadilhas Extracelulares , Neoplasias , Humanos , Armadilhas Extracelulares/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Progressão da Doença , Animais , Transição Epitelial-Mesenquimal , Neutrófilos/metabolismo , Neutrófilos/imunologia , Proliferação de CélulasRESUMO
Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.
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Lesão Pulmonar Aguda , Lipopolissacarídeos , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/farmacologia , ATPase Trocadora de Sódio-Potássio/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27-retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.
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Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Endossomos/metabolismo , SARS-CoV-2 , Nexinas de Classificação/química , COVID-19/virologia , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cristalografia por Raios X , Citosol/metabolismo , Endocitose , Perfilação da Expressão Gênica , Células HEK293 , Células HeLa , Homeostase , Humanos , Lentivirus , Lisossomos/metabolismo , Peptídeos/química , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Nexinas de Classificação/metabolismo , Internalização do VírusRESUMO
Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.
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GABAérgicos , Receptores da Colecistocinina , Masculino , Feminino , Camundongos , Animais , GABAérgicos/farmacologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Neurônios GABAérgicos/fisiologia , Camundongos Knockout , Interneurônios , Colecistocinina , Ácido gama-Aminobutírico/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Acoplados a Proteínas G/genéticaRESUMO
The development of new synthetic methods for B-H bond activation has been an important research area in boron cluster chemistry, which may provide opportunities to broaden the application scope of boron clusters. Herein, we present a new reaction strategy for the direct site-selective B-H functionalization of nido-carboranes initiated by photoinduced cage activation via a noncovalent cage···π interaction. As a result, the nido-carborane cage radical is generated through a single electron transfer from the 3D nido-carborane cage to a 2D photocatalyst upon irradiation with green light. The resulting transient nido-carborane cage radical could be directly probed by an advanced time-resolved EPR technique. In air, the subsequent transformations of the active nido-carborane cage radical have led to efficient and selective B-N, B-S, and B-Se couplings in the presence of N-heterocycles, imines, thioethers, thioamides, and selenium ethers. This protocol also facilitates both the late-stage modification of drugs and the synthesis of nido-carborane-based drug candidates for boron neutron capture therapy (BNCT).
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We have reported previously that during hypoxia exposure, the expression of mature miR-17â¼92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo. Here, we investigated the mechanisms regulating this biphasic expression of miR-17â¼92 in PASMC in hypoxia. We measured the level of primary miR-17â¼92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3% O2, 6 h) induced the level of primary miR-17â¼92, whereas long-term hypoxia exposure (3% O2, 24 h) decreased its level, suggesting a biphasic regulation of miR-17â¼92 expression at the transcriptional level. We found that short-term hypoxia-induced upregulation of miR-17â¼92 was hypoxia-inducible factor 1α (HIF1α) and E2F1 dependent. Two HIF1α binding sites on miR-17â¼92 promoter were identified. We also found that long-term hypoxia-induced suppression of miR-17â¼92 expression could be restored by silencing of p53. Mutation of the p53-binding sites in the miR-17â¼92 promoter increased miR-17â¼92 promoter activity in both normoxia and hypoxia. Our findings suggest that the biphasic transcriptional regulation of miR-17â¼92 during hypoxia is controlled by HIF1/E2F1 and p53 in PASMC: during short-term hypoxia exposure, stabilization of HIF1 and induction of E2F1 induce the transcription of miR-17â¼92, whereas during long-term hypoxia exposure, hyperphosphorylation of p53 suppresses the expression of miR-17â¼92.NEW & NOTEWORTHY We showed that the biphasic transcriptional regulation of miR-17â¼92 during hypoxia is controlled by two distinct mechanisms: during short-term hypoxia exposure, induction of HIF1 and E2F1 upregulates miR-17â¼92. Longer hypoxia exposure induces hyperphosphorylation of p53 at ser15, which leads to its binding to miR-17â¼92 promoter and inhibition of its expression. Our findings provide novel insights into the spatiotemporal regulation of miR-17â¼92 that may play a role in the development of human lung diseases including pulmonary hypertension (PH).
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Fator de Transcrição E2F1 , Subunidade alfa do Fator 1 Induzível por Hipóxia , MicroRNAs , Artéria Pulmonar , Proteína Supressora de Tumor p53 , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fosforilação , Humanos , Animais , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genética , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Transcrição Gênica , Hipóxia Celular/genética , Miócitos de Músculo Liso/metabolismo , Regiões Promotoras Genéticas/genética , Camundongos , Hipóxia/metabolismo , Hipóxia/genética , Serina/metabolismo , Regulação da Expressão Gênica , Células CultivadasRESUMO
Ferroptosis has been implicated in several neurological disorders and may be therapeutically targeted. However, the susceptibility to ferroptosis varies in different cells, and inconsistent results have been reported even using the same cell line. Understanding the effects of key variables of in vitro studies on ferroptosis susceptibility is of critical importance to facilitate drug discoveries targeting ferroptosis. Here, we showed that increased cell seeding density leads to enhanced resistance to ferroptosis by reducing intracellular iron levels. We further identified iron-responsive protein 1 (IRP1) as the key protein affected by cell density, which affects the expression of ferroportin or transferrin receptor and results in altered iron levels. Such observations were consistent across different cell lines, indicating that cell density should be tightly controlled in studies of ferroptosis. Since cell densities vary in different brain regions, these results may also shed light on selective regional vulnerability observed in neurological disorders.
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Ferroptose , Homeostase , Proteína 1 Reguladora do Ferro , Ferro , Ferro/metabolismo , Ferroptose/fisiologia , Homeostase/fisiologia , Humanos , Proteína 1 Reguladora do Ferro/metabolismo , Proteína 1 Reguladora do Ferro/genética , Contagem de Células , Animais , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , CamundongosRESUMO
Accurate identification of antibiotic resistance genes (ARGs) is crucial for improving treatment and controlling the spread of antibiotic-resistant bacteria (ARB). Herein, a novel PCR-free, centrifugation-free, and label-free magnetic fluorescent biosensor (MFB) was developed by combining polyA-medium DNA-polyT (mDNA, which contained a partial sequence of a target DNA), gold nanoparticle (AuNP)-anchored magnetic nanoparticle (Au@Fe3O4), complementary strand DNA (CS) of the target DNA, DNA concatamer with G-triplex (G3), and thioflavin T (ThT). Thereinto, Au@Fe3O4 nanoparticles were first capped by mDNA strands within 20 min using a simple hot drying method, and then CS was added and hybridized with mDNA on Au@Fe3O4. Second, a DNA concatamer was used to bind with CS on Au@Fe3O4. When an ARG was present in the sample, the CS would recognize it and release the DNA concatamer into solution by a toehold-mediated strand displacement reaction. Finally, under magnetic separation, the free DNA concatamers with G3 were taken out easily and bound with ThT, resulting in strong fluorescence signals. The fluorescence intensity of ThT was positively correlated with the concentration of the ARG. The whole analysis was accomplished within 1.5 h using 96-well plates. Remarkably, our MFB was universal; eight ARGs were detected by replacing the corresponding mDNA and CS in this study. To verify the practicability of our method, 12 clinically isolated strains were analyzed. The results of the MFB method were in good agreement with those of the quantitative real-time PCR method with an area under the curve of 0.92 (95% confidence interval: 0.8479 to 0.9932), sensitivity of 92.00%, and specificity of 91.55%. Above all, the MFB assay established here is simple, low-cost, and universal and has great potential for applications in the identification of ARGs.
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Técnicas Biossensoriais , Nanopartículas Metálicas , Antibacterianos/farmacologia , Ouro , Calefação , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , DNA/genética , DNA/análise , Técnicas Biossensoriais/métodosRESUMO
Complete sample digestion is a prerequisite for acquiring high-quality analytical results for geological samples. Closed-vessel acid digestion (bomb) has typically been used for the total digestion of refractory geological samples. However, the long digestion time (4-5 days) and insoluble fluoride complexes still pose challenges for digesting refractory geological samples using this approach. In this study, an efficient and simplified digestion technique combining ultrafine powders from planetary ball milling with bomb digestion was developed for trace element analysis of refractory geological samples: peridotite and granitoid. The method shows two significant improvements compared with previous approaches. (1) By performing dry planetary ultrafine milling, the initial 200 mesh peridotite (<74 µm) could be reduced to 800 mesh (<20 µm) in 6 min at a ball-to-powder mass ratio of approximately 15 using 3 mm tungsten carbide milling balls. (2) Complete peridotite and granitoid dissolution were achieved in approximately 2 h, 60 times faster than what is achievable using previous methods (2 h vs 120 h). Moreover, ultrafine powders effectively suppressed insoluble fluoride formation during bomb digestion. A suite of peridotite and granitoid reference materials were measured to evaluate the stability of this method. This efficient, simple, and reliable sample digestion method could benefit geological, food, environmental, and other fields requiring solid sample decomposition via wet acid, fusion, combustion, or dry ashing.
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Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.
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Corantes Fluorescentes , Tirosina 3-Mono-Oxigenase , Peixe-Zebra , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Tirosina 3-Mono-Oxigenase/metabolismo , Tirosina 3-Mono-Oxigenase/análise , Animais , Camundongos , Humanos , Imagem Óptica , Linhagem Celular Tumoral , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismoRESUMO
G-quadruplex structures within the nuclear genome (nG4) is an important regulatory factor, while the function of G4 in the mitochondrial genome (mtG4) still needs to be explored, especially in human sperms. To gain a better understanding of the relationship between mtG4 and mitochondrial function, it is crucial to develop excellent probes that can selectively visualize and track mtG4 in both somatic cells and sperms. Herein, based on our previous research on purine frameworks, we attempted for the first time to extend the conjugated structure from the C-8 site of purine skeleton and discovered that the purine derivative modified by the C-8 aldehyde group is an ideal platform for constructing near-infrared probes with extremely large Stokes shift (>220 nm). Compared with the compound substituted with methylpyridine (PAP), the molecule substituted with methylthiazole orange (PATO) showed better G4 recognition ability, including longer emission (â¼720 nm), more significant fluorescent enhancement (â¼67-fold), lower background, and excellent photostability. PATO exhibited a sensitive response to mtG4 variation in both somatic cells and human sperms. Most importantly, PATO helped us to discover that mtG4 was significantly increased in cells with mitochondrial respiratory chain damage caused by complex I inhibitors (6-OHDA and rotenone), as well as in human sperms that suffer from oxidative stress. Altogether, our study not only provides a novel ideal molecular platform for constructing high-performance probes but also develops an effective tool for studying the relationship between mtG4 and mitochondrial function in both somatic cells and human sperms.
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Corantes Fluorescentes , Purinas , Humanos , Purinas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Doenças Mitocondriais/metabolismo , Regulação para Cima , Genoma Mitocondrial , Quadruplex G , Mitocôndrias/metabolismo , Raios Infravermelhos , Células HeLaRESUMO
Salvia miltiorrhiza is commonly used as a Chinese herbal medicine to treat different cardiovascular and cerebrovascular illnesses due to its active ingredients. Environmental conditions, especially drought stress, can affect the yield and quality of S. miltiorrhiza. However, moderate drought stress could improve the quality of S. miltiorrhiza without significantly reducing the yield, and the mechanism of this initial drought resistance is still unclear. In our study, transcriptome and metabolome analyses of S. miltiorrhiza under different drought treatment groups (CK, A, B, and C groups) were conducted to reveal the basis for its drought tolerance. We discovered that the leaves of S. miltiorrhiza under different drought treatment groups had no obvious shrinkage, and the malondialdehyde (MDA) contents as well as superoxide dismutase (SOD) and peroxidase (POD) activities dramatically increased, indicating that our drought treatment methods were moderate, and the leaves of S. miltiorrhiza began to initiate drought resistance. The morphology of root tissue had no significant change under different drought treatment groups, and the contents of four tanshinones significantly enhanced. In all, 5213, 6611, and 5241 differentially expressed genes (DEGs) were shared in the A, B, and C groups compared with the CK group, respectively. The results of KEGG and co-expression analysis showed that the DEGs involved in plant-pathogen interactions, the MAPK signaling pathway, phenylpropanoid biosynthesis, flavonoid biosynthesis, and plant hormone signal transduction responded to drought stress and were strongly correlated with tanshinone biosynthesis. Furthermore, the results of metabolism analysis indicated that 67, 72, and 92 differentially accumulated metabolites (DAMs), including fumarate, ferulic acid, xanthohumol, and phytocassanes, which were primarily involved in phenylpropanoid biosynthesis, flavonoid biosynthesis, and diterpenoid biosynthesis pathways, were detected in these groups. These discoveries provide valuable information on the molecular mechanisms by which S. miltiorrhiza responds to drought stress and will facilitate the development of drought-resistant and high-quality S. miltiorrhiza production.
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Secas , Metaboloma , Salvia miltiorrhiza , Transcriptoma , Salvia miltiorrhiza/genética , Salvia miltiorrhiza/metabolismo , Salvia miltiorrhiza/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genética , Folhas de Planta/genética , Folhas de Planta/metabolismo , Folhas de Planta/fisiologiaRESUMO
The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.
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Glucose Oxidase , Lipossomos , Sorafenibe , Lipossomos/química , Humanos , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Animais , Sorafenibe/farmacologia , Linhagem Celular Tumoral , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Metabolismo Energético , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/química , IndóisRESUMO
The identification of differentially expressed genes between different cell groups is a crucial step in analyzing single-cell RNA-sequencing (scRNA-seq) data. Even though various differential expression analysis methods for scRNA-seq data have been proposed based on different model assumptions and strategies recently, the differentially expressed genes identified by them are quite different from each other, and the performances of them depend on the underlying data structures. In this paper, we propose a new ensemble learning-based differential expression analysis method, scDEA, to produce a more stable and accurate result. scDEA integrates the P-values obtained from 12 individual differential expression analysis methods for each gene using a P-value combination method. Comprehensive experiments show that scDEA outperforms the state-of-the-art individual methods with different experimental settings and evaluation metrics. We expect that scDEA will serve a wide range of users, including biologists, bioinformaticians and data scientists, who need to detect differentially expressed genes in scRNA-seq data.
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RNA , Análise de Célula Única , Perfilação da Expressão Gênica/métodos , Aprendizado de Máquina , RNA/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Sequenciamento do ExomaRESUMO
MOTIVATION: Spatially resolved gene expression profiles are the key to exploring the cell type spatial distributions and understanding the architecture of tissues. Many spatially resolved transcriptomics (SRT) techniques do not provide single-cell resolutions, but they measure gene expression profiles on captured locations (spots) instead, which are mixtures of potentially heterogeneous cell types. Currently, several cell-type deconvolution methods have been proposed to deconvolute SRT data. Due to the different model strategies of these methods, their deconvolution results also vary. RESULTS: Leveraging the strengths of multiple deconvolution methods, we introduce a new weighted ensemble learning deconvolution method, EnDecon, to predict cell-type compositions on SRT data in this work. EnDecon integrates multiple base deconvolution results using a weighted optimization model to generate a more accurate result. Simulation studies demonstrate that EnDecon outperforms the competing methods and the learned weights assigned to base deconvolution methods have high positive correlations with the performances of these base methods. Applied to real datasets from different spatial techniques, EnDecon identifies multiple cell types on spots, localizes these cell types to specific spatial regions and distinguishes distinct spatial colocalization and enrichment patterns, providing valuable insights into spatial heterogeneity and regionalization of tissues. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/Zhangxf-ccnu/EnDecon. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Perfilação da Expressão Gênica , Transcriptoma , Software , Simulação por Computador , Aprendizado de MáquinaRESUMO
To explore the optoelectronic wetting droplet transport mechanism, a transient numerical model of optoelectrowetting (OEW) under the coupling of flow and electric fields is established. The study investigates the impact of externally applied voltage, dielectric constant of the dielectric layer, and interfacial tension between the two phases on the dynamic behavior of droplets during transport. The proposed model employs an improved Young's equation to calculate the instantaneous voltage and contact angle of the droplet on the dielectric layer. Results indicate that, under the influence of OEW, significant variations in the interface contact angle of droplets occur in bright and dark regions, inducing droplet movement. Moreover, the dynamic behavior of droplet transport is closely associated with various parameters, including externally applied voltage, dielectric layer material, and interfacial tension between the two phases, all of which impact the contact angle and, consequently, the transport process. By summarizing the influence patterns of the three key parameters studied, the optimization of droplet transport performance is achieved. The study employs two-dimensional simulation models to emulate the droplet motion under the influence of the electric field, investigating the OEW droplet transport mechanism. The continuous movement of droplets involves three stages: initial wetting, continuous transport, and reaching a steady position. The findings contribute theoretical support for the efficient design of digital microfluidic devices for OEW droplet movement and the selection of key parameters for droplet manipulation.
Assuntos
Molhabilidade , Modelos Teóricos , Simulação por Computador , Tensão Superficial , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodosRESUMO
Tris(2,4,6-trichlorophenyl)methyl (TTM) group has been widely used for constructing organic radicals, but the poor optical stabilities limit the application prospects of the TTM radicals. In this work, the rigid B- and N-embedded dioxygen-bridged (BO and NO) units were attached to the TTM skeleton as the strong electron-withdrawing and electron-donating groups, respectively. The rigidity and strong electronic effect of the BO and NO units contribute to the high chemical and optical stability of BO-TTM and NO-TTM radicals. Notably, NO-TTM exhibits near-infrared emission at 830â nm with a narrow full width at half maximum (FWHM) of 55â nm (100â meV), while BO-TTM shows blue-shifted luminescence at 635â nm and a narrower FWHM of merely 43â nm (130â meV). This study has developed a methodology to produce highly efficient and enduring luminescent radicals, which could tune emission properties such as wavelength and FWHM.