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Studies using antigen-presenting systems at the single-cell and ensemble levels can provide complementary insights into T-cell signaling and activation. Although crucial for advancing basic immunology and immunotherapy, there is a notable absence of synthetic material toolkits that examine T cells at both levels, and especially those capable of single-molecule-level manipulation. Here we devise a biomimetic antigen-presenting system (bAPS) for single-cell stimulation and ensemble modulation of T-cell recognition. Our bAPS uses hexapod heterostructures composed of a submicrometer cubic hematite core (α-Fe2O3) and nanostructured silica branches with diverse surface modifications. At single-molecule resolution, we show T-cell activation by a single agonist peptide-loaded major histocompatibility complex; distinct T-cell receptor (TCR) responses to structurally similar peptides that differ by only one amino acid; and the superior antigen recognition sensitivity of TCRs compared with that of chimeric antigen receptors (CARs). We also demonstrate how the magnetic field-induced rotation of hexapods amplifies the immune responses in suspended T and CAR-T cells. In addition, we establish our bAPS as a precise and scalable method for identifying stimulatory antigen-specific TCRs at the single-cell level. Thus, our multimodal bAPS represents a unique biointerface tool for investigating T-cell recognition, signaling and function.
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Ativação Linfocitária , Linfócitos T , Linfócitos T/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Apresentação de Antígeno , Dióxido de Silício/química , Compostos Férricos/química , Peptídeos/química , Peptídeos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Nanoestruturas/química , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismoRESUMO
Light in the environment greatly impacts a variety of brain functions, including sleep. Clinical evidence suggests that bright light treatment has a beneficial effect on stress-related diseases. Although stress can alter sleep patterns, the effect of bright light treatment on stress-induced sleep alterations and the underlying mechanism are poorly understood. Here, we show that bright light treatment reduces the increase in nonrapid eye movement (NREM) sleep induced by chronic stress through a di-synaptic visual circuit consisting of the thalamic ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), lateral habenula (LHb), and rostromedial tegmental nucleus (RMTg). Specifically, chronic stress causes a marked increase in NREM sleep duration and a complementary decrease in wakefulness time in mice. Specific activation of RMTg-projecting LHb neurons or activation of RMTg neurons receiving direct LHb inputs mimics the effects of chronic stress on sleep patterns, while inhibition of RMTg-projecting LHb neurons or RMTg neurons receiving direct LHb inputs reduces the NREM sleep-promoting effects of chronic stress. Importantly, we demonstrate that bright light treatment reduces the NREM sleep-promoting effects of chronic stress through the vLGN/IGL-LHb-RMTg pathway. Together, our results provide a circuit mechanism underlying the effects of bright light treatment on sleep alterations induced by chronic stress.
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Habenula , Sono de Ondas Lentas , Animais , Camundongos , Sono , Núcleo Celular , Corpos GeniculadosRESUMO
Small extracellular vesicles (sEVs) assume pivotal roles as vital messengers in intercellular communication, boasting a plethora of biological functions and promising clinical applications. However, efficient isolation and sensitive detection of sEVs continue to present formidable challenges. In this study, we report a novel method for fast isolation and highly sensitive multicolor visual detection of sEVs using aptamer-functionalized polydopamine nanospheres (SIMPLE). In the SIMPLE strategy, aptamer-functionalized polydopamine nanospheres (Apt-PDANS) with 170 nm diameters were synthesized and exhibited a remarkable ability to selectively bind to specific proteins on the surface of sEVs. The binding between sEVs and Apt-PDANS engenders an increase in the overall size of the sEVs, allowing fast isolation of sEVs by filtration (a filter membrane with a pore size of 200 nm). The fast isolation strategy not only circumvents the interference posed by unbound proteins and excessive probes as well as the intricacies associated with conventional ultracentrifugation methods but also expedites the separation of sEVs. Concurrently, the incorporation of Fe3+-doped PDANS permits the multicolor visual detection of sEVs, enabling quantitative analysis by the discernment of visual cues. The proposed strategy achieves a detection limit of 3.2 × 104 sEV mL-1 within 1 h, devoid of any reliance on instrumental apparatus. Furthermore, we showcase the potential application of this methodology in epithelial-mesenchymal transition monitoring and cancer diagnosis, while also envisioning its widespread adoption as a straightforward, rapid, sensitive, and versatile platform for disease monitoring and functional exploration.
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δ-MnO2 is a promising cathode material for aqueous aluminium-ion batteries (AAIBs) for its layered crystalline structure with large interlayer spacing. However, the excellent Al ion storage performance of δ-MnO2 cathode remains elusive due to the frustrating structural collapse during the intercalation of high ionic potential Al ion species. Here, it is discovered that introducing heterogeneous metal dopants with high bond dissociation energy when bonded to oxygen can significantly reinforce the structural stability of δ-MnO2 frameworks. This reinforcement translates to stable cycling properties and high specific capacity in AAIBs. Vanadium-doped δ-MnO2 (V-δ-MnO2) can deliver a high specific capacity of 518 mAh g-1 at 200 mA g-1 with remarkable cycling stability for 400 cycles and improved rate capabilities (468, 339, and 285 mAh g-1 at 0.5, 1, and 2 A g-1, respectively), outperforming other doped δ-MnO2 materials and the reported AAIB cathodes. Theoretical and experimental studies indicate that V doping can substantially improve the cohesive energy of δ-MnO2 lattices, enhance their interaction with Al ion species, and increase electrical conductivity, collectively contributing to high ion storage performance. These findings provide inspiration for the development of high-performance cathodes for battery applications.
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BACKGROUND: Nonsuicidal self-injury (NSSI) is a serious problem in the adolescent population worldwide. Childhood trauma and bullying have been identified as risk factors for NSSI. We explored the relationships among Childhood trauma, Bullying victimization and the severity of NSSI behaviours, and test the effect of Bullying victimization in mediating the association between Childhood trauma and the NSSI behaviours. METHODS: A total of 123 adolescents were recruited. They were diagnosed with depression or depressive episodes of bipolar disorder and had experienced NSSI in the last year. They were assessed using the Chinese version of the Childhood Trauma Questionnaire (CTQ-C), the Revised Olweus Bullying Victimization Questionnaire (OBVQ-R), and the Adolescent Self-Harm Questionnaire (ASHQ). RESULTS: Females presented a significantly greater prevalence of sexual abuse and relationship bullying than boys. Individuals in the younger age group (10-14 years) presented a greater incidence of emotional neglect, verbal bullying, relationship bullying, and total bullying, and their NSSI score was also higher than that of those in the older age group (15-19 years). Only children show a greater prevalence of sexual abuse than nononly children. Single-parent families scored higher on emotional abuse, emotional neglect, physical neglect and physical bullying than two-parent families. There was a significant positive correlation between each dimension of childhood trauma and all the dimensions of bullying, between childhood trauma and NSSI, and between bullying and NSSI. Childhood trauma can not only directly affect the severity of NSSI but also indirectly aggravate the severity of NSSI through bullying victimization. The mediating effects of bullying victimization on emotional abuse, physical abuse, emotional neglect and physical neglect were 14%, 21%, 20%, 13% and 20%, respectively. CONCLUSION: There was a significant positive correlation between childhood trauma and bullying, between childhood trauma and NSSI, and between bullying and NSSI. Childhood trauma can not only directly affect the severity of NSSI but also indirectly aggravate the severity of NSSI through bullying victimization. Bullying victimization played the partial mediating effects between Childhood trauma and NSSI.
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Bullying , Vítimas de Crime , Comportamento Autodestrutivo , Humanos , Adolescente , Bullying/psicologia , Masculino , Feminino , Criança , Vítimas de Crime/psicologia , Comportamento Autodestrutivo/psicologia , Comportamento Autodestrutivo/epidemiologia , Experiências Adversas da Infância/psicologia , Fatores de Risco , Adulto Jovem , Maus-Tratos Infantis/psicologia , China/epidemiologia , Prevalência , Inquéritos e QuestionáriosRESUMO
Lung cancer is the most diagnosed malignant cancer and the leading cause of cancer-related deaths worldwide, with advanced stage and metastasis being a major issue. The mechanism leading to metastasis is not yet understood. Here, we found that KRT16 is upregulated in metastatic lung cancer tissues and correlated with poor overall survival. Knockdown of KRT16 inhibits metastasis of lung cancer both in vitro and in vivo. Mechanistically, KRT16 interacts with vimentin, and depletion of KRT16 leads to downregulation of vimentin. KRT16 acquired its oncogenic ability by stabilizing vimentin, and vimentin is required for KRT16-driven metastasis. FBXO21 mediates the polyubiquitination and degradation of KRT16, and vimentin inhibits KRT16 ubiquitination and degradation by impairing its interaction with FBXO21. Significantly, IL-15 inhibits metastasis of lung cancer in a mouse model through upregulation of FBXO21, and the level of IL-15 in circulating serum was significantly higher in nonmetastatic lung cancer patients than in metastatic patients. Our findings indicate that targeting the FBXO21/KRT16/vimentin axis may benefit lung cancer patients with metastasis.
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Interleucina-15 , Neoplasias Pulmonares , Animais , Camundongos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Interleucina-15/metabolismo , Neoplasias Pulmonares/metabolismo , Metástase Neoplásica , Transdução de Sinais , Vimentina/metabolismo , HumanosRESUMO
As one of the most significant imaging modalities currently available, magnetic resonance imaging (MRI) has been extensively utilized for clinically accurate cancer diagnosis. However, low signal-to-noise ratio (SNR) and low specificity for tumors continue to pose significant challenges. Inspired by the distance-dependent magnetic resonance tuning (MRET) phenomenon, the tumor microenvironment (TME)-activated off-on T1-T2 dual-mode MRI nanoswitch is presented in the current study to realize the sensitive early diagnosis of tumors. The tumor-specific nanoswitch is designed and manufactured on the basis of PDGFB-conjugating ferroferric oxide coated by Mn-doped silica (PDGFB-FMS), which can be degraded under the high-concentration GSH and low pH in TME to activate the T1-T2 dual-mode MRI signals. The tumor-specific off-on dual-mode MRI nanoswitch can significantly improve the SNR and is used successfully for the accurate diagnosis of early-stage tumors, particularly for orthotopic prostate cancer. In addition, the systemic delivery of the nanoswitch did not cause blood or tissue damage, and it can be excreted out of the body in a timely manner, demonstrating excellent biosafety. Overall, the strategy is a significant step in the direction of designing off-on dual-mode MRI nanoprobes to improve imaging accuracy, which opens up new avenues for the development of new MRI probes.
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Meios de Contraste , Neoplasias , Masculino , Humanos , Proteínas Proto-Oncogênicas c-sis , Neoplasias/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Dióxido de Silício , Microambiente TumoralRESUMO
Chemodynamic therapy of cancer is limited by insufficient endogenous H2O2 generation and acidity in the tumor microenvironment (TME). Herein, we developed a biodegradable theranostic platform (pLMOFePt-TGO) involving composite of dendritic organosilica and FePt alloy, loaded with tamoxifen (TAM) and glucose oxidase (GOx), and encapsulated by platelet-derived growth factor-B (PDGFB)-labeled liposomes, that effectively uses the synergy among chemotherapy, enhanced chemodynamic therapy (CDT), and anti-angiogenesis. The increased concentration of glutathione (GSH) present in the cancer cells induces the disintegration of pLMOFePt-TGO, releasing FePt, GOx, and TAM. The synergistic action of GOx and TAM significantly enhanced the acidity and H2O2 level in the TME by aerobiotic glucose consumption and hypoxic glycolysis pathways, respectively. The combined effect of GSH depletion, acidity enhancement, and H2O2 supplementation dramatically promotes the Fenton-catalytic behavior of FePt alloys, which, in combination with tumor starvation caused by GOx and TAM-mediated chemotherapy, significantly increases the anticancer efficacy of this treatment. In addition, T2-shortening caused by FePt alloys released in TME significantly enhances contrast in the MRI signal of tumor, enabling a more accurate diagnosis. Results of in vitro and in vivo experiments suggest that pLMOFePt-TGO can effectively suppress tumor growth and angiogenesis, thus providing an exciting potential strategy for developing satisfactory tumor theranostics.
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Ferroptose , Neoplasias , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral , Peróxido de Hidrogênio/metabolismo , Neoplasias/tratamento farmacológico , Apoptose , Glucose Oxidase/metabolismoRESUMO
Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is widely applied in mapping macrobiomolecules in tissues, but it is still limited in profiling low-molecular-weight (MW) compounds (typically metabolites) due to ion interference and suppression by organic matrices. Here, we present a versatile "top-down" strategy for rational engineering of carbon material-based matrices, by which heteroatom-doped graphene quantum dots (HGQDs) were manufactured for LDI MS detection and imaging of small biomolecules. The HGQDs derived from parent materials inherited the π-conjugated networks and doping sites for promoting energy transfer and negative ion generation, while their extremely small size guaranteed the matrix uniformity and signal reproducibility in LDI MSI. Compared to other HGQDs, nitrogen-doped graphene quantum dots (NGQDs) exhibited superior capability of assisting LDI of various small molecules, including amino acids, fatty acids, saccharides, small peptides, nucleobases, anticancer drugs, and bisphenol pollutants. Density functional theory simulations also corroborated that the LDI efficiency was markedly raised by the proton-capturing pyridinic nitrogen species and compromised by the electron-deficient boron dopants. NGQDs-assisted LDI MS further enabled label-free investigation on enzyme kinetics using an ordinary short peptide as the substrate. Moreover, due to the high salt tolerance and signal reproducibility, the proposed negative-ion NGQDs-assisted LDI MSI was able to reveal the abundance and distribution of low-MW species in rat brain tissue and achieved the imaging of low-MW lipids in coronally sectioned rat brains subjected to traumatic brain injury. Our work offers a new route for customizing nanomaterial matrices toward LDI MSI of small biomolecules in biomedical and pathological research.
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Grafite , Pontos Quânticos , Animais , Lasers , Nitrogênio , Peptídeos/análise , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.
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Cocaína , Córtex Motor , Cocaína/farmacologia , Exercício Físico , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Transmissão SinápticaRESUMO
The figure of merit (FOM) of plasmon lattice resonance (PLR) sensors based on the array of metal/Si/SiO2nanoparticles has been investigated. We demonstrate the shape and material of metal nanoparticles have remarkable effects on the PLR and FOM. FOM is governed by full-widths at half maximum (FWHM) and sensitivity of the PLR. Three different types of PLR can be generated by changing Ag nanoparticles' shapes (pillars, cubes, spheres). One (named PLR1) is mainly originated from the coupling between Mie resonance of individual Si nanopillars and diffraction waves. PLR1of Ag/Si/SiO2nanoparticle arrays is limited in sensing applications due to lower intensity (for Ag pillars and Ag cubes), or smaller FOM (for Ag spheres). The other two are named PLR2. PLR2of Ag/Si/SiO2nanoparticle array with Ag pillars (or Ag cubes) is mainly originated from the coupling between the quadrupole resonance of individual Ag nanopillars (or Ag cubes) and diffraction waves. While PLR2of Ag/Si/SiO2nanoparticle array with Ag spheres is mainly originated from the coupling between dipole resonance of individual Ag nanospheres and diffraction waves. The optimal Ag nanoparticles' shape in FOM is pillar due to the smallest FWHM of PLR2of Ag/Si/SiO2nanoparticle array with Ag pillars. Meanwhile, a comparison of FOM between Au, Ag and Al nanopillars of fixed size is made. The optimal material of metal nanopillars to obtain a high FOM is Ag due to higher sensitivity and narrower FWHM.
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AIMS: Yak is a dominant ruminant, well adapted to grazing on pasture year around in the harsh climate of the 3000-meter-high Qinghai-Tibetan Plateau. The complex microbial community that resides within the yak rumen is responsible for fermentation and contributes to its climatic adaptation. This study aimed to characterize the rumen microbiota responses to wide seasonal variations, especially those necessary for survival in the cold seasons. METHODS AND RESULTS: In the present study, we performed 16s rRNA gene sequencing to investigate the seasonal variations in microbiota composition, diversity and associated volatile fatty acids (VFAs) in yak rumen. The results showed that rumen microbiota were dominated by Bacteroides (72.13%-78.54%) and Firmicutes; the relative abundance of Firmicutes was higher in summer (17.44%) than in winter (10.67%; p < 0.05). The distribution of taxa differed among spring, summer and winter rumen communities (PERMANOVA, p = 0.001), whereas other taxa (e.g., Fibrobacter, Verrucomicrobia, Anaerostipes and Paludibacter), which could potentially help overcome harsh climate conditions were observed in higher abundance during the cold spring and winter seasons. The highest total VFA concentration in the yak rumen was obtained in summer (p < 0.05), followed by spring and winter, and both positive and negative correlations between VFAs and specific genera were revealed. CONCLUSIONS: Microbiota in yak rumen appear to be highly responsive to seasonal variations. Considering environmental factors, we suggest that seasonal adaptation by microbial communities in rumen enables their hosts to survive seasonal scarcity and cold stress in the spring and winter. SIGNIFICANCE AND IMPACT OF STUDY: The present study furthers our understanding of how microbial adaptation to seasonal variations in nutrient availability and climate may function in high plateau ruminants, providing insights into the tripartite relationship between the environment, host and microbiota.
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Microbiota , Rúmen , Animais , Bovinos , Ácidos Graxos Voláteis , Microbiota/fisiologia , RNA Ribossômico 16S/genética , Estações do AnoRESUMO
Animal carcasses introduce large amounts of nitrates and ammonium into the soil ecosystem. Some of this ammonium is transformed from nitrite through the nrfA-type microbial community. However, it is unclear how nrfA-type microorganisms respond to the decomposition of corpses. This study applied high-throughput sequencing to characterize the ecological succession of nrfA-type microbial communities in grassland soil. Our results showed that Cyclobacterium and Trueperella were the predominant genera for nrfA-type communities in soil with a decomposing corpse (experimental group), while Cyclobacterium and Archangium were dominant in soil without a corpse (control group). The alpha diversity indexes and the resistance and resilience indexes of the microbial communities initially increased and then decreased during decomposition. Compared with the control group, nrfA-encoding community structure in the experimental group gradually became divergent with succession and temporal turnover accelerated. Network analysis revealed that the microbial communities of the experimental group had more complex interactions than those of the control groups. Moreover, the bacterial community assembly in the experimental group was governed by stochastic processes, and the communities of the experimental group had a weaker dispersal capacity than those of the control group. Our results reveal the succession patterns of the nrfA-type microbial communities during degradation of wild animal corpses, which can offer references for demonstrating the ecological mechanism underlying the changes in the nrfA-type microbial community during carcass decay. KEY POINTS: ⢠Corpse decay accelerates the temporal turnover of the nrfA-type community in soil. ⢠Corpse decay changes the ecological succession of the nrfA-type community in soil. ⢠Corpse decay leads to a complex co-occurrence pattern of the nrfA-type community in soil.
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Compostos de Amônio , Microbiota , Animais , Animais Selvagens , Cadáver , Solo/química , Microbiologia do SoloRESUMO
BACKGROUND: This study was performed to investigate the association between symptoms and signs in patients with meibomian gland dysfunction (MGD). METHODS: Data were obtained from 122 MGD patients who were recruited for intense pulsed light therapy from November 2017 to April 2018 and the severity of their symptoms and signs at baseline were observed and recorded. Spearman correlation analyses were performed to analyze the relationships between SPEED score and signs. Subjects were divided into different subgroups based on possible influencing factors, and the differences in symptoms and signs were compared between different subgroups. Then influencing factors were controlled by regression analysis to explore the relationship between symptoms and signs and the strong factors affecting symptoms and signs. RESULTS: Analysis of baseline data showed that SPEED scores were not correlated with TBUT, CFSS, MGYSS or any index of eyelid margin abnormality (p > 0.05). In addition, abnormalities of lid margins, including hyperemia, thickening, rounding, hyperkeratinization, and telangiectasia around orifices, were more likely to occur in older patients, menopausal patients, and patients living in northern China. Multiple linear regression analysis indicated that there was still no correlation between symptoms and signs (p > 0.05) after adjusting for influencing factors. Further analysis suggested that each influencing factor has different effects on symptoms and signs, among which menopause affects the SPEED score (R = -4.112, p = 0.025), and age and region have significant effects on eyelid margin abnormalities. CONCLUSIONS: In conclusion, the results demonstrated a poor correlation between symptoms and signs in MGD patients. Age, hormone, and a dry environment may influence the disease, which suggests that the severity of the disease needs to be comprehensively assessed.
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Síndromes do Olho Seco , Doenças Palpebrais , Disfunção da Glândula Tarsal , Idoso , Feminino , Humanos , Glândulas Tarsais , Estudos Prospectivos , LágrimasRESUMO
Bisphenol A (BPA), a phenolic compound, is harmful to humans and animals as its residue in the water threatens multiple organs, especially the kidney. Low selenium (Se) diets are consumed in many regions of the world, and poor Se status has exacerbating effect on toxicity of several environmental chemicals. Here, we described the discovery path of Se deficiency aggravation on autophagy in BPA treated chicken kidney through regulating nitric oxide (NO) and adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways. The actual dietary Se intake for chickens was 0.30 mg/kg in control group and 0.03 mg/kg in Low-Se group, and BPA exposure concentration for chickens was 0.05 g/kg. Chicken embryo kidney (CEK) cells were used in vitro and the BPA exposure concentration for CEK cells was 150 nM. We found that BPA significantly increased levels of NO and inducible nitric oxide synthase, activated AMPK/mTOR signaling pathways, thereby triggering p62/LC3/Beclin1 signaling, resulting in formations of autophagosome and autolysosome, and finally stimulating autophagy in the chicken kidney. Additionally, Se deficiency promoted the occurrence of autophagy in BPA-treated kidneys. Altogether, our findings showed that Se deficiency exacerbates BPA-induced renal autophagy in chickens via regulation of NO and AMPK/mTOR signaling pathways. These findings will improve our understandings of the mechanisms of nephrotoxicity of BPA and detoxification by Se in chickens. In addition, further work is required to determine if Se status of exposed populations needs to be considered in future epidemiological assessments.
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Galinhas , Selênio , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Animais , Autofagia , Compostos Benzidrílicos , Embrião de Galinha , Galinhas/metabolismo , Humanos , Rim/metabolismo , Mamíferos/metabolismo , Óxido Nítrico/metabolismo , Fenóis , Selênio/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
Dibutyl phthalate (DBP) is a phthalic acid ester (PAE) that has posed a health hazard to the organisms. Naringenin (NRG) is a flavanone compound that has shown protection against several environmental chemicals through suppression of oxidative stress and activation of phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) signaling pathway. Herein, swine testis (ST) cells were treated with 1.8 µM of DBP or/and 25.39 nM of NRG for 24 h, we described the discovery path of NRG inhibition on apoptosis in DBP-exposed ST cells through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We first found that the anti-apoptosis effect of NRG is dependent on mitochondrial pathway through flow cytometry and related gene/protein expression, and then we detected PI3K/AKT pathway-related gene/protein expression, and established a computational docking assay between NRG and PTEN. We found that NRG specifically binds to three basic residues (His93, Lys125, Lys128) of P loop in PTEN, as well as phosphatase domains (Asp92, His93, Cys124, Lys125, Ala126, Lys128, and Arg130) in active dephosphorylation pockets, thereby reducing PTEN level and activating PI3K/AKT signaling pathway, and further inhibiting oxidative stress and mitochondrial pathway apoptosis. Taken together, our results push forward that NRG deserves further attention as a potential antagonistic therapy against DBP through targeting PTEN to inhibit oxidative stress and activate PI3K/AKT signaling pathway.
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Flavanonas , Fosfatidilinositol 3-Quinases , Animais , Dibutilftalato/toxicidade , Flavanonas/farmacologia , Masculino , Estresse Oxidativo , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Suínos , Testículo/metabolismo , Treonina/metabolismo , Treonina/farmacologiaRESUMO
BACKGROUND: Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. METHODS: We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. RESULTS: Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan-Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835-76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078-0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047-0.689; p = 0.012) was further reduced. CONCLUSIONS: NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.
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Glomerulonefrite por IGA , Síndrome Nefrótica , Podócitos , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/etiologia , Podócitos/patologia , Proteinúria/patologia , Estudos RetrospectivosRESUMO
Nowadays, there is a tradeoff between the deep-learning module-compression ratio and the module accuracy. In this paper, a strategy for refining the pruning quantification and weights based on neural network filters is proposed. Firstly, filters in the neural network were refined into strip-like filter strips. Then, the evaluation of the filter strips was used to refine the partial importance of the filter, cut off the unimportant filter strips and reorganize the remaining filter strips. Finally, the training of the neural network after recombination was quantified to further compress the computational amount of the neural network. The results show that the method can significantly reduce the computational effort of the neural network and compress the number of parameters in the model. Based on experimental results on ResNet56, this method can reduce the number of parameters to 1/4 and the amount of calculation to 1/5, and the loss of model accuracy is only 0.01. On VGG16, the number of parameters is reduced to 1/14, the amount of calculation is reduced to 1/3, and the accuracy loss is 0.5%.
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Compressão de Dados , Aprendizado Profundo , Redes Neurais de Computação , Fenômenos FísicosRESUMO
In this study, a fluorine-containing flow modifier (Si-DF) with low surface energy is successfully synthesized, which is applied to fabricate ideal electronic packaging materials (BN/PPS composites) with high thermal conductivity, excellent dielectric properties, processability, and toughness by conventional melt blending. Si-DPF is located at the interface between the BN fillers and the PPS matrix, which not only improves the dispersion of BN fillers but also strengthens the interaction. With the help of 5 wt% Si-DF, BN/PPS/Si-DF (70/25/5) still exhibits the high thermally conductive coefficient (3.985 W/m·K) and low dielectric constant (3.76 at 100 MHz) although BN fillers are loaded as high as 70 wt%. Moreover, the sample processes a lower stable torque value (2.5 N·m), and the area under the stress-strain curves is also increased. This work provides an efficient way to develop high-performance polymer-based composites with high thermally conductive coefficients and low dielectric constants for electronic packaging applications.
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PURPOSE: This study aims to investigate the characteristics, potential risk factors and associated severity of keratoconus on the east coast of China. METHODS: In this case-control study, patients diagnosed with keratoconus were invited to fill in the online electronic questionnaire designed with the help of the App named WenJuanXing. Several questions like, sex, age of diagnosis and eye care habits were administered to each subject through this e-questionnaire. Corneal topographies at diagnosis taken from Pentacam were also collected. RESULTS: Totally 391 Chinese keratoconus outpatients were enrolled in this study, among which 159 patients were newly diagnosed. Only three patients (0.77%) had a positive family history of keratoconus. Atopy could be identified in 66.0% of our patients. A total of 357 patients (91.3%) mentioned the habit of eye rubbing, with 191 patients (48.8%) rubbing their eyes frequently. Patients with younger age at onset (p = 0.005), male sex (p = 0.042), frequent eye rubbing (p = 0.003) and smoke (p = 0.002) were found significantly associated with increased risk of acute hydrops. In newly diagnosed patients, 79.9% had the maximum keratometry (Kmax) more than 52D, with males and patients aged 21-30 being even more serious (p = 0.009; p = 0.005). Besides, in patients aged over 21, frequent eye rubbing was significantly associated with steeper Kmax and more severe astigmatism (all p < 0.05). CONCLUSION: Our results suggest that frequent eye rubbing is closely related to the severity of keratoconus in Chinese patients. Chinese keratoconus patients always had much serious disease condition at the time of diagnosis. Thus, increasing the publicity of keratoconus and advocating appropriate eye care habits are needed urgently in China. REGISTRATION: The research was retrospectively registered, and the trial registration number is ChiCTR1900021273, and the registration date is 2019/02/09.