RESUMO
Three bis-formylfluorenimide ligands with different bridging groups were designed and synthesized, leading to the successful preparation of six novel alkylaluminum complexes through their reaction with alkylaluminum reagents (AlMe3 or AlEt3). Complexes 1 and 2 were obtained by the reaction of 1,2-propylene-bridged diamine (L1) with AlMe3 or AlEt3. By reacting 1,2-cyclohexylene-bridged diamine (L2) with AlMe3 or AlEt3 to obtain complexes 3 and 4. The above ligands formed a bidentate four-coordinate structure with alkylaluminum, which involved the elimination of one alkyl group as the ligand reacted with alkylaluminum. The complexes 5 and 6 were synthesized through the reaction of 1,2-phenylene-bridged diamine (L3) with AlEt3 in toluene or tetrahydrofuran. Notably, L3 exhibited unique reactivity compared with the other ligands, which formed a tridentate four-coordinated structure when reacting with alkylaluminum. The formation of the tridentate complex resulted from the introduction of a benzimidazole derivative or tetrahydrofuran (THF) molecule along with the elimination of two alkyl groups during its coordination with alkylaluminum. All complexes were characterized via 1H NMR, 13C NMR, and elemental analysis, with structural determination confirmed through X-ray. Furthermore, the catalytic activity in the hydroboration reaction of aldehyde, ketone, and imines was investigated with these complexes as catalysts. Among them, complex 1 demonstrated excellent catalytic performance (up to 99% yield) and broad substrate compatibility (more than 30 substrates) at low catalyst loading (1 mol %) under mild reaction conditions.
RESUMO
Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.
Assuntos
Injúria Renal Aguda , COVID-19 , Diabetes Mellitus Experimental , Camundongos , Animais , SARS-CoV-2 , COVID-19/complicações , Quercetina/farmacologia , Diabetes Mellitus Experimental/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Camundongos Endogâmicos , Pontos de Checagem do Ciclo CelularRESUMO
In this paper, the novel fluorescence probe XP based on Schiff-base was designed, synthesized and characterized, which could detect Y3+selectively and sensitively. The recognition mechanism of XP toward Y3+ was studied by Job's plot and HRMS. It was investigated that stoichiometric ratio of the probe XP conjugated with Y3+ was 1:2. And the detection limit was calculated as 0.30 µM. In addition, Y3+ was recognized by the test paper made from XP. And the probe XP could detect Y3+ selectively in Caenorhabditis elegans and the main organs of mice. Thus, XP was considered to have some potential for application in bioimaging.
Assuntos
Corantes Fluorescentes , Ítrio , Camundongos , Animais , Espectrometria de Fluorescência/métodos , Bases de SchiffRESUMO
Clopidogrel, a P2Y12 inhibitor, is a novel anti-fibrosis agent for chronic kidney disease (CKD), but its mechanisms remain unclear, which we investigated by silencing P2Y12 or treating unilateral ureteral obstruction (UUO) in LysM-Cre/Rosa Tomato mice with clopidogrel in vivo and in vitro. We found that P2Y12 was significantly increased and correlated with progressive renal fibrosis in CKD patients and UUO mice. Phenotypically, up to 82% of P2Y12-expressing cells within the fibrosing kidney were of macrophage origin, identified by co-expressing CD68/F4/80 antigens or a macrophage-lineage-tracing marker Tomato. Unexpectedly, more than 90% of P2Y12-expressing macrophages were undergoing macrophage-to-myofibroblast transition (MMT) by co-expressing alpha smooth muscle actin (α-SMA), which was also confirmed by single-cell RNA sequencing. Functionally, clopidogrel improved the decline rate of the estimated glomerular filtration rate (eGFR) in patients with CKD and significantly inhibited renal fibrosis in UUO mice. Mechanistically, P2Y12 expression was induced by transforming growth factor ß1 (TGF-ß1) and promoted MMT via the Smad3-dependent mechanism. Thus, silencing or pharmacological inhibition of P2Y12 was capable of inhibiting TGF-ß/Smad3-mediated MMT and progressive renal fibrosis in vivo and in vitro. In conclusion, P2Y12 is highly expressed by macrophages in fibrosing kidneys and mediates renal fibrosis by promoting MMT via TGF-ß/Smad3 signaling. Thus, P2Y12 inhibitor maybe a novel and effective anti-fibrosis agent for CKD.
Assuntos
Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Clopidogrel/metabolismo , Clopidogrel/farmacologia , Clopidogrel/uso terapêutico , Fibrose , Rim , Nefropatias/etiologia , Nefropatias/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/genéticaRESUMO
BACKGROUND: Preimplantation genetic testing for aneuploidy (PGT-A) was demonstrated to be superior to conventional IVF in reducing the incidence of miscarriage and abnormal offspring after the first embryo transfer (ET). PGT-A requires several embryo trophectoderm cells, but its negative impacts on embryo development and long-term influence on the health conditions of conceived children have always been a concern. As an alternative, noninvasive PGT-A (niPGT-A) approaches using spent blastocyst culture medium (SBCM) achieved comparable accuracy with PGT-A in several pilot studies. The main objective of this study is to determine whether noninvasive embryo viability testing (niEVT) results in better clinical outcomes than conventional IVF after the first embryo transfer. Furthermore, we further investigated whether niEVT results in higher the live birth rate between women with advanced maternal age (AMA, > 35 years old) and young women or among patients for whom different fertilization protocols are adopted. METHODS: This study will be a double-blind, multicenter, randomized controlled trial (RCT) studying patients of different ages (20-43 years) undergoing different fertilization protocols (in vitro fertilization [IVF] or intracytoplasmic sperm injection [ICSI]). We will enroll 1140 patients at eight reproductive medical centers over 24 months. Eligible patients should have at least two good-quality blastocysts (better than grade 4 CB). The primary outcome will be the live birth rate of the first embryo transfer (ET). Secondary outcomes will include the clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, cumulative live birth rate, ectopic pregnancy rate, and time to pregnancy. DISCUSSION: In this study, patients who undergo noninvasive embryo viability testing (niEVT) will be compared to women treated by conventional IVF. We will determine the effects on the pregnancy rate, miscarriage rate, and live birth rate and adverse events. We will also investigate whether there is any difference in clinical outcomes among patients with different ages and fertilization protocols (IVF/ICSI). This trial will provide clinical evidence of the effect of noninvasive embryo viability testing on the clinical outcomes of the first embryo transfer. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) Identifier: ChiCTR2100051408. 9 September 2021.
Assuntos
Aborto Espontâneo , Coeficiente de Natalidade , Criança , Feminino , Gravidez , Humanos , Adulto , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Injeções de Esperma Intracitoplásmicas , Taxa de Gravidez , Aneuploidia , Fertilização in vitro , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Chest CT scan is an effective way to detect and diagnose COVID-19 infection. However, features of COVID-19 infection in chest CT images are very complex and heterogeneous, which make segmentation of COVID-19 lesions from CT images quite challenging. OBJECTIVE: To overcome this challenge, this study proposes and tests an end-to-end deep learning method called dual attention fusion UNet (DAF-UNet). METHODS: The proposed DAF-UNet improves the typical UNet into an advanced architecture. The dense-connected convolution is adopted to replace the convolution operation. The mixture of average-pooling and max-pooling acts as the down-sampling in the encoder. Bridge-connected layers, including convolution, batch normalization, and leaky rectified linear unit (leaky ReLU) activation, serve as the skip connections between the encoder and decoder to bridge the semantic gap differences. A multiscale pyramid pooling module acts as the bottleneck to fit the features of COVID-19 lesion with complexity. Furthermore, dual attention feature (DAF) fusion containing channel and position attentions followed the improved UNet to learn the long-dependency contextual features of COVID-19 and further enhance the capacity of the proposed DAF-UNet. The proposed model is first pre-trained on the pseudo label dataset (generated by Inf-Net) containing many samples, then fine-tuned on the standard annotation dataset (provided by the Italian Society of Medical and Interventional Radiology) with high-quality but limited samples to improve performance of COVID-19 lesion segmentation on chest CT images. RESULTS: The Dice coefficient and Sensitivity are 0.778 and 0.798 respectively. The proposed DAF-UNet has higher scores than the popular models (Att-UNet, Dense-UNet, Inf-Net, COPLE-Net) tested using the same dataset as our model. CONCLUSION: The study demonstrates that the proposed DAF-UNet achieves superior performance for precisely segmenting COVID-19 lesions from chest CT scans compared with the state-of-the-art approaches. Thus, the DAF-UNet has promising potential for assisting COVID-19 disease screening and detection.
Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
The novel biomarker, insulin-like growth factor binding protein 7 (IGFBP7), is used clinically to predict different types of acute kidney injury (AKI) and has drawn significant attention as a urinary biomarker. However, as a secreted protein in the circulation of patients with AKI, it is unclear whether IGFBP7 acts as a key regulator in AKI progression, and if mechanisms underlying its upregulation still need to be determined. Here we found that IGFBP7 is highly expressed in the blood and urine of patients and mice with AKI, possibly via a c-Jun-dependent mechanism, and is positively correlated with kidney dysfunction. Global knockout of IGFBP7 ameliorated kidney dysfunction, inflammatory responses, and programmed cell death in murine models of cisplatin-, kidney ischemia/reperfusion-, and lipopolysaccharide-induced AKI. IGFBP7 mainly originated from kidney tubular epithelial cells. Conditional knockout of IGFBP7 from the kidney protected against AKI. By contrast, rescue of IGFBP7 expression in IGFBP7-knockout mice restored kidney damage and inflammation. IGFBP7 function was determined in vitro using recombinant IGFBP7 protein, IGFBP7 knockdown, or overexpression. Additionally, IGFBP7 was found to bind to poly [ADP-ribose] polymerase 1 (PARP1) and inhibit its degradation by antagonizing the E3 ubiquitin ligase ring finger protein 4 (RNF4). Thus, IGFBP7 in circulation acts as a biomarker and key mediator of AKI by inhibiting RNF4/PARP1-mediated tubular injury and inflammation. Hence, over-activation of the IGFBP7/PARP1 axis represents a promising target for AKI treatment.
Assuntos
Injúria Renal Aguda , Inibidor Tecidual de Metaloproteinase-2 , Adenosina Difosfato Ribose , Animais , Biomarcadores , Cisplatino/toxicidade , Inflamação , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Lipopolissacarídeos , Camundongos , Camundongos Knockout , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Herein, a novel strategy was proposed for identifying carbon monoxide (CO), which plays a crucial part in living systems. For the first time, we have managed to design, synthesize, and characterize successfully this new Cu2+-assisted fluorescent probe (DPHP) in detecting CO. Compared with the commonly adopted Pd0-mediated Tsuji-Trost reaction recognition method, such a new strategy did not engage costly palladium (II) salt and generated no leaving group, indicating a satisfactory anti-interference ability. The recognition mechanism was confirmed by IR, 1H NMR titration, HR-MS, cyclic voltammetry, X-ray photoelectron spectroscopy, electron paramagnetic resonance, and optical properties. Surprisingly, it was found that the new method achieved high selectivity and rapid identification of CO with a lower limit of detection (1.7 × 10-8 M). More intriguingly, it could recognize endogenous and exogenous CO in HeLa cells. The cytotoxicity of this new method was so low that it allowed the detection of CO in mice and zebrafish. Basically, our results trigger a novel viewpoint of rationally designing and synthesizing advanced materials for CO detection with unique features, impelling new research in detection chemistry.
Assuntos
Monóxido de Carbono , Corantes Fluorescentes , Animais , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Camundongos , Imagem Óptica/métodos , Peixe-ZebraRESUMO
Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by insulin resistance facilitates intimal hyperplasia of type 2 diabetes mellitus (T2DM) and N6-methyladenosine (m6A) methylation modification mediates the VSMC proliferation. This study aimed to reveal the m6A methylation modification regulatory mechanism. In this study, m6A demethylase FTO was elevated in insulin-treated VSMCs and T2DM mice with intimal injury. Functionally, FTO knockdown elevated m6A methylation level and further restrained VSMC proliferation and migration induced by insulin. Mechanistically, FTO knockdown elevated Smooth muscle 22 alpha (SM22α) expression and m6A-binding protein IGF2BP2 enhanced SM22α mRNA stability by recognizing and binding to m6A methylation modified mRNA. In vivo studies confirmed that the elevated m6A modification level of SM22α mRNA mitigated intimal hyperplasia in T2DM mice. Conclusively, m6A methylation-mediated elevation of SM22α restrained VSMC proliferation and migration and ameliorated intimal hyperplasia in T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Animais , Movimento Celular/fisiologia , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Hiperplasia/metabolismo , Hiperplasia/patologia , Insulinas/metabolismo , Metilação , Camundongos , Músculo Liso Vascular/patologia , RNA Mensageiro/metabolismoRESUMO
A stable 3d-4f heterometallic cluster, namely, {Dy4Ni5L10(NO3)4(CO3)4(CH3OH)2}·CH3CN (Dy4Ni5, HL = 8-hydroxyquinoline), has been solvothermally synthesized and structurally characterized. The compound exhibits an interesting structure in which a tetrahedron based on 4f ions interpenetrates with a square pyramid based on 3d ions. Besides, a unique intermolecular interaction was found in Dy4Ni5, giving rise to its high stability not only when it is in the solid state but also when it dissolves in organic solvents. In addition, the magnetic behavior of solid Dy4Ni5 and the magneto-optical activity of the Dy4Ni5 solution were also studied.
RESUMO
Currently, the tuberculosis (TB) detection model based on chest X-ray images has the problem of excessive reliance on hardware computing resources, high equipment performance requirements, and being harder to deploy in low-cost personal computer and embedded devices. An efficient tuberculosis detection model is proposed to achieve accurate, efficient, and stable tuberculosis screening on devices with lower hardware levels. Due to the particularity of the chest X-ray images of TB patients, there are fewer labeled data, and the deep neural network model is difficult to fully train. We first analyzed the data distribution characteristics of two public TB datasets, and found that the two-stage tuberculosis identification (first divide, then classify) is insufficient. Secondly, according to the particularity of the detection image(s), the basic residual module was optimized and improved, and this is regarded as a crucial component of this article's network. Finally, an efficient attention mechanism was introduced, which was used to fuse the channel features. The network architecture was optimally designed and adjusted according to the correct and sufficient experimental content. In order to evaluate the performance of the network, it was compared with other lightweight networks under personal computer and Jetson Xavier embedded devices. The experimental results show that the recall rate and accuracy of the E-TBNet proposed in this paper are better than those of classic lightweight networks such as SqueezeNet and ShuffleNet, and it also has a shorter reasoning time. E-TBNet will be more advantageous to deploy on equipment with low levels of hardware.
Assuntos
Redes Neurais de Computação , Tuberculose , Humanos , Radiografia , Tórax , Raios XRESUMO
Existing smart radiation devices suffer from numerous disadvantages such as large thicknesses, limited dimensions, or requirements for sustained electrical power. The present study addresses these issues by proposing a smart thermal control coating based on CaF2/VO2 core-shell (CaF2@VO2) structured microspheres prepared by a solvent/hydrothermal-calcination method and distributed within an easily applied polymer matrix. Here, the dielectric-to-metallic transition property of the VO2 shell material with increasing temperature is used to regulate the optical scattering and absorption characteristics of the CaF2@VO2 core-shell microspheres to realize a positive and reversible increase in the emissivity of the coating from 0.47 at 30 °C to 0.83 at 90 °C. The mechanisms behind this effect are investigated by theoretical analyses and numerical simulations. The present work can expect to promote the further research and development of new coating materials for smart thermal control applications.
RESUMO
Alcohol consumption causes renal injury and compromises kidney function. The underlying mechanism of the alcoholic kidney disease remains largely unknown. In the present study, an alcoholic renal fibrosis animal model was first employed which mice received liquid diet containing alcohol for 4 to 12 weeks. The Masson's Trichrome staining analysis showed that kidney fibrosis increased at week 8 and 12 in the animal model that was further confirmed by albumin assay, Western blot, immunostaining and real-time PCR of fibrotic indexes (collagen I and α-SMA). In vitro analysis also confirmed that alcohol significantly induced fibrotic response (collagen I and α-SMA) in HK2 tubular epithelial cells. Importantly, both in vivo and in vitro studies showed alcohol treatments decreased Smad7 and activated Smad3. We further determined how the alcohol affected the balance of Smad7 (inhibitory Smad) and Smad3 (regulatory Smad). Genome-wide methylation sequencing showed an increased DNA methylation of many genes and bisulfite sequencing analysis showed an increased DNA methylation of Smad7 after alcohol ingestion. We also found DNA methylation of Smad7 was mediated by DNMT1 in ethyl alcohol (EtOH)-treated HK2 cells. Knockdown of Nox2 or Nox4 decreased DNMT1 and rebalanced Smad7/Smad3 axis, and thereby relieved EtOH-induced fibrotic response. The inhibition of reactive oxygen species by the intraperitoneal injection of apocynin attenuated renal fibrosis and restored renal function in the alcoholic mice. Collectively, we established novel in vivo and in vitro alcoholic kidney fibrosis models and found that alcohol induces renal fibrosis by activating oxidative stress-induced DNA methylation of Smad7. Suppression of Nox-mediated oxidative stress may be a potential therapy for long-term alcohol abuse-induced kidney fibrosis.
Assuntos
Metilação de DNA/genética , Etanol/efeitos adversos , Nefropatias/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Proteína Smad7/metabolismo , Acetofenonas/farmacologia , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Túbulos Renais/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
MLKL is a central mediator for necroptosis. Its knockout significantly relieves acute kidney injury (AKI). However, its upstream regulatory mechanism in AKI has not been fully elucidated. We recently reviewed how microRNAs (miRNAs), a type of well-studied epigenetic regulator, play critical roles in AKI. Here, we evaluated miRNAs that potentially target MLKL and evaluated their function in human tubular epithelial cells in response to toxic and ischemic insults. TargetScan analysis showed that miR-194-5P, miR-338-3P, miR-500a-3P, and miR-577 had MLKL binding sites. Although all 4 miRNAs are reduced in AKI, our data show that only hsa-miR-500a-3P was significantly suppressed in cisplatin-treated human tubular epithelial (HK2) cells. We further found that hsa-miR-500a-3P alleviated cisplatin-induced HK2 cell death, which was confirmed by transmission electron microscopy and flow cytometry. In addition, overexpression of hsa-miR-500a-3P decreased kidney injury molecule-1 mRNA and protein levels. Real-time PCR, ELISA, and immunofluorescence data show that hsa-miR-500a-3P protected against inflammatory response, evidenced by decreased monocyte chemotactic protein-1 and proinflammatory cytokines TNF-α and IL-8. Further, hsa-miR-500a-3P attenuated P65 NF-κB phosphorylation and promoter activity. Mechanistically, luciferase reporter assay showed that hsa-miR-500a-3P bound the 3'UTR of MLKL, thereby suppressing phosphorylation and membrane translocation of MLKL. In agreement with these findings, we identified that overexpression of hsa-miR-500a-3P attenuated cell injury and the inflammatory response in response to sodium azide treatment in an in vitro model. Results show that circulating exosomes from patients with AKI down-regulated miR-500a-3P, which suppressed cell injury and inflammation in HK2 cells. hsa-miR-500a-3P alleviated toxic and ischemic insults that were triggered by cell necroptosis and the inflammatory response in human HK2 cells by targeting MLKL. This may serve as a novel therapeutic target for treatment of AKI.-Jiang, L., Liu, X.-Q., Ma, Q., Yang, Q., Gao, L., Li, H.-D., Wang, J.-N., Wei, B., Wen, J., Li, J., Wu, Y.-G., Meng, X.-M. hsa-miR-500a-3P alleviates kidney injury by targeting MLKL-mediated necroptosis in renal epithelial cells.
Assuntos
Injúria Renal Aguda/genética , Apoptose/genética , Células Epiteliais/patologia , Rim/patologia , MicroRNAs/genética , Necrose/genética , Proteínas Quinases/genética , Regiões 3' não Traduzidas/genética , Linhagem Celular , Regulação para Baixo/genética , Exossomos/genética , Humanos , Inflamação/genética , Interferon-alfa/genética , Interleucina-8/genética , Necrose/patologia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genéticaRESUMO
Endogenous retroviruses (ERVs), which are abundant in mammalian genomes, can modulate the expression of nearby genes, and their expression is dynamic and stage-specific during early embryonic development in mice and humans. However, the functions and mechanisms of ERV elements in regulating embryonic development remain unclear. Here, we utilized several methods to determine the contribution of ERVs to the makeup and regulation of transcripts during embryonic genome activation (EGA). We constructed an ERV library and embryo RNA-seq library (IVF_2c and IVF_8c) of goat to serve as our research basis. The GO and KEGG analysis of nearby ERV genes revealed that some ERV elements may be associated with embryonic development. RNA-seq results were consistent with the features of EGA. To obtain the transcripts derived from the ERV sequences, we blasted the ERV sequences with embryonic transcripts and identified three lncRNAs and one mRNA that were highly expressed in IVF-8c rather than in IVF-2c (q-value <0.05). Then, we validated the expression patterns of nine ERV-related transcripts during early developmental stages and knocked down three high-expression transcripts in EGA. The knockdown of lncRNA TCONS_00460156 or mRNA HSD17B11 significantly decreased the developmental rate of IVF embryos. Our findings suggested that some transcripts from ERVs are essential for the early embryonic development of goat, and analyzing the ERV expression profile during goat EGA may help elucidate the molecular mechanisms of ERV in regulating embryonic development.
Assuntos
Desenvolvimento Embrionário/genética , Retrovirus Endógenos/genética , Cabras/embriologia , Cabras/genética , Animais , Células Cultivadas , Clonagem Molecular , Técnicas de Cultura Embrionária/veterinária , Embrião de Mamíferos , Retrovirus Endógenos/metabolismo , Feminino , Fertilização in vitro/veterinária , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes/veterinária , Masculino , Organismos Geneticamente Modificados , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , RNA-Seq/veterinária , Análise de Sequência de RNARESUMO
Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antineoplásicos/administração & dosagem , Cisplatino/efeitos adversos , Necroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Injúria Renal Aguda/genética , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/fisiopatologia , Animais , Humanos , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologiaRESUMO
BACKGROUND: Double lumen intubation and one-lung ventilation should be applied without delay in cases of traumatic main bronchial rupture. In most cases, when the patients' vital signs have been stabilized, the repair can be performed. However, when one-lung ventilation is complicated by traumatic wet lung, the mortality rate is likely to be much higher. CASE PRESENTATION: In this case, the patient experienced a left main bronchial rupture, bilateral traumatic wet lung, and acute respiratory distress syndrome (ARDS) because of severe thoracic trauma. Though the patient was treated with intubation and mechanical ventilation (MV), his oxygenation was still not stable. Thus, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was initiated; upon improvement of oxygenation, the patient received an exploratory thoracotomy. Unfortunately, the rupture proved to be irreparable, resulting in a total left pneumonectomy. As there was severe ARDS caused by trauma, ECMO and ultra-low tidal volume (VT) MV strategy (3 ml/kg) were utilized for lung protection post-op. ECMO was sustained up to the 10th day, and MV until the 20th day, post-operation. With the support of MV, ECMO and other comprehensive measures, the patient made a recovery. CONCLUSION: V-V ECMO and ultra-low VT MV helped this thoracic trauma patient survive the lung edema period and prevented ventilator associated pneumonia (VAP). In extreme situations, with the support of ECMO, the tidal volume may be lowered to 3 ml/kg.
Assuntos
Pneumonectomia/efeitos adversos , Edema Pulmonar/diagnóstico por imagem , Síndrome do Desconforto Respiratório/terapia , Traumatismos Torácicos/complicações , Oxigenação por Membrana Extracorpórea , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Edema Pulmonar/etiologia , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Traumatismos Torácicos/cirurgia , Volume de Ventilação PulmonarRESUMO
OBJECTIVE: To investigate the image quality and x-ray dose associated with a transmission computed tomography (CT) component implemented within the same platform of an experimental benchtop x-ray fluorescence CT (XFCT) system for multimodal preclinical imaging applications. METHODS: Cone-beam CT scans were performed using an experimental benchtop CTâ+âXFCT system and a cylindrically-shaped 3D-printed polymethyl methacrylate phantom (3âcm in diameter, 7âcm in height) loaded with various concentrations (0.05-1âwt. %) of gold nanoparticles (GNPs). Two commercial CT quality assurance phantoms containing 3D line-pair (LP) targets and contrast targets were also scanned. The x-ray beams of 40 and 62âkVp, both filtered by 0.08âmm Cu and 0.4âmm Al, were used with 17âms of exposure time per projection at three current settings (2.5, 5, and 10âmA). The ordered-subset simultaneous algebraic reconstruction and total variation-minimization methods were used to reconstruct images. Sparse projection and short scan were considered to reduce the x-ray dose. The contrast-to-noise ratio (CNR) and modulation transfer function (MTF) were calculated. RESULTS: The lowest detectable concentration of GNPs (CNRâ>â5) and the highest spatial resolution (per MTF50%) were 0.10âwt. % and 9.5âLP/CM, respectively, based on the images reconstructed from 360 projections of the 40âkVp beam (or x-ray dose of 3.44 cGy). The background noise for the image resulting in the lowest GNP detection limit was 25 Hounsfield units. CONCLUSION: The transmission CT component within the current experimental benchtop CT + XFCT system produced images deemed acceptable for multimodal (CTâ+âXFCT) imaging purposes, with less than 4âcGy of x-ray dose.
Assuntos
Tomografia Computadorizada de Feixe Cônico/instrumentação , Imageamento Tridimensional , Limite de Detecção , Imagem Multimodal , Imagens de Fantasmas , Doses de Radiação , Razão Sinal-RuídoRESUMO
BACKGROUND: Spectral computed tomography (CT) has the capability to resolve the energy levels of incident photons, which has the potential to distinguish different material compositions. Although material decomposition methods based on x-ray attenuation characteristics have good performance in dual-energy CT imaging, there are some limitations in terms of image contrast and noise levels. OBJECTIVE: This study focused on multi-material decomposition of spectral CT images based on a deep learning approach. METHODS: To classify and quantify different materials, we proposed a multi-material decomposition method via the improved Fully Convolutional DenseNets (FC-DenseNets). A mouse specimen was first scanned by spectral CT system based on a photon-counting detector with different energy ranges. We then constructed a training set from the reconstructed CT images for deep learning to decompose different materials. RESULTS: Experimental results demonstrated that the proposed multi-material decomposition method could more effectively identify bone, lung and soft tissue than the basis material decomposition based on post-reconstruction space in high noise levels. CONCLUSIONS: The new proposed approach yielded good performance on spectral CT material decomposition, which could establish guidelines for multi-material decomposition approaches based on the deep learning algorithm.
Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/métodos , Tomografia Computadorizada por Raios X/métodos , Animais , Calibragem , Camundongos , Fótons , Razão Sinal-RuídoRESUMO
This paper is concerned with the estimation of time-varying networks for high-dimensional nonstationary time series. Two types of dynamic behaviors are considered: structural breaks (i.e., abrupt change points) and smooth changes. To simultaneously handle these two types of time-varying features, a two-step approach is proposed: multiple change point locations are first identified on the basis of comparing the difference between the localized averages on sample covariance matrices, and then graph supports are recovered on the basis of a kernelized time-varying constrained L 1 -minimization for inverse matrix estimation (CLIME) estimator on each segment. We derive the rates of convergence for estimating the change points and precision matrices under mild moment and dependence conditions. In particular, we show that this two-step approach is consistent in estimating the change points and the piecewise smooth precision matrix function, under a certain high-dimensional scaling limit. The method is applied to the analysis of network structure of the S&P 500 index between 2003 and 2008.