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2.
Aging (Albany NY) ; 122020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028265

RESUMO

Increasing evidence suggests that inflammation is associated with the development of acute ischemic stroke (AIS). The neutrophil-to-lymphocyte ratio (N/L) is an important marker of inflammation and is highly correlated with mortality in stroke patients in recent studies. The N/L of patients who experience hemorrhagic transformation (HT) after AIS is know, but any relationship between N/L and large artery atherosclerosis (LAA) remains unclear, this is our present topic. We enrolled 185 patients with LAA-type HT in the development cohort from a prospective, consecutive, hospital-based stroke registry to this end. We matched these patients to 213 LAA patients who did not develop HT as controls. The incidence of HT after LAA was significantly greater (P<0.01) in patients with higher N/L. We developed a predictive nomogram (incorporating age, systolic blood pressure, the National Institutes of Health Stroke Scale, and the N/L) for LAA patients. The predictive power was good (area under the curve, AUC: 0.832, 95%CI: 0.791-0.872). Our findings were further validated in a validation cohort of 202 patients with AIS attributable to LAA (AUC:0.836, 95%CI:0.781-0.891). In summary, a high N/L is associated with an increased risk for HT after LAA.

3.
Nucleic Acids Res ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32030426

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with MDM2 by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.

5.
Sci Rep ; 10(1): 2971, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060367

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Chem Commun (Camb) ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068210

RESUMO

Two tetraphenylethene-based tetracationic dicyclophanes 1 and 2 were synthesized via a one-step SN2 reaction. Based on the central TPE unit and the slight difference of the outer linkers, 1 and 2 exhibited a classic aggregation-induced emission but contrasting mechanochromic luminescence under grinding, vaporing, or hydrostatic pressure in the solid state, and photochemical reactions with various emitting colours induced by photoirradiation in the solution state.

7.
Cell Prolif ; : e12773, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020692

RESUMO

OBJECTIVES: SIRT1 is an antioxidative factor, but its mechanism in methamphetamine (MA)-induced lung injury remains unclear. The purpose of this study is to determine whether MA can disrupt the integrity of alveolar epithelial barrier, whether SIRT1 is involved in MA-induced chronic lung injury and whether Resveratrol (Res) can protect the integrity of alveolar epithelial cells by regulating ROS to activate SIRT1/PTEN/p-Akt pathway. MATERIALS AND METHODS: The rats were randomly divided into control group and MA group. Extracted lungs were detected by Western blot, HE staining and immunohistochemistry. The alveolar epithelial cells were treated with MA or/and Res, following by Western blot, LDH leakage assay and flow cytometry. MOE is used for bio-informatics prediction. RESULTS: Chronic exposure to MA can cause slower growth ratio of weight, increased RVI and induced lung injury including the reduced number of alveolar sacs and the thickened alveolar walls. MA-induced apoptosis was associated with SIRT1-related oxidative stress. Res suppressed ROS levels, activated SIRT1, negatively regulated PTEN, phosphorylated Akt, reduced LDH leakage, increased the expression of ZO-1 and E-cadherin and inhibited the apoptosis of alveolar epithelial cells to attenuate MA-induced higher permeability of alveolar epithelium. CONCLUSIONS: MA disrupted the integrity of alveolar epithelial barrier. Res inhibited oxidative stress and reversed MA-induced higher permeability and apoptosis of alveolar epithelium by the activation of SIRT1/PTEN/p-Akt pathway.

8.
Drug Des Devel Ther ; 14: 285-296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021111

RESUMO

Ivermectin, a dihydro derivative of avermectin (AVM), was introduced into the veterinary, agricultural and aquaculture markets for animal health in 1981. Ivermectin was soon adopted in 1987 as a human medicine that was originally used for the treatment of onchocerciasis, a parasitic infection. Since then, ivermectin has also been used to control other human diseases and has exerted a significant effect on human health and welfare. In the past decade, many published studies have attempted to determine the role of ivermectin in cancer. In this review, we summarize the published studies to define the current progress in the characterization of ivermectin. Ivermectin causes cell death in cancer cell lines by inducing PAK1-mediated cytostatic autophagy, caspase-dependent apoptosis and immunogenic cell death (ICD) through the modulation of some pathways, including the WNT-T cell factor (TCF), Hippo and Akt/mTOR pathways. Ivermectin can affect the growth and proliferation of cancer cells and plays several different roles, such as its functions as an RNA helicase, a small-molecule mimetic of the surface-induced dissociation (SID) peptide, an activator of chloride channel receptors, and an inducer of mitochondrial dysfunction and oxidative stress. In addition, ivermectin induces the multidrug resistance protein (MDR), has potent anti-mitotic activity, targets angiogenesis and inhibits cancer stem-like cells (CSCs). Many studies have proven that ivermectin exerts antitumour effects and might thus benefit patients with cancer after sufficient clinical trials.

9.
Br J Ophthalmol ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051138

RESUMO

AIMS: To report the clinical manifestations, ultrastructure and evaluate the efficacy of therapeutic lamellar keratectomy (TLK) and penetrating keratoplasty (PK) for microsporidial stromal keratitis (MSK). METHODS: Fourteen MSK cases between 2009 and 2018 were recruited. Each patient's clinical presentation, light microscopy, histopathology, PCR and electron microscopy (EM) of corneal samples were reviewed. RESULTS: The patients were 70.0±4.7 years old (average follow-up, 4.5 years). Time from symptoms to presentation was 10.6±13.0 weeks. The corneal manifestations were highly variable. Corneal scrapings revealed Gram stain positivity in 12 cases (85.7%) and modified Ziehl-Neelsen stain positivity in 9 (64.3%). Histopathology revealed spores in all specimens, while sequencing of small subunit rRNA-based PCR products identified Vittaforma corneae in 82% of patients. EM demonstrated various forms of microsporidial sporoplasm in corneal keratocytes. All patients were treated with topical antimicrobial agents or combined with oral antiparasitic medications for >3 weeks. As all patients were refractory to medical therapy, they ultimately underwent surgical intervention (TLK in 7, PK in 6 and 1 received TLK first, followed by PK). Postoperatively, the infection was resolved in 78.6% of the patients. Nevertheless, a high recurrence rate (21.4%) was noted during 3-year follow-up, with only two patients retained a final visual acuity ≥20/100. CONCLUSION: MSK usually presents with a non-specific corneal infiltration refractory to antimicrobial therapy. The diagnosis relies on light microscopic examinations on corneal scrapings and histopathological analyses. Surgical intervention is warranted by limiting the infection; however, it was associated with an overall poor outcome.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32008746

RESUMO

3' uridylation is an essential modification associated with coding and noncoding RNA degradation in eukaryotes. In Arabidopsis, HESO1 was first identified as the major nucleotidyl transferase that uridylates most unmethylated miRNAs, and URT1 was later reported to play a redundant but important role in miRNA uridylation when HESO1 is absent. Two enzymes work sequentially and collaboratively to tail different forms of the same miRNAs in vivo. For mRNA, however, URT1 becomes the main enzyme to uridylate the majority of mRNA and repairs their deadenylated ends to restore the binding site for Poly(A) Binding Protein (PABP). HESO1, on the other hand, targets mostly the mRNAs with very short oligo(A) tails and fails in fulfilling the same task. To understand the structural basis these two functional homologues possess for their different substrate preferences and catalytic behaviors, we first determined the crystal structures of URT1 in the absence and presence of UTP. Our structures, together with functional assay and sequence analysis, indicated that URT1 has a conserved UTP-recognition mechanism analogue to the terminal uridylyl transferases from other species whereas HESO1 may evolve separately to recognize UTP in a different way. Moreover, URT1 N552 may be an important residue in interacting with 3' nucleotide of RNA substrate. The URT1 structure we determined represents the first structure of uridylyl transferase from plants, shedding light on the mechanisms of URT1/HESO1-dependent RNA metabolism.

11.
BMC Cancer ; 20(1): 42, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952506

RESUMO

Following publication of the original article [1], the authors reported an error in Fig 5 of this article, graphs presenting FCM and immunofluorescent for CD4T, CD8T and NK cell of the Control Groups (LL2, LL2-irradation, MCS-irradiation) were inadvertently duplicated from another parallel experiment.

12.
Oncologist ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31957916

RESUMO

BACKGROUND: Because beneficial response and progression-free survival (PFS) were achieved by well-designed clinical trials with tyrosine kinase inhibitors (TKIs) in patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC), the overall survival (OS) and improvement of therapeutic outcomes in the real world have been anticipated. SUBJECTS, MATERIALS, AND METHODS: This prospective, single-center, real-world study assessed the predictive significance of clinicopathological features on disease control rate (DCR), objective response rate (ORR), PFS, and OS in a cohort of 72 patients with progressive RR-DTC treated with sorafenib at an initial dose of 200 mg twice daily. RESULTS: Disease control, objective response, and biochemical effectiveness were achieved in 73.3%, 21.7%, and 77.9% of patients, respectively. The median PFS and OS were 17.6 and 28.9 months, respectively. Multivariate analyses showed that hand-foot syndrome (HFS) was an independent predictor for better DCR and ORR, and 131 I-avidity for higher ORR. In univariate analyses, longer PFS and OS were observed in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, pathologically well DTC, lung-only metastasis, absence of bone metastasis, biochemically nonineffective response, HFS, or radiological disease control. In multivariate analyses, only well DTC and ECOG PS ≤2 remained as independent prognostic factors for more favorable PFS and OS, respectively, whereas the absence of bone metastasis and biochemically nonineffective response independently predicted superior PFS and OS. CONCLUSION: This study demonstrated that clinicopathological features might play a vital role in predicting therapeutic outcomes in patients with progressive RR-DTC treated with sorafenib, warranting further optimization of candidates for TKIs. IMPLICATIONS FOR PRACTICE: This prospective, single-center, real-world study was designed to investigate the significance of clinicopathological features in predicting response, progression-free survival, and overall survival in patients with progressive radioiodine-refractory differentiated thyroid cancer (DTC) treated with sorafenib. Multivariate analyses showed that hand-foot syndrome was an independent predictor for better response. Meanwhile, well DTC, Eastern Cooperative Oncology Group performance status ≤2, biochemically nonineffective response, and the absence of bone metastasis were independent prognostic factors for more favorable survival. This study demonstrated that clinicopathological features might play a vital role in predicting outcomes in sorafenib-treated patients with radioiodine-refractory DTC, warranting optimization of indications.

13.
Methods Mol Biol ; 2117: 265-270, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31960385

RESUMO

Chemically induced cell fate conversion, including reprogramming to pluripotent stem cells and direct reprogramming to somatic cells, has been proved to be an alternative strategy with many advantages, in comparison with conventional transcription factors- or microRNAs-enabled cell reprogramming. Many functional and desirable cells have been generated via the chemically induced reprogramming. Neural stem cells (NSCs) hold great potential in basic research and clinical application. Here, we describe a detailed protocol for converting mouse fibroblasts into NSCs by a cocktail of chemical compounds.

14.
J Neurosci ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964717

RESUMO

Dendritic arborization is highly regulated and requires tight control of dendritic growth, branching, cytoskeletal dynamics and ion channel expression to ensure proper function. Abnormal dendritic development can result in altered network connectivity, which has been linked to neurodevelopmental disorders including Autism Spectrum Disorders (ASDs). How neuronal growth control programs tune dendritic arborization to ensure function is still not fully understood. Using Drosophila dendritic arborization (da) neurons as a model, we identified the conserved Ste20-like kinase Tao as a negative regulator of dendritic arborization. We show that Tao kinase activity regulates cytoskeletal dynamics and sensory channel localization required for proper sensory function in both, male and female flies. We further provide evidence for functional conservation of Tao kinase showing that its ASD-linked human orthologue, Tao kinase 2 (Taok2), could replace Drosophila Tao and rescue dendritic branching, dynamic microtubule alterations and behavioral defects. However, several ASD-linked Taok2 variants displayed impaired rescue activity suggesting Tao/Taok2 mutations can disrupt sensory neuron development and function. Consistently, we show that Tao kinase activity is required in developing and as well as adult stages for maintaining normal dendritic arborization and sensory function to regulate escape and social behavior. Our data suggest an important role for Tao kinase signaling in cytoskeletal organization to maintain proper dendritic arborization and sensory function, providing a strong link between developmental sensory aberrations and behavioral abnormalities relevant for Taok2-dependent ASDs.SIGNIFICANCE STATEMENTASDs are linked to abnormal dendritic arbors. However, the mechanisms of how dendritic arbors develop to promote functional and proper behavior are unclear. We identified Drosophila Tao kinase, the orthologue of the ASD risk gene Taok2, as a regulator of dendritic arborization in sensory neurons. We show that Tao kinase regulates cytoskeletal dynamics, controls sensory ion channel localization, and is required to maintain somatosensory function in vivo Interestingly, ASD-linked human Taok2 mutations rendered it non-functional, while its wildtype form could restore neuronal morphology and function in Drosophila lacking endogenous Tao. Our findings provide evidence for a conserved role of Tao kinase in dendritic development and function of sensory neurons, suggesting aberrant sensory function might be a common feature of ASDs.

15.
J Cell Mol Med ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970877

RESUMO

Clinical efficacy of differentiation therapy with mitogen-activated protein kinase inhibitors (MAPKi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAFV600E -MAPK-induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAFV600E -mutant (BCPAP and K1) and BRAF-wild-type (TPC-1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine-metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine-metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAFV600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi-induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAFV600E -mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAFV600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.

16.
Elife ; 92020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31975689

RESUMO

Worms with increased levels of the epigenetic mark H3K9me2 have a longer lifespan that can be passed down to future generations.

17.
J Virol ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896596

RESUMO

Mosquito-borne flaviviruses consist of a positive-sense genome RNA flanked by the untranslated regions (UTRs). There is a panel of highly complex RNA structures in the UTRs with critical functions. For instance, Xrn1-resistant RNAs (xrRNAs) halt Xrn1 digestion and lead to the production of subgenomic flaviviral RNA (sfRNA). Conserved short direct repeats (DRs), also known as conserved sequences (CS) and repeated conserved sequences (RCS), have been identified as one of RNA elements locating downstream of xrRNAs, but their biological function remains unknown. In this study, we uncovered that the specific DRs involve the production of specific sfRNA in both mammalian and mosquito cells. Biochemical assays and structural remodeling demonstrate that the base pairings in the stem of these DRs control sfRNA formation by maintaining the binding affinity of the corresponding xrRNAs to Xrn1. Based on these finding, we proposed that DRs functions like a bracket holding Xrn1-xrRNA complex for sfRNA formation.IMPORTANCE Flaviviruses include many important human pathogens. The production of subgenomic flaviviral RNAs (sfRNAs) is important for viral pathogenicity as a common feature of flaviviruses. sfRNAs are formed through the incomplete degradation of viral genomic RNA by the cytoplasmic 5'-3' exoribonuclease Xrn1 halted at the Xrn1-resistant RNA (xrRNA) structures within the 3'-UTR. The 3'-UTRs of the flavivirus genome also contain distinct short direct repeats (DRs), such as RCS3, CS3, RCS2 and CS2. However, the biological functions of these ancient primary DR sequences remain largely unknown. Here, we found that DR sequences involve in sfRNA formation and viral virulence, and provide novel targets for the rational design of live-attenuated flavivirus vaccine.

18.
J Am Chem Soc ; 142(4): 2051-2058, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31905287

RESUMO

Supramolecular polymers based on host-guest molecular recognition have emerged as promising platforms for the development of smart materials. However, the studies on them are primarily conducted in solution and/or in the gel state. In contrast, little is known about dynamic properties and applications of supramolecular polymers in bulk. Herein, we present a self-cross-linking supramolecular polymer network (SPN) as a model system to understand the bulk properties controlled by noncovalent interactions. Specifically, the SPN monomer is composed of two benzo-21-crown-7 (B21C7) host units and two dialkylammonium salt guest moieties on a four-arm core, wherein complementary host-guest complexation drives the formation of the SPN with [2]pseudorotaxane linkages between B21C7 and ammonium motifs. The dynamic and reversible behaviors of the linkages are evaluated by measurement of viscoelasticity. The results indicate that the host-guest molecular recognition becomes highly dynamic at elevated temperature. Moreover, the relatively high activation energy of the SPN manifests itself as a new type of thermoplastic material with network topology freezing glass transition. Finally, we demonstrate how these findings provide insights into the malleability and processability of the SPN by simple demos. The fundamental understanding gained from the research on this SPN in bulk will facilitate the advancement and application of supramolecular materials.

19.
J Ovarian Res ; 13(1): 9, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969186

RESUMO

BACKGROUND: The limitation of current biomarker of early stage ovarian cancer and the anatomical location of ovarian (depths of the pelvic) make ovarian cancer difficult to be detected in early stage. Growing evidence shows exosomes as key information transmitters, it carried molecules, such as miRNAs, proteins, lipids, double-stranded DNA have been reported as promising biomarkers in many diseases. However, little is known about the protein and lipid composition of ovarian cancer. METHODS: Here, we report proteomic and lipidomic analysis of exosomes derived from ovarian cancer cells (SKOV-3) and ovarian surface epithelial cells (HOSEPiC). RESULTS: A total of 1433 proteins and 1227 lipid species were identified from two cell line derived exosomes. Several lipid species and proteins significantly differ in SKOV-3 derived exosomes compared to those from HOSEPiC. For example, we noted that ChE and ZyE species were in general more abundant in exosomes from SKOV-3 than from HOSEPiC; Collagen type V alpha 2 chain (COL5A2) and lipoprotein lipase (LPL) were significantly higher in SKOV-3 derived exosomes than HOSEpic (p < 0.05). CONCLUSIONS: Our research indicates the promising role of exosomal proteins and lipids in the early diagnosis of ovarian cancer.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31985407

RESUMO

Convolutional neural networks have gained a remarkable success in computer vision. However, most usable network architectures are hand-crafted and usually require expertise and elaborate design. In this paper, we provide a block-wise network generation pipeline called BlockQNN which automatically builds high-performance networks using the Q-Learning paradigm with epsilon-greedy exploration strategy. The optimal network block is constructed by the learning agent which is trained to choose component layers sequentially. We stack the block to construct the whole auto-generated network. To accelerate the generation process, we also propose a distributed asynchronous framework and an early stop strategy. The block-wise generation brings unique advantages: (1) it yields state-of-the-art results in comparison to the hand-crafted networks on image classification, particularly, the best network generated by BlockQNN achieves 2.35% top-1 error rate on CIFAR-10. (2) it offers tremendous reduction of the search space in designing networks, spending only 3 days with 32 GPUs. A faster version can yield a comparable result with only 1 GPU in 20 hours. (3) it has strong generalizability in that the network built on CIFAR also performs well on the larger-scale dataset. The best network achieves very competitive accuracy of 82.0% top-1 and 96.0% top-5 on ImageNet.

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