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1.
PLoS One ; 15(2): e0228439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027693

RESUMO

In recent years, the number of vulnerabilities discovered and publicly disclosed has shown a sharp upward trend. However, the value of exploitation of vulnerabilities varies for attackers, considering that only a small fraction of vulnerabilities are exploited. Therefore, the realization of quick exclusion of the non-exploitable vulnerabilities and optimal patch prioritization on limited resources has become imperative for organizations. Recent works using machine learning techniques predict exploited vulnerabilities by extracting features from open-source intelligence (OSINT). However, in the face of explosive growth of vulnerability information, there is room for improvement in the application of past methods to multiple threat intelligence. A more general method is needed to deal with various threat intelligence sources. Moreover, in previous methods, traditional text processing methods were used to deal with vulnerability related descriptions, which only grasped the static statistical characteristics but ignored the context and the meaning of the words of the text. To address these challenges, we propose an exploit prediction model, which is based on a combination of fastText and LightGBM algorithm and called fastEmbed. We replicate key portions of the state-of-the-art work of exploit prediction and use them as benchmark models. Our model outperforms the baseline model whether in terms of the generalization ability or the prediction ability without temporal intermixing with an average overall improvement of 6.283% by learning the embedding of vulnerability-related text on extremely imbalanced data sets. Besides, in terms of predicting the exploits in the wild, our model also outperforms the baseline model with an F1 measure of 0.586 on the minority class (33.577% improvement over the work using features from darkweb/deepweb). The results demonstrate that the model can improve the ability to describe the exploitability of vulnerabilities and predict exploits in the wild effectively.

2.
Chem Commun (Camb) ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040110

RESUMO

Here, a hollowed-out Au@AgPt core-frame nanostructure is carved in the presence of PtCl62- via galvanic replacement (GR) reaction, during which the dissolution of Ag atoms from the {100} facets and the deposition of Pt atoms on the active edges of the nanocubes occur. Both ex situ and in situ monitoring of the plasmonic and structural evolutions at the single-particle level, confirmed also by theoretical simulations, shows a three-phase mechanism involved.

3.
J Affect Disord ; 264: 130-137, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056742

RESUMO

BACKGROUND: To examine the association between narcolepsy and anxiety disorders. METHODS: This population-based, retrospective case-control study analyzed Taiwan's National Health Insurance Research Database between 2000 and 2013. We included narcoleptic patients aged at least 12 years, diagnosed according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 347. The cases and the propensity score-matched controls were selected in a 1:4 ratio. Each subject with anxiety disorders (ICD-9-CM code 300) was required to visit the outpatient clinic at least three times within a year. Multivariate logistic regression and interaction analyses were used to calculate the association between anxiety disorders and narcolepsy. RESULTS: This study enrolled 478 and 1912 subjects with and without narcolepsy, respectively. After adjusting for covariates, patients with anxiety disorders had an approximately 2.7 odds ratio of developing narcolepsy when compared to the control subjects (adjusted odds ratio [aOR)] = 2.7; 95% confidence interval [CI] = 1.699-4.344). Interaction analysis and subgroup analysis showed a higher incidence of previously diagnosed anxiety disorders in narcoleptic patients aged 12 to 17 years and female patients (aOR = 25.9; 95% CI = 15.194-42.896; aOR = 3.6; 95% CI = 1.818-7.062, respectively). LIMITATIONS: The narcolepsy and anxiety disorders were not distinguished by validated structural diagnostic instruments. CONCLUSIONS: The results of this study revealed higher comorbidity rates of anxiety disorders in narcoleptic patients. The incidence of previously diagnosed anxiety disorders was higher in narcoleptic patients aged 12 to 17 years and female patients.

4.
J Cardiothorac Surg ; 15(1): 36, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066478

RESUMO

BACKGROUND: Mediastinal teratoma is a rare disease, many cases were reported before, but few articles focus on large case analyses. The objective of this article is to summarize the clinical characteristics of benign mediastinal teratoma and the experience of surgical treatment, especially thoracoscopic surgery for benign mediastinal teratoma. METHODS: The clinical data of 108 patients with benign mediastinal teratoma confirmed by operation and pathology from January 1992 to January 2018 were analyzed retrospectively. The clinical symptoms, imaging examination, surgical methods and prognosis of all patients were analyzed. We compared the difference of thoracoscopic surgery and thoracotomy surgery using 102 patients underwent only chest surgery. Normally distributed continuous variables were compared by independent sample t test. Categorical variables were analyzed by chi-square test. RESULTS: Imaging examination showed that all 108 cases of mediastinal teratoma were located in the anterior region of mediastinum. All cases underwent surgical resection, postoperative pathology confirmed that all cases were benign. 1 case was taken simple neck collar incision, 5 case was taken median thoracotomy combined with neck incision, other 102 cases were taken thoracoscopic surgery (22) or thoracotomy surgery (80). 4 cases were treated with partial pericardial resection due to adhesions, 12 cases underwent partial pericardial resection, 5 cases underwent lobectomy, 9 cases underwent wedge resection of lobe, and 2 patients underwent anonymous vein angioplasty. 1 case underwent second operation because of postoperative bleeding, 1 case of chylothorax, 1 case of recurrent laryngeal nerve injury, 2 cases of wound infection, 1 case of secondary pulmonary infection. 106 cases were followed up, period from 12 months to 10 years, no recurrence of tumor was found. Comparing to take thoracotomy surgery, patients underwent thoracoscopic surgery has strong advantage on intraoperative blood loss and hospital stay days after surgery (P < 0.05). tumor maximum diameter is larger for thoracotomy surgery group, as well as more patients suffer estimated adhesions from preoperative imaging. so we compared above parameters in patients with tumor diameter less than 10 cm with or without estimated adhesions from preoperative imaging, a strong advantage still can be found in thoracoscopic surgery group, inpatients with estimated adhesions from preoperative imaging, intraoperative blood loss (38.75 ± 15.53 vs 169.17 ± 208.82., P = 0.04) and hospital stay days after surgery (5.50 ± 0.93 vs 9.43 ± 6.54., P = 0.04) were better. In patients without estimated adhesions from preoperative imaging, intraoperative blood loss (46.67 ± 10.00 vs 110.53 ± 123.13., P = 0.06) and hospital stay days after surgery (4.70 ± 1.16 vs 7.53 ± 2.32., P = 0.01) were better. Especially, in thoracoscopic surgery group, hospital stay days after surgery was significantly shorter. CONCLUSION: The clinical manifestations and imaging performance of benign mediastinal teratoma were complicated, and the surgical treatment was effective. Compared with traditional thoracotomy surgery, thoracoscopic surgery can improve patients' quality of life, less intraoperative blood loss, and less hospital stay days after surgery, so if condition is permitted, thoracoscopic surgery should be a better choice.

5.
J Neurooncol ; 146(3): 417-426, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32020472

RESUMO

INTRODUCTION: The failure of immune checkpoint inhibitor (ICPi) on glioblastoma (GBM) treatment underscores the need for improving therapeutic strategy. We aimed to change tumor associated macrophage (TAM) from M2 type (anti-inflammatory) to M1 (pro-inflammatory) type to increase the therapeutic response of ICPi. We proposed that combined rapamycin (R) and hydroxychloroquine (Q) preferentially induce M2 cells death, as fatty acid oxidation was their major source of energy. METHODS: Macrophage polarization was characterized on mice and human macrophage cell lines by specific cytokines stimulation with or without RQ treatment under single culture or co-culture with GBM cell lines. Tumor sizes were evaluated on subcutaneous and intracranial GL261 mice models with or without RQ, anti-PD1 mAb treatment. Tumor volumes assessed by MRI scan and proportions of tumor infiltrating immune cells analyzed by flow cytometry were compared. RESULTS: In vitro RQ treatment decreased the macrophages polarization of M2, increased the phagocytic ability, and increased the lipid droplets accumulation. RQ treatment decreased the expression levels of CD47 and SIRPα on tumor cells and macrophage cells in co-culture experiments. The combination of RQ and anti-PD1 treatment was synergistic in action. Enhanced the intra-tumoral M1/M2 ratio, the CD8/CD4 ratio in the intracranial GL261 tumor model after RQ treatment were evident. CONCLUSION: We provide a rationale for manipulating the macrophage phenotype and increased the therapeutic effect of ICPi. To re-educate and re-empower the TAM/microglia opens an interesting avenue for GBM treatment.

6.
Int J Biol Sci ; 16(4): 671-681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32025214

RESUMO

Background: Activation of macrophages and infiltration are key events in acute liver injury (ALI). Kv1.3 plays an important role in regulating immunologic functions of macrophages and is extensively recognized as a potential ion channel for immunological diseases. Objective: We hypothesized that blockage of Kv1.3 may influence ALI by inhibiting macrophages infiltration in damaged liver tissues. Methods: Margatoxin was administered into the peritoneal cavity of ALI mice. The impact of this treatment on ALI and macrophage migration in vivo and in vitro was determined using immunohistochemistry, transwell migration, and wound healing assays. Results: MgTX treatment alleviated ALI in mice, as evidenced by reduced macrophage infiltration in liver tissues and lower serum levels of liver ALT and AST. RNA-seq profiling analysis showed that the most obvious change by MgTX treatment was downregulation of δ-catenin, a protein known to be associated with macrophage migration. The effect of MgTX on macrophage migration and involvement of δ-catenin was confirmed by transwell and wound healing assays. Overexpression of δ-catenin in RAW264.7 cells promoted migration, an event that was suppressed upon silencing of δ-catenin. Mechanistically, the expression of RhoA was regulated by the overexpression or knockdown of δ-catenin. Conclusion: These findings suggest a role for blockage of Kv1.3 channel in macrophage migration and reveal a new target in the treatment of ALI.

7.
Anal Chem ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32048509

RESUMO

Isothermal nucleic acid amplification technology has widely adopted for analytical chemistry with the purpose for sensitivity improvement. Herein we present an ultrasensitive concatenated hybridization chain reaction (C-HCR) based surface-enhanced Raman scattering (SERS) immunoassay by forming antibody-antigen-aptamer heterosandwich structures with the model analyte of total prostate specific antigens (tPSA). In the C-HCR, two HCRs, one proceeds with two hairpins, and the other with four biotin-modified hairpins, are coupled, making the formation of DNA nanofirecrackers with the lengths longer than 200 nm and more than four hundred million of binding site of streptavidin modified enzymes. This type of DNA nanofirecrackers through the aptamer encoded linker strand to form heterosandwich structures could provide a general signal application platform such as enzyme catalysis with high amplification efficiency. As a proof of concept, Au@Ag core-shell nanostructures based SERS immunoassay with excellent signal amplification has been developed by employing the streptavidin modified alkaline phosphatase (SA-ALP) through its catalysis of 2-phospho-L-ascorbic acid trisodium salt (AAP) to form Au@Ag core-shell nanostructures via the formation of ascorbic acid (AA) to reduce AgNO3 and deposition of silver element on gold nanorods (AuNRs). The newly developed method has a detection limit as low as 0.94 fg/mL, and has successfully achieved the detection of serum samples from clinical patients, which was consistent with the clinical test results, showing that this C-HCR strategy to form DNA nanofirecrackers has great potential in clinical applications.

8.
J Virol ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051278

RESUMO

Arenaviruses Lassa (LASV), Junín (JUNV) and Machupo (MACV) can cause severe and fatal diseases in humans. Although these pathogens are closely related, the host immune responses to these virus infections differs remarkably with direct implications in viral pathogenesis. LASV infection is immunosuppressive with very low level interferon response. In contrast, JUNV and MACV infections stimulate a robust IFN response in a RIG-I-dependent manner and readily activate PKR, a known host dsRNA sensor. In response to infection with RNA viruses, host non-self RNA sensors recognize viral-derived dsRNA as danger signals and initiate innate immune responses. Arenavirus nucleoproteins (NPs) contain a highly conserved exoribonuclease (ExoN) motif, through which LASV NP has been shown to degrade virus-derived immunostimulatory dsRNA in biochemical assays. In this study, we for the first time present evidence that LASV restricts dsRNA accumulation during infection. Although JUNV and MACV NPs also have the ExoN motif, dsRNA readily accumulated in infected cells and often co-localized with dsRNA sensors. Moreover, LASV co-infection diminished the dsRNA accumulation and IFN response in JUNV-infected cells. Disruption of LASV NP ExoN with mutation led to dsRNA accumulation and impaired LASV replication in minigenome systems. Importantly, both LASV NP and RNA polymerase L protein were required to diminish dsRNA accumulation and IFN response in JUNV infection. For the first time, we discovered a collaboration between LASV NP ExoN and L protein in limiting dsRNA accumulation. Our new findings provide mechanistic insights into the differential host innate immune responses to highly pathogenic arenavirus infections.SignificanceArenavirus NPs contain a highly conserved DEDDh ExoN motif, through which LASV NP degrades virus-derived, immunostimulatory dsRNA in biochemical assays to eliminate the danger signal and inhibit innate immune response. Nevertheless, the function of NP ExoN in arenavirus infection remains to be defined. In this study, we discovered that LASV potently restricts dsRNA accumulation during infection and minigenome replication. In contrast, although the NPs of JUNV and MACV also harbor the ExoN motif, dsRNA readily formed during JUNV and MACV infections accompanied by IFN and PKR responses. Interestingly, LASV NP alone was not sufficient to limit dsRNA accumulation. Instead, both LASV NP and L protein were required to restrict immunostimulatory dsRNA accumulation. Our findings provide novel and important insights to the mechanism for the distinct innate immune response to these highly pathogenic arenaviruses and open new directions for future studies.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32040293

RESUMO

Graphene has been applied to thermal technology including boiling and condensation heat transfer, from which the pool boiling enhancement is relay by adjusting the surface morphology and wettability that favorable to catalyze the vaporization on fluid/graphene interface. However, previous works using graphene or reduced graphene oxide (RGO) flakes coatings, where the morphology of graphene coating are non-uniform and most of the underlying structured cavities are sealed by graphene flakes. This block the studies for a long time to unravel the mechanism behind the enhanced boiling performance by graphene coatings. Moreover, the previous work relay on using water-based pool boiling, which limits the scope of its practical applications since the versatile non-polar refrigerant are been widely used in boiling heat transfer. In this letter, the pool boiling was carried out on plain copper surface to study the effect of fluorinated graphene (F-graphene) coating using non-polar refrigerant R-141b as working fluid along with bubble dynamic visualization. It was found out the increase of contact angle leads to more active cavities and enhances heat transfer performance up to twice by applying the F-graphene coating. by applying the F-graphene coating. Moreover, the mechanism of graphene-enhanced heat transfer performance was unrivaled and mainly attributed to the comprising the hydrophobic surface and effective cavity structure. This research provides a practical and reliable route for enhancing the heat transfer through F-graphene-coatings, which pave the way for potential applications in graphene-based thermal technologies.

10.
Biofabrication ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31974317

RESUMO

Microwell arrays have emerged as three-dimensional substrates for cell culture due to their simplicity of fabrication and promise for high-throughput applications such as 3D cell-based assays for drug screening. To date, most microwells have had cylindrical geometries. Motivated by our previous findings that cells display 3D physiological characteristics when grown in the spherical micropores of monodisperse foam scaffolds [1, 2], here we engineered novel microwells shaped as spherical caps with obtuse polar angles, yielding narrow apertures. When used as bare substrates, these microwells were suitable for culturing cell spheroids; the narrow apertures sterically hindered unattached cultured cells from rolling out of microwells under agitation. When only the walls of the microwell were conjugated with extracellular matrix proteins, cells remained confined in the microwells. Epithelial cells proliferated and burst out of the aperture, and cell polarity was oriented based on the distribution of extracellular matrix proteins in the microwells. Surprisingly, single fibroblast cells in spherical wells of various diameters (40-200 µm) underwent cell-cycle arrest, while cells in circular cylindrical microwells continued to proliferate. Spatial confinement was not sufficient to cause cell-cycle arrest; however, confinement in a constant negative-curvature microenvironment led to cell-cycle arrest. Overall, these investigations demonstrate that this spherical microwell substrate constitutes a novel basic research tool for elucidating how cells respond to dimensionality and microenvironment with radii of curvature at the cellular length scale.

11.
J Med Syst ; 44(2): 52, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915982

RESUMO

With the rapid development of technologies such as artificial intelligence, blockchain, cloud computing, and big data, Medical Cyber Physical Systems (MCPS) are increasingly demanding data security, while cloud storage solves the storage problem of complex medical data. However, it is difficult to realize data security sharing. The decentralization feature of blockchain is helpful to solve the problem that the secure authentication process is highly dependent on the trusted third party and implement data security transmission. In this paper, the blockchain technology is used to describe the security requirements in authentication process, and a network model of MCPS based on blockchain is proposed. Through analysis of medical data storage architecture, it can ensure that data can't be tampered and untrackable. In the security authentication phase, bilinear mapping and intractable problems can be used to solve the security threat in the authentication process of medical data providers and users. It can avoid the credibility problem of the trusted third party, and also can realize the ?thyc=10?>two-way authentication between the hospital and blockchain node. Then, BAN logic is used to analyze security protocols, and formal analysis and comparison of security protocols are also made. The results show that the MCPS based on blockchain not only realizes medical treatment data sharing, but also meet the various security requirements in the security authentication phase. In addition, the storage and computing overhead costs is ideal. Therefore, the proposed scheme is more suitable for secure sharing of medical big data.

12.
ACS Appl Mater Interfaces ; 12(4): 4815-4820, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31898447

RESUMO

Taking the advantages of excellent optical properties, biocompatibility, and photostability of carbon dots, herein, we developed polarity-sensitive polymer carbon dots (PCDs) for visualizing of cellular polarity to real-time monitoring autophagy changes without perturbing the cellular status. The PCDs can be prepared by simply mixing dopamine (DA), H2O2, and o-phenylenediamine (o-PDA) in a common beaker without the need for any special equipment or external energy supply, and the preparation could be completed within 3 min at room temperature. Interestingly, the polarity-sensitive PCDs could emit various types of fluorescence and are insensitive to the excitation light when dispersed in different water/dioxane systems with different polarities. Based on the polarity-sensitive emission of the PCDs, the change of polarity during autophagy has been successfully monitored in living cells. Moreover, the change of polarity detected by PCDs is autophagy-specific (does not occur during apoptosis), occurs under different autophagy-inducing situations (starvation, rapamycin, and trehalose), and requires a normal autophagic flux, showing that PCDs rapidly prepared by polymerization cross-linking at room temperature can be functionally applied in the case of autophagy-related physiological or pathological processes.

13.
Molecules ; 25(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936396

RESUMO

BACKGROUND: Natural meroterpenes derived from phloroglucinols and ß-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, however, the chemical diversity of this type of skeletons in Nature is limited. METHODS: To expand the chemical space and explore their inhibitory activities against α-glucosidase (EC 3.2.1.20), we employed ß-caryophyllene and some natural moieties (4-hydroxycoumarins, lawsone or syncarpic acid) to synthesize new types of meroterpene-like skeletons. All the products (including side products) were isolated and characterized by NMR, HR-MS, and ECD. RESULTS: In total, 17 products (representing seven scaffolds) were generated through a one-pot procedure. Most products (12 compounds) showed more potential activity (IC50 < 25 µM) than the positive controls (acarbose and genistein, IC50 58.19, and 54.74 µM, respectively). Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 µM) in a mixed-type manner. The CD analysis indicated that compound 7 could bind to α-glucosidase and influence the enzyme's secondary structure. CONCLUSIONS: Compound 7 could serve as a new type of template compound to develop α-glucosidase inhibitors. Full investigation of a biomimic reaction can be used as a concise strategy to explore diverse natural-like skeletons and search for novel lead compounds.

14.
Acta Pharmacol Sin ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911638

RESUMO

Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 µmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (NaV), calcium (CaV), and delayed rectifier potassium (IK) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC50 values in the range of 1.3-13.3 µmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (IA) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.

15.
New Phytol ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909485

RESUMO

Lignin is a major component of cell wall biomass and decisively affects biomass utilisation. Engineering of lignin biosynthesis is extensively studied, while lignin modification often causes growth defects. We developed a strategy for cell-type-specific modification of lignin to achieve improvements in cell wall property without growth penalty. We targeted a lignin-related transcription factor, LTF1, for modification of lignin biosynthesis. LTF1 can be engineered to a nonphosphorylation form which is introduced into Populus under the control of either a vessel-specific or fibre-specific promoter. The transgenics with lignin suppression in vessels showed severe dwarfism and thin-walled vessels, while the transgenics with lignin suppression in fibres displayed vigorous growth with normal vessels under phytotron, glasshouse and field conditions. In-depth lignin structural analyses revealed that such cell-type-specific downregulation of lignin biosynthesis led to the alteration of overall lignin composition in xylem tissues reflecting the population of distinctive lignin polymers produced in vessel and fibre cells. This study demonstrates that fibre-specific suppression of lignin biosynthesis resulted in the improvement of wood biomass quality and saccharification efficiency and presents an effective strategy to precisely regulate lignin biosynthesis with desired growth performance.

16.
Org Biomol Chem ; 18(5): 964-974, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31930265

RESUMO

A facile one-step reaction of [60]fullerene with cinnamaldehydes and amines promoted by magnesium perchlorate/ferric perchlorate under air conditions afforded a series of rare amino-substituted cyclopentafullerenes in moderate to good yields. Stereoselectivity was readily achieved. Secondary amines exclusively produced N,N-disubstituted cyclopentafullerenes as cis isomers, while arylamines gave N-monosubstituted cyclopentafullerenes with a preference of cis isomers as major products. N-Monosubstituted cyclopentafullerenes could be further converted into other scarce cyclopentafullerenes in the presence of acid chloride or paraformaldehyde. A possible reaction pathway was proposed to elucidate the formation of amino-substituted cyclopentafullerenes.

17.
J Virol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996435

RESUMO

Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within endemic regions in Argentina. The live attenuated vaccine strain, Candid #1 (Can), is approved for use in endemic regions and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for the attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the GP complex of Can, which is otherwise present in the wild type pathogenic JUNV, causes GPC retention in the ER. Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER.ImportanceThe development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in endemic regions within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.

18.
Mol Carcinog ; 59(3): 293-303, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31916307

RESUMO

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High-grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell-cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox-treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral-mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X-ray repair cross-complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

19.
Microcirculation ; : e12608, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31991513

RESUMO

OBJECTIVE: We aimed to determine whether high-dose nitroglycerin, a nitric oxide donor, preserves erythrocyte deformability during cardiopulmonary bypass and examines the signaling pathway of nitric oxide in erythrocytes. METHODS: In a randomized and controlled fashion, forty-two patients undergoing cardiac surgery with hypothermic cardiopulmonary bypass were allocated to high-dose (N = 21) and low-dose groups (N = 21). During rewarming period, patients were given intravenous nitroglycerin with an infusion rate 5 and 1 µg·kg-1 ·min-1 in high-dose and low-dose groups, respectively. Tyrosine phosphorylation level of non-muscle myosin IIA in erythrocyte membrane was used as an index of erythrocyte deformability and analyzed using immunoblotting. RESULTS: Tyrosine phosphorylation of non-muscle myosin IIA was significantly enhanced after bypass in high-dose group (3.729 ± 1.700 folds, P = .011) but not low-dose group (1.545 ± 0.595 folds, P = .076). Phosphorylation of aquaporin 1, vasodilator-stimulated phosphoprotein, and focal adhesion kinase in erythrocyte membrane was also upregulated in high-dose group after bypass. Besides, plasma nitric oxide level was highly correlated with fold change of non-muscle myosin IIA phosphorylation (Pearson's correlation coefficient .871). CONCLUSIONS: High-dose nitroglycerin administered during cardiopulmonary bypass improves erythrocyte deformability through activating phosphorylation of aquaporin 1, vasodilator-stimulated phosphoprotein, and focal adhesion kinase in erythrocytes.

20.
Eur Radiol ; 30(2): 816-822, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650266

RESUMO

OBJECTIVES: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for nasopharyngeal carcinoma (NPC) merged T4N0-2 and T1-4N3 to create stage IVa. In the present study, we aimed to assess the difference in clinical outcomes and patterns of failure between 8th AJCC T4N0-2 and T1-4N3 NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We included 3107 patients with stage IVa NPC disease (1871 with T4N0-2 and 1236 with T1-4N3) according to the 8th AJCC staging system. Overall survival (OS) was the primary endpoint. The clinical outcomes between T4N0-2 and T1-4N3 patients were compared. RESULTS: T1-4N3 patients had significantly worse 3-year OS (84.1% vs. 89.2%; p < 0.001) and distant metastasis-free survival (DMFS; 78.3% vs. 85.9%; p < 0.001), but better local relapse-free survival (LRFS; 94.9% vs. 92.2%; p = 0.003), as compared with T4N0-2 patients. Multivariate analysis showed that T1-4N3 was still an independent adverse prognostic factor for both DMFS (hazard ratio [HR] = 1.517, 95% confidence interval [CI] = 1.274-1.806, p < 0.001) and OS (HR = 1.315, 95% CI = 1.100-1.572, p = 0.003), whereas T4N0-2 was an independent adverse prognostic factor for LRFS (HR = 1.581, 95% CI = 1.158-2.158, p = 0.004). CONCLUSIONS: In terms of the OS, T4N0-2 patients had better prognosis compared with T1-4N3 patients, and the patterns of failure differed between T4N0-2 and T1-4N3 patients. We believe that future modifications of the AJCC/UICC staging system should separate T4N0-2 from T1-4N3. KEY POINTS: • In nasopharyngeal carcinoma, T4N0-2 patients tended to develop local relapse, whereas T1-4N3 patients were more likely to develop distant metastasis. • In terms of overall survival, T4N0-2 patients had better prognosis than T1-4N3 patients. • T4N0-2 should be separated from T1-4N3 in the UICC/AJCC staging system.

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