Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 129
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Phys Chem Chem Phys ; 21(36): 20252-20261, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31490472

RESUMO

We used molecular dynamics simulations to study the shock propagation, inhomogeneous deformation, and initiation of the chemical reaction characteristics of nearly fully dense reactive Ni-Al composites. For shocks with piston velocities Up ≤ 2.0 km s-1, particle velocity dispersion was observed at the shock front, which increased on increasing the shock strength. Plastic deformation mainly occurred at the grain boundaries or grain junction during the shock rise and was accompanied by the generation of a potential hot spot in the region where severe plasticity happens. The composite exhibited higher strength and lower reactivity than the mixtures with certain porosity. In addition, the shock-induced premature melting of Al led to the expansion of particle velocity dispersion from the wavefront to the shocked zone and the formation of a heterogeneous velocity field for stronger shocks beyond critical Up (2.5 km s-1). The velocity heterogeneity in the shocked region led to localized shear, strong erosion of Ni, and occurrence of ultrafast chemical reactions. Therefore, the shock-induced premature melting of Al led to the mechanochemical effect and played a role in the shock-induced chemical reaction in the reactive metal system.

2.
Int J Low Extrem Wounds ; : 1534734619868123, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31409158

RESUMO

Deep venous thrombosis (DVT) of the lower extremities is a common complication after total knee arthroplasty (TKA). This study aimed to investigate the potential associations between serum lipids and the risk of DVT after TKA in patients with primary knee osteoarthritis (OA). A total of 431 patients who received TKA caused by primary knee OA were randomly enrolled. According to the results of the color Doppler ultrasound of bilateral lower extremities deep veins on the third day postoperatively, patients were divided into DVT and non-DVT groups. Comparisons of preoperative serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1, and apolipoprotein B were then performed by the Student's t test, χ2 test, and multivariate logistic regression analysis. For females, DVT patients had a higher serum LDL-C level at baseline (P = .043) compared with non-DVT patients. A higher LDL-C value was significantly associated with an elevated DVT risk following TKA in female patients (P = .037). In female patients with primary knee OA, preoperative serum LDL-C level may have an association with DVT risk after TKA. The relatively small male sample size may limit the accuracy of the findings.

3.
Parasitology ; 146(10): 1305-1312, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31148526

RESUMO

This study examined Echinococcus spp. genotypes and genetic variants isolated from humans as well as domestic and wild animals from the Qinghai-Tibetan Plateau Area using the cox1 gene. All samples except the pika isolates were identified as the Echinococcus granulosus sensu stricto. Sixteen different haplotypes with considerable intraspecific variation were detected and characterized in mitochondrial cox1 sequences. The parsimonious network of cox1 haplotypes showed star-like features, and the neutrality indexes computed via Tajima's D and Fu's Fs tests showed high negative values in E. granulosus s. s., indicating deviations from neutrality; the Fst values were low among the populations, implying that the populations were not genetically differentiated. The pika isolates were identified as E. multilocularis and E. shiquicus. Only one haplotype was recognized in the pika isolates. E. granulosus s. s. was the predominant species found in animals and humans, followed by E. multilocularis and E. shiquicus, with high genetic diversity circulating among the animals and humans in this area. Further studies are needed to cover many sample collection sites and larger numbers of pathogen isolates, which may reveal abundant strains and/or other haplotypes in the hydatid cysts infecting human and animal populations of the QTPA, China.

5.
PLoS One ; 14(5): e0216949, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31100082

RESUMO

The development of an effective vaccine against HIV infection remains a global priority. Dendritic cell (DC)-based HIV immunotherapeutic vaccine is a promising approach which aims at optimizing the HIV-specific immune response using primed DCs to promote and enhance both the cellular and humoral arms of immunity. Since the Ebola virus envelope glycoprotein (EboGP) has strong DC-targeting ability, we investigated whether EboGP is able to direct HIV particles towards DCs efficiently and promote potent HIV-specific immune responses. Our results indicate that the incorporation of EboGP into non-replicating virus-like particles (VLPs) enhances their ability to target human monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). Also, a mucin-like domain deleted EboGP (EboGPΔM) can further enhanced the MDDCs and MDMs-targeting ability. Furthermore, we investigated the effect of EboGP on HIV immunogenicity in mice, and the results revealed a significantly stronger HIV-specific humoral immune response when immunized with EboGP-pseudotyped HIV VLPs compared with those immunized with HIV VLPs. Splenocytes harvested from mice immunized with EboGP-pseudotyped HIV VLPs secreted increased levels of macrophage inflammatory proteins-1α (MIP-1α) and IL-4 upon stimulation with HIV Env and/or Gag peptides compared with those harvested from mice immunized with HIV VLPs. Collectively, this study provides evidence for the first time that the incorporation of EboGP in HIV VLPs can facilitate DC and macrophage targeting and induce more potent immune responses against HIV.

6.
Plant Sci ; 283: 1-10, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31128679

RESUMO

Colletotrichum higginsianum causes anthracnose disease in a wide range of cruciferous crops and has been used as a model system to study plant-pathogen interactions and pathogenicity of hemibiotrophic plant pathogens. Conidiation, hyphae growth, appressorial development and appressorial penetration are significant steps during the infection process of C. higginsianum. However, the mechanisms of these important steps during infection remain incompletely understood. To further investigate the mechanisms of the plant-C. higginsianum interactions during infection progress, we characterized Cyclase-Associated Protein (ChCAP) gene. Deletion of the ChCAP gene resulted in reduction in conidiation and hyphal growth rate. The pathogenicity of ΔChCAP mutants was significantly reduced with much smaller lesion on the infected leaves compared to that of wild type strain with typically water-soaked and dark necrotic lesions on Arabidopsis leaves. Further study demonstrated that the appressorial formation rate, turgor pressure, penetration ability and switch from biotrophic to necrotrophic phases decreased obviously in ΔChCAP mutants, indicating that the attenuated pathogenicity of ΔChCAP mutants was due to these defective phenotypes. In addition, the ΔChCAP mutants sectored on PDA with abnormal, dark color, vesicle-like colony morphology and hyphae tip. Moreover, the ΔChCAP mutants had a reduced intracellular cAMP levels and exogenous cAMP can partially rescue the defects of ΔChCAP mutants in appressorial formation and penetration rate, but not in colony morphology, conidial shape and virulence, indicating that ChCAP is a key component in cAMP signaling pathway and likely play other roles in biology of C. higginsianum. In summary, our findings support the role of ChCAP in regulating conidiation, intracellular cAMP level, hyphal growth, appressorial formation, penetration ability and pathogenicity of this hemibiotrophic fungus.


Assuntos
Colletotrichum/crescimento & desenvolvimento , AMP Cíclico/metabolismo , Proteínas Fúngicas/fisiologia , Hifas/crescimento & desenvolvimento , Esporos Fúngicos/crescimento & desenvolvimento , Arabidopsis/microbiologia , Colletotrichum/metabolismo , Colletotrichum/patogenicidade , Colletotrichum/fisiologia , Proteínas Fúngicas/metabolismo , Hifas/fisiologia , Filogenia , Doenças das Plantas/microbiologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Esporos Fúngicos/fisiologia , Estresse Fisiológico
7.
Antiviral Res ; 167: 68-77, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953674

RESUMO

Lassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.

8.
Heart Vessels ; 34(10): 1608-1614, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30963302

RESUMO

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a newly emerging biomarker with strong pro-inflammatory effects, and is an independent risk predictor of atherosclerotic plaque rupture and thrombosis. In addition, ischemic modified albumin (IMA) is another important marker for the evaluation of myocardial ischemia, and has been approved by the U.S. Food and Drug Administration. The objective of this study was to investigate serum Lp-PLA2 and IMA in the early diagnosis, progression and prognosis of acute coronary syndrome (ACS). Serum Lp-PLA2 and IMA were detected using an AU5800 automatic biochemical analyzer in samples from 180 patients with ACS [n = 60 with unstable angina pectoris (UA), n = 56 with non-ST segment elevation myocardial infarction (NSTEMI), and n = 64 with ST segment elevation myocardial infarction (STEMI)] and 60 healthy control subjects. The relationship between Lp-PLA2 and IMA with Gensini score and the number of coronary artery lesions was explored, and logistic regression was conducted to identify risk factors for major adverse cardiovascular events (MACE). Serum Lp-PLA2 and IMA were significantly higher in all ACS subgroups compared to the control group (P < 0.05), were positively associated with the severity of ACS based on the Gensini score (P < 0.05), and were significantly higher in patients with double- and triple-vessel lesions compared to those with single-vessel lesions and healthy controls (P < 0.05). Logistic regression identified Lp-PLA2, IMA, and troponin I levels as independent risk factors for MACE. Lp-PLA2 and IMA were predictive of the degree of myocardial ischemia in patients with ACS, and may provide important clinical significance for the early diagnosis of ACS and the choice of treatment strategy.

9.
Dev Neurosci ; 41(1-2): 67-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999297

RESUMO

Prenatal ethanol exposure alters brain structure, functional connectivity, and behavior in humans and rats. Behavioral changes include deficits in executive function, which requires cooperative activity between the frontal cortices and other brain regions. In this study, we analyzed the functional connectivity and neurochemical levels of the prefrontal cortex (PFC) using resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) in ethanol-exposed (Eth) and control (Ctr) rats. Pregnant Long-Evans rats were fed a liquid diet containing ethanol (2.1-6.46% v/v ethanol) from gestational days 6 to 21 (Eth). Ctr animals received an isocaloric, isonutritive liquid diet. In young adulthood, male and female offspring underwent in vivo MRI using a 7.0-Tesla system. 1H-MRS from the PFC and whole brain rsfMRI were obtained on the animals. Seed-based functional connectivity analysis was performed with seeds placed in the PFC, matching the voxel of MRS. Male, but not female, Eth rats showed less functional connectivity between PFC and dorsal striatum than Ctr animals. In Eth males glucose levels were significantly lower, and in Eth females lower levels of phosphorylcholine but an increased gamma-aminobutyric acid/glutamate ratio were observed in the PFC compared with Ctr animals. Prenatal ethanol alters brain metabolism and functional connectivity of the PFC in a sex-dependent manner.

10.
Antiviral Res ; 165: 1-10, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30836107

RESUMO

Among the five currently recognized type viruses within the genus Ebolavirus, Reston virus (RESTV) is not known to cause disease in humans, although asymptomatic infections have been confirmed in the past. Intriguingly, despite the absence of pathogenicity in humans, RESTV is highly lethal to nonhuman primates and has been isolated from domestic pigs co-infected with other viruses in the Philippines and China. Whether infection in these animals can support the eventual emergence of a human-pathogenic RESTV remains unclear and requires further investigation. Unfortunately, there is currently no lethal small animal model available to investigate RESTV pathogenicity or pan-ebolavirus therapeutics. Here we show that wild type RESTV is uniformly lethal in ferrets. In this study, ferrets were challenged with 1260 TCID50 of wild type RESTV either intramuscularly or intranasally and monitored for clinical signs, survival, virus replication, alteration in serum biochemistry and blood cell counts. Irrespective of the route of challenge, viremia occurred in all ferrets on day 5 post-infection, and all animals succumbed to infection between days 9 and 11. Additionally, several similarities were observed between this model and the other ferret models of filovirus infection, including substantial decreases in lymphocyte and platelet counts and abnormalities in serum biochemistry indicating hepatic injury. The ferret model represents the first uniformly lethal model for RESTV infection, and it will undoubtedly prove useful for evaluating virus pathogenicity as well as pan-ebolavirus countermeasures.

11.
Mol Imaging ; 18: 1536012118821034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799683

RESUMO

MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor, is a susceptibility gene for autism spectrum disorder (ASD). Genetically altered mice with a kinase-inactive Met offer a potential model for understanding neural circuit organization changes in autism. Here, we focus on the somatosensory thalamocortical circuitry because distinct somatosensory sensitivity phenotypes accompany ASD, and this system plays a major role in sensorimotor and social behaviors in mice. We employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity and neurotransmission of wild-type, heterozygous Met-Emx1, and fully inactive homozygous Met-Emx1 mice. Met-Emx1 brains showed impaired maturation of large-scale somatosensory network connectivity when compared with wild-type controls. Significant sex × genotype interaction in both network features and glutamate/gamma-aminobutyric acid (GABA) balance was observed. Female Met-Emx1 brains showed significant connectivity and glutamate/GABA balance changes in the somatosensory thalamocortical system when compared with wild-type brains. The glutamate/GABA ratio in the thalamus was correlated with the connectivity between the somatosensory cortex and the thalamus in heterozygous Met-Emx1 female brains. The findings support the hypothesis that aberrant functioning of the somatosensory thalamocortical system is at the core of the conspicuous somatosensory behavioral phenotypes observed in Met-Emx1 mice.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Proteínas Proto-Oncogênicas c-met/genética , Córtex Somatossensorial/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Mapeamento Encefálico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Somatossensorial/metabolismo , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
12.
J Struct Biol ; 205(3): 44-52, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30742895

RESUMO

The 2-carboxy-6-hydroxyoctahydroindole (Choi) moiety is a hallmark of aeruginosins, a class of cyanobacterial derived bioactive linear tetrapeptides that possess antithrombotic activity. The biosynthetic pathway of Choi has yet to be resolved. AerE is a cupin superfamily enzyme that was shown to be involved in the biosynthesis of Choi, but its exact role remains unclear. This study reports the functional characterization and structural analyses of AerE. Enzymatic observation reveals that AerE can dramatically accelerate 1,3-allylic isomerization of the non-aromatic decarboxylation product of prephenate, dihydro-4-hydroxyphenylpyruvate (H2HPP). This olefin isomerization reaction can occur non-enzymatically and is the second step of the biosynthetic pathway from prephenate to Choi. The results of comparative structural analysis and substrate analogue binding geometry analysis combined with the results of mutational studies suggest that AerE employs an induced fit strategy to bind and stabilize the substrate in a particular conformation that is possibly favorable for 1,3-allylic isomerization of H2HPP through coordinate bonds, hydrogen bonds, π-π conjugation interaction and hydrophobic interactions. All of these interactions are critical for the catalytic efficiency.

13.
Phys Chem Chem Phys ; 21(14): 7272-7280, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30624453

RESUMO

We investigate the shock response of Ni + Al reactive nanoparticle systems through molecular dynamics simulations. The powder configurations with varying arrangements and densities are constructed by stacking equal-sized Ni and Al particles based on five typical crystal structures, i.e., zinc-blende, NaCl, CsCl, AuCu and the close-packed. The effects of configuration and shock strength on mechanochemical and diffusion processes in the shock-induced chemical reactions are characterized. A reaction kinetic model is developed to describe these behaviors, assess the extent of mechanochemical effect, and explain the occurrence of ultra-fast reaction. Significant dependence of shock wave velocity, plastic deformation, temperature response, chemistry and microstructure change on particle packing and density is observed under shock loading at the same piston velocity, but we see a relatively weak dependency on the stacking mode with the same density. Our results indicate the important role of particle coordination number and density in shock response of energetic powder materials.

14.
Cell Host Microbe ; 25(1): 49-58.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629918

RESUMO

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Ebolavirus/patogenicidade , Furões/virologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Linhagem Celular , Cercopithecus aethiops , Modelos Animais de Doenças , Feminino , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Células HEK293 , Doença pelo Vírus Ebola/virologia , Humanos , Células Matadoras Naturais , Macaca , Macaca fascicularis , Masculino , Primatas , Análise de Sobrevida , Resultado do Tratamento , Proteínas Virais/imunologia
15.
Cell Host Microbe ; 25(1): 39-48.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629917

RESUMO

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/uso terapêutico , Antivirais , Modelos Animais de Doenças , Ebolavirus/patogenicidade , Epitopos/imunologia , Feminino , Filoviridae/imunologia , Cobaias , Doença pelo Vírus Ebola/virologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Recombinantes/imunologia , Resultado do Tratamento
16.
Med Sci Monit ; 25: 324-332, 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30632520

RESUMO

BACKGROUND Osteoporosis is a common disorder leading to bone loss. At present, the treatment options available for the management of osteoporosis are limited. The present investigation evaluated the protective effect of fangchinoline against osteoporosis and also postulates the possible mechanism of action. MATERIAL AND METHODS Osteoporosis was induced by subcutaneously injecting prednisolone (2.5 mg/pellet) for 4 weeks. Fangchinoline 1, 3 and 10 mg/kg was given intraperitoneally for the period. Protective effects of fangchinoline were assessed by estimating microarchitectural parameters and bone mineral density (BMD) in the vertebrae tissues, and biochemical parameters were also determined in the serum of rats with prednisolone-induced osteoporosis. Moreover, gene expression of microtubule-associated protein 1A/1B-light chain 3 (LC3), B cell lymphoma 2 (Bcl-2), caspase-3, bone morphogenetic protein 2 (BMP2), Beclin-1, autophagy-related 5 (ATG-5), Runt-related transcription factor 2 (RUNX-2), and receptor activator of nuclear factor kappa-b ligand (RANKL) protein in the vertebrae tissue were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay. RESULTS There was a significant (p<0.01) decrease in the BMD and microarchitectural parameters in the vertebrae tissue of the fangchinoline-treated group compared to the prednisolone group. We also found that treatment with fangchinoline attenuated the altered expressions of LC3, Bcl-2, caspase-3, BMP2, Beclin-1, ATG-5, RUNX-2, and RANKL protein in the prednisolone-induced osteoporosis rats. Moreover, levels of biochemical parameters were attenuated in the serum of fangchinoline-treated and prednisolone-induced osteoporosis rat. Histopathology revealed that the apoptosis of osteoblasts was decreased in the fangchinoline-treated group compared to the prednisolone group of rats. CONCLUSIONS Fangchinoline inhibits apoptosis of osteoblasts and protects against bone loss in prednisolone-induced osteoporosis rats by inducing autophagy.


Assuntos
Benzilisoquinolinas/farmacologia , Densidade Óssea/efeitos dos fármacos , Osteoporose/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzilisoquinolinas/metabolismo , Reabsorção Óssea/tratamento farmacológico , China , Modelos Animais de Doenças , Masculino , Osteoblastos/efeitos dos fármacos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Prednisolona/efeitos adversos , Prednisolona/farmacologia , Ratos , Ratos Wistar
17.
Nat Commun ; 10(1): 105, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631063

RESUMO

The 2013-2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/imunologia , Marburgvirus/imunologia , Doenças dos Primatas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Ebolavirus/classificação , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunoterapia/métodos , Marburgvirus/efeitos dos fármacos , Marburgvirus/fisiologia , Doenças dos Primatas/terapia , Doenças dos Primatas/virologia , Primatas , Resultado do Tratamento
18.
Protein Expr Purif ; 154: 112-117, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30240633

RESUMO

Carboxyl-terminal repeat domain (CTD) of the largest subunit Rpb1 of RNA polymerace II is essential for transcription regulation. Heptapeptide repeat of CTD of Rpb1 is phosphorylated by carboxyl-terminal repeat domain kinase (CTDK-I), composed of CTK1, CTK2 and CTK3, in order to regulate transcription and transcription associated processes. The yeast specific protein CTK3 binds to cyclin CTK2 to form a heterodimer serving as a regulational factor to control CTK1 activity by binding to CTK1. Structural information of CTK2-CTK3 complex is yet to be elucidated. Here, we report the co-expression of CTK2-CTK3 complex from Saccharomyces cerevisiae with N-terminal His6-tag in CTK3 in Escherichia coli (E. coli), purification of the complex by four chromatographic steps and crystallization of the complex as well as the diffraction data collection and processing. This study provides some essential information and a guide for structural and functional study of CTK2-CTK3 complex and CTDK-I in the future.

19.
J Virol ; 93(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541860

RESUMO

Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans, with fatality rates reaching 90% and with no licensed specific therapeutics to treat ill patients. Advances over the past 5 years have firmly established monoclonal antibody (MAb)-based products as the most promising therapeutics for treating EBOV infections, but production is costly and quantities are limited; therefore, MAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal F(ab')2 fragments from horses hyperimmunized with an EBOV vaccine. The F(ab')2 was found to potently neutralize West African and Central African EBOV in vitro Treatment of nonhuman primates (NHPs) with seven doses of 100 mg/kg F(ab')2 beginning 3 or 5 days postinfection (dpi) resulted in a 100% survival rate. Notably, NHPs for which treatment was initiated at 5 dpi were already highly viremic, with observable signs of EBOV disease, which demonstrated that F(ab')2 was still effective as a therapeutic agent even in symptomatic subjects. These results show that F(ab')2 should be advanced for clinical testing in preparation for future EBOV outbreaks and epidemics.IMPORTANCE EBOV is one of the deadliest viruses to humans. It has been over 40 years since EBOV was first reported, but no cure is available. Research breakthroughs over the past 5 years have shown that MAbs constitute an effective therapy for EBOV infections. However, MAbs are expensive and difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since EBOV is endemic in several third world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antiserum F(ab')2 fragments from horses vaccinated with an EBOV vaccine, and we tested the protectiveness in monkeys. We showed that F(ab')2 was effective in 100% of monkeys even after the animals were visibly ill with EBOV disease. Thus, F(ab')2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

20.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 30(11): 1077-1082, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30541649

RESUMO

OBJECTIVE: To observe the indexes of liver injury and the expression of inflammation-related factor interleukin-10 (IL-10) in rats with severe acute pancreatitis (SAP), and to discuss the correlation between the expression of IL-10 and the related factors of liver injury in SAP rats at different altitudes. METHODS: 280 male Wistar rats with SPF grade aged 5 to 6 months were divided into four groups according to random number table with 70 rats in each group, and the rats were placed in different altitudes such as Xi'an (at an altitude of 1 027 m), Xining (at an altitude of 2 260 m), Xinghai (at an altitude of 3 300 m) and Wenquan (at an altitude of 3 950 m). The rats in each altitude were randomly divided into sham operation group (Sham group, n = 10) and SAP 1, 6, 12, 24 hours groups (all n = 15). SAP rat model was reproduced by injecting sodium cholate into the posterior membrane of pancreas, and the rats of Sham group were only turned pancreas over several times after opening the abdomen and then closed the abdomen. The rats were sacrificed at the corresponding time points after model reproduction in SAP groups, and rats in Sham group were sacrificed at 6 hours after sham operation. At the same time, the abdominal aorta blood was harvested, and the contents of serum amylase (AMY), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined by automatic biochemical analyzer. Liver tissues were harvested, and the expression level of IL-10 was determined by immunohistochemistry. Pancreatic tissues were harvested, and hematoxylin-eosin (HE) staining was performed to observe the pathological changes under light microscopy. The correlations among the indicators were analyzed by Pearson correlation. RESULTS: At different altitudes, no significant abnormality was found in the pancreas of Sham group, but significant pathological changes were found in the pancreas of all SAP groups, mainly manifested as pancreatic acinar swelling, inflammatory cell infiltration, vascular congestion and hemorrhage, acinar cell degeneration and dissolution, changes in glandular lobule structure, peri-pancreatic fat necrosis, and continuous aggravation with the increasing of time and altitude. At the same altitude, the pancreatic pathology score, the serum AMY, ALT and AST levels, and the hepatic IL-10 expression were all significantly increased in all the SAP groups as compared with those in Sham group, and they were continuously increased with time. In Sham group, there was no statistically significant difference in pancreatic pathology score, AMY, ALT, AST, or IL-10 level among different altitudes. At the corresponding time point after model reproduction, the pancreatic pathology score, AMY, ALT, AST and IL-10 levels in the SAP groups were also shown a continuous rising tendency with altitude increase, and the differences in above parameters of SAP 24 hours group in Wenquan area were statistically significant as compared with those of Sham group [pathology score: 11.06±0.94 vs. 0.23±0.15, AMY (mmol/L): 2 706.6±208.3 vs. 336.5±94.3, ALT (U/L): 267.00±5.37 vs. 52.00±4.84, AST (U/L): 465.88±11.02 vs. 139.00±11.61, IL-10 (A value): 0.579±0.006 vs. 0.281±0.006, all P < 0.05]. It was shown by correlation analysis that IL-10 of SAP rats at different altitudes was positively correlated with pancreatic pathology score, AMY, ALT and AST, the correlation coefficient (r value) between IL-10 and the above indicators in the Wenquan area with the highest altitude was 0.959, 0.928, 0.977, 0.983, respectively (all P < 0.01). CONCLUSIONS: The severity of SAP rats was positively correlated with altitude. IL-10 was involved in the pathological expression process of SAP liver damage, and its expression level was positively correlated with altitude and the degree of SAP liver damage.


Assuntos
Altitude , Interleucina-10/metabolismo , Fígado/lesões , Pancreatite/metabolismo , Doença Aguda , Animais , Masculino , Ratos , Ratos Wistar , Índice de Gravidade de Doença
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA