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1.
Neurol Sci ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044668

RESUMO

OBJECTIVE: Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup tools including traditional tools, automatically volumetric analysis, high-density EEG (HD-EEG) source imaging (HD-ESI), and stereoelectroencephalography (SEEG). METHODS: Nine patients diagnosed with TLE-AE who underwent resective surgeries encompassing the amygdala were retrospectively studied. HD-ESI was obtained using 256-channel HD-EEG on the individualized head model. For automatic volumetric analysis, 48 matched controls were enrolled. Diagnosis and surgical strategies were based on a comprehensive workup following the anatomo-electro-clinical principle. RESULTS: At post-operative follow-up (average 30.9 months), eight patients had achieved Engel class I and one Engel class II recovery. HD-ESI yielded unifocal source estimates in anterior mesial temporal region in 85.7% of cases. Automatic volumetric analysis showed the AE sides were consistent with the values determined through other preoperative workup tools. Furthermore, the amygdala volume of the affected sides in AE was significantly greater than that of the larger sides in controls (p < 0.001). Meanwhile, the amygdala volume lateral index (LI) of AE was significantly higher than in controls (p < 0.001). SEEG analysis showed that ictal onsets arose from the enlarged amygdala (and hippocampus) in all cases. CONCLUSION: In addition to traditional workup tools, automatic volumetric analysis, HD-ESI on individualized head model, and invasive SEEG can provide evidence of epileptogenicity in TLE-AE. Resective surgical strategies encompassing the amygdala result in better prognosis. In suspected TLE cases, more attention should be focused on detecting enlargement of amygdala which sometimes is "hidden" in "MR-negative" non-MTS cases.

2.
Clin Genet ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009833

RESUMO

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically-actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59-ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome-wide analysis, including chromosomal microarray and exome/genome sequencing.

3.
BMC Bioinformatics ; 21(1): 433, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008305

RESUMO

BACKGROUND: Precise disease module is conducive to understanding the molecular mechanism of disease causation and identifying drug targets. However, due to the fragmentization of disease module in incomplete human interactome, how to determine connectivity pattern and detect a complete neighbourhood of disease based on this is still an open question. RESULTS: In this paper, we perform exploratory analysis leading to an important observation that through a few intermediate nodes, most separate connected components formed by disease-associated proteins can be effectively connected and eventually form a complete disease module. And based on the topological properties of these intermediate nodes, we propose a connect separate connected components (C3) method to detect a succinct disease module by introducing a relatively small number of intermediate nodes, which allows us to obtain more pure disease module than other methods. Then we apply C3 across a large corpus of diseases to validate this connectivity pattern of disease module. Furthermore, the connectivity of the perturbed genes in multi-omics data such as The Cancer Genome Atlas also fits this pattern. CONCLUSIONS: C3 tool is not only useful in detecting a clearly-defined connected disease neighbourhood of 299 diseases and cancer with multi-omics data, but also helpful in better understanding the interconnection of phenotypically related genes in different omics data and studying complex pathological processes.

4.
Life Sci ; 262: 118509, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33010280

RESUMO

Phosphoesterase complex (Pho), a major active component of barley malt, has been demonstrated to be clinically effective in relieving alcoholic fatty liver disease (AFLD), and several lines of evidence have suggested that microbial dysbiosis, caused by chronic alcohol overconsumption, plays a key role in the progression of AFLD. The current study aimed to investigate the modulatory effect of Pho on gut microflora. The microbiota diversity, determined via detection of the V4 region of 16S rDNA genes, was analyzed in rats fed the Lieber-Decarli diet. Gut permeability was evaluated via mucus layer staining. Dysbiosis-associated chronic inflammation was investigated by observing the expression of the following inflammatory molecules in the liver: tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), chemokine (C-X-C motif) ligand 1 (CXCL-1) and interleukin 1 beta (IL-1ß). Pyrosequencing revealed that the gut microbiota in Pho-treated rats was different from that of AFLD rats at both the phylum and genus levels. In addition, Pho significantly alleviated dysbiosis-associated disruption of gut permeability and inflammation, increased mucus layer thickness and downregulated TNF-α, MCP-1, CXCL-1 and IL-1ß expression. In summary, the current results revealed that the microflora, gut barrier and chronic inflammation in AFLD may be modulated by Pho.

5.
Eur Radiol ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33000304

RESUMO

OBJECTIVE: To analyze missed rib fractures and proper time for evaluation on CT at different ages and to determine factors that favor missed fractures. METHODS: One hundred patients with rib fractures who underwent CT were classified into three groups according to their age: young, middle-aged, and elderly. CT was performed within 1 to 6 weeks after trauma. The imaging features and temporal changes of rib fractures were analyzed. RESULTS: At the first CT during the initial week, 638 ribs were detected with one or several fractures, overall 838 fractures were confirmed, and 6 were suspected. In the next 2-6 weeks, 47 occult rib fractures were additionally detected. The number of additionally diagnosed fractures was the highest in respectively the 3rd week among younger, 4th week in the middle-aged, and 6th week in the elderly groups. The detection of occult rib fractures was significantly delayed in the middle-aged and elderly groups compared with the young group (p < 0.05). The time to form bony callus was also significantly (p < 0.05) delayed with age, with significantly (p < 0.05) more time needed to form bony callus in the middle-aged (23.8 ± 4.5 days) and elderly (28.48 ± 5.1 days) groups than in the young group (18.0 ± 2.2 days). CONCLUSIONS: Most rib fractures can be detected within the first week after trauma. Detection of occult rib fractures will be delayed with increase of age, and repeated CT scanning should be appropriately postponed in patients at different ages. Trabecula, inner and outer plates, costal angle, and cartilage are the primary locations for occult and subtle fractures which should be carefully evaluated. KEY POINTS: • More rib fractures can be detected on repeated CT scans, especially for subtle and occult rib fractures. • Detection of all rib fractures helps relieve the patient's concerns and determine the degree of personal injury for appropriate evaluation.

6.
Genomics ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32971214

RESUMO

In this study, RNA sequencing was used to identify the hepatic gene expression profile in grass carp associated with luteinizing hormone-releasing hormone agonist (LHRH-A) treatment. A total of 93,912,172 reads were generated by HiSeq 4000 sequencing platform. After filtering, 83,450,860 clean reads were mapped to the reference genome. By calculating the FPKM of genes, 1475 differentially expressed genes were identified. PPAR signaling pathway was enriched with upregulated genes in LHRH-A injection group showing the regulation of the lipid metabolism by LHRH-A. The expression of eight key genes in PPAR signaling pathway was confirmed by qPCR and the results suggested that ACSL4A, ACSL4B, ANGPTL4, LPL, RXRBA and SLC27A1B were significantly stimulated by LHRH-A injection. This investigation provides the evidence that LHRH-A could play a role in lipid metabolism.

7.
Ann Thorac Surg ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32971061

RESUMO

BACKGROUND: Anomalous origin of one pulmonary artery from the aorta (AOPA) is a rare and potentially deadly anomaly. Little research, aside from case reports on APOA, has been published, especially for patients with late referrals. METHODS: We performed a retrospective review of 57 patients with AOPA who underwent reimplantation from 2009 to 2019. Two different reimplantation methods were used to correct the anomaly, including direct anastomosis in 36 and angioplasty with autologous tissue in 21 patients. RESULTS: The median age at repair was 2.8 months (range, 8 days-3.6 years). Hospital death occurred in 2 patients (3.5%). Five patients (9.1%) with a median age of 9.3 months (range, 5.2 months-3.6 years) experienced pulmonary hypertensive crisis. Patients older than 4.9 months were more likely to experience pulmonary hypertensive crisis (P=0.001). The 2-year freedom from postoperative pulmonary artery (PA) stenosis rate was 75.3% among those who underwent direct anastomosis and 46.8% among those who underwent autologous tissue angioplasty (χ2=4.878, P=0.027). Angioplasty with autologous tissue (hazard ratio, 5.03; 95% confidence interval, 1.61-15.71; P=0.005) and an innately smaller diameter of the aberrant PA (hazard ratio, 0.65; 95% confidence interval, 0.45-0.92; P=0.015) were two independent risk factors for postoperative PA stenosis. CONCLUSIONS: Surgical reimplantation in AOPA patients has resulted in favorable early and mid-term outcomes. Pulmonary hypertensive crisis occurs more commonly in patients diagnosed after 4.9 months. Reimplantation with autologous tissue augmentation and an intrinsically smaller diameter in affected PAs are two independent risk factors for postoperative PA stenosis.

8.
J Hepatol ; 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32987030

RESUMO

BACKGROUND: Current antiviral therapies help keep hepatitis B virus (HBV) under control, but they are not curative. A cure for chronic hepatitis B (CHB) is lacking due to the inability of current therapies to eliminate the intracellular viral replication intermediate termed covalently closed-circular DNA (cccDNA). Therefore, there is an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: Here, we screened 2000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanized liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanized liver mouse model. Mechanistic study found that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited cccDNA transcription activity, which was correlated with establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: This study reports a novel small molecule that targets HBx to combat chronic HBV infection and reveals a function of NQO1 in HBV replication through the regulation HBx protein stability.

9.
Sensors (Basel) ; 20(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987849

RESUMO

Unmanned Aerial Vehicles (UAVs) have been widely applied for pesticide spraying as they have high efficiency and operational flexibility. However, the pesticide droplet drift caused by wind may decrease the pesticide spraying efficiency and pollute the environment. A precision spraying system based on an airborne meteorological monitoring platform on manned agricultural aircrafts is not adaptable for. So far, there is no better solution for controlling droplet drift outside the target area caused by wind, especially by wind gusts. In this regard, a UAV trajectory adjustment system based on Wireless Sensor Network (WSN) for pesticide drift control was proposed in this research. By collecting data from ground WSN, the UAV utilizes the wind speed and wind direction as inputs to autonomously adjust its trajectory for keeping droplet deposition in the target spraying area. Two optimized algorithms, namely deep reinforcement learning and particle swarm optimization, were applied to generate the newly modified flight route. At the same time, a simplified pesticide droplet drift model that includes wind speed and wind direction as parameters was developed and adopted to simulate and compute the drift distance of pesticide droplets. Moreover, an LSTM-based wind speed prediction model and a RNN-based wind direction prediction model were established, so as to address the problem of missing the latest wind data caused by communication latency or a lack of connection with the ground nodes. Finally, experiments were carried out to test the communication latency between UAV and ground WSN, and to evaluate the proposed scheme with embedded Raspberry Pi boards in UAV for feasibility verification. Results show that the WSN-assisted UAV trajectory adjustment system is capable of providing a better performance of on-target droplet deposition for real time pesticide spraying with UAV.

10.
Mol Ecol Resour ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985096

RESUMO

Largemouth bass (LMB; Micropterus salmoides) has been an economically important fish in North America, Europe, and China. This study obtained a chromosome-level genome assembly of LMB using PacBio and Hi-C sequencing. The final assembled genome is 964 Mb, with contig N50 and scaffold N50 values of 1.23 Mb and 36.48 Mb, respectively. Combining with RNA sequencing data, we annotated a total of 23,701 genes. Chromosomal assembly and syntenic analysis proved that, unlike most Perciformes with the popular haploid chromosome number of 24, LMB has only 23 chromosomes (Chr), among which the Chr1 seems to be resulted from a chromosomal fusion event. LMB is phylogenetically closely related to European seabass and spotted seabass, diverging 64.1 million years ago (mya) from the two seabass species. Eight gene families comprising 294 genes associated with ionic regulation were identified through positive selection, transcriptome and genome comparisons. These genes involved in iron facilitated diffusion (such as claudin, aquaporins, sodium channel protein and so on) and others related to ion active transport (such as sodium/potassium-transporting ATPase and sodium/calcium exchanger). The claudin gene family, which is critical for regulating cell tight junctions and osmotic homeostasis, showed a significant expansion in LMB with 27 family members and 68 copies for salinity adaptation. In summary, we reported the first high-quality LMB genome, and provided insights into the molecular mechanisms of LMB adaptation to fresh and brackish water. The chromosome-level LMB genome will also be a valuable genomic resource for in-depth biological and evolutionary studies, germplasm conservation and genetic breeding of LMB.

11.
Clin Infect Dis ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32745196

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of SARS-CoV-2-specific neutralizing antibodies (NAbs) in COVID-19 patients. METHODS: Blood samples (n=173) were collected from 30 COVID-19 patients over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs, using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. RESULTS: SARS-CoV-2-specific NAb titers were low for the first 7-10 d after symptom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 d (IQR 24-59 d) after symptom onset. NAb titers in 93·3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34·8% (IQR 19·6-42·4%). NAb titers increased over time in parallel with the rise in IgG antibody levels, correlating well at week 3 (r = 0·41, p & 0·05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including SCF, TRAIL, and M-CSF. CONCLUSIONS: These data provide useful information regarding dynamic changes in NAbs in COVID-19 patients during the acute and convalescent phases.

12.
J Phys Chem Lett ; : 7510-7516, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32813525

RESUMO

Structural inhomogeneity of the liquid-vapor interface, such as the spatial orientation of molecular specific groups and the non-uniform distribution of hydrogen-bonded (HB) clusters, is crucial for understanding the physicochemical processes therein. Although the molecular orientation at the outermost layer was authenticated, to date, direct experimental evidence of the in situ existence of different-sized HB clusters, as a long-standing theoretical argument, is still lacking. Here we report time-delayed electron-impact tandem mass spectrometry, and its powerful ability to identify the local structures of the liquid-vapor interface of 1-propanol is demonstrated not only by mapping the molecular orientations both in the outermost layer and in the subsurface but also by validating the existence of the HB molecular dimers in the subsurface by detecting their protonated ions. We further distinguish two different sources of the protonated dimer: the gas-phase protonation of the neutral dimer that evaporates in advance and the time-lag evaporation of the protonated dimer produced in the subsurface. This methodology is a brand-new way to explore the microstructures and the electron-driven chemical reactions in different local regions of the liquid-vapor interface.

13.
J Sci Food Agric ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737882

RESUMO

BACKGROUND: Efficient utilization of dietary fibers (DFs) is important for optimizing feed resource utilization and animal health. The aim of the current study was to assess the effects of DFs with varying physicochemical properties (bulky, viscous, and fermentable) on fermentation kinetics and microbial composition during in vitro fermentation by fecal inoculum from lactating sow. According to the physicochemical properties, three different DFs, lignocellulose (LC), modified cassava starch (MCS) and konjac flour (KF) were selected as bulky fiber, fermentable fiber and viscous fiber respectively. Gas production, short-chain fatty acids (SCFAs) profiles and microbial composition were monitored during the fermentation. RESULTS: Results showed that the gas production in 72 h (GP72h ) ranked as: KF > MCS > LC (P < 0.05). The halftime of asymptotic gas production ranked as: KF < MCS = LC (P < 0.001). At 36 h of fermentation, MCS group showed higher concentrations of formic acid and lactate than LC and KF groups, whereas KF group showed higher concentrations of propionate and butyrate than LC and MCS groups (P < 0.05). At 72 h of fermentation, KF group showed higher concentrations of formic acid, lactate and propionate than LC and MCS groups, whereas MCS group showed higher concentrations of acetate and butyrate than LC and KF groups (P < 0.05). At 36 h of fermentation, Anaerovibrio and Erysipelatoclostridium abundances were higher in KF group, whereas Proteiniclasticum abundance was higher in MCS group. At 72 h of fermentation, the abundance of Fibrobacter in LC group was higher than that in MCS and KF groups. In addition, we also observed that the abundances of certain specific bacteria (Anaerovibrio and Erysipelatoclostridium) were closely related to the SCFAs production (propionate and butyrate) at different fermentation times. CONCLUSION: Collectively, the present study revealed that KF is a fast fermentation fiber which could produce propionate and butyrate rapidly, whereas LC is difficult to be fermented by bacteria. In addition, the fermentation of DFs with different physicochemical properties had divergent impacts on microbial composition and SCFA production. These findings deepen our understanding of the mechanisms of interaction between DFs and intestinal microbiota, and provide new ideas for the rational use of fiber resources in lactating sows.

14.
Biomed Res Int ; 2020: 1563874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832543

RESUMO

A sensitive and reliable ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagles. The effects of dexmedetomidine on the pharmacokinetics of parecoxib and valdecoxib in beagles were studied. The plasma was precipitated by acetonitrile, and the two analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm); the mobile phase was acetonitrile and 0.1% formic acid with gradient mode, and the flow rate was 0.4 mL/min. In the negative ion mode, the two analytes and internal standard (IS) were monitored by multiple reaction monitoring (MRM), and the mass transition pairs were as follows: m/z 369.1 → 119.1 for parecoxib, m/z 313.0 → 118.0 for valdecoxib, and m/z 380.0 → 316.0 for celecoxib (IS). Six beagles were designed as a double cycle self-control experiment. In the first cycle, after intramuscular injection of parecoxib 1.33 mg/kg, 1.0 mL blood samples were collected at different times (group A). In the second cycle, the same six beagles were intravenously injected with 2 µg/kg dexmedetomidine for 7 days after one week of washing period. On day 7, after intravenous injection of 2 µg/kg dexmedetomidine for 0.5 hours, 6 beagle dogs were intramuscularly injected with 1.33 mg/kg parecoxib, and blood samples were collected at different time points (group A). The concentration of parecoxib and valdecoxib was detected by UPLC-MS/MS, and the main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the experimental conditions, the method has a good linear relationship for both analytes. The interday and intraday precision was less than 8.07%; the accuracy values were from -1.20% to 2.76%. C max of parecoxib in group A and group B was 2148.59 ± 406.13 ng/mL and 2100.49 ± 356.94 ng/mL, t 1/2 was 0.85 ± 0.36 h and 0.85 ± 0.36 h, and AUC(0-t) was 2429.96 ± 323.22 ng·h/mL and 2506.38 ± 544.83 ng·h/mL, respectively. C max of valdecoxib in group A and group B was 2059.15 ± 281.86 ng/mL and 2837.39 ± 276.78 ng/mL, t 1/2 was 2.44 ± 1.55 h and 2.91 ± 1.27 h, and AUC(0-t) was 4971.61 ± 696.56 ng·h/mL and 6770.65 ± 453.25 ng·h/mL, respectively. There was no significant change in the pharmacokinetics of parecoxib in groups A and B. C max and AUC(0 - ∞) of valdecoxib in group A were 37.79% and 36.19% higher than those in group B, respectively, and t 1/2 was increased from 2.44 h to 2.91 h. V z /F and CL z /F were correspondingly reduced, respectively. The developed UPLC-MS/MS method for simultaneous determination of parecoxib and valdecoxib in beagle plasma was specific, accurate, rapid, and suitable for the pharmacokinetics and drug-drug interactions of parecoxib and valdecoxib. Dexmedetomidine can inhibit the metabolism of valdecoxib in beagles and increase the exposure of valdecoxib, but it does not affect the pharmacokinetics of parecoxib.

15.
Br J Anaesth ; 125(4): 492-504, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32798069

RESUMO

Postoperative delirium is a relatively common and serious complication. It increases hospital stay by 2-3 days and is associated with a 30-day mortality of 7-10%. It is most prevalent in older patients, those with existing neurocognitive disorders, and those undergoing complex or emergency procedures. Preclinical and clinical research in recent years has uncovered more about the pathophysiology of postoperative delirium and may yield more potential therapeutic options. Using the enhanced recovery pathway framework of risk stratification, risk reduction, and rescue treatment, we have reviewed the current clinical evidence on the validity of delirium prediction scores for the surgical population, the effectiveness of perioperative delirium risk reduction interventions, and management options for established delirium. Effective perioperative interventions include depth of anaesthesia monitoring, intraoperative dexmedetomidine infusion, and multimodal analgesia. Choice of general anaesthetic agent may not be associated with significant difference in delirium risk. Several other factors, such as preoperative fasting, temperature control, and blood pressure management have some association with the risk of postoperative delirium; these will require further studies. Because of the limited treatment options available for established delirium, we propose that risk assessment and perioperative risk reduction may be the most effective approaches in managing postoperative delirium.


Assuntos
Delírio/terapia , Complicações Pós-Operatórias/terapia , Comportamento de Redução do Risco , Transfusão de Sangue , Delírio/prevenção & controle , Hidratação , Humanos , Manejo da Dor , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios , Medição de Risco
16.
Genes Dis ; 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32837985

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative virus of the coronavirus disease 2019 (COVID-19) pandemic. To establish a safe and convenient assay system for studying entry inhibitors and neutralizing antibodies against SARS-CoV-2, we constructed a codon-optimized, full-length C-terminal mutant spike (S) gene of SARS-CoV-2. We generated a luciferase (Luc)-expressing pseudovirus containing the wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone. The key parameters for this pseudovirus-based assay, including the S mutants and virus incubation time, were optimized. This pseudovirus contains a Luc reporter gene that enabled us to easily quantify virus entry into angiotensin-converting enzyme 2 (ACE2)-expressing 293T cells. Cathepsin (Cat)B/L inhibitor E-64d could significantly block SARS-CoV-2 pseudovirus infection in 293T-ACE2 cells. Furthermore, the SARS-CoV-2 spike pseudotyped virus could be neutralized by sera from convalescent COVID-19 patients or recombinant ACE2 with the fused Fc region of human IgG1. Thus, we developed a pseudovirus-based assay for SARS-CoV-2, which will be valuable for evaluating viral entry inhibitors and neutralizing antibodies against this highly pathogenic virus.

17.
Circ Res ; 127(8): 997-1022, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32762496

RESUMO

RATIONALE: Plaque rupture is the proximate cause of most myocardial infarctions and many strokes. However, the molecular mechanisms that precipitate plaque rupture are unknown. OBJECTIVE: By applying proteomic and bioinformatic approaches in mouse models of protease-induced plaque rupture and in ruptured human plaques, we aimed to illuminate biochemical pathways through which proteolysis causes plaque rupture and identify substrates that are cleaved in ruptured plaques. METHODS AND RESULTS: We performed shotgun proteomics analyses of aortas of transgenic mice with macrophage-specific overexpression of urokinase (SR-uPA+/0 mice) and of SR-uPA+/0 bone marrow transplant recipients, and we used bioinformatic tools to evaluate protein abundance and functional category enrichment in these aortas. In parallel, we performed shotgun proteomics and bioinformatics studies on extracts of ruptured and stable areas of freshly harvested human carotid plaques. We also applied a separate protein-analysis method (protein topography and migration analysis platform) to attempt to identify substrates and proteolytic fragments in mouse and human plaque extracts. Approximately 10% of extracted aortic proteins were reproducibly altered in SR-uPA+/0 aortas. Proteases, inflammatory signaling molecules, as well as proteins involved with cell adhesion, the cytoskeleton, and apoptosis, were increased. ECM (Extracellular matrix) proteins, including basement-membrane proteins, were decreased. Approximately 40% of proteins were altered in ruptured versus stable areas of human carotid plaques, including many of the same functional categories that were altered in SR-uPA+/0 aortas. Collagens were minimally altered in SR-uPA+/0 aortas and ruptured human plaques; however, several basement-membrane proteins were reduced in both SR-uPA+/0 aortas and ruptured human plaques. Protein topography and migration analysis platform did not detect robust increases in proteolytic fragments of ECM proteins in either setting. CONCLUSIONS: Parallel studies of SR-uPA+/0 mouse aortas and human plaques identify mechanisms that connect proteolysis with plaque rupture, including inflammation, basement-membrane protein loss, and apoptosis. Basement-membrane protein loss is a prominent feature of ruptured human plaques, suggesting a major role for basement-membrane proteins in maintaining plaque stability.

18.
Mil Med Res ; 7(1): 40, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854781

RESUMO

BACKGROUND: Heat stroke (HS) is a serious, life-threatening disease. However, there is no scoring system for HS so far. This research is to establish a scoring system that can quantitatively assess the severity of exertional heat stroke (EHS). METHODS: Data were collected from a total of 170 exertional heat stroke (EHS) patients between 2005 and 2016 from 52 hospitals in China. Univariate statistical methods and comparison of the area under the receiver operating characteristic (ROC) curve (AUC) were used to screen exertional heat stroke score (EHSS) parameters, including but not limited body temperature (T), Glasgow Coma Scale (GCS) and others. By comparing the sizes of the AUCs of the APACHE II, SOFA and EHSS assessments, the effectiveness of EHSS in evaluating the prognosis of EHS patients was verified. RESULTS: Through screening with a series of methods, as described above, the present study determined 12 parameters - body temperature (T), GCS, pH, lactate (Lac), platelet count (PLT), prothrombin time (PT), fibrinogen (Fib), troponin I (TnI), aspartate aminotransferase (AST), total bilirubin (TBIL), creatinine (Cr) and acute gastrointestinal injury (AGI) classification - as EHSS parameters. It is a 0-47 point system designed to reflect increasing severity of heat stroke. Low (EHSS< 20) and high scores (EHSS> 35) showed 100% survival and 100% mortality, respectively. We found that AUCEHSS > AUCSOFA > AUCAPACHE II. CONCLUSION: A total of 12 parameters - T, GCS, pH, Lac, PLT, PT, Fib, TnI, AST, TBIL, Cr and gastrointestinal AGI classification - are the EHSS parameters with the best effectiveness in evaluating the prognosis of EHS patients. As EHSS score increases, the mortality rate of EHS patients gradually increases.

19.
Int Immunopharmacol ; 88: 106860, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32771949

RESUMO

BACKGROUD: Panax notoginseng saponin R1 (PNS-R1) is one of the most important chemical monomers derived from the panax notoginseng, and our previous study found that PNS-R1 reduced glucocorticoid-induced apoptosis in asthmatic airway epithelial cells. Thus, in this study, we explored the effects of the PNS-R1 on inflammation of allergic asthma. METHODS: The asthmatic mice were administered 15 mg/kg PNS-R1 by intraperitoneal injection three days before sensitized to OVA. The effects of PNS-R1 on asthmatic mice were detected by airway hyperresponsiveness, inflammation, mucus hypersecretion and inflammatory cytokines such as interleukin (IL)-13, IL-4, IL-5, IL-8 and tumor necrosis factor (TNF)-α were studied. We also treated human bronchial epithelial cells (16HBE) with house dust mites (HDM) and then detected the secretion of cellular inflammatory factors (IL-13 and TNF-α). Western blot and immunofluorescence were used to examine the effect of PNS-R1 on TNF-α/NF-κB pathway. TNF-α/NF-κB/IKK signal pathway activator was used in PNS-R1-treated asthmatic mice. RESULTS: PNS-R1 significantly reduced the airway inflammatory, mucus secretion and hyperresponsiveness in asthma model. It also reduced the levels of IL-13, IL-4, IL-5 and IL-8 in bronchoalveolar lavage fluid (BALF) and IgE and OVA-specific IgE in serum for asthma mice. PNS-R1 reduced IL-13 and TNF-α secretion in HDM-treated 16HBE cells. In addition, PNS-R1 suppressed TNF-α/NF-κB pathway in both asthmatic mice and 16HBE. Activation of NF-kB pathway reversed the therapeutic effect of PNS-R1 on asthmatic mice. CONCLUSION: The results indicated that PNS-R1 effectively suppresses allergic airway inflammation of asthma partly through TNF-α/NF-κB pathway. PNS-R1 may play a potential role in allergic asthma treatment in the future.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32764524

RESUMO

A healthy lifestyle and regular physical activity are highly recommended for older adults. However, there has been limited research into testing lifestyle intervention effects on physical activity in older adults with hypertension. The purpose of this study was to assess the association of lifestyle intervention effects with physical activity and blood pressure in older adults with hypertension, accounting for social support and perceived stress as control variables. This study performed a secondary analysis of a two-arm randomized controlled trial. A total of 196 participants were randomly assigned to a six-month lifestyle intervention group or a control group. Hierarchical multiple regression analyses demonstrated that lifestyle intervention effects were not significantly associated with improvements in physical activity and blood pressure, but the final regression models were statistically significant (all p < 0.001). The result revealed that only physical activity frequency at baseline was significantly related to improvement in physical activity. Systolic blood pressure (SBP) at baseline and monthly income were significantly associated with change in SBP, while age and diastolic blood pressure (DBP) at baseline were significantly related to change in DBP. The findings provide empirical evidence for developing and optimizing lifestyle interventions for future research and clinical practice in this population.

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