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1.
Clin Infect Dis ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609506

RESUMO

BACKGROUND: The longitudinal antigen-specific immunity in COVID-19 convalescents is crucial for long-term protection upon individual re-exposure to SARS-CoV-2, and even more pivotal for ultimately achieving population-level immunity. To better understand the features of immune memory in individuals with different disease severities at one year post-disease onset we conducted this cohort study. METHODS: We conducted a systematic antigen-specific immune evaluation in 101 COVID-19 convalescents, who had asymptomatic, mild, moderate, or severe disease, through two visits at months 6 and 12 post-disease onset. The SARS-CoV-2-specific antibodies, comprising NAb, IgG, and IgM, were assessed by mutually corroborated assays, i.e. neutralization, enzyme-linked immunosorbent assay (ELISA), and microparticle chemiluminescence immunoassay (MCLIA). Meanwhile, the T-cell memory against SARS-CoV-2 spike, membrane and nucleocapsid proteins was tested through enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining (ICS), and tetramer staining-based flow cytometry, respectively. RESULTS: SARS-CoV-2-specific IgG antibodies, and also NAb can persist among over 95% COVID-19 convalescents from 6 months to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12m post-disease onset. Notably, the percentages of convalescents with positive SARS-CoV-2-specific T-cell responses (at least one of the SARS-CoV-2 antigen S1, S2, M and N protein) were 71/76 (93%) and 67/73 (92%) at 6m and 12m, respectively. Furthermore, both antibody and T-cell memory levels of the convalescents were positively associated with their disease severity. CONCLUSIONS: SARS-CoV-2-specific cellular and humoral immunities are durable at least until one year after disease onset.

2.
Oncogene ; 40(46): 6417-6429, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34601505

RESUMO

Tumor cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. How these metabolic processes are integrated to fuel cancer cell growth remains largely unknown. Deciphering the regulatory mechanisms is vital to develop targeted strategies for tumor-selective therapies. We herein performed an unbiased and functional siRNA screen against 96 deubiquitinases, which play indispensable roles in cancer and are emerging as therapeutic targets, and identified USP29 as a top candidate essential for metabolic reprogramming that support biosynthesis and survival in tumor cells. Integrated metabolic flux analysis and molecular investigation reveal that USP29 directly deubiquitinates and stabilizes MYC and HIF1α, two master regulators of metabolic reprogramming, enabling adaptive response of tumor cells in both normoxia and hypoxia. Systemic knockout of Usp29 depleted MYC and HIF1α in MYC-driven neuroblastoma and B cell lymphoma, inhibited critical metabolic targets and significantly prolonged survival of tumor-bearing mice. Strikingly, mice homozygous null for the Usp29 gene are viable, fertile, and display no gross phenotypic abnormalities. Altogether, these results demonstrate that USP29 selectively coordinates MYC and HIF1α to integrate metabolic processes critical for cancer cell growth, and therapeutic targeting of USP29, a potentially targetable enzyme, could create a unique vulnerability given deregulation of MYC and HIF1α frequently occurs in human cancers.

3.
J Biol Eng ; 15(1): 22, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384456

RESUMO

T7 Expression System is a common method of ensuring tight control and high-level induced expression. However, this system can only work in some bacterial strains in which the T7 RNA Polymerase gene resides in the chromosome. In this study, we successfully introduced a chromosomal copy of the T7 RNA Polymerase gene under control of the lacUV5 promoter into Escherichia coli BW25113. The T7 Expression System worked efficiently in this mutant strain named BW25113-T7. We demonstrated that this mutant strain could satisfactorily produce 5-Aminolevulinic Acid via C5 pathway. A final study was designed to enhance the controllability of T7 Expression System in this mutant strain by constructing a T7 Promoter Variants Library. These efforts advanced E. coli BW25113-T7 to be a practical host for future metabolic engineering efforts.

4.
Geohealth ; 5(8): e2021GH000439, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34377880

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, was first identified in Wuhan, China, in December 2019. As the number of COVID-19 infections and deaths worldwide continues to increase rapidly, the prevention and control of COVID-19 remains urgent. This article aims to analyze COVID-19 from a geographical perspective, and this information can provide useful insights for rapid visualization of spatial-temporal epidemic information and identification of the factors important to the spread of COVID-19. A new type of vitalization method, called the point grid map, is integrated with calendar-based visualization to show the spatial-temporal variations in COVID-19. The combination of mixed geographically weighted regression (mixed GWR) and extreme gradient boosting (XGBoost) is used to identify the potential factors and the corresponding importance. The visualization results clearly reflect the spatial-temporal patterns of COVID-19. The quantified results reveal that the impact of population outflow from Wuhan is the most important factor and indicate statistically significant spatial heterogeneity. Our results provide insights into how multisource big geodata can be employed within the framework of integrating visualization and analytical methods to characterize COVID-19 trends. In addition, this work can help understand the influential factors for controlling and preventing epidemics, which is important for policy design and effective decision-making for controlling COVID-19. The results reveal that one of the most effective ways to control COVID-19 include controlling the source of infection, cutting off the transmission route, and protecting vulnerable groups.

5.
Adv Ther ; 38(7): 3973-3985, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34101144

RESUMO

INTRODUCTION: Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. METHODS: Forty subjects were enrolled in an open-label study consisting of three panels (50 mg single dose; 100 mg single dose followed by 100 mg once-daily multiple doses for 10 days; a 200 mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. RESULTS: Anacetrapib was absorbed after administration of a single oral dose, with a median Tmax of 3.0-5.0 h and elimination half-life of 105.3-122.3 h. The AUC and Cmax of anacetrapib increased in a slightly less than dose-proportional manner over a dose range of 50-200 mg. Once-daily administration of 100 mg of anacetrapib for 10 days resulted in a median Tmax of 5.0 h with an apparent half-life of 193.7 h on Day 10 of multiple dosing. Anacetrapib accumulation ratios (Day 10 of multiple dosing/Day 1) were 1.39 (AUC0-24 h), 1.11 (Cmax) and 2.57 (C24 h). CONCLUSION: The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. TRIAL REGISTRATION: chinadrugtrials.org.cn identifier number CTR20130983.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol , Oxazolidinonas , Área Sob a Curva , China , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Oxazolidinonas/efeitos adversos
6.
AMB Express ; 11(1): 78, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34057622

RESUMO

Isolating relevant microorganisms is still a substantial challenge that limits the use of bacteria in the maintenance of human health. To confirm which media and which bacterial colony densities can enrich certain kinds of bacteria, we selected eight common media and used them to enrich the gut microorganisms on agar plates. Then, we calculated the numbers of bacterial colonies and collected the bacterial culture mixtures from each kind of medium. Using the Illumina HiSeq platform, we analyzed the composition and diversity of the culture-enriched gut bacterial community. Our data suggested that medium supplemented with blood could increase the diversity of the bacterial community. In addition, beef powder and peptone could significantly change the culture-enriched bacterial community. A moderate density (100-150 colony-forming units per plate) was optimal for obtaining the highest diversity on the agar. Similarly, membrane transport was significantly enriched in the moderate-density group, which indicated a more active metabolism in this density range. Overall, these results reveal the optimal culture conditions, including the densities of colonies and nutritional components for various gut bacteria, that provide a novel strategy for isolating bacteria in a way that is targeted and avoids blinded and repetitive work.

7.
Front Genet ; 12: 585058, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868359

RESUMO

Kawasaki disease (KD) causes acute systemic vasculitis and has unknown etiology. Since the acute stage of KD is the most relevant, the aim of the present study was to identify hub genes in acute KD by bioinformatics analysis. We also aimed at constructing microRNA (miRNA)-messenger RNA (mRNA) regulatory networks associated with acute KD based on previously identified differentially expressed miRNAs (DE-miRNAs). DE-mRNAs in acute KD patients were screened using the mRNA expression profile data of GSE18606 from the Gene Expression Omnibus. The functional and pathway enrichment analysis of DE-mRNAs were performed with the DAVID database. Target genes of DE-miRNAs were predicted using the miRWalk database and their intersection with DE-mRNAs was obtained. From a protein-protein interaction (PPI) network established by the STRING database, Cytoscape software identified hub genes with the two topological analysis methods maximal clique centrality and Degree algorithm to construct a miRNA-hub gene network. A total of 1,063 DE-mRNAs were identified between acute KD and healthy individuals, 472 upregulated and 591 downregulated. The constructed PPI network with these DE-mRNAs identified 38 hub genes mostly enriched in pathways related to systemic lupus erythematosus, alcoholism, viral carcinogenesis, osteoclast differentiation, adipocytokine signaling pathway and tumor necrosis factor signaling pathway. Target genes were predicted for the up-regulated and down-regulated DE-miRNAs, 10,203, and 5,310, respectively. Subsequently, 355, and 130 overlapping target DE-mRNAs were obtained for upregulated and downregulated DE-miRNAs, respectively. PPI networks with these target DE-mRNAs produced 15 hub genes, six down-regulated and nine upregulated hub genes. Among these, ten genes (ATM, MDC1, CD59, CD177, TRPM2, FCAR, TSPAN14, LILRB2, SIRPA, and STAT3) were identified as hub genes in the PPI network of DE-mRNAs. Finally, we constructed the regulatory network of DE-miRNAs and hub genes, which suggested potential modulation of most hub genes by hsa-miR-4443 and hsa-miR-6510-5p. SP1 was predicted to potentially regulate most of DE-miRNAs. In conclusion, several hub genes are associated with acute KD. An miRNA-mRNA regulatory network potentially relevant for acute KD pathogenesis provides new insights into the underlying molecular mechanisms of acute KD. The latter may contribute to the diagnosis and treatment of acute KD.

8.
Neuroscience ; 465: 85-94, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33895342

RESUMO

Autism spectrum disorder (ASD) is a widespread, complex and serious neurodevelopmental disorder. Complex genetic and environmental factors are thought to contribute to the development of ASD. Genome-wide association analysis has identified multiple autism-related genes. Mutation of the phosphatase and tensin homolog (Pten) is closely related to autism and accounts for 5-17% of cases of autism. However, the detailed mechanism is still unclear. Recently, mitochondrial dysfunction was tightly associated with ASD pathogenesis, such as developmental degeneration, learning and various behavioral disorders. The mitochondrial DNA (mtDNA) copy number in children with autism is also significantly increased. The correlation between Pten and mitochondrial dysfunction in autism is still unknown. In this study, we examined how Pten regulates mitochondrial biogenesis through the AKT/GSK-3ß/PGC-1α signaling pathways. We found that PTEN could dephosphorylate AKT to inhibit its activity, leading to decreased GSK3ß phosphorylation. This decrease in GSK3ß phosphorylation, which could activate itself, increased PGC-1α phosphorylation to promote its degradation and then regulated mitochondrial biogenesis by NRF-1 and TFAM downstream of PGC-1α. In the Valproic acid (VPA) induced autism mouse model, the PTEN protein level was significantly decreased while PGC-1α and COX IV levels were increased in the hippocampus and cortex. Our data suggest that there is a correlation between PTEN and mitochondrial dysfunction and this correlation may be a potential mechanism of ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , DNA Mitocondrial , Estudo de Associação Genômica Ampla , Glicogênio Sintase Quinase 3 beta , Humanos , Biogênese de Organelas , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Mol Brain ; 14(1): 67, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33845857

RESUMO

The rodent whisker-barrel cortex system has been established as an ideal model for studying sensory information integration. The barrel cortex consists of barrel and septa columns that receive information input from the lemniscal and paralemniscal pathways, respectively. Layer 5a is involved in both barrel and septa circuits and play a key role in information integration. However, the role of layer 5a in the development of the barrel cortex remains unclear. Previously, we found that calretinin is dynamically expressed in layer 5a. In this study, we analyzed calretinin KO mice and found that the dendritic complexity and length of layer 5a pyramidal neurons were significantly decreased after calretinin ablation. The membrane excitability and excitatory synaptic transmission of layer 5a neurons were increased. Consequently, the organization of the barrels was impaired. Moreover, layer 4 spiny stellate cells were not able to properly gather, leading to abnormal formation of barrel walls as the ratio of barrel/septum size obviously decreased. Calretinin KO mice exhibited deficits in exploratory and whisker-associated tactile behaviors as well as social novelty preference. Our study expands our knowledge of layer 5a pyramidal neurons in the formation of barrel walls and deepens the understanding of the development of the whisker-barrel cortex system.

10.
Drug Des Devel Ther ; 15: 1101-1110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727798

RESUMO

Purpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials. Methods: Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10. Results: In the SAD study, the median time to reach maximum concentration (Tmax) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (Rac, Cmax) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC. Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine.


Assuntos
Tiamina/análogos & derivados , Administração Oral , Adolescente , Adulto , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Tiamina/administração & dosagem , Tiamina/farmacocinética , Adulto Jovem
11.
JCI Insight ; 6(4)2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33476301

RESUMO

The coronavirus disease 19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst public health crisis in a century. However, knowledge about the dynamics of antibody responses in patients with COVID-19 is still poorly understood. In this study, we performed a serological study with serum specimens collected at the acute and the convalescent phases from 104 patients with severe COVID-19 who were part of the first wave of COVID-19 cases in Wuhan, China. Our findings revealed that neutralizing antibodies to SARS-CoV-2 are persistent for at least 6 months in patients with severe COVID-19, despite that IgG levels against the receptor binding domain (RBD) and nucleocapsid protein (N) IgG declined from the acute to the convalescent phase. Moreover, we demonstrate that the level of RBD-IgG is capable of correlating with SARS-CoV-2-neutralizing activities in COVID-19 serum. In summary, our findings identify the magnitude, functionality, and longevity of antibody responses in patients with COVID-19, which sheds light on the humoral immune response to COVID-19 and would be beneficial for developing vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/sangue , Anticorpos Antivirais/isolamento & purificação , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/virologia , China , Estudos de Coortes , Feminino , Humanos , Soros Imunes , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina G/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Sobreviventes , Fatores de Tempo
12.
Biosaf Health ; 2(4): 199-201, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33235990

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic has spread in 220 countries/regions to wreak havoc to human beings around the world. At present, the second wave of COVID-19 has begun in many European countries. The complete control of COVID-19 is very urgent. Although China quickly brought the virus under control, there have been eight sporadic outbreaks in China since then. Both in Xinfadi of Beijing and Dalian outbreak of COVID-19, environmental swab samples related to imported cold chain food were tested nucleic acid positive for SARS-CoV-2. In this outbreak in Qingdao, we directly isolated SARS-CoV-2 from the cod outer package's surface swab samples. This is the first time worldwide, SARS-CoV-2 were isolated from the imported frozen cod outer package's surface, which showed that imported frozen food industry could import SARS-CoV-2 virus.

13.
Biomed Pharmacother ; 129: 110475, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32768960

RESUMO

Damaged lesion remedial is a devastating impediment of diabetes that escorts to noteworthy disease state, predominantly bottom end diseases. Herbal outputs have exposed to be effectual in managing skin abrasions. Kirenol is recognized to encourage angiogenesis, fibroblast propagation, and exposure of cytokines and development factors concerned in wound remedial. The current study is executed to appraise the wound curing action of kirenol in streptozotocin-persusded diabetic rats by macroscopic parameters, histopathological, enzymatic, and biomolecular methods. Proportion of injure disclosure and reduction was augmented in the kirenol managed group. Histopathological examination exposed declined inflammatory cell applicability and amplified production of fibroblasts, new blood vessels, and displacement of collagen subsequent to kirenol treatment. RT-PCR study displayed diminished concentration of NF-κB, COX-2, iNOS, MMP-2 and MMP-9 levels in reply to kirenol. In accordance with all above findings our present study indicates that kirenol upholds wound medicinal prospective in hyperglycemic circumstances and might be constructive as a dealing and management for unceasing lesions in diabetic patients.


Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diterpenos/farmacologia , Mediadores da Inflamação/metabolismo , Metaloproteinases da Matriz/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Regulação para Baixo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/genética , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos Wistar
14.
Front Genet ; 11: 575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655618

RESUMO

Background: Direct transdifferentiation of adult somatic cells into insulin-producing cells (IPCs) is a promising approach for cell-based therapies for type 1 diabetes mellitus. Liver cells are an ideal source for generating IPCs because they have regenerative ability and a developmental process similar to that of the pancreas. Pancreas versus liver fate is regulated by TALE homeoprotein (TGIF2) during development. Here, we wanted to investigate whether TGIF2 could enhance the efficiency of transdifferentiation of hepatocytes into IPCs induced by three pancreatic transcription factors (pTFs), i.e., Pdx1, NeuroD, and Mafa, which are crucial for pancreatic development in the embryo. Methods: The in vitro transcribed (IVT) mRNAs of TGIF2 and the three pTFs were synthesized in vitro and sequentially supplemented in hepatocytes. On day 6, the expression of transcription factors was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), and insulin expression was detected by immunofluorescence. Glucose-stimulated insulin secretion was assessed by enzyme-linked immunosorbent assay (ELISA). The key genes controlling cell polarity and the Wnt/PCP signaling pathway were assayed by qRT-PCR, and the level of JNK protein phosphorylation, which regulates the Wnt/PCP signaling pathway, was detected by western blotting. Results: IVT mRNAs could be efficiently transfected into hepatocytes. Quantitative real-time polymerase chain reaction results revealed that compared with ectopic expression of the three pTFs alone, ectopic expression of the three pTFs plus TGIF2 could strongly reduce hepatic gene expression and subsequently improve the induction of a set of pancreatic genes. Immunofluorescence analysis showed that TGIF2 expression could double the transdifferentiation yield; 30% of the cells were insulin positive if induced by TGIF2 plus the 3 pTFs, while only 15% of the cells were insulin positive if induced by the three pTFs alone. ELISA analysis confirmed that glucose-stimulated insulin secretion was less efficient after transfection with the three pTFs alone. The differentiated cells derived from the addition of TGIF2 mRNA could form islet-like clusters. By contrast, the cells differentiated with the three pTFs did not form clusters under the same conditions. Tgif2 induced transdifferentiation more efficiently by remodeling the expression of genes in the Wnt/PCP pathway. Overexpression of TGIF2 in hepatocytes could activate the expression of key genes controlling cell polarity and genes in the Wnt/PCP signaling pathway, increasing the level of JNK protein phosphorylation. Conclusions: Our study established a novel footprint-free protocol for efficient transdifferentiation of hepatocytes into IPCs using IVT mRNAs of TGIF2 and 3 pTFs, which paved the way toward a clinical application.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32714913

RESUMO

Host response biomarkers offer a promising alternative diagnostic solution for identifying acute respiratory infection (ARI) cases involving influenza infection. However, most of the published panels involve multiple genes, which is problematic in clinical settings because polymerase chain reaction (PCR)-based technology is the most widely used genomic technology in these settings, and it can only be used to measure a small number of targets. This study aimed to identify a single-gene biomarker with a high diagnostic accuracy by using integrated bioinformatics analysis with XGBoost. The gene expression profiles in dataset GSE68310 were used to construct a co-expression network using weighted correlation network analysis (WGCNA). Fourteen hub genes related to influenza infection (blue module) that were common to both the co-expression network and the protein-protein interaction network were identified. Thereafter, a single hub gene was selected using XGBoost, with feature selection conducted using recursive feature elimination with cross-validation (RFECV). The identified biomarker was oligoadenylate synthetases-like (OASL). The robustness of this biomarker was further examined using three external datasets. OASL expression profiling triggered by various infections was different enough to discriminate between influenza and non-influenza ARI infections. Thus, this study presented a workflow to identify a single-gene classifier across multiple datasets. Moreover, OASL was revealed as a biomarker that could identify influenza patients from among those with flu-like ARI. OASL has great potential for improving influenza diagnosis accuracy in ARI patients in the clinical setting.

16.
J Org Chem ; 85(14): 9230-9243, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32578431

RESUMO

An efficient route for the coupling of maleimides with chromones at the C5-position has been developed under Ru(II) catalysis. It could provide 1,4-addition products and oxidative Heck-type products by switching additives. Benzoic acid led to the formation of 1,4-addition products under solvent-free conditions, and silver acetate was promoted to the generation of oxidative Heck-type products. Various maleimides and chromones were suitable for this transformation, affording the desired products with good to excellent yields in a short reaction time. To understand the mechanism of this reaction, deuteration studies and control experiments have been performed.

17.
Drug Des Devel Ther ; 14: 1219-1226, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273684

RESUMO

Purpose: Aprepitant is used to prevent nausea and vomiting associated with moderately and highly emetogenic chemotherapy. In this open-label, 2-period study, the safety, tolerability, and pharmacokinetics (PK) of aprepitant (EMEND®) were evaluated in healthy Chinese and Caucasian subjects. Patients and Methods: Twelve Chinese and 12 Caucasian subjects were to receive a 125 mg single-dose of aprepitant during period 1; subsequently, after 15 days washout, only Chinese subjects were to receive the 3-day regimen in period 2. In each period, serial blood samples were collected and analyzed by a validated liquid chromatographic and mass spectrometric method to characterize aprepitant PK across both groups. Results: In both Chinese and Caucasian subjects, there were no serious adverse events. AUC0-∞, Cmax, Tmax, and t1/2 were largely comparable between the two ethnicities. Comparing the result of period 1 in Chinese and Caucasian subjects, the geometric least-squares mean maximum plasma concentrations (Cmax) were 1482 ng/mL and 1435 ng/mL, and the area under the concentration-time curve (AUC0-∞) 34,035 hr·ng/mL and 34,188 hr·ng/mL. In period 2, the geometric mean AUC0-24 on Day 1 and Day 3 were 19,446 hr·ng/mL and 27,843 hr·ng/mL, and the geometric mean Cmax on Day 1 and Day 3 were 1423 ng/mL and 1757 ng/mL, respectively. Conclusion: Aprepitant is generally safe and well tolerated in healthy Chinese and Caucasian subjects. Aprepitant PK is comparable between Chinese and Caucasian subjects following single-dose administration. The PK following a clinical 3-day regimen on healthy Chinese subjects has been characterized.


Assuntos
Aprepitanto/farmacocinética , Administração Oral , Adolescente , Adulto , Aprepitanto/administração & dosagem , Aprepitanto/sangue , Grupo com Ancestrais do Continente Asiático , Tolerância a Medicamentos , Grupo com Ancestrais do Continente Europeu , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Virus Genes ; 56(3): 288-297, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193781

RESUMO

The capability of high-throughput sequencing (HTS) for detection of known and unknown viruses timely makes it a powerful tool for public health emergency response. Third-generation sequencing (TGS) offers advantages in speed and length of detection over second-generation sequencing (SGS). Here, we presented the end-to-end workflows for both Oxford Nanopore MinION and Pacbio Sequel on a viral disease emergency event, along with Ion Torrent PGM as a reference. A specific pipeline for comparative analysis on viral genomes recovered by each platform was assembled, given the high errors of base-calling for TGS platforms. All the three platforms successfully identified and recovered at least 85% Norovirus GII genomes. Oxford Nanopore MinION spent the least sample-to-answer turnaround time with relatively low but enough accuracy for taxonomy classification. Pacbio Sequel recovered the most accurate viral genome, while spending the longest time. Overall, Nanopore metagenomics can rapidly characterize viruses, and Pacbio Sequel can accurately recover viruses. This study provides a framework for designing the appropriate experiments that are likely to lead to accurate and rapid virus emergency response.


Assuntos
Emergências , Sequenciamento de Nucleotídeos em Larga Escala , Saúde Pública , Viroses/epidemiologia , Viroses/virologia , Vírus/classificação , Vírus/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Filogenia , Vigilância em Saúde Pública
19.
Medicine (Baltimore) ; 99(4): e18683, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977858

RESUMO

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.


Assuntos
Fenilacetatos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiofenos/farmacologia , Adulto , Clopidogrel/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Fenilacetatos/administração & dosagem , Fenilacetatos/efeitos adversos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Testes de Função Plaquetária , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Adulto Jovem
20.
Acta Biochim Biophys Sin (Shanghai) ; 51(12): 1267-1275, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31750892

RESUMO

Hepatic stellate cell (HSC) line LX-2 is activated by liver cancer stem-like cells (LCSLCs) and produces various cytokines that make up most of the hepatocellular carcinoma (HCC) microenvironment. The new genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), shows anticancer effects in multiple malignancies by controlling forkhead box M1 (FOXM1). In this study, we aimed to assess whether DFOG disrupts the crosstalk between human HSC LX-2 cells and LCSLCs. Distinct generations of MHCC97H-derived spheres were obtained with the second generation considered as LCSLCs which displayed enhanced self-renewal ability and elevated expression levels of CD133, CD44, and EpCAM proteins, as well as tumorigenicity, as revealed by colony formation assay in vitro and tumorigenicity assay in vivo. LX-2 and MHCC97H cells were co-cultured with/without DFOG (1, 5, and 10 µM, respectively) using the transwell system. FOXM1 overexpression and/or knockdown were employed for mechanistic investigations. Our results suggested that Co-CM promoted LX-2 cell transformation into liver cancer-associated HSCs. Meanwhile, FOXM1 was up-regulated and the level of hepatocyte growth factor (HGF) was increased in LX-2 cells and in the supernatant after Co-CM stimulation. Sphere and colony formation abilities in MHCC97H cells, and protein levels of CD133, CD44, and EpCAM, were also markedly elevated. DFOG dose-dependently inhibited the above effects, similar to FOXM1 knockdown in LX-2 cells. FOXM1 overexpression reversed the inhibitory effects of DFOG or FOXM1 knockdown or both on LX-2 cell activation and LCSLC feature induction in MHCC97H cells by LCSLC/LX-2 co-culture. This study demonstrated that DFOG disrupts the crosstalk between HSCs and LCSLCs to suppress LCSLC features via down-regulating FOXM1 expression and reducing HGF secretion in HSCs.


Assuntos
Proteína Forkhead Box M1/metabolismo , Genisteína/análogos & derivados , Células Estreladas do Fígado/efeitos dos fármacos , Fator de Crescimento de Hepatócito/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
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