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1.
Cell Res ; 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34837059

RESUMO

Host cellular receptors play key roles in the determination of virus tropism and pathogenesis. However, little is known about SARS-CoV-2 host receptors with the exception of ACE2. Furthermore, ACE2 alone cannot explain the multi-organ tropism of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV, suggesting the involvement of other receptor(s). Here, we performed genomic receptor profiling to screen 5054 human membrane proteins individually for interaction with the SARS-CoV-2 capsid spike (S) protein. Twelve proteins, including ACE2, ASGR1, and KREMEN1, were identified with diverse S-binding affinities and patterns. ASGR1 or KREMEN1 is sufficient for the entry of SARS-CoV-2 but not SARS-CoV in vitro and in vivo. SARS-CoV-2 utilizes distinct ACE2/ASGR1/KREMEN1 (ASK) receptor combinations to enter different cell types, and the expression of ASK together displays a markedly stronger correlation with virus susceptibility than that of any individual receptor at both the cell and tissue levels. The cocktail of ASK-related neutralizing antibodies provides the most substantial blockage of SARS-CoV-2 infection in human lung organoids when compared to individual antibodies. Our study revealed an interacting host receptome of SARS-CoV-2, and identified ASGR1 and KREMEN1 as alternative functional receptors that play essential roles in ACE2-independent virus entry, providing insight into SARS-CoV-2 tropism and pathogenesis, as well as a community resource and potential therapeutic strategies for further COVID-19 investigations.

2.
Front Cardiovasc Med ; 8: 735118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504882

RESUMO

Objective: This study sought to investigate the diagnostic value of dynamic CT myocardial perfusion imaging (CT-MPI) combined with coronary CT angiography (CCTA) in acute coronary syndrome (ACS) patients without obstructive coronary angiography. Methods: Consecutive ACS patients with normal or non-obstructive coronary angiography findings who had cardiac magnetic resonance (CMR) contraindications or inability to cooperate with CMR examinations were prospectively enrolled and referred for dynamic CT-MPI + CCTA + late iodine enhancement (LIE). ACS etiology was determined according to combined assessment of coronary vasculature by CCTA, quantified myocardial blood flow (MBF) and presence of LIE. Results: Twenty two patients were included in the final analysis. CCTA revealed two cases of side branch occlusion and one case of intramural hematoma which were overlooked by invasive angiography. High risk plaques were observed in 6 (27.3%) patients whereas myocardial ischemia was presented in 19 (86.4%) patients with varied extent and severity. LIE was positive in 13 (59.1%) patients and microvascular obstruction was presented in three cases with side branch occlusion or spontaneous intramural hematoma. The specific etiology was identified in 20 (90.9%) patients, of which the most common cause was cardiomyopathies (41%), followed by microvascular dysfunction (14%) and plaque disruption (14%). Conclusion: Dynamic CT-MPI + CCTA was able to reveal the potential etiologies in majority of patients with ACS and non-obstructive coronary angiography. It may be a useful alternative to CMR for accurate etiology evaluation.

3.
Front Neurosci ; 15: 698967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512242

RESUMO

Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.

4.
Cardiovasc Diagn Ther ; 11(4): 956-966, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34527519

RESUMO

Background: Myocardial blood flow (MBF), CT fractional flow reserve (CT-FFR) and high-risk plaque (HRP) features have been revealed to be associated with patients' prognosis. However, direct intra-individual comparison of these CT-derived parameters has not been explored yet. The aim of this study was to investigate the prognostic value of CT-derived MBF, CT-FFR and HRP features for predicting major adverse cardiac events (MACEs). Methods: Consecutive patients with chest pain and intermediate-to-high pre-test probability of coronary artery disease (CAD) were prospectively enrolled. All patients were referred for dynamic CT myocardial perfusion imaging (CT-MPI) + coronary CT angiography (CCTA) and followed up for at least 1 year. MBFischemic (mean MBF of all ischemic segments), MBFratio (MBF of ischemic segments/MBF of reference segments), CT-FFR and HRP features were measured and multivariate analysis was used to evaluate the predictive value of all above parameters for MACEs. Results: One hundred and forty-two patients were included into final analysis. MBFischemic and MBFratio was significantly lower in patients with MACE compared to patients without MACE (87 vs. 153 mL/100 mL/min and 0.64 vs. 0.95, both P<0.001). Similarly, CT-FFR was also markedly lower in patients with MACE (0.58 vs. 0.88, P<0.001) whereas coronary artery calcium score (CACS) was significantly higher (1,038.9 vs. 34.2, P<0.001). According to ROC curve analysis, MBFischemic, MBFratio and CACS had largest area under curve (AUC =0.872, 0.855 and 0.813 respectively, all P<0.001) for identifying patients with MACE. After adjusted by multivariate analysis, MBFischemic (hazard ratio =23.382, P=0.003) and CACS (hazard ratio =3.759, P=0.029) were revealed to be the independent predictors for MACE where CT-FFR and HRP features failed to have prognostic value. Conclusions: MBFischemic derived from dynamic CT-MPI was the strongest predictor for MACE, followed by CACS. MBFischemic outperformed HRP features and CT-FFR for prediction of unfavorable clinical outcome.

5.
Brief Bioinform ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34505138

RESUMO

After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein-protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

6.
Genome Biol Evol ; 13(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469545

RESUMO

A large portion of animal and plant genomes consists of noncoding DNA. This part includes tandemly repeated sequences and gained attention because it offers exciting insights into genome biology. We investigated satellite-DNA elements of the platyhelminth Schistosoma mansoni, a parasite with remarkable biological features. Schistosoma mansoni lives in the vasculature of humans causing schistosomiasis, a disease of worldwide importance. Schistosomes are the only trematodes that have evolved separate sexes, and the sexual maturation of the female depends on constant pairing with the male. The schistosome karyotype comprises eight chromosome pairs, males are homogametic (ZZ) and females are heterogametic (ZW). Part of the repetitive DNA of S. mansoni are W-elements (WEs), originally discovered as female-specific satellite DNAs in the heterochromatic block of the W-chromosome. Based on new genome and transcriptome data, we performed a reanalysis of the W-element families (WEFs). Besides a new classification of 19 WEFs, we provide first evidence for stage-, sex-, pairing-, gonad-, and strain-specific/preferential transcription of WEs as well as their mobile nature, deduced from autosomal copies of full-length and partial WEs. Structural analyses suggested roles as sources of noncoding RNA-like hammerhead ribozymes, for which we obtained functional evidence. Finally, the variable WEF occurrence in different schistosome species revealed remarkable divergence. From these results, we propose that WEs potentially exert enduring influence on the biology of S. mansoni. Their variable occurrence in different strains, isolates, and species suggests that schistosome WEs may represent genetic factors taking effect on variability and evolution of the family Schistosomatidae.

7.
Nanotechnology ; 33(1)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34571493

RESUMO

Substitution of commercial Pt/C electrocatalysts with efficient carbon-based ones for oxygen reduction reaction (ORR) still remains a huge challenge. For practical ORR applications it is significant to design robust 3D network nanostructures in that they do not require polymer binders. For conventional powder catalysts, they must be combined with substrate, leading to their shedding and degradation. In this work, vertically-aligned N-doped carbon nanowalls/diamond (N-CNWs/D) films are synthesized by means of a microwave plasma chemical vapor deposition technique, where nitrogen doping is conducted during the growth process and a subsequent facile annealing treatment under Ar atmosphere. The obtained Ar treated N-CNWs/D film exhibits an ORR onset potential of 835 mV (versus reversible hydrogen electrode) in 0.1 mol l-1KOH solution in a four-electron reaction pathway. It also displays excellent tolerance toward methanol crossover and long-term stability (e.g. a current density loss of only 10% even after 16 h measurement). The boosting ORR performance can be attributed to the activated pyridinic N dopant at abundant edge sites and enlarged electrochemical surface areas of N-CNWs/D films. This work not only develops a controllable strategy to fabricate binder-free carbon-based ORR electrocatalysts, but also paves a way to in-depth understand actual active sites in terms of ORR pathway mechanisms.

8.
Vessel Plus ; 52021.
Artigo em Inglês | MEDLINE | ID: mdl-34017939

RESUMO

Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: "dry" and "wet". Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1's proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

9.
Int J Cardiol ; 334: 142-147, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932431

RESUMO

BACKGROUND: Ischemia with non-obstructive coronary arteries (INOCA) is not uncommon in clinical practice. However, the incidence and imaging characteristics of INOCA on dynamic CT myocardial perfusion imaging (CT-MPI) remains unclear. We aimed to investigate the prevalence and disease features of INOCA as evaluated by dynamic CT-MPI + coronary CT angiography (CCTA). METHODS: Patients with suspected chronic coronary syndrome and intermediate-to-high pre-test probability of obstructive CAD (according to updated Diamond and Forrester Chest Pain Prediction Rule) were referred for dynamic CT-MPI + CCTA and retrospectively included. Various parameters, including myocardial blood flow (MBF) and high-risk plaque (HRP) features, were measured. INOCA was diagnosed if patients were revealed to have myocardial ischemia and absence of obstructive stenosis. RESULTS: 314 patients were finally included. 20 patients (6.4%) were observed to have myocardial ischemia without obstructive stenosis. In addition, 138 patients (43.9%) had normal or near normal findings, 101 patients (32.2%) had obstructive stenosis without myocardial ischemia and 55 patients (17.5%) had obstructive stenosis with myocardial ischemia. Compared with patients with normal/near normal findings, patients with INOCA showed a higher prevalence of positive remodeling (40.0% vs. 17.4%, p = 0.04). In patients with obstructive stenosis, the mean age, calcium score and incidence of spotty calcification, positive remodeling as well as HRPs were significantly higher than those in patients with INOCA (p < 0.05 for all). CONCLUSIONS: The overall prevalence of INOCA was low in patients with suspected chronic coronary syndrome. HRPs were less frequently presented in patients with INOCA, compared with patients having obstructive coronary stenosis.


Assuntos
Doença da Artéria Coronariana , Estenose Coronária , Isquemia Miocárdica , Imagem de Perfusão do Miocárdio , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/epidemiologia , Vasos Coronários/diagnóstico por imagem , Humanos , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/epidemiologia , Valor Preditivo dos Testes , Prevalência , Estudos Retrospectivos
10.
Sci Adv ; 7(11)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33692103

RESUMO

How metabolic status controls the fates of different types of leukemia cells remains elusive. Using a SoNar-transgenic mouse line, we demonstrated that B cell acute lymphoblastic leukemia (B-ALL) cells had a preference in using oxidative phosphorylation. B-ALL cells with a low SoNar ratio (SoNar-low) had enhanced mitochondrial respiration capacity, mainly resided in the vascular niche, and were enriched with more functional leukemia-initiating cells than that of SoNar-high cells in a murine B-ALL model. The SoNar-low cells were more resistant to cytosine arabinoside (Ara-C) treatment. cyclic adenosine 3',5'-monophosphate response element-binding protein transactivated pyruvate dehydrogenase complex component X and cytidine deaminase to maintain the oxidative phosphorylation level and Ara-C-induced resistance. SoNar-low human primary B-ALL cells also had a preference for oxidative phosphorylation. Suppressing oxidative phosphorylation with several drugs sufficiently attenuated Ara-C-induced resistance. Our study provides a unique angle for understanding the potential connections between metabolism and B-ALL cell fates.

11.
Curr Med Res Opin ; 37(6): 917-927, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33729889

RESUMO

BACKGROUND: To develop a sensitive and clinically applicable risk assessment tool identifying coronavirus disease 2019 (COVID-19) patients with a high risk of mortality at hospital admission. This model would assist frontline clinicians in optimizing medical treatment with limited resources. METHODS: 6415 patients from seven hospitals in Wuhan city were assigned to the training and testing cohorts. A total of 6351 patients from another three hospitals in Wuhan, 2169 patients from outside of Wuhan, and 553 patients from Milan, Italy were assigned to three independent validation cohorts. A total of 64 candidate clinical variables at hospital admission were analyzed by random forest and least absolute shrinkage and selection operator (LASSO) analyses. RESULTS: Eight factors, namely, Oxygen saturation, blood Urea nitrogen, Respiratory rate, admission before the date the national Maximum number of daily new cases was reached, Age, Procalcitonin, C-reactive protein (CRP), and absolute Neutrophil counts, were identified as having significant associations with mortality in COVID-19 patients. A composite score based on these eight risk factors, termed the OURMAPCN-score, predicted the risk of mortality among the COVID-19 patients, with a C-statistic of 0.92 (95% confidence interval [CI] 0.90-0.93). The hazard ratio for all-cause mortality between patients with OURMAPCN-score >11 compared with those with scores ≤ 11 was 18.18 (95% CI 13.93-23.71; p < .0001). The predictive performance, specificity, and sensitivity of the score were validated in three independent cohorts. CONCLUSIONS: The OURMAPCN score is a risk assessment tool to determine the mortality rate in COVID-19 patients based on a limited number of baseline parameters. This tool can assist physicians in optimizing the clinical management of COVID-19 patients with limited hospital resources.


Assuntos
COVID-19 , Medição de Risco/métodos , COVID-19/epidemiologia , COVID-19/mortalidade , China , Hospitalização/estatística & dados numéricos , Humanos , Itália , Fatores de Risco
12.
Cell Metab ; 33(2): 258-269.e3, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421384

RESUMO

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.


Assuntos
Corticosteroides/uso terapêutico , COVID-19/tratamento farmacológico , Linfócitos/citologia , Neutrófilos/citologia , Corticosteroides/efeitos adversos , Área Sob a Curva , COVID-19/mortalidade , COVID-19/patologia , COVID-19/virologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Tempo de Internação , Modelos de Riscos Proporcionais , Curva ROC , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
13.
Acta Pharmacol Sin ; 42(10): 1630-1641, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33495515

RESUMO

Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral immunity. Recent evidence shows that gut dysbiosis is involved in the pathogenesis of RSV infection. Therefore; pharmacological and therapeutic strategies aiming to readjust the gut dysbiosis are increasingly important for the treatment of RSV infection. In this study, we evaluated the therapeutic effects of a probiotic mixture on RSV-infected mice. This probiotic mixture consisted of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917 and VSL#3 was orally administered to neonatal mice on a daily basis either for 1 week in advance or for 3 days starting from the day of RSV infection. We showed that administration of the probiotics protected against RSV-induced lung pathology by suppressing RSV infection and exerting an antiviral response via alveolar macrophage (AM)-derived IFN-ß. Furthermore, administration of the probiotics reversed gut dysbiosis and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in RSV-infected mice, which consequently led to elevated serum SCFA levels. Moreover, administration of the probiotics restored lung microbiota in RSV-infected mice. We demonstrated that the increased production of IFN-ß in AMs was attributed to the increased acetate in circulation and the levels of Corynebacterium and Lactobacillus in lungs. In conclusion, we reveal that probiotics protect against RSV infection in neonatal mice through a microbiota-AM axis, suggesting that the probiotics may be a promising candidate to prevent and treat RSV infection, and deserve more research and development in future.

14.
Cell Mol Neurobiol ; 41(5): 961-975, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32323150

RESUMO

Compound 511 (511) is specially developed for opioid addiction treatment based on the Ancient Chinese drug rehabilitation literature, and its composition has profound effects in the treatment of drug addiction in various clinical trials and animal experiments. The effect of 511 on the rewarding properties of morphine and craving responses and its potential mechanisms remain unclear. Here, we have applied a conditioned place preference (CPP) paradigm in mice to measure morphine-induced rewarding effects under the treatment of 511. Then we used the RNA sequencing strategy to screen its potential mechanisms. In our research, firstly, we found 511 could decrease CPP score, locomotor activity, self-administration, jumping behavior, weight loss, wet-dog shakes, and stereotyped behavior. Then the brain VTA region tissues were performed mRNA sequencing to detect potential mechanisms. We found the brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were downregulated in morphine-induced CPP, whereas the decreased BDNF and TrkB were reversed after 511 treatment. We retested the levels of BDNF and TrkB using qRT-PCR and Western blot and found the similar results to mRNA sequencing. It has been widely reported that BDNF-TrkB signaling in the VTA is involved in multiple facets of addiction, including reward and motivation, so we focused on the BDNF-TrkB signaling to investigate the anti-addiction mechanisms of 511 in morphine addiction mice. We studied the downstream pathway of BDNF-TrkB and the soma size of dopaminergic neurons. The results showed 511 could increase the phosphorylation levels of PI3K and AKT, which were decreased in morphine-induced CPP. Simultaneously, 511 could decrease the level of PLCγ1 and the phosphorylation levels of ERK and S6K, which were increased in morphine-induced CPP. In addition, 511 also enlarged the soma size of VTA dopaminergic neurons, which was reduced in morphine-induced CPP. Hence, our research indicated 511 maybe mediate the BDNF-TrkB signaling in VTA to improve morphine addiction behavior.

15.
Eur Radiol ; 31(1): 525-534, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32794126

RESUMO

OBJECTIVES: To investigate the diagnostic performance of absolute myocardial blood flow (MBF), MBFratio, and visual analysis of dynamic CT myocardial perfusion imaging (CT-MPI) for the detection of hemodynamically significant coronary stenosis. METHODS: Consecutive patients with chest pain and intermediate-to-high pre-test probability of obstructive coronary artery disease were prospectively enrolled. All patients were referred for dynamic CT-MPI and fractional flow reserve (FFR) measurements within 4 weeks. Absolute MBF, MBFratio (mean MBF of stenosis-subtended territories versus that of reference territories), and visually identified perfusion defect were tested for the diagnostic performance with reference to FFR. RESULTS: Sixty-two patients with 95 target vessels were included for final analysis. The mean radiation dose for dynamic CT-MPI was 3.0 (2.2-4.0) mSv. The mean lesion-based absolute MBF value was significantly lower in ischemic segments than that in non-ischemic segments (78.0 (65.0-86.0) mL/min/100 mL vs. 133.0 (117.5-163.8) mL/min/100 mL, p < 0.001). Similarly, the lesion-based MBFratio was also markedly lower in territories with positive FFR results (0.52 (0.44-0.64) vs. 0.93 (0.91-0.97), p < 0.001). According to per-lesion ROC curve analysis, MBF and MBFratio had a similar area under the curve (AUC) for detecting hemodynamically significant lesions (AUC = 0.942 vs. 0.956, p = 0.413), which were larger than that of visual analysis (AUC = 0.802, both p < 0.01). The vessel-based sensitivity, specificity, and diagnostic accuracy were 84.3%, 97.7%, and 90.5% for MBF and 96.1%, 93.2%, and 94.7% for MBFratio. CONCLUSIONS: Absolute MBF and MBFratio had similarly excellent diagnostic performance with reference to FFR. In addition, these two parameters outperformed visual analysis for the detection of myocardial ischemia. KEY POINTS: • The mean MBF and MBFratio were significantly lower in ischemic segments than those in non-ischemic segments. • Absolute MBF and MBFratio had similar AUCs for the detection of hemodynamically significant lesions (AUC = 0.942 vs. 0.956, p = 0.413), which were larger than that of visual analysis (AUC = 0.802, both p < 0.01). • The vessel-based sensitivity, specificity, and diagnostic accuracy were 84.3%, 97.7%, and 90.5% for absolute MBF and 96.1%, 93.2%, and 94.7% for MBFratio.


Assuntos
Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Imagem de Perfusão do Miocárdio , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Humanos , Perfusão , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
16.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339149

RESUMO

Tanshinones, the major bioactive components in Salvia miltiorrhiza Bunge (Danshen), are synthesized via the mevalonic acid (MVA) pathway or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway and the downstream biosynthesis pathway. In this study, the bacterial component lipopolysaccharide (LPS) was utilized as a novel elicitor to induce the wild type hairy roots of S. miltiorrhiza. HPLC analysis revealed that LPS treatment resulted in a significant accumulation of cryptotanshinone (CT) and dihydrotanshinone I (DTI). qRT-PCR analysis confirmed that biosynthesis genes such as SmAACT and SmHMGS from the MVA pathway, SmDXS and SmHDR from the MEP pathway, and SmCPS, SmKSL and SmCYP76AH1 from the downstream pathway were markedly upregulated by LPS in a time-dependent manner. Furthermore, transcription factors SmWRKY1 and SmWRKY2, which can activate the expression of SmDXR, SmDXS and SmCPS, were also increased by LPS. Since Ca2+ signaling is essential for the LPS-triggered immune response, Ca2+ channel blocker LaCl3 and CaM antagonist W-7 were used to investigate the role of Ca2+ signaling in tanshinone biosynthesis. HPLC analysis demonstrated that both LaCl3 and W-7 diminished LPS-induced tanshinone accumulation. The downstream biosynthesis genes including SmCPS and SmCYP76AH1 were especially regulated by Ca2+ signaling. To summarize, LPS enhances tanshinone biosynthesis through SmWRKY1- and SmWRKY2-regulated pathways relying on Ca2+ signaling. Ca2+ signal transduction plays a key role in regulating tanshinone biosynthesis in S. miltiorrhiza.


Assuntos
Abietanos/biossíntese , Cálcio/metabolismo , Lipopolissacarídeos/farmacologia , Salvia miltiorrhiza/metabolismo , Sinalização do Cálcio , Furanos/metabolismo , Fenantrenos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Salvia miltiorrhiza/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Nat Commun ; 11(1): 6411, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339816

RESUMO

Over 250 million people suffer from schistosomiasis, a tropical disease caused by parasitic flatworms known as schistosomes. Humans become infected by free-swimming, water-borne larvae, which penetrate the skin. The earliest intra-mammalian stage, called the schistosomulum, undergoes a series of developmental transitions. These changes are critical for the parasite to adapt to its new environment as it navigates through host tissues to reach its niche, where it will grow to reproductive maturity. Unravelling the mechanisms that drive intra-mammalian development requires knowledge of the spatial organisation and transcriptional dynamics of different cell types that comprise the schistomulum body. To fill these important knowledge gaps, we perform single-cell RNA sequencing on two-day old schistosomula of Schistosoma mansoni. We identify likely gene expression profiles for muscle, nervous system, tegument, oesophageal gland, parenchymal/primordial gut cells, and stem cells. In addition, we validate cell markers for all these clusters by in situ hybridisation in schistosomula and adult parasites. Taken together, this study provides a comprehensive cell-type atlas for the early intra-mammalian stage of this devastating metazoan parasite.


Assuntos
Mamíferos/parasitologia , Parasitos/citologia , Parasitos/crescimento & desenvolvimento , Schistosoma mansoni/citologia , Schistosoma mansoni/crescimento & desenvolvimento , Análise de Célula Única , Animais , Esôfago/metabolismo , Éxons/genética , Regulação da Expressão Gênica , Humanos , Células Musculares/metabolismo , Sistema Nervoso/citologia , Neurônios/citologia , Parasitos/genética , Schistosoma mansoni/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Transcrição Genética
18.
ACS Omega ; 5(42): 27455-27462, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33134708

RESUMO

Solvents assist in the debinding of stereolithography-based 3D-printed alumina green bodies. The green bodies subsequently undergo thermal debinding and sintering to obtain alumina ceramics. In this study, several solvents were tested, including polyethylene glycol, oxalic acid, ammonium hydroxide, ethyl alcohol, methyl methacrylate, butyl acetate, dimethyl carbonate, methanol, ethyl acetate, and sec-butyl alcohol. The tested solvents during the debinding process showed different effects on microstructure and properties of 3D-printed alumina ceramics due to the variable aspects of their solubility toward the binders. The microstructure of the samples changed significantly after green bodies underwent solvent debinding, thermal debinding, and sintering, leading to loose spongy structures, porous aggregates, and compact structures, respectively. Shrinkage, bulk density, and open porosity changed slightly due to the debinding function of different solvents. Polyethylene glycol-impregnated samples displayed the minimum shrinkage in length direction (5.3%). Ethyl alcohol-impregnated sample showed minimum shrinkage in width (4.8%) and height (11.5%) directions. Ammonium hydroxide-impregnated samples exhibited minimum bulk density (2.8 g/cm3) and maximum open porosity (28.3%). Dimethyl carbonate-impregnated samples presented minimum flexural strength (32.6 MPa), and oxalic acid-impregnated samples revealed maximum flexural strength (63.4 MPa). In sum, the as-obtained ceramics would be used as ceramic cores for hollow blades in aircraft engines due to their high open porosity and moderate flexural strength.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33224256

RESUMO

Background: Since December 2019, coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 infection has emerged in Wuhan and rapidly spread throughout China and even to other countries. Combined therapy with modern medicine and traditional Chinese medicine has been proposed, in which Shen Zhu San (SZS) was regarded as one of the basic prescriptions. Methods: Network pharmacological approaches along with candidate compound screening, target prediction, target tissue location, protein-protein interaction network, gene ontology (GO), KEGG enrichment analyses, and gene microarray analyses were applied. Results: A total of 627 targets of the 116 active ingredients of SZS were identified. Targets in immune cells and tissues were much more abundant than those in other tissues. A total of 597 targets were enriched in the GO biological cellular process, while 153 signaling pathways were enriched according to the KEGG analysis. A total of 450 SARS-related targets were integrated and intersected with the targets of SZS to identify 40 common targets that were significantly enriched in five immune function aspects of the immune system process during GO analysis. Several inflammation-related pathways were found to be significantly enriched throughout the study. Conclusions: The therapeutic mechanisms of the effects of SZS on COVID-19 potentially involve four effects: suppressing cytokine storms, protecting the pulmonary alveolar-capillary barrier, regulating the immune response, and mediating cell death and survival.

20.
Science ; 369(6511): 1649-1653, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32973031

RESUMO

Schistosome parasites kill 250,000 people every year. Treatment of schistosomiasis relies on the drug praziquantel. Unfortunately, a scarcity of molecular tools has hindered the discovery of new drug targets. Here, we describe a large-scale RNA interference (RNAi) screen in adult Schistosoma mansoni that examined the function of 2216 genes. We identified 261 genes with phenotypes affecting neuromuscular function, tissue integrity, stem cell maintenance, and parasite survival. Leveraging these data, we prioritized compounds with activity against the parasites and uncovered a pair of protein kinases (TAO and STK25) that cooperate to maintain muscle-specific messenger RNA transcription. Loss of either of these kinases results in paralysis and worm death in a mammalian host. These studies may help expedite therapeutic development and invigorate studies of these neglected parasites.


Assuntos
Anti-Helmínticos/farmacologia , Proteínas de Helminto/antagonistas & inibidores , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/tratamento farmacológico , Animais , Anti-Helmínticos/química , Anti-Helmínticos/uso terapêutico , Genes de Helmintos , Testes Genéticos , Proteínas de Helminto/genética , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/genética , Esquistossomose mansoni/parasitologia , Transcrição Genética/efeitos dos fármacos
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