MooSeeker: A Metabolic Pathway Design Tool Based on Multi-Objective Optimization Algorithm.

Recently, metabolic pathway design has attracted considerable attention and become an increasingly important area in metabolic engineering. Manual or computational methods have been introduced to retrieve the metabolic pathway. These methods model metabolic pathway design as a single-objective optimization problem with the weighted sum of a variety of criteria as the final score. While these methods have demonstrated promising results, the majority of current methods do not account for comparisons and competition among criteria. Here, we propose MooSeeker, a metabolic pathway design tool based on the multi-objective optimization algorithm that aims to trade off all the criteria optimally. The metabolic pathway design problem is characterized as a multi-objective optimization problem with three objectives including pathway length, thermodynamic feasibility and theoretical yield. In order to digitize the continuous metabolic pathway, MooSeeker develops the encoding strategy, BioCrossover and BioMutation operators to search for the candidate pathways. Finally, MooSeeker outputs the Pareto optimal solutions of the candidate metabolic pathways with three criterion values. The experiment results show that MooSeeker is capable of constructing the experimentally validated pathways and finding the higher-performance pathway than the single-objective-based methods.

Digital inclusive finance and consumption-based embodied carbon emissions: A dual perspective of consumption and industry upgrading.

Promoting the development of financial instruments can influence carbon emission reduction in the context of the carbon peaking and carbon neutrality goals. There are currently no theoretical mechanisms to explain whether and how digital inclusive finance, as a new type of financial service, influences residential consumption-based embodied carbon emissions. This study employs the mediation model, moderation model, and moderated mediation model to empirically evaluate the influence mechanism of digital inclusive finance on consumption-based embodied carbon emissions per capita in China from 2011 to 2019. The findings demonstrate that the development of digital inclusive finance increases residents' consumption-based embodied carbon emissions by upgrading consumption level and consumption structure, but that upgrading industrial structure does indeed have a significantly negative moderating effect in implications paths, causing consumption-based embodied carbon emissions to shift from positive to negative. This study, by focusing on the advancement of digital inclusive finance, offers policymakers suggestions for reducing consumption-based embodied carbon emissions from the standpoints of consumption upgrading and industrial structure upgrading, respectively.

Pristimerin alleviates cigarette smoke-induced inflammation in chronic obstructive pulmonary disease via inhibiting NF-κB pathway.

Cigarette smoke (CS) is a risk factor for chronic obstructive pulmonary disease (COPD), which can exacerbate inflammation and oxidative stress. Pristimerin (Pris) is a natural compound with antioxidant and anti-inflammatory effects. We managed to evaluate the protective effects of Pris on CS-induced COPD. The CS-induced COPD mice model and cell model were constructed. The effects of Pris treatment on lung function, inflammatory cell infiltration, myeloperoxidase (MPO), and pathological changes of lung tissues in mice model were evaluated. The impacts of Pris treatment on inflammatory factors, chemokines, and oxidative stress parameters in mice lung tissues and cells were determined by kits. The viability of human bronchial epithelial cells after Pris treatment was tested by CCK-8. The activation of NF-κB pathway was confirmed by Western blot and immunofluorescence. CS treatment impaired lung function, reduced weight of mice, and enhanced inflammatory cell infiltration, MPO, and lung tissue damage, but these effects of CS were reversed by Pris treatment. Furthermore, Pris treatment downregulated the levels of malondialdehyde, IL-6, IL-1ß, TNF-α, CXCL1, and CXLC2, but upregulated superoxide dismutase and catalase levels. Pris treatment could overturn CS-induced activation of the NF-κB pathway. Pris alleviates CS-induced COPD by inactivating NF-κB pathway.

High Expression of lncRNA HEIH is Helpful in the Diagnosis of Non-Small Cell Lung Cancer and Predicts Poor Prognosis.

BACKGROUND: This study aims to investigate the expression and clinical value of long non-coding RNA (lncRNA) HEIH in peripheral blood of patients with non-small cell lung cancer (NSCLC). METHODS: Healthy subjects (N=70), patients with lung squamous cell carcinoma (LUSC, N=70) and patients with lung adenocarcinoma (LUAD, N=80) were included. LncRNA HEIH expression in peripheral blood of included subjects was detected using RT-qPCR. According to the median expression of lncRNA HEIH, LUSC and LUAD patients were allocated into lncRNA HEIH high/low expression groups. The correlation between lncRNA HEIH and clinical indicators of patients was analyzed; Logistic multifactor regression was used to analyze the independent risk factors influencing lncRNA HEIH level. Receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of lncRNA HEIH and carcinoembryonic antigen (CEA) in LUSC/LUAD patients. MedCalc-Comparison of ROC curves was used to compare the area under ROC curve. The cumulative survival rates of lncRNA HEIH high/low expression group were analyzed by Kaplan-Meier curve. COX multivariate analysis was used to assess the independent factors affecting prognosis of NSCLC. RESULTS: LncRNA HEIH in peripheral blood of LUSC/LUAD patients was higher than that in healthy controls, with no evident difference between LUSC and LUAD groups. In LUSC/LUAD patients, TNM stage, lymph node metastasis, distal metastasis, and CEA were independent risk factors affecting lncRNA HEIH; patients with high lncRNA HEIH expression had larger pack-years and tumor size, higher CEA level and tumor stage, and higher risk of lymph node metastasis and distal metastasis. LncRNA HEIH had higher diagnostic efficiency than CEA in NSCLC patients. High expression of lncRNA HEIH predicted poor prognosis in patients with NSCLC and was an independent risk factor for prognosis of NSCLC. CONCLUSION: High expression of lncRNA HEIH is helpful in the diagnosis of NSCLC and predicts poor prognosis.

Cryptococcosis in patients with hematological diseases: a 14-year retrospective clinical analysis in a Chinese tertiary hospital.

BACKGROUND: Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare. METHODS: HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed. RESULTS: In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events. CONCLUSIONS: CNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases.

Dectin-2 polymorphism associated with pulmonary cryptococcosis in HIV-uninfected Chinese patients.

Dectin-2 is a C-type lectin receptor that can recognize critical structures of fungi and involve in the host immune response after pulmonary fungal infections. We aimed to investigate the association between Dectin-2 genetic polymorphisms and cryptococcosis among a series of human immunodeficiency virus (HIV)-uninfected Chinese patients. In this case control study, a total of 251 patients with cryptococcosis and 464 healthy controls were included. One tag-single nucleotide polymorphism (SNP) (rs11045418) located at 5'-flanking region of Dectin-2 gene was selected and genotyped in this study. Among 251 patients, there were 108 (43%) meningitis patients including 73 (67.7%) healthy ones, 74 (29.5%) pulmonary infected patients including 49 (66.2%) healthy ones, and 69 (27.5%) patients with both neural and pulmonary infection including 38 (55.1%) immunocompetent ones. One hundred and forty-three (74 plus 69) patients with pulmonary cryptococcosis and 177 (108 plus 69) patients with cryptococcal meningitis were compared with controls, respectively. Three samples from 143 pulmonary infected patients failed in genotyping. There was a significant difference between 86 immunocompetent pulmonary infected patients and controls in the overdominant model (C/T vs. T/T + C/C; OR, 0.59; 95%CI, 0.37-0.94; P, .026). Similar but not significant difference was found between the overall pulmonary infected patients and the controls in the overdominant model (OR, 0.77; 95%CI, 0.52-1.12; P, .17). No such difference was found between controls and patients with cryptococcal meningitis. Our study firstly showed a genetic association between Dectin-2 and pulmonary cryptococcosis.

In vitro and in vivo evidence for amphotericin B as a P-glycoprotein substrate on the blood-brain barrier.

Amphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.

Identification of clinically relevant fungi and prototheca species by rRNA gene sequencing and multilocus PCR coupled with electrospray ionization mass spectrometry.

BACKGROUND: Multilocus PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) is a new strategy for pathogen identification, but information about its application in fungal identification remains sparse. METHODS: One-hundred and twelve strains and isolates of clinically important fungi and Prototheca species were subjected to both rRNA gene sequencing and PCR/ESI-MS. Three regions of the rRNA gene were used as targets for sequencing: the 5' end of the large subunit rRNA gene (D1/D2 region), and the internal transcribed spacers 1 and 2 (ITS1 and ITS2 regions). Microbial identification (Micro ID), acquired by combining results of phenotypic methods and rRNA gene sequencing, was used to evaluate the results of PCR/ESI-MS. RESULTS: For identification of yeasts and filamentous fungi, combined sequencing of the three regions had the best performance (species-level identification rate of 93.8% and 81.8% respectively). The highest species-level identification rate was achieved by sequencing of D1/D2 for yeasts (92.2%) and ITS2 for filamentous fungi (75.8%). The two Prototheca species could be identified to species level by D1/D2 sequencing but not by ITS1 or ITS2. For the 102 strains and isolates within the coverage of PCR/ESI-MS identification, 87.3% (89/102) achieved species-level identification, 100% (89/89) of which were concordant to Micro ID on species/complex level. The species-level identification rates for yeasts and filamentous fungi were 93.9% (62/66) and 75% (27/36) respectively. CONCLUSIONS: rRNA gene sequencing provides accurate identification information, with the best results obtained by a combination of ITS1, ITS2 and D1/D2 sequencing. Our preliminary data indicated that PCR/ESI-MS method also provides a rapid and accurate identification for many clinical relevant fungi.