Inhibit or promote? Trade-off effect of dissolved organic matter on the laccase-mediator system.

A biocatalytic system comprising fungal laccase and mediators can generate phenol radicals and efficiently eliminate various triarylmethane dyes. This study systematically explores the kinetic impact of dissolved organic matter (DOM), represented by humic substance (HS consisting of 90% fulvic acid, from lignite), on the decolorization of seven typical triarylmethane dyes by Trametes versicolor laccase and twenty natural mediators. Among these, 4-hydroxybenzyl alcohol (4-HA) and methyl violet (MV) undergo in-depth investigation regarding degradation products, pathways, and reaction mechanisms. In instances where HS hampers laccase-alone decolorization, such as malachite green, Coomassie brilliant blue, bromophenol blue, and acid magenta, this inhibition may persist despite mediator introduction. Conversely, in cases where HS facilitates decolorization, such as crystalline violet and ethyl violet, most laccase-mediator systems (LMSs) can still benefit. For MV decolorization by laccase and 4-HA, HS's kinetic effect is controlled by concentration and reaction time. A 5 mg/L HS increased the decolorization rate from 50% to 67% within the first hour, whereas 10 mg/L HS only achieved 45%. After 16 h of reaction, HS's impact on decolorization rate diminishes. Furthermore, the addition of HS enhances precipitation production, probably due to its involvement in polymerization with MV and mediator. Computational simulations and spectral monitoring reveal that low HS concentrations accelerate laccase-mediated demethylation by disrupting the chromophores bound to MV, thus promoting the decolorization of MV. Conversely, inhibition by high HS concentrations stems from the competitive binding of the enzyme pocket to the mediator, and the reduction of phenol free radicals in the system. Molecular docking and kinetic simulations revealed that laccase forms complexes with both the mediator and MV. Interestingly, the decolorization of MV occurred through a non-radical mechanism in the presence of HS. This work provided a reference for screening of high catalytic performance mediators to remove triarylmethane dyes in the actual water environment.

Impacts of systemic treatments on health-related quality of life for patients with metastatic colorectal cancer: a systematic review and network meta-analysis.

OBJECTIVE: There is limited evidence of comparative results among different treatments regarding impacts of Health-Related Quality of Life (HRQoL) for patients with metastatic colorectal cancer (mCRC). We aimed to compare efficacy of systemic treatments on HRQoL among patients with mCRC. METHODS: We collected randomized controlled trials (RCTs) reported in English up until July 2023, from databases including PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and prominent conference databases, for this Bayesian network meta-analysis. Phase 2 or 3 trials that evaluated at least two therapeutic regimens were included. Primary outcomes were short-term and long-term mean changes in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) scores. Secondary outcome was mean change in EQ-5D health utility scores. Mean differences (MDs) with 95% confidence intervals (CIs) were used as effect size. Subgroup analysis was performed based on whether patients received systemic treatments before. We conducted various sensitivity analyses, including differentiating between chemotherapy types, and analyzed patient cohorts with non-specified gene expression levels as well as those with target KRAS expression statuses. The current systematic review protocol was registered on PROSPERO (CRD42023453315 and CRD42023420498). RESULTS: Immunotherapy and targeted therapy significantly improved HRQoL over chemotherapy, with MDs of 9.27 (95% CI: 3.96 to 14.6) and 4.04 (95% CI: 0.11 to 7.94), respectively. Monotherapy significantly outperformed both combination therapy (MD 5.71, 95%CI 0.78 to 10.63) and no active treatment (MD 3.7, 95%CI 1.41 to 6.01) regarding GHS/QoL in the short-term. Combining targeted therapy with chemotherapy did not improve HRQoL. Focusing on HRQoL, cetuximab excelled when gene expression baselines were unspecified. Subgroup and sensitivity analyses upheld these robust findings, unaffected by model or patient baseline characteristics. Evidence from clinical trials without specific gene level data suggested that monotherapies, especially targeted therapies such as cetuximab, demonstrated superiority in HRQoL. For KRAS wild-type patients, no significant HRQoL differences emerged between chemotherapy, targeted therapy, or their combination.. CONCLUSIONS: Targeted therapies and immunotherapy demonstrate superior HRQoL benefits, monotherapy such as cetuximab is associated with significant improvements as compared to combination therapy. However, tailoring these results to individual gene expression profiles requires more evidence.

Sotorasib versus Docetaxel for treatment of US and Chinese patients with advanced non-small-cell lung cancer with KRAS p.G12C-mutated: A cost-effectiveness analysis to inform drug pricing.

BACKGROUND: The cost-effectiveness of sotorasib and its reasonable price in the United States (US) and China remain unknown. Our objective was to estimate the price at which sotorasib could be economical as second-line treatment for advanced non-small-cell lung cancer patients with Kirsten rat sarcoma viral oncogene homolog p.G12C-mutation in 2 countries. METHODS: We conducted an economic evaluation from the perspective of US and Chinese payers. To analyze US patients, we built a partitioned survival model. However, since we lacked Asian-specific overall survival data, we created a state transition model for the Chinese patients. We obtained patients' baseline characteristics and clinical data from CodeBreaK200, while utilities and costs were gathered from public databases and published literature. We calculated costs (US dollar), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. We conducted price simulation to guide pricing strategies. Additionally, we assessed the reliability of our results through sensitivity analyses, scenario analyses, and subgroup analyses. RESULTS: The incremental cost-effectiveness ratios of sotorasib compared to docetaxel were $1501,852 per quality-adjusted life-years (QALY) in the US and $469,106/QALY in China, respectively, which meant sotorasib was unlikely to be economical at the currently available price of $20,878 (240 × 120 mg) in both countries. Price simulation results revealed that sotorasib would be preferred at a price lower than $1400 at the willingness-to-pay threshold of $37,376 in China and a price lower than $2220 at the willingness-to-pay threshold of $150,000 in the US. Sensitivity, scenario, and subgroup analyses showed that these conclusions were generally robust, the model was most sensitive to the utilities of progression-free survival and post-progression survival. CONCLUSIONS: Sotorasib could potentially be a cost-effective therapy in the US and China following price reductions. Our evidence-based pricing strategy can assist decision-makers and clinicians in making optimal decisions. However, further analysis of budget impact and affordability is needed.

Cost-effectiveness analysis of atezolizumab in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen: a United Kingdom health care perspective.

Background: Cost-effectiveness of atezolizumab, as a treatment for advanced non-small-cell lung cancer (NSCLC) patients who cannot receive a platinum-containing regimen,was still unknown. Our objective was to evaluate the cost-effectiveness of atezolizumab vs. chemotherapy in this indication from the perspective of UK healthcare system. Methods: From the global, randomised, open-label, phase III IPSOS trial, clinical inputs and patient characteristics were obtained. A partitioned survival model with three health states was built: Progression-free survival, progressed disease and death. A lifetime time horizon was applied, with an annual discount rate of 3.5%. Additionally, the willingness-to-pay threshold of £50,000/QALY was utilized. Primary outcomes were quality-adjusted life-year (QALY), costs, and incremental cost-effectiveness ratio (ICER). Sensitivity, scenario, and subgroup analyses were used to assess the reliability of base-case results. Price simulations were carried out in order to provide information for the pricing strategy at specific willingness-to-pay threshold. Results: In the base-case analysis, atezolizumab resulted in a gain of 0.28 QALYs and an ICER of £94,873/QALY compared to chemotherapy, demonstrating no cost-effectiveness. Price simulation results revealed that atezolizumab would be preferred at a price lower than £2,215 (a reduction of 41.8%) at the willingness-to-pay threshold of £50,000. Sensitivity, scenario and subgroup analyses revealed these conclusions were generally robust, the model was most sensitive to the price of atezolizumab and subsequent medication. Furthermore, atezolizumab was found to be more cost-effective for patients displaying a positive PD-L1 expression, with an ICER of £72,098/QALY as compared to chemotherapy. Conclusion: Atezolizumab is not cost-effective for patients with advanced NSCLC ineligible for platinum-containing regimen, potential price reduction is necessary.

Occurrence of microplastics in the seawater and atmosphere of the South China Sea: Pollution patterns and interrelationship.

Microplastic (MP) pollution is a serious global environmental problem, particularly in marine ecosystems. However, the pollution patterns of MPs in the ocean and atmosphere, particularly the sea-air interrelationship, remain unclear. Therefore, the abundance, distribution patterns, and sources of MPs in the seawater and atmosphere of the South China Sea (SCS) were comparatively investigated. The results showed that MPs were prevalent in the SCS with an average abundance of 103.4 ± 98.3 items/m3 in the seawater and 4.62 ± 3.60 items/100 m3 in the atmosphere. The spatial analysis indicated that the pollution patterns of seawater MPs were mainly determined by land-based discharge and sea surface currents, whereas atmospheric MPs were predominantly determined by air parcel trajectory and wind conditions. The highest MP abundance of 490 items/m3 in seawater was found at a station near Vietnam with current vortices. However, the highest MP abundance of 14.6 items/100 m3 in the atmosphere was found in air parcels with low-speed southerly winds from Malaysia. Similar MP compositions (e.g., polyethylene terephthalate, polystyrene, and polyethylene) were observed in the two environmental compartments. Furthermore, similar MP characteristics (e.g., shape, color, and size) in the seawater and atmosphere of the same region suggested a close relationship between the MPs in the two compartments. For this purpose, cluster analysis and calculation of the MP diversity integrated index were performed. The results showed an obvious dispersion between the two compartment clusters and a higher diversity integrated index of MPs in seawater than in the atmosphere, thus implying higher compositional diversity and more complex sources of MPs in seawater relative to the atmosphere. These findings deepen our understanding of MP fate and patterns in the semi-enclosed marginal sea environment and highlight the potential interrelationship of MPs in the air-sea system.

Performance of a prestressed efficiently prefabricated beam-column connection.

Analyzing the seismic performance and flexural capacity of beam-column joints is crucial in structural design phase. The purpose of this paper is to investigate the seismic performance and flexural capacity of precast prestressed efficiently fabricated frame (PPEFF) joints. Reverse cyclic load tests and flexural capacity analysis are conducted. The damage modes, hysteresis curves, skeleton curves, stiffness degradation, ductility, and energy dissipation capacity of five PPEFF joint specimens with different reinforcement rates of the energy-dissipating bars and shear reinforcement are obtained. The results show that the damage pattern of the specimen is ideal, i.e., the plastic hinge region at the end of the beam is severely damaged, whereas the remainder of the beam is slightly damaged. Increasing the reinforcement rate of the energy-consuming steel bars enhances the load capacity, energy dissipation capacity, and initial stiffness of the joint but reduces the ductility performance. The maximum change in ductility was 5.31 for the reinforcement rate of energy-consuming steel bars ranging from 0.38% to 0.59%. In addition, the flexural capacity of the PPEFF joint is evaluated, considering the influence of the shear steel on the yielding and ultimate states. An equation of the flexural capacity is derived. A good agreement is observed between the experimental and calculation results, verifying the correctness of the proposed flexural capacity equation.

Removal of levofloxacin by an oleaginous microalgae Chromochloris zofingiensis in the heterotrophic mode of cultivation: Removal performance and mechanism.

Microalgae-based technology is an environmental-friendly and cost-effective method for treating antibiotics-contaminated wastewater. This work investigated the removal of levofloxacin (LEV) by an oleaginous microalgae Chromochloris zofingiensis under photoautotrophic and heterotrophic conditions. The results showed that the significantly higher biomass production, accumulation of extracellular polymeric substance and LEV removal efficiency were achieved in heterotrophic C. zofingiensis compared with the photoautotrophic ones. The removal efficiencies under the heterotrophic condition were 97%, 88% and 76% at 1, 10, and 100 mg/L LEV, respectively. HPLC-MS/MS and RNA-Seq analyses suggested that LEV could be bioaccumulated and biodegraded by heterotrophic C. zofingiensis through the reactions of defluorination, hydroxylation, demethylation, ring cleavage, oxidation, dehydrogenation, denitrification, and decarboxylation. The chemical composition of the algal biomass obtained after LEV treatment indicated the potential of this alga for removing LEV from wastewaters and simultaneously producing biodiesel, astaxanthin, and other products. Collectively, this research shows that the heterotrophic C. zofingiensis can be identified as a promising candidate for removing LEV in wastewater remediation.

Evaluation of ergosterol composition and esterification rate in fungi isolated from mangrove soil, long-term storage of broken spores, and two soils.

Ergosterol is an important fungal-specific biomarker, but its use for fungal biomass estimation is still varied. It is important to distinguish between free and esterified ergosterols, which are mainly located on the plasma membrane and the cytosolic lipid particles, respectively. The present study analyzes free and esterified ergosterol contents in: (1) the fifty-nine strains of culturable fungi isolated from mangrove soil, (2) the broken spores of the fungus Ganoderma lucidum stored in capsule for more than 12 years, and (3) the mangrove soil and nearby campus wood soil samples by high performance liquid chromatography (HPLC). The results show that the contents of free and esterified ergosterols varied greatly in fifty-nine strains of fungi after 5 days of growth, indicating the diversity of ergosterol composition in fungi. The average contents of free and total ergosterols from the fifty-nine strains of fungi are 4.4 ± 1.5 mg/g and 6.1 ± 1.9 mg/g dry mycelia, respectively, with an average ergosterol esterification rate of 27.4%. The present study suggests that the fungi might be divided into two classes, one is fungi with high esterification rates (e.g., more than 27%) such as Nectria spp. and Fusarium spp., and the other is fungi with low esterification rates (e.g., less than 27%) such as Penicillium spp. and Trichoderma spp. Moreover, the ergosterol esterification rate in the spores of G. lucidum is 91.4% with a very small amount of free ergosterol (0.015 mg/g), compared with 41.9% with a higher level of free ergosterol (0.499 mg/g) reported in our previous study in 2007, indicating that free ergosterol degrades more rapidly than esterified ergosterol. In addition, the ergosterol esterification rates in mangrove soil and nearby campus wood soil samples range from 0 to 39.0%, compared with 80% in an old soil organic matter reported in a previous study, indicating the potential relationship between aging degree of fungi or soil and esterification rate. The present study proposes that both free and esterified ergosterols should be analyzed for fungal biomass estimation. When the ergosterol esterification rates in soils are higher, free ergosterol might be a better marker for fungal biomass. It is speculated that the ergosterol esterification rate in soils might contain some important information, such as the age of old-growth forests over time scales of centuries to millennia, besides the senescence degree of fungal mycelia in soils. KEY POINTS: • Fungi might be divided into two classes depending on ergosterol esterification rates. • Ergosterol esterification rate of broken spores stored for long time raised evidently. • Both free and esterified ergosterols should be analyzed for fungal biomass estimate. • Free ergosterol is a better marker for fungal biomass with a high esterification rate.

Characterization of Matrix Metalloprotease-9 Gene from Nile tilapia (Oreochromis niloticus) and Its High-Level Expression Induced by the Streptococcus agalactiae Challenge.

The bacterial diseases of tilapia caused by Streptococcus agalactiae have resulted in the high mortality and huge economic loss in the tilapia industry. Matrix metalloproteinase-9 (MMP-9) may play an important role in fighting infection. However, the role of MMP-9 in Nile tilapia against S. agalactiae is still unclear. In this work, MMP-9 cDNA of Nile tilapia (NtMMP-9) has been cloned and characterized. NtMMP-9 has 2043 bp and encodes a putative protein of 680 amino acids. NtMMP-9 contains the conserved domains interacting with decorin and inhibitors via binding forces compared to those in other teleosts. Quantitative real-time-polymerase chain reaction (qPCR) analysis reveals that NtMMP-9 distinctly upregulated following S. agalactiae infection in a tissue- and time-dependent response pattern, and the tissues, including liver, spleen, and intestines, are the major organs against a S. agalactiae infection. Besides, the proteolytic activity of NtMMP-9 is also confirmed by heterologous expression and zymography, which proves the active function of NtMMP-9 interacting with other factors. The findings indicate that NtMMP-9 was involved in immune responses against the bacterial challenge at the transcriptional level. Further work will focus on the molecular mechanisms of NtMMP-9 to respond and modulate the signaling pathways in Nile tilapia against S. agalactiae invasion and the development of NtMMP-9-related predictive biomarkers or vaccines for preventing bacterial infection in the tilapia industry.

Efficient Conversion of Cane Molasses Towards High-Purity Isomaltulose and Cellular Lipid Using an Engineered Yarrowia lipolytica Strain in Fed-Batch Fermentation.

: Cane molasses is one of the main by-products of sugar refineries, which is rich in sucrose. In this work, low-cost cane molasses was introduced as an alternative substrate for isomaltulose production. Using the engineered Yarrowia lipolytica, the isomaltulose production reached the highest (102.6 g L-¹) at flask level with pretreated cane molasses of 350 g L-¹ and corn steep liquor of 1.0 g L-¹. During fed-batch fermentation, the maximal isomaltulose concentration (161.2 g L-¹) was achieved with 0.96 g g-¹ yield within 80 h. Simultaneously, monosaccharides were completely depleted, harvesting the high isomaltulose purity (97.4%) and high lipid level (12.2 g L-¹). Additionally, the lipids comprised of 94.29% C16 and C18 fatty acids, were proved suitable for biodiesel production. Therefore, the bioprocess employed using cane molasses in this study was low-cost and eco-friendly for high-purity isomaltulose production, coupling with valuable lipids.