China has pledged to peak carbon emissions before 2030 and strive to achieve carbon neutrality before 2060. However, the significant variations of provincial carbon emissions make it unclear whether ...they can jointly fulfill the national carbon peak and neutrality goal. Thus, this study predicts the emission trajectories at provincial level in China by employing the extended STIRPAT (Stochastic Impacts by Regression on Population, Affluence, and Technology) model to see the feasibility and time of reaching peak carbon emissions and carbon neutrality. We found that most provinces can achieve peak emission before 2030 but challenging to achieve carbon neutrality before 2060, even considering the ecological carbon sink. The provincial neutrality time is concentrated between 2058 and 2070; the sooner the carbon emission peaks, the earlier the carbon neutral will be realized. The aggregated carbon emissions at provincial level show that China can achieve its carbon emission peak of 9.64–10.71 Gt before 2030, but it is unlikely to achieve the carbon neutrality goal before 2060 without carbon capture, utilization, and storage (CCUS). With high CCUS development, China is expected to achieve carbon neutrality in 2054–2058, irrespective of the socio-economic scenarios. With low CCUS development, China's carbon neutrality target will be achieved only under the accelerated-improvement scenario, while it will postpone to 2061 and 2064 under the continued-improvement and the business-as-usual scenarios, respectively.
Early detection and effective treatment of severe COVID-19 patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control ...individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model was validated using 10 independent patients, 7 of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 COVID-19 patients, leading to 16 correct assignments. We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation, complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.
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•93 proteins show differential expression in severe COVID-19 patient sera•204 metabolites in COVID-19 patient sera correlate with disease severity•A model composed of 29 serum factors shows patient stratification potential•Pathway analysis highlights metabolic and immune dysregulation in COVID-19 patients
Proteomic and metabolomic analysis of COVID-19 sera identifies differentially expressed factors that correlate with disease severity and highlights dysregulation of multiple immune and metabolic components in clinically severe patients.
Invasive species can successfully and rapidly colonize new niches and expand ranges via founder effects and enhanced tolerance towards environmental stresses. However, the underpinning molecular ...mechanisms (i.e., gene expression changes) facilitating rapid adaptation to harsh environments are still poorly understood. The red seaweed Gracilaria vermiculophylla, which is native to the northwest Pacific but invaded North American and European coastal habitats over the last 100 years, provides an excellent model to examine whether enhanced tolerance at the level of gene expression contributed to its invasion success. We collected G. vermiculophylla from its native range in Japan and from two non‐native regions along the Delmarva Peninsula (Eastern United States) and in Germany. Thalli were reared in a common garden for 4 months at which time we performed comparative transcriptome (mRNA) and microRNA (miRNA) sequencing. MRNA‐expression profiling identified 59 genes that were differently expressed between native and non‐native thalli. Of these genes, most were involved in metabolic pathways, including photosynthesis, abiotic stress, and biosynthesis of products and hormones in all four non‐native sites. MiRNA‐based target‐gene correlation analysis in native/non‐native pairs revealed that some target genes are positively or negatively regulated via epigenetic mechanisms. Importantly, these genes are mostly associated with metabolism and defence capability (e.g., metal transporter Nramp5, senescence‐associated protein, cell wall‐associated hydrolase, ycf68 protein and cytochrome P450‐like TBP). Thus, our gene expression results indicate that resource reallocation to metabolic processes is most likely a predominant mechanism contributing to the range‐wide persistence and adaptation of G. vermiculophylla in the invaded range. This study, therefore, provides molecular insight into the speed and nature of invasion‐mediated rapid adaption.
Abstract
Atmospheric aerosol nucleation contributes to approximately half of the worldwide cloud condensation nuclei. Despite the importance of climate, detailed nucleation mechanisms are still ...poorly understood. Understanding aerosol nucleation dynamics is hindered by the nonreactivity of force fields (FFs) and high computational costs due to the rare event nature of aerosol nucleation. Developing reactive FFs for nucleation systems is even more challenging than developing covalently bonded materials because of the wide size range and high dimensional characteristics of noncovalent hydrogen bonding bridging clusters. Here, we propose a general workflow that is also applicable to other systems to train an accurate reactive FF based on a deep neural network (DNN) and further bridge DNN-FF-based molecular dynamics (MD) with a cluster kinetics model based on Poisson distributions of reactive events to overcome the high computational costs of direct MD. We found that previously reported acid-base formation rates tend to be significantly underestimated, especially in polluted environments, emphasizing that acid-base nucleation observed in multiple environments should be revisited.
•Styrax potently inhibits CYP3A and moderately inhibits CYP1A, 2A6, 2C8, 2C9, 2C19 and 2E1.•Styrax strongly inhibits warfarin 10-hydroxylation in liver microsomes from both humans and rats.•Styrax ...significantly increases the plasma exposure and half-life of warfarin in rats.•Five pentacyclic triterpenoid acids occurring in Styrax are identified as strong CYP3A inhibitors.
Styrax, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa. It is unclear whether Styrax or Styrax-related herbal medicines may trigger clinically relevant herb-drug interactions.
This study was carried out to investigate the inhibitory effects of Styrax on human cytochrome P450 enzymes (CYPs) and to clarify whether this herb may modulate the pharmacokinetic behavior of the CYP-substrate drug warfarin when co-administered.
The inhibitory effects of Styrax on CYPs were assayed in human liver microsomes (HLM), while the pharmacokinetic interactions between Styrax and warfarin were investigated in rats. The bioactive constituents in Styrax with strong CYP3A inhibitory activity were identified and their inhibitory mechanisms were carefully investigated.
The inhibitory effects of Styrax on human CYPs were assayed in vitro, while the pharmacokinetic interactions between Styrax and warfarin were studied in rats. Fingerprinting analysis of Styrax coupled with LC-TOF-MS/MS profiling and CYP inhibition assays were used to identify the constituents with strong CYP3A inhibitory activity. The inhibitory mechanism of oleanonic acid (the most potent CYP3A inhibitor occurring in Styrax) against CYP3A4 was investigated by a panel of inhibition kinetics analyses and in silico analysis.
In vitro assays demonstrated that Styrax extract strongly inhibited human CYP3A and moderately inhibited six other tested human CYPs, as well as potently inhibited warfarin 10-hydroxylation in liver microsomes from both humans and rats. In vivo assays demonstrated that compared with warfarin given individually in rats, Styrax (100 mg/kg) significantly prolonged the plasma half-life of warfarin by 2.3-fold and increased the AUC(0-inf) of warfarin by 2.7-fold when this herb was co-administrated with warfarin (2 mg/kg) in rats. Two LC fractions were found with strong CYP3A inhibitory activity and the major constituents in these fractions were characterized by LC-TOF-MS/MS. Five pentacyclic triterpenoid acids (including epibetulinic acid, betulinic acid, betulonic acid, oleanonic acid and maslinic acid) present in Styrax were potent CYP3A inhibitors, and oleanonic acid was a competitive inhibitor against CYP3A-mediated testosterone 6β-hydroxylation.
Styrax and the pentacyclic triterpenoid acids occurring in this herb strongly modulate the pharmacokinetic behavior of warfarin via inhibition of CYP3A.
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Objectives
This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the ...pharmacokinetic behaviour of the co‐administered CYP‐substrate drug apatinib.
Methods
Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC‐MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats.
Key findings
Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In‐vivo assays demonstrated that HSYW could significantly prolong the plasma half‐life of apatinib by 7.4‐fold and increase the AUC0–inf (nm·h) of apatinib by 43%, when HSYW (10 ml/kg) was co‐administered with apatinib (10 mg/kg) in rats.
Conclusions
Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half‐life of apatinib both in vitro and in vivo.
This study constructs tourism spatial gravity models with multi-destination and multi-origin interaction conditions, using consumer utility and travel probability theories. It also explores, through ...spatial correlation methods, the spatial differentiation characteristics of the tourism system in an urban agglomeration under the influence of a high-speed railway network from the perspectives of city tourism competitiveness and resident travel potential. The research finds that the high-speed railway has an increasing influence on the urban agglomeration tourism system, widening the hierarchical difference and causing the reverse balance to have an integration effect. The influence of high-speed railways has the obvious cluster node and corridor lock-in effect, which has strengthened the core-peripheral structure of the urban agglomeration tourism system. Peripheral cities with high-speed railways are more obviously affected, but their ranking-order changes in the urban agglomeration tourism system are not significant because of comprehensive location weaknesses. Because of the complex spatial differentiation, researchers need to use multi-spatial statistical methods to carry out integrated studies and obtain useful optimization strategies.
The contamination of food by pathogens is a serious problem in global food safety, and current methods of detection are costly, time-consuming, and cumbersome. Therefore, it is necessary to develop ...rapid, portable, and sensitive assays for foodborne pathogens. In addition, assays for foodborne pathogens must be resistant to interference resulting from the complex food matrix to prevent false positives and negatives. In this study, hemin and reduced graphene oxide-MoS2 sheets (GMS) were used to design a near-infrared (NIR)-responsive photoelectrochemical (PEC) aptasensor with target-induced photocurrent polarity switching based on a hairpin aptamer (Hp) with a G-quadruplex motif. A ready-to-use analytical device was developed by immobilizing GMS on the surface of a commercial screen-printed electrode, followed by the attachment of the aptamer. In the presence of Escherichia coli O157:H7, the binding sites of Hp with the G-quadruplex motif were opened and exposed to hemin, leading to the formation of a G-quadruplex/hemin DNAzyme. Crucially, after binding to hemin, the charge transfer pathway of GMS changes, resulting in a switch of the photocurrent polarity. Further, G-quadruplex/hemin DNAzyme enhanced the cathodic photocurrent, and the proposed sensor exhibited a wide linear range ((25.0–1.0) × 107 CFU/mL), a low limit of detection (2.0 CFU/mL), and good anti-interference performance. These findings expand the applications of NIR-responsive PEC materials and provide versatile PEC methods for detecting biological analytes, especially for food safety testing.
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•A novel activatable near-infrared (NIR) fluorogenic substrate (DDAO-ol) for human pancreatic lipase (hPL) was devised.•DDAO-ol is found with the best combination of stability, ...specificity, sensitivity and reactivity towards hPL.•DDAO-ol offers a practical tool for high-throughput screening and characterizing hPL inhibitors.•DDAO-ol offers a powerful visualization tool for in situ sensing and imaging of PL in living cells, tissues and organs.
Human pancreatic lipase (hPL), a crucial digestive enzyme responsible for the digestion of dietary lipids in humans, has been validated as a key target for treating obesity and as a potential biomarker for diagnosis of pancreatic diseases. This study aims to devise a novel and highly specific near-infrared (NIR) fluorogenic substrate for sensing and imaging of human pancreatic lipase (hPL) in biological systems. To achieve this aim, the oleate esters of various NIR fluorophores are rationally designed on the basis of the enzymatic properties and the preferred substrates of hPL. Following virtual screening and experimental validation, DDAO-ol is found with the best combination of stability, specificity, sensitivity and reactivity towards hPL. Under physiological conditions, DDAO-ol can be rapidly hydrolyzed by hPL to release the fluorophore DDAO, which emits strong NIR fluorescence signal around 660 nm. DDAO-ol offers a novel and practical tool to construct the assay for high-throughput screening and characterizing hPL inhibitors, which strongly facilitates the discovery of novel anti-obesity agents targeting hPL. Meanwhile, DDAO-ol is also a powerful visualization tool for sensing and imaging of mammalian pancreatic lipase (PL) in living systems (including living cells, tissues and organs) with low cytotoxicity and high imaging resolution. Collectively, this study reports a novel and highly specific NIR fluorogenic substrate for hPL, which offers a practical and reliable tool for deciphering the biological functions of hPL and the relevance of this key digestive enzyme to diseases.
Psoraleae Fructus (the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae ...Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions (HDI) or herb-endobiotic interactions (HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus; the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes (DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.
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