Ice sheet and precession controlled subarctic Pacific productivity and upwelling over the last 550,000 years.

The polar oceans play a vital role in regulating atmospheric CO2 concentrations (pCO2) during the Pleistocene glacial cycles. However, despite being the largest modern reservoir of respired carbon, the impact of the subarctic Pacific remains poorly understood due to limited records. Here, we present high-resolution, 230Th-normalized export productivity records from the subarctic northwestern Pacific covering the last five glacial cycles. Our records display pronounced, glacial-interglacial cyclicity superimposed with precessional-driven variability, with warm interglacial climate and high boreal summer insolation providing favorable conditions to sustain upwelling of nutrient-rich subsurface waters and hence increased export productivity. Our transient model simulations consistently show that ice sheets and to a lesser degree, precession are the main drivers that control the strength and latitudinal position of the westerlies. Enhanced upwelling of nutrient/carbon-rich water caused by the intensification and poleward migration of the northern westerlies during warmer climate intervals would have led to the release of previously sequestered CO2 from the subarctic Pacific to the atmosphere. Our results also highlight the significant role of the subarctic Pacific in modulating pCO2 changes during the Pleistocene climate cycles, especially on precession timescale ( ~ 20 kyr).

TransGEM: a molecule generation model based on Transformer with gene expression data.

MOTIVATION: It is difficult to generate new molecules with desirable bioactivity through ligand-based de novo drug design, and receptor-based de novo drug design is constrained by disease target information availability. The combination of artificial intelligence and phenotype-based de novo drug design can generate new bioactive molecules, independent from disease target information. Gene expression profiles can be used to characterize biological phenotypes. The Transformer model can be utilized to capture the associations between gene expression profiles and molecular structures due to its remarkable ability in processing contextual information. RESULTS: We propose TransGEM (Transformer-based model from gene expression to molecules), which is a phenotype-based de novo drug design model. A specialized gene expression encoder is used to embed gene expression difference values between diseased cell lines and their corresponding normal tissue cells into TransGEM model. The results demonstrate that the TransGEM model can generate molecules with desirable evaluation metrics and property distributions. Case studies illustrate that TransGEM model can generate structurally novel molecules with good binding affinity to disease target proteins. The majority of genes with high attention scores obtained from TransGEM model are associated with the onset of the disease, indicating the potential of these genes as disease targets. Therefore, this study provides a new paradigm for de novo drug design, and it will promote phenotype-based drug discovery. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/hzauzqy/TransGEM.

Metabolites of pathogenic microorganisms database (MPMdb) and its seed metabolite applications.

Seed metabolites are the combination of essential compounds required by an organism across various potential environmental conditions. The seed metabolites screening framework based on the network topology approach can capture important biological information of species. This study aims to identify comprehensively the relationship between seed metabolites and pathogenic bacteria. A large-scale data set was compiled, describing the seed metabolite sets and metabolite sets of 124,192 pathogenic strains from 34 genera, by constructing genome-scale metabolic models. The enrichment analysis method was used to screen the specific seed metabolites of each species/genus of pathogenic bacteria. The metabolites of pathogenic microorganisms database (MPMdb) (http://qyzhanglab.hzau.edu.cn/MPMdb/) was established for browsing, searching, predicting, or downloading metabolites and seed metabolites of pathogenic microorganisms. Based on the MPMdb, taxonomic and phylogenetic analyses of pathogenic bacteria were performed according to the function of seed metabolites and metabolites. The results showed that the seed metabolites could be used as a feature for microorganism chemotaxonomy, and they could mirror the phylogeny of pathogenic bacteria. In addition, our screened specific seed metabolites of pathogenic bacteria can be used not only for further tapping the nutritional resources and identifying auxotrophies of pathogenic bacteria but also for designing targeted bactericidal compounds by combining with existing antimicrobial agents.IMPORTANCEMetabolites serve as key communication links between pathogenic microorganisms and hosts, with seed metabolites being crucial for microbial growth, reproduction, external communication, and host infection. However, the large-scale screening of metabolites and the identification of seed metabolites have always been the main technical bottleneck due to the low throughput and costly analysis. Genome-scale metabolic models have become a recognized research paradigm to investigate the metabolic characteristics of species. The developed metabolites of pathogenic microorganisms database in this study is committed to systematically predicting and identifying the metabolites and seed metabolites of pathogenic microorganisms, which could provide a powerful resource platform for pathogenic bacteria research.

Composition and sources of suspended particles in the Pacific Arctic region.

During the 6th (2014) and 7th (2016) Chinese Arctic Expedition (CHINARE), samples of suspended particulate matter (SPM) were collected from both surface (depth: <1.0 m) and subsurface (depth: approximately between 10 and 150 m) waters over the northern shelf of the Bering Sea and in the western Arctic Ocean. To investigate the distribution and sources of organic matter in both the surface water and the vertical profile, the concentration and stable carbon isotopic composition of SPM, particulate organic carbon (POC), and particulate nitrogen (only in surface water samples) were determined, and some particle samples were selected for examination using scanning electron microscopy. Results showed apparent geographical partitioning and temporal variation in both the concentration and the composition of SPM. Higher SPM concentrations were observed in nearshore, shelf break, and sea ice edge areas; the distribution of POC concentration displayed a similar pattern, with higher values found from the northern part of the Bering Shelf to southern parts of the Chukchi Shelf. In surface water, SPM mainly comprised clay and detrital minerals with higher POC contents, lighter δ13C values, and higher POC/PN ratios, indicating organic matter predominantly derived from terrestrial sources in areas south of St. Lawrence Island and north of 73°N. The downward trend of heavier δ13C values, together with reduction in clay and detrital minerals, suggests that vertical transport of SPM is hindered by stratification, resulting in transport of terrestrial materials toward northern basin areas. In the Chukchi Slope and Canada Basin areas, extremely light δ13C values (as low as -33.41‰ PDB) were mainly observed at depths of 20-60 m, where the Polar Mixed Layer (PML) intersects with the Upper Halocline Layer (UHL). Under the condition of low sea ice extent in 2016, the POC-δ13C values were heavier in the PML than in the UHL in the Chukchi Slope and Canada Basin areas. These findings provide insights into the sources, transport, and fate of organic matter in the Pacific Arctic region, which have important implications for understanding the biogeochemical cycles and ecosystem dynamics in this remote and rapidly changing environment.

Heavy metals and Pb isotopes in sediment cores from the Bering and Chukchi seas: Implications for environmental changes and human activities over the past century.

The Bering Sea and the Chukchi Sea are important regions for marine ecosystems and climate change. However, the historical deposition and sources of metals in these regions are poorly understood. In this study, we utilized Pb isotopes and multi-element concentrations (Ni, Cu, Fe, Mn, Zn, Cd, Pb) coupled with Pb-210 dating to investigate the historical deposition and source identification of metals in sediment cores collected from the Bering Sea and the Chukchi Sea. Our findings reveal that the transport of organic matter was mainly transported by marine and terrestrial sources in the Bering and Chukchi Sea, respectively. Historical variations of metals were similar in both seas, showing an increasing trend of metals (excluding Mn) from the 1960s to the 1990s, followed by a gradual decrease after the 1990s, which can be attributed to the development of industrial and gasoline emission. The results of the geo-accumulation index indicated that sediment in both seas was relatively unpolluted with metals. Additionally, Pb isotopic ratios suggested that natural weathering was the primary source of Pb in the area, but the use and phase-out of gasoline were also well-reconstructed. This study provides valuable information for assessing environmental changes and human activities over the past century in the Arctic and subarctic Ocean.

Transporter proteins knowledge graph construction and its application in drug development.

Transporters are the main determinant for pharmacokinetics characteristics of drugs, such as absorption, distribution, and excretion of drugs in humans. However, it is difficult to perform drug transporter validation and structure analysis of membrane transporter proteins by experimental methods. Many studies have demonstrated that knowledge graphs (KG) could effectively excavate potential association information between different entities. To improve the effectiveness of drug discovery, a transporter-related KG was constructed in this study. Meanwhile, a predictive frame (AutoInt_KG) and a generative frame (MolGPT_KG) were established based on the heterogeneity information obtained from the transporter-related KG by the RESCAL model. Natural product Luteolin with known transporters was selected to verify the reliability of the AutoInt_KG frame, its ROC-AUC (1:1), ROC-AUC (1:10), PR-AUC (1:1), PR-AUC (1:10) are 0.91, 0.94, 0.91 and 0.78, respectively. Subsequently, the MolGPT_KG frame was constructed to implement efficient drug design based on transporter structure. The evaluation results showed that the MolGPT_KG could generate novel and valid molecules and that these molecules were further confirmed by molecular docking analysis. The docking results showed that they could bind to important amino acids at the active site of the target transporter. Our findings will provide rich information resources and guidance for the further development of the transporter-related drugs.

Spatiotemporal variations, surface inventory, and cross regional impact of current-use organoamine pesticides in Chinese Marginal Seas.

Current-use Organoamine Pesticides (CUOAPs) are a growing concern as emerging pesticide pollutants that were initially discovered on a large scale in Chinese Marginal Seas (CMSs). The highest level was detected in the East China Sea in the late spring and decreased in the following order: East China Sea (early spring) > the South China Sea > the Bohai Sea. The crucial role played by the Yangtze and Yellow rivers as significant terrestrial sources were established. The fluctuations in the land application and riverine input led to variations in the source, distribution, and seasonal patterns of CUOAPs. Terrestrial-exported CUOAPs were transported and redistributed spatially by the surface ocean currents, resulting in significant regional disparities. The results displayed a pronounced terrestrial source signature and a cross-regional impact. By the ocean current transport, CMSs will likely become a secondary source region for the surrounding seas.

Spatial distribution and risk assessment of conazole fungicides in surface seawater of the East China Sea.

Conazole fungicides (CFs), the common-used pesticide in agriculture distributed widely in the environment. This research analyzed the occurrence, potential sources, and risks of eight CFs in the East China Sea surface seawater in the early summer of 2020. The total CF concentration ranged from 0.30 to 6.20 ng/L, with an average value of 1.64 ± 1.24 ng/L. Fenbuconazole, hexaconazole, and triadimenol were the major CFs that comprised >96 % of the total concentration. The Yangtze River was identified as the significant source of CFs from the coastal regions to the off-shore inputs. Ocean current was the first-order factor controlling the content and distribution of CFs in the East China Sea. Although risk assessment revealed CFs posed a low or no substantial risk to ecology and human health, long-term monitoring was also encouraged. This study provided a theoretical foundation for assessing CFs' pollution levels and potential risks in the East China Sea.

Isolation, characterization and differentiation of dermal papilla cells from Small-tail Han sheep.

Dermal papilla cells (DPCs) are the key dermal component of the hair follicle that directly regulates hair follicle development, growth and regeneration. Successfully isolated and cultured DPCs from Small-tail Han sheep could provide a good model for the study of hair follicle development mechanism in vitro. DPCs were isolated using enzyme digestion and dissecting microscope from Small-tail Han sheep. Adherent cells were identified by cell characteristics, particular gene expression, differentiation capability to adipocyte and osteoblast using specific differentiation mediums. Additionally, flow cytometry was used to detect the cell cycle of DPCs. Cells originating from the dermal papilla showed the morphological appearance of mesenchymal cells (fibroblast-like cells). Purified DPCs were positive for α-SMA (α smooth muscle actin) and vimentin; in addition to their strong proliferation abilities in vitro, these DPCs can be differentiated into adipocyte and osteoblasts lineage under appropriate culture condition. DPCs were successfully isolated and subcultured from Small-tail Han sheep, which exhibited progenitor cell features and multiple differentiation potency. It provides a material for studying the molecular mechanism of hair follicle development and hair cycle, which will promote wool production in the future.

Occurrence, seasonal variations, and eco-risk of currently using organochlorine pesticides in surface seawater of the East China Sea and Western Pacific Ocean.

We studied 19 targets currently using organochlorine pesticides (CUOCPs) from 98 samples in the Western Pacific Ocean and the East China Sea collected in 2019, 2020, and 2021. The samples were analyzed using a novel High-throat/High-volume Solid-Phase Extraction method. Eighteen individual CUOCPs were above the method detection limits. The levels of ∑19CUOCPs ranged from 0.13 to 17.80 ng/L, with an average of 3.13 ± 14.67 ng/L. Dicofol was the main pollutant in the Western Pacific Ocean, while Pyridaben dominated the East China Sea. In the summer, land-source input was the primary source in the Western Pacific Ocean and the East China Sea. Historical residues were the main source in the East China Sea in spring. In the summer, the ecological risk assessment results indicated a relatively low risk to the Western Pacific Ocean and the East China Sea.

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a mortal threat to human health. The elucidation of the relationship between peripheral immune cells and the development of inflammation is essential for revealing the pathogenic mechanism of COVID-19 and developing related antiviral drugs. The immune cell metabolism-targeting therapies exhibit a desirable anti-inflammatory effect in some treatment cases. In this study, based on differentially expressed gene (DEG) analysis, a genome-scale metabolic model (GSMM) was reconstructed by integrating transcriptome data to characterize the adaptive metabolic changes in peripheral blood mononuclear cells (PBMCs) in severe COVID-19 patients. Differential flux analysis revealed that metabolic changes such as enhanced aerobic glycolysis, impaired oxidative phosphorylation, fluctuating biogenesis of lipids, vitamins (folate and retinol), and nucleotides played important roles in the inflammation adaptation of PBMCs. Moreover, the main metabolic enzymes such as the solute carrier (SLC) family 2 member 3 (SLC2A3) and fatty acid synthase (FASN), responsible for the reactions with large differential fluxes, were identified as potential therapeutic targets. Our results revealed the inflammation regulation potentials of partial metabolic reactions with differential fluxes and their metabolites. This study provides a reference for developing potential PBMC metabolism-targeting therapy strategies against COVID-19.

[Preparation of luciferase-expressing mRNA and expression characteristics of mRNA delivered by electroporation in vivo].

In this study, we aimed to construct a non-replication mRNA platform and explore the side effects of electroporation-mediated delivery of mRNA on the mice as well as the expression features of the mRNA. With luciferase gene as a marker, in vitro transcription with T7 RNA polymerase was carried out for the synthesis of luciferase-expressed mRNA, followed by enzymatic capping and tailing. The mRNA was delivered in vivo by electroporation via an in vivo gene delivery system, and the expression intensity and duration of luciferase in mice were observed via an in vivo imaging system. The results demonstrated that the mRNA transcripts were successfully expressed both in vitro and in vivo. The electroporation-mediated delivery of mRNA had no obvious side effects on the mice. Luciferase was expressed successfully in all the mRNA-transduced mice, while the expression intensity and duration varied among individuals. Overall, the expression level peaked on the first day after electroporation and rapidly declined on the fourth day. This study is of great importance for the construction of non-replication mRNAs and their application in vaccine or antitumor drug development.

Occurrence, spatial distributions, and ecological risk of pyrethroids in coastal regions of South Yellow and East China Seas.

Pyrethroids are increasingly receiving attention as aqueous micropollutants, but their presence has been reported only in a few small coastal areas. In this study, we investigated the distribution, sources, and risks of nine pyrethroids in large marine zones. The 40 seawater samples were collected from the South Yellow Sea (SYS) and East China Sea (ECS) in China, during the spring of 2020, using a high-volume, solid-phase extraction method. The total pyrethroid concentrations ranged from 0.72 to 1.82 ng L-1 in the SYS and from 0.02 to 11.0 ng L-1 in the ECS. We used cluster analysis to classify pollutant sources into five categories, and discussed the influence of sources on the transport and distribution of pyrethroids in each group. Ecological risk assessment indicated that pyrethroids pose a high risk to crustaceans and a negligible risk to others. These results are important for understanding the behavior of pyrethroids in marine environments.

Terrigenous export and ocean currents' diffusion of organophosphorus flame retardants along China's adjacent seas.

High demands for but strict regulatory measures on Organophosphorus Flame Retardants (OPFRs) have resulted in mainland China transitioning from the region that imports OPRFs to one that exports these substances. Simultaneously, large quantities of terrigenous OPFRs have been exported to adjacent seas by the major river systems, particularly the Yangtze River. This study examined the presence of ten OPFRs in China's adjacent seas. High levels of OPFRs were observed in seas south of mainland China, with Tris (2-chloroethyl) phosphate (TCEP) and Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) dominant. The terrigenous OPFRs were redistributed by the ocean surface currents, with OPFRs tending to accumulate in regions with lower current speed. The producers of OPFRs are mainly distributed along the Haihe, Yellow, and Yangtze river systems. The application of OPFRs to electric vehicle charging stations, charging connectors, and 5G infrastructure in the Chinese mainland will likely drive rapid growth in OPFR related industry in the future. The diffusion trend map of OPFR indicated that the Bohai Sea and the central northern Yellow Sea are at high risk of ecological damage in the spring. The offshore region of the north of the South China Sea tended to aggregate more OPFRs in summer. Regions of the OPFR aggregation effect were at a higher risk of ecological damage.

Preparation of Pseudo-typed H5 Avian Influenza Viruses with Calcium Phosphate Transfection Method and Measurement of Antibody Neutralizing Activity.

Since 1996, A/goose/Guangdong/1/96-lineage highly pathogenic avian influenza (HPAI) H5 viruses have been causing flu outbreaks in poultry and wild birds. Occasionally, humans also fall victim to it, which results in high mortality. Nonetheless, HPAI virus research is often hindered, considering that it must be handled within biosafety level 3 laboratories. To address this issue, pseudoviruses are adopted as an alternative to wild-type viruses in some experiments of H5 HPAI studies. Pseudoviruses prove to be the ideal tools to study neutralizing antibodies against H5 HPAI viruses. This protocol describes the procedures and critical steps of H5 HPAI pseudovirus preparations and pseudovirus neutralization assays. Also, it discusses the troubleshooting, limitation, and modifications of these assays.

Novel electrolyte additive of graphene oxide for prolonging the lifespan of zinc-ion batteries.

Aqueous zinc-ion batteries have attracted the attention of the industry due to their low cost, good environmental friendliness, and competitive gravimetric energy density. However, zinc anodes, similar to lithium, sodium and other alkali metal anodes, are also plagued by dendrite problems. Zinc dendrites can penetrate through polymer membranes, and even glass fiber membranes which seriously hinders the development and application of aqueous zinc-ion batteries. To resolve this issue, certain additives are required. Here we have synthesized an electrochemical graphene oxide with novel electrolyte based on tryptophan, which allows to obtain few-layered sheets with a remarkably uniform morphology, good aqueous solution dispersion, easy preparation and environmental friendliness. We used this electrochemical graphene oxide as an additive to the electrolyte for aqueous zinc-ion batteries. The results of phase-field model combined with experimental characterization revealed that the addition of this material effectively promotes the uniform distribution of the electric field and the Zn-ion concentration field, reduces the nucleation overpotential of Zn metal, and provides a more uniform deposition process on the metal surface and improved cyclability of the aqueous Zn-ion battery. The resultant Zn∣Zn symmetric battery with the electrochemical graphene oxide additive affords a stable Zn anode, which provided service for more than 500 h at 0.2 mA cm-2and even more than 250 h at 1.0 mA cm-2. The Coulombic efficiency (98.7%) of Zn∣Cu half-cells and thus cyclability of aqueous Zn-ion batteries using electrochemical graphene oxide is significantly better compared to the additive-free electrolyte system. Therefore, our approach paves a promising avenue to foster the practical application of aqueous Zn-ion batteries for energy storage.

Agent Clustering Strategy Based on Metabolic Flux Distribution and Transcriptome Expression for Novel Drug Development.

The network module-based method has been used for drug repositioning. The traditional drug repositioning method only uses the gene characteristics of the drug but ignores the drug-triggered metabolic changes. The metabolic network systematically characterizes the connection between genes, proteins, and metabolic reactions. The differential metabolic flux distribution, as drug metabolism characteristics, was employed to cluster the agents with similar MoAs (mechanism of action). In this study, agents with the same pharmacology were clustered into one group, and a total of 1309 agents from the CMap database were clustered into 98 groups based on differential metabolic flux distribution. Transcription factor (TF) enrichment analysis revealed the agents in the same group (such as group 7 and group 26) were confirmed to have similar MoAs. Through this agent clustering strategy, the candidate drugs which can inhibit (Japanese encephalitis virus) JEV infection were identified. This study provides new insights into drug repositioning and their MoAs.

Occurrence, distribution and risk assessment of organophosphate ester flame retardants and plasticizers in surface seawater of the West Pacific.

Twenty-eight samples of surface seawater were collected from the West Pacific Ocean during 2019 using a high-volume solid-phase extraction with high-throughput organic analysis (Hi-throat/Hi-volume SPE) method, and concentrations of 10 organophosphate ester flame retardants and plasticizers (OPEs) were determined. The total OPE concentration in the samples was 3.02-48.4 ng L-1 (mean 25.0 ± 10.5 ng L-1), with tris(2-chloroethyl) phosphate (TCEP) being the largest contributor. Cluster analysis results showed off-shore input from the coast of East and Southeast Asia was an important source of these chemicals. Tri-p-tolyl phosphate (TpTP) should also be considered for long-term monitoring, because of its high detection frequency. Results of a risk assessment indicated low ecological risk to species in the West Pacific Ocean for TPhP and ΣOPEs. Hazard quotients (HQs) were all <1, indicating that the health risk to humans from these chemicals was at acceptable levels.

Distribution of eight organophosphorus pesticides and their oxides in surface water of the East China Sea based on high volume solid phase extraction method.

In this study, we reported the occurrence of eight organophosphorus pesticides (OPPs) in the East China Sea. Forty samples were collected and analysed with a high volume solid phase extraction method (Hi-throat/Hi-volume SPE) in the early summer of 2020. All the target OPPs were detected in the surface water at one or more stations in the East China Sea, and the concentrations of ΣOPPs were in the range 0.0775-3.09 ng/L (mean: 0.862 ± 0.624 ng/L). Terbufos sulfone and fenthion were the main pollutants in this area, probably resulting from pesticide use in China and other countries. The off-shore input from coastal regions was suggested to be a major source of OPP pollution in the East China Sea, and the movement of ocean currents played an important role in their transportation because around 0.86 t OPPs passed through the Tsushima Strait from the East China Sea each month. An ecological risk assessment showed that these OPPs presented a high risk to species in the East China Sea, whereas they posed no health risk to humans under both the median and high exposure scenario.

Isolating different natural and anthropogenic PAHs in the sediments from the northern Bering-Chukchi margin: Implications for transport processes in a warming Arctic.

Polycyclic aromatic hydrocarbons (PAHs) have become the dominating burden in the Arctic ecosystems, but their transport pathways and relative importance of different sources in the Arctic remained unclear, and this would be further complicated by climate change. Here we interpreted 27 PAHs in 34 surface sediments from the northern Bering-Chukchi margin. We integrated source apportionment methods (including diagnostic ratios, principal component analysis, hierarchical analysis, and positive matrix factorization (PMF) model) together with geochemistry parameters, which reveal a gradually clear picture of the spatial patterns of different sources. The total PAH concentrations (50.4 to 896.0 ng/g dw) exhibited a "hilly" shape with the increase of latitude, showing the highest level of PAHs in the northeast Chukchi Sea. The total BaP toxic equivalent quotient (TEQ) for carcinogenic compounds was from 1.06 to 33.3 ng TEQ/g. Most PAHs showed positive correlations with silt content, total organic carbon, stable carbon isotopes and black carbon (p < 0.01 or 0.05). Generally, source apportionment methods revealed an increasing petrogenic source of PAHs with latitudes. The PMF model further differentiated two petrogenic (36.7%), two pyrogenic (softwood and fossil fuel combustion, 35.5%) and one in-situ biogenic source (Perylene, 27.8%). An extremely high petrogenic signal was captured in the Canada Basin margin, possibly originating from the Mackenzie River via ice drifting with Beaufort Gyre, while another petrogenic source may come from coal deposit erosion by deglaciation. Softwood combustion (characterized by Retene) exhibited exclusively higher contribution in the northeast Chukchi Sea and might result from the increasing wildfire in Alaska due to climate change, whereas fossil fuel combustion exhibited similar contributions across different latitudes. Our results revealed natural PAHs as important "inside sources" in the Arctic, which are highly sensitive to global warming and deserves more attention.