De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.

FragGrow: A Web Server for Structure-Based Drug Design by Fragment Growing within Constraints.

Fragment growing is an important ligand design strategy in drug discovery. In this study, we present FragGrow, a web server that facilitates structure-based drug design by fragment growing. FragGrow offers two working modes: one for growing molecules through the direct replacement of hydrogen atoms or substructures and the other for growing via virtual synthesis. FragGrow works by searching for suitable fragments that meet a set of constraints from an indexed 3D fragment database and using them to create new compounds in 3D space. The users can set a range of constraints when searching for their desired fragment, including the fragment's ability to interact with specific protein sites; its size, topology, and physicochemical properties; and the presence of particular heteroatoms and functional groups within the fragment. We hope that FragGrow will serve as a useful tool for medicinal chemists in ligand design. The FragGrow server is freely available to researchers and can be accessed at https://fraggrow.xundrug.cn.

Optimizing the management of electrophysiology labs in Chinese hospitals using a discrete event simulation tool.

BACKGROUND: The growing demand for electrophysiology (EP) treatment in China presents a challenge for current EP care delivery systems. This study constructed a discrete event simulation (DES) model of an inpatient EP care delivery process, simulating a generalized inpatient journey of EP patients from admission to discharge in the cardiology department of a tertiary hospital in China. The model shows how many more patients the system can serve under different resource constraints by optimizing various phases of the care delivery process. METHODS: Model inputs were based on and validated using real-world data, simulating the scheduling of limited resources among competing demands from different patient types. The patient stay consists of three stages, namely: the pre-operative stay, the EP procedure, and the post-operative stay. The model outcome was the total number of discharges during the simulation period. The scenario analysis presented in this paper covers two capacity-limiting scenarios (CLS): (1) fully occupied ward beds and (2) fully occupied electrophysiology laboratories (EP labs). Within each CLS, we investigated potential throughput when the length of stay or operative time was reduced by 10%, 20%, and 30%. The reductions were applied to patients with atrial fibrillation, the most common indication accounting for almost 30% of patients. RESULTS: Model validation showed simulation results approximated actual data (137.2 discharges calculated vs. 137 observed). With fully occupied wards, reducing pre- and/or post-operative stay time resulted in a 1-7% increased throughput. With fully occupied EP labs, reduced operative time increased throughput by 3-12%. CONCLUSIONS: Model validation and scenario analyses demonstrated that the DES model reliably reflects the EP care delivery process. Simulations identified which phases of the process should be optimized under different resource constraints, and the expected increases in patients served.

MolTaut: A Tool for the Rapid Generation of Favorable Tautomer in Aqueous Solution.

Fast and proper treatment of the tautomeric states for drug-like molecules is critical in computer-aided drug discovery since the major tautomer of a molecule determines its pharmacophore features and physical properties. We present MolTaut, a tool for the rapid generation of favorable states of drug-like molecules in water. MolTaut works by enumerating possible tautomeric states with tautomeric transformation rules, ranking tautomers with their relative internal energies and solvation energies calculated by AI-based models, and generating preferred ionization states according to predicted microscopic pKa. Our test shows that the ranking ability of the AI-based tautomer scoring approach is comparable to the DFT method (wB97X/6-31G*//M062X/6-31G*/SMD) from which the AI models try to learn. We find that the substitution effect on tautomeric equilibrium is well predicted by MolTaut, which is helpful in computer-aided ligand design. The source code of MolTaut is freely available to researchers and can be accessed at https://github.com/xundrug/moltaut. To facilitate the usage of MolTaut by medicinal chemists, we made a free web server, which is available at http://moltaut.xundrug.cn. MolTaut is a handy tool for investigating the tautomerization issue in drug discovery.

High-altitude hypoxia-induced rat alveolar cell injury by increasing autophagy.

Autophagy has been implicated in the pathogenesis of various lung diseases. This study aimed to investigate the role of autophagy in lung injury induced by high-altitude hypoxia. Wistar rats were randomized into four groups for exposure to normal altitude or high altitude for 1, 7, 14 and 21 days with no treatment or with the treatment of 1 mg/kg rapamycin or 2 mg/kg 3-methyladenine (3-MA) for consecutive 21 days respectively. In control rats, the alveolar structure was intact with regularly arranged cells. However, inflammatory cell infiltration and shrunk alveoli were observed in rats exposed to hypoxia. Rapamycin treatment led to many shrunken alveoli with a large number of red blood cells in them. In contrast, 3-MA treatment led to almost intact alveoli or only a few shrunken alveoli. Compared to the control group exposure to high-altitude hypoxia for longer periods resulted in the aggravation of the lung injury, the formation of autophagosomes with a double-membrane structure and increased levels of Beclin-1 and LC3-II in alveolar tissues. Rapamycin treatment resulted in significant increase in Beclin-1 and LC3-II levels and further aggravation of alveolar tissue damage, while 3-MA treatment led to opposite effects. In conclusion, exposure to high-altitude hypoxia can induce autophagy of alveolar cells, which may be an important mechanism of high-altitude hypoxia-induced lung injury. The inhibition of autophagy may be a promising therapy strategy for high-altitude hypoxia-induced lung injury.

MolHyb: A Web Server for Structure-Based Drug Design by Molecular Hybridization.

Molecular hybridization is a widely used ligand design method in drug discovery. In this study, we present MolHyb, a web server for structure-based ligand design by molecular hybridization. The input of MolHyb is a protein file and a seed compound file. MolHyb tries to generate novel ligands through hybridizing the seed compound with helper compounds that bind to the same protein target or similar proteins. To facilitate the job of getting helper compounds, we compiled a modeled protein-ligand structure database as an extension to crystal structures in the PDB database by placing the bioactive compounds in ChEMBL into their corresponding 3D protein binding pocket properly. MolHyb works by searching for helper compounds from the protein-ligand structure database and migrating chemical moieties from helper compounds to the seed compound efficiently. Hybridization is performed at both cyclic and acyclic bonds. The users can also input their own helper compounds to MolHyb. We hope that MolHyb will be a useful tool for rational drug design. MolHyb is freely available at http://molhyb.xundrug.cn/.

AA-Score: a New Scoring Function Based on Amino Acid-Specific Interaction for Molecular Docking.

The protein-ligand scoring function plays an important role in computer-aided drug discovery and is heavily used in virtual screening and lead optimization. In this study, we developed a new empirical protein-ligand scoring function with amino acid-specific interaction components for hydrogen bond, van der Waals, and electrostatic interactions. In addition, hydrophobic, π-stacking, π-cation, and metal-ligand interactions are also included in the new scoring function. To better evaluate the performance of the AA-Score, we generated several new test sets for evaluation of scoring, ranking, and docking performances, respectively. Extensive tests show that AA-Score performs well on scoring, docking, and ranking as compared to other widely used traditional scoring functions. The performance improvement of AA-Score benefits from the decomposition of individual interaction into amino acid-specific types. To facilitate applications, we developed an easy-to-use tool to analyze protein-ligand interaction fingerprint and predict binding affinity using the AA-Score. The source code and associated running examples can be found at https://github.com/xundrug/AA-Score-Tool.

Occurrence, Spatial Distribution and Health Risk of Hexabromocyclododecane (HBCD) in Source Water in the Lower Yangtze River, China.

The occurrence and health risk of hexabromocyclododecane (HBCD), a brominated flame retardant with its three diastereoisomers, in drinking water sources in the lower Yangtze River in China was investigated. Its concentration ranged from 0.58 to 3.71 ng/L and averaged at 1.18 ng/L. Among the three diastereoisomers of α-, ß- and γ-HBCD, γ-HBCD was the dominant one accounting for 44% (ranging 27-82%) to the total concentration. Source of HBCD in the contaminated site was discussed according to its spatial distribution and diastereoisomer profile. The margin of exposure (MOE) approach was applied to evaluate the health risk of HBCD through drinking water by estimated exposure and derived reference dose. The MOE was 17 for adults and 12 for children in the worst-case scenario, suggesting a trivial health concern.

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections.

Mediterranean spotted fever is a reemerging acute tick-borne infection produced by the α-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells. Of the 104 proteins whose abundance changed significantly in the R. conorii-infected human umbilical vein endothelial cells' secretome, 46 proteins were up-regulated: 45 were host secreted proteins (including cytokines), and 1 was a rickettsial protein, the putative N-acetylmuramoyl-l-alanine amidase RC0497. Proteins with sequence highly homologous to RC0497 were found to be shared by many species of the spotted fever group rickettsiae, but not typhus group rickettsiae. Quantitative targeted proteomics studies of plasma from a mouse model of sublethal and lethal R. conorii identified RC0497 in the blood, and its circulating levels were proportionally associated with infection outcome. Finally, the presence of RC0497 in the serum samples from a cohort of humans presenting with acute rickettsioses was confirmed. The detection of RC0497 has the potential to be a sensitive and specific marker for acute rickettsial spotted rickettsioses.

Perfluoroalkyl substances in drinking water sources along the Yangtze River in Jiangsu Province, China: Human health and ecological risk assessment.

Perfluoroalkyl substances (PFASs) in source water is of growing concern for its adverse effects on human health and wildlife as well. The Yangtze River is the vital drinking water source in Jiangsu Province of China, but little attention has been paid on PFASs. The occurrence, spatial distribution and temporal trend of PFASs in 21 water sources along the Jiangsu section of the Yangtze River was investigated with sampling from 2018 to 2020. Moreover, health risk of PFASs was assessed by estimated intake dose and derived tolerable intake dose, while ecological risk was assessed by selected effect concentration and environmental exposure. PFASs concentrations in source water ranged from 12.0 to 128 ng/L, with perfluorooctanoic acid (PFOA) as the dominated congener. Fluorine chemical industry lead to a great increase of perfluorohexanoic acid (PFHxA) in its nearest water source. The estimated daily intake of PFASs through drinking was 0.54 and 0.82 ng/kg bw/day for adults and children. The major health risk was from perfluorooctane sulfonate (PFOS) and PFOA for their toxicity on liver, reproduction, development and immunity, with the maximum hazard quotient of 0.029 and 0.043 for adults and children in the worst scenario. The ecological risks from PFASs on nine species groups ranged from 2.7 × 10-10 to 5.2. PFOA and Perfluorobutane sulfonate (PFBS) were causing significant risk on wildlife, particularly on worms, mussels, and fish, which may further influence the structure and processes in the foodweb. Overall, PFASs, especially PFOS, PFOA and PFBS, induced considerable risk on human health and aquatic species in some hotspot area. It would be necessary to include them into monitoring in China and develop standards for different protection purposes.

The Role of Biochar in Reducing the Bioavailability and Migration of Persistent Organic Pollutants in Soil-Plant Systems: A Review.

The amendment of biochar in soils contaminated with persistent organic pollutants (POPs) is an environmentally friendly in situ remediation measure. Numerous studies focused on the application of biochars to reduce the uptake of POPs by plants in soils. In this review, we summarized the role of biochar in reducing the migration of POPs in soil-plant systems. The mechanisms of biochar reducing the bioavailability of POPs in the soil, i.e. immobilization and promoted biodegradation, and the influencing factors are fully discussed. Especially in rhizosphere amended with biochar, the synergistic effect of POPs-root exudates-microorganisms on the reduced bioavailability of POPs is analyzed. This paper suggests that future researches should focus on the long-term environmental fate of POPs sorbed on high-temperature biochars and the long-term impacts of low-temperature biochars on the interaction of POPs-root exudates-rhizosphere microorganisms. All the above are necessary for efficient and safe use of biochar for remediating POP-contaminated farmland soils.

Type II Epithelial-Mesenchymal Transition Upregulates Protein N-Glycosylation To Maintain Proteostasis and Extracellular Matrix Production.

Type II epithelial-mesenchymal transition (EMT) plays a vital role in airway injury, repair, and remodeling. Triggered by growth factors, such as transforming growth factor beta (TGFß), EMT induced a biological process that converts epithelial cells into secretory mesenchymal cells with a substantially increased production of extracellular matrix (ECM) proteins. Epithelial cells are not professional secretory cells and produce few ECM proteins under normal conditions. The molecular mechanism underlying the transformation of the protein factory and secretory machinery during EMT is significant because ECM secretion is central to the pathogenesis of airway remodeling. Here we report that type II EMT upregulates the protein N-glycosylation of ECMs. The mechanism study reveals that the substantial increase in synthesis of ECM proteins in EMT activates the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 (XBP1) axis of the unfolded protein response (UPR) coupled to the hexosamine biosynthesis pathway (HBP). These two pathways coordinately up-regulate the protein N-glycosylation of ECM proteins and increase ER folding capacity and ER-associated degradation (ERAD), which improve ER protein homeostasis and protect transitioned cells from proteotoxicity. Inhibition of the alternative splicing of XBP1 or protein N-glycosylation blocks ECM protein secretion, indicating the XBP1-HBP plays a prominent role in regulating the secretion of ECM proteins in the mesenchymal transition. Our data suggest that the activation of XBP1-HBP pathways and elevation of protein N-glycosylation is an adaptive response to maintain protein quality control and facilitate the secretion of ECM proteins during the mesenchymal transition. The components of the XBP1-HBP pathways may be therapeutic targets to prevent airway remodeling.

Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus-Induced Lower Respiratory Tract Infections.

Lower respiratory tract infections from respiratory syncytial virus (RSV) are due, in part, to secreted signals from lower airway cells that modify the immune response and trigger airway remodeling. To understand this process, we applied an unbiased quantitative proteomics analysis of the RSV-induced epithelial secretory response in cells representative of the trachea versus small airway bronchiolar cells. A workflow was established using telomerase-immortalized human epithelial cells that revealed highly reproducible cell type-specific differences in secreted proteins and nanoparticles (exosomes). Approximately one third of secretome proteins are exosomal; the remainder are from lysosomal and vacuolar compartments. We applied this workflow to three independently derived primary human cultures from trachea versus bronchioles. A total of 577 differentially expressed proteins from control supernatants and 966 differentially expressed proteins from RSV-infected cell supernatants were identified at a 1% false discovery rate. Fifteen proteins unique to RSV-infected primary human cultures from trachea were regulated by epithelial-specific ets homologous factor. A total of 106 proteins unique to RSV-infected human small airway epithelial cells was regulated by the transcription factor NF-κB. In this latter group, we validated the differential expression of CCL20/macrophage-inducible protein 3α, thymic stromal lymphopoietin, and CCL3-like 1 because of their roles in Th2 polarization. CCL20/macrophage-inducible protein 3α was the most active mucin-inducing factor in the RSV-infected human small airway epithelial cell secretome and was differentially expressed in smaller airways in a mouse model of RSV infection. These studies provide insights into the complexity of innate responses and regional differences in the epithelial secretome participating in RSV lower respiratory tract infection-induced airway remodeling.

Quantitative Assessment of the Effects of Trypsin Digestion Methods on Affinity Purification-Mass Spectrometry-based Protein-Protein Interaction Analysis.

Affinity purification-mass spectrometry (AP-MS) has become the method of choice for discovering protein-protein interactions (PPIs) under native conditions. The success of AP-MS depends on the efficiency of trypsin digestion and the recovery of the tryptic peptides for MS analysis. Several different protocols have been used for trypsin digestion of protein complexes in AP-MS studies, but no systematic studies have been conducted on the impact of trypsin digestion conditions on the identification of PPIs. Here, we used NFκB/RelA and Bromodomain-containing protein 4 (BRD4) as baits and test five distinct trypsin digestion methods (two using "on-beads," three using "elution-digestion" protocols). Although the performance of the trypsin digestion protocols change slightly depending on the different baits, antibodies and cell lines used, we found that elution-digestion methods consistently outperformed on-beads digestion methods. The high-abundance interactors can be identified universally by all five methods, but the identification of low-abundance RelA interactors is significantly affected by the choice of trypsin digestion method. We also found that different digestion protocols influence the selected reaction monitoring (SRM)-MS quantification of PPIs, suggesting that optimization of trypsin digestion conditions may be required for robust targeted analysis of PPIs.

Selective Affinity Enrichment of Nitrotyrosine-Containing Peptides for Quantitative Analysis in Complex Samples.

Protein tyrosine nitration by oxidative and nitrate stress is important in the pathogenesis of many inflammatory or aging-related diseases. Mass spectrometry analysis of protein nitrotyrosine is very challenging because the non-nitrated peptides suppress the signals of the low-abundance nitrotyrosine (NT) peptides. No validated methods for enrichment of NT-peptides are currently available. Here we report an immunoaffinity enrichment of NT-peptides for proteomics analysis. The effectiveness of this approach was evaluated using nitrated protein standards and whole-cell lysates in vitro. A total of 1881 NT sites were identified from a nitrated whole-cell extract, indicating that this immunoaffinity-MS method is a valid approach for the enrichment of NT-peptides, and provides a significant advance for characterizing the nitrotyrosine proteome. We noted that this method had higher affinity to peptides with N-terminal nitrotyrosine relative to peptides with other nitrotyrosine locations, which raises the need for future study to develop a pan-specific nitrotyrosine antibody for unbiased, proteome-wide analysis of tyrosine nitration. We applied this method to quantify the changes in protein tyrosine nitration in mouse lungs after intranasal poly(I:C) treatment and quantified 237 NT sites. This result indicates that the immunoaffinity-MS method can be used for quantitative analysis of protein nitrotyrosines in complex samples.

BRD4 mediates NF-κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation.

Chronic epithelial injury triggers a TGF-ß-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-ß induces the mesenchymal cell state and determined its mechanism. We observed that TGF-ß stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-κB/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-ß challenge in a mouse model. These data provide a detailed mechanism for how activated NF-κB and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.

Urban and rural transport of semivolatile organic compounds at regional scale: A multimedia model approach.

Urban areas are generally regarded as major sources of some semivolatile organic compounds and other persistent organic pollutants (POPs) to the surrounding regions. Huge differences in contaminant emissions between urban and rural areas directly affect their fate in environmental media. Little is known about POPs behavior between urban and rural areas at a regional scale. A spatially resolved Berkeley-Trent-Urban-Rural Fate Model (BETR-UR) was designed by coupling land cover information to simulate the transport of POPs between urban and rural areas, and the Bohai Rim was used as a case study to estimate Polycyclic Aromatic Hydrocarbon (PAH) fate. The processes of contaminant fate including emission, inter-compartmental transfer, advection and degradation in urban and rural areas were simulated in the model. Simulated PAH concentrations in environmental media of urban and rural areas were very close to measured values. The model accuracy was highly improved, with the average absolute relative error for PAH concentrations reduced from 37% to 3% compared with unimproved model results. PAH concentrations in urban soil and air were considerably higher than those in rural areas. Sensitivity analysis showed temperature was the most influential parameter for Phen rather than for Bap, whose fate was more influenced by emission rate, compartment dimension, transport velocity and chemical persistence. Uncertainty analysis indicated modeled results in urban media had higher uncertainty than those in rural areas due to larger variations of emissions in urban areas. The differences in urban and rural areas provided us with valuable guidance on policy setting for urban-rural POP control.

Emerging and legacy per- and polyfluoroalkyl substances (PFAS) in fluorochemical wastewater along full-scale treatment processes: Source, fate, and ecological risk.

The increasing applications of emerging per- and polyfluoroalkyl substances (PFAS) have raised global concern. However, the release of emerging PFAS from the fluorochemical industry remains unclear. Herein, the occurrence of 48 emerging and legacy PFAS in wastewater from 10 fluorochemical manufacturers and mass flows of PFAS in a centralized wastewater treatment plant were investigated. Their distribution and ecological risk in neighboring riverine water were also evaluated. In wastewater from fluorochemical manufacturers, PFAS concentrations were in the range of 14,700-5200,000 ng/L and 2 H,2 H-perfluorooctanoic acid (6:2 FTCA), perfluorooctanoic acid (PFOA), N-ethyl perfluorooctane sulfonamide (N-EtFOSA), and 1 H,1 H,2 H,2 H-perfluorodecanesulfonate (8:2 FTS) were the major PFAS detected. Several PFAS displayed increased mass flows after wastewater treatment, especially PFOA and 6:2 FTCA. The mass flows of PFAS increased from - 20% to 233% after the activated sludge system but decreased by only 0-13% after the activated carbon filtration. In riverine water, PFAS concentrations were in the range of 5900-39,100 ng/L and 6:2 FTCA, 1 H,1 H,2 H,2 H-perfluorodecyl phosphate monoester (8:2 monoPAP), 1 H,1 H,2 H,2 H-perfluorooctyl phosphate monoester (6:2 monoPAP), PFOA, and perfluorohexanoic acid (PFHxA) were the major PFAS detected. PFOA and 6:2 FTCA exhibited comparable hazard quotients for ecological risk. Current wastewater treatment processes cannot fully remove various PFAS discharged by fluorochemical manufacturers, and further investigations on their risk are needed for better chemical management.

Transport and health risk of legacy and emerging per-and polyfluoroalkyl substances in the water cycle in an urban area, China: Polyfluoroalkyl phosphate esters are of concern.

Polyfluoroalkyl phosphate esters (PAPs) are a group of emerging alternatives to the legacy per- and polyfluoroalkyl substances (PFAS). To better understand the transport and risk of PAPs in the water cycle, 21 PFAS including 4 PAPs and 17 perfluoroalkyl acids were investigated in multiple waterbodies in an urban area, China. PFAS concentrations ranged from 85.8 to 206 ng/L, among which PAPs concentrations ranged from 35.0 to 71.8 ng/L, in river and lake water with major substances of perfluorooctanoic acid (PFOA), 6:2 fluorotelomer phosphate (6:2 monoPAP), and 8:2 fluorotelomer phosphate (8:2 monoPAP). As transport pathways, municipal wastewater and precipitation were investigated for PFAS mass loading estimation, and PAPs transported via precipitation more than municipal wastewater discharge. Concentrations of PFAS in tap water and raw source water were compared, and PAPs cannot be removed by drinking water treatment. In tap water, PFAS concentrations ranged from 132 to 271 ng/L and among them PAPs concentrations ranged from 41.6 to 61.9 ng/L. Human exposure and health risk to PFAS via drinking water were assessed, and relatively stronger health risks were induced from PFOS, PAPs, and PFOA. The environmental contamination and health risk of PAPs are of concern, and management implications regarding their sources, exposure, and hazards were raised.