DrugFlow: An AI-Driven One-Stop Platform for Innovative Drug Discovery.

Artificial intelligence (AI)-aided drug design has demonstrated unprecedented effects on modern drug discovery, but there is still an urgent need for user-friendly interfaces that bridge the gap between these sophisticated tools and scientists, particularly those who are less computer savvy. Herein, we present DrugFlow, an AI-driven one-stop platform that offers a clean, convenient, and cloud-based interface to streamline early drug discovery workflows. By seamlessly integrating a range of innovative AI algorithms, covering molecular docking, quantitative structure-activity relationship modeling, molecular generation, ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction, and virtual screening, DrugFlow can offer effective AI solutions for almost all crucial stages in early drug discovery, including hit identification and hit/lead optimization. We hope that the platform can provide sufficiently valuable guidance to aid real-word drug design and discovery. The platform is available at https://drugflow.com.

pOpsicle: An all-optical reporter system for synaptic vesicle recycling combining pH-sensitive fluorescent proteins with optogenetic manipulation of neuronal activity.

pH-sensitive fluorescent proteins are widely used to study synaptic vesicle (SV) fusion and recycling. When targeted to the lumen of SVs, fluorescence of these proteins is quenched by the acidic pH. Following SV fusion, they are exposed to extracellular neutral pH, resulting in a fluorescence increase. SV fusion, recycling and acidification can thus be tracked by tagging integral SV proteins with pH-sensitive proteins. Neurotransmission is generally activated by electrical stimulation, which is not feasible in small, intact animals. Previous in vivo approaches depended on distinct (sensory) stimuli, thus limiting the addressable neuron types. To overcome these limitations, we established an all-optical approach to stimulate and visualize SV fusion and recycling. We combined distinct pH-sensitive fluorescent proteins (inserted into the SV protein synaptogyrin) and light-gated channelrhodopsins (ChRs) for optical stimulation, overcoming optical crosstalk and thus enabling an all-optical approach. We generated two different variants of the pH-sensitive optogenetic reporter of vesicle recycling (pOpsicle) and tested them in cholinergic neurons of intact Caenorhabditis elegans nematodes. First, we combined the red fluorescent protein pHuji with the blue-light gated ChR2(H134R), and second, the green fluorescent pHluorin combined with the novel red-shifted ChR ChrimsonSA. In both cases, fluorescence increases were observed after optical stimulation. Increase and subsequent decline of fluorescence was affected by mutations of proteins involved in SV fusion and endocytosis. These results establish pOpsicle as a non-invasive, all-optical approach to investigate different steps of the SV cycle.

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis.

All currently licensed medications for multiple sclerosis (MS) target the immune system. Albeit promising preclinical results demonstrated disease amelioration and remyelination enhancement via modulating oligodendrocyte lineage cells, most drug candidates showed only modest or no effects in human clinical trials. This might be due to the fact that remyelination is a sophistically orchestrated process that calls for the interplay between oligodendrocyte lineage cells, neurons, central nervous system (CNS) resident innate immune cells, and peripheral immune infiltrates and that this process may somewhat differ in humans and rodent models used in research. To ensure successful remyelination, the recruitment and activation/repression of each cell type should be regulated in a highly organized spatio-temporal manner. As a result, drug candidates targeting one single pathway or a single cell population have difficulty restoring the optimal microenvironment at lesion sites for remyelination. Therefore, when exploring new drug candidates for MS, it is instrumental to consider not only the effects on all CNS cell populations but also the optimal time of administration during disease progression. In this review, we describe the dysregulated mechanisms in each relevant cell type and the disruption of their coordination as causes of remyelination failure, providing an overview of the complex cell interplay in CNS lesion sites.

Influence of fuel oil on Platymonas helgolandica: An acute toxicity evaluation to amino acids.

It is highly likely that the toxicity of water accommodated fractions (WAF) will influence marine microalgae, and consequently lead to potential risk for the marine ecological environment. However, it was often neglected whether WAF can influence the transformation of relative compounds in organisms. The metabolism of amino acids (AAs) can be used to track physiological changes in microalgae because amino acids are the basis of proteins and enzymes. In this study, using marine Chlorophyta Platymonas helgolandica as the test organism, the effects of different concentrations of WAF on AA compositions and stable carbon isotope ratios (δ13C) of individual AAs of Platymonas helgolandica were investigated. The results showed that the WAF of #180 fuel oil had an obvious suppressing effect on the growth and chlorophyll a content of microalgae. The growth inhibitory rate at 96 h was 80.66% at a WAF concentration of 0.50 mg L-1 compared with the control. Furthermore, seven among the 16 AAs, including alanine, cysteine, proline, aspartic acid, lysine, histidine and tyrosine, had relatively high abundance. Under the glycolysis pathway, the cysteine abundance was higher than control, meaning that the biosynthesized pathway of alanine through cysteine as a precursor could be damaged. Phosphoenolpyruvate (PEP) was an important synthesis precursor of alanine (leucine) and aromatic AA family (Phenylalanine and tyrosine), and played an important role in δ13CAAs fractionation under the WAF stress. Under the TCA pathway, to protect cell metabolism activities under WAF stress, the δ13C value of threonine and proline abundance in microalgae with the increase in WAF stress. Therefore, δ13CAAs fractionation can be used as a novel method for toxicity evaluation of WAF on future.

Field study on bioaccumulation and translocation of polybrominated diphenyl ethers in the sediment-plant system of a national nature reserve, North China.

Polybrominated diphenyl ethers (PBDEs) are the ubiquitous contaminants in the coastal wetlands, with high persistence and toxicity. Environmental behaviors of PBDEs in sediment-plant system is a hot research area, where much uncertainties still occurred in field environment. In this study, the sediments and Suaeda heteroptera were synchronously collected to investigate the bioaccumulation and translocation of PBDEs in Liaohe coastal wetland. Mean concentrations of PBDEs in sediments, roots, stems and leaves were 8.37, 6.64, 2.42 and 1.40 ng/g d.w., respectively. Tissue-specific accumulation of PBDEs were detected in Suaeda heteroptera, with predominant accumulation in roots. Congener patterns of PBDEs were similar between sediments and roots, demonstrating root uptake as the key pathway of PBDE bioaccumulation. The proportions of lower brominated congeners increased from roots to leaves, implying the congener-specific translocation. Meanwhile, the lower brominated congeners exhibited higher sediment-tissue bioaccumulation (AFs) and translocation factors (TFs) compared to higher brominated congeners in Suaeda heteroptera, further verifying their preferential translocation. AFs and TFs of PBDEs were both not correlated with their log Kow, which was inconsistent with those of laboratory studies, reflecting the complicated behaviors of PBDEs in field environment. This is the first comprehensive report on bioaccumulation and translocation of PBDEs within Suaeda heteroptera in Liaohe coastal wetland.

Effect of water accommodated fractions of fuel oil on fixed carbon and nitrogen by microalgae: Implication by stable isotope analysis.

Effect of water accommodated fractions (WAF) of #180 fuel oil on fixed carbon and nitrogen in microalgae was studied by stable isotopes. Platymonas helgolandica, Heterosigma akashiwo and Nitzschia closterium were exposed to five WAF concentrations for 96 h. The δ13C value of microalgae was significantly lower than that of the control group, indicated that carbon was limited in the WAF concentrations. The δ13C value of microalgae appeared peak valley at 48 h in control group, corresponding to the enhanced capacity in carbon fixation during microalgae photosynthesis. The physiological acclimation capacity of microalgae was revealed by the occurrence time when the δ13C value was in peak valley, and thus the physiological acclimation capacity of microalgae decreased in the order of Nitzschia closterium > Heterosigma akashiwo > Platymonas helgolandica. Principal component analysis (PCA) were applied to the δ13C value in order to verify the "hormesis" phenomenon in microalgae. The δ13C value could discriminate between stimulatory effects at low doses and inhibitory effects at high doses. In addition, the present study also investigated the effect of the nitrogen on microalgae growth. Because microalgae could still absorb the NO3-N and release of NO2-N and NH4-N in present study, the nitrogen cycle in microalgae was in the equilibrium status. The δ15N value in microalgae exhibited no obvious change with the increasing of WAF concentrations at the same time. However, due to the enrichment of nitrogen, the δ15N value first increased gradually with the time and finally was stable. Overall, the fractionation of carbon and nitrogen stable isotopes illustrated that the effect of carbon on the growth of microalgae was more prominent than nitrogen. Stable isotopes was used to investigate the influence of WAF on fixed carbon and nitrogen in microalgae growth, providing a fundamental theoretical guidance for risk assessment of marine ecological environment.

Assessing microbial degradation degree and bioavailability of BDE-153 in natural wetland soils: Implication by compound-specific stable isotope analysis.

Microbial degradation is an important pathway for the attenuation of polybrominated diphenyl ethers (PBDEs) in natural soils. In this study, the compound-specific stable isotope analysis (CSIA) was applied to characterize microbial degradation of BDE-153, one of the prevailing and toxic PBDE congeners, in natural wetland soils. During the 45-day incubation, the residual percentages of BDE-153 decreased to 67.9% and 73.6% in non-sterilized soils spiked with 1.0 and 5.0 µg/g, respectively, which were both much lower than those in sterilized soils (96.0% and 97.2%). This result indicated that microbial degradation could accelerate BDE-153 elimination in wetland soils. Meanwhile, the significant carbon isotope fractionation was observed in non-sterilized soils, with δ13C of BDE-153 shifting from -29.4‰ to -26.7‰ for 1.0 µg/g and to -27.2‰ for 5.0 µg/g, respectively, whilst not in sterilized soils. This phenomenon indicated microbial degradation could induce stable carbon isotope fractionation of BDE-153. The carbon isotope enrichment factor (εc) for BDE-153 microbial degradation was first determined as -7.58‰, which could be used to assess the microbial degradation and bioavailability of BDE-153 in wetland soils. Based on δ13C and εc, the new methods were developed to dynamically and quantitatively estimate degradation degree and bioavailability of BDE-153 during degradation process, respectively, which could exclude interference of physical processes. This work revealed that CSIA was a promising method to investigate in situ microbial degradation of PBDEs in field studies.

The influence of carbon limitation on growth of Heterosigma akashiwo: A case study in fatty acids composition.

Heterosigma akashiwo is an algal blooms species, and thus selected as the target microalgae in this work. This study attempted to investigate the influence of carbon limitation on the growth of H. akashiwo. Experiments were carried out in CO2-unlimited and CO2-limited systems (both include three nutritional groups). The stable isotope signatures and compound-specific stable three nutritional groups carbon isotopic composition of fatty acids were measured. Here we hypothesized that the carbon limitation could lead to the enriched of stable isotope ratios in the H. akashiwo. The results showed that carbon limitation made δ13C and δ13CFAs values more and more enriched in H. akashiwo. δ13C values were enriched in normal group of H. akashiwo within CO2-limited. δ15N values were enriched in nitrogen deficiency of H. akashiwo within both CO2-unlimited and CO2-limited. Furthermore, compared with the exponential phase, the enriched in δ13C was detected during the stationary phase in H. akashiwo within CO2-limited. A total of 8 major FAs were detected in H. akashiwo. Within CO2-unlimited, nitrogen deficiency promoted the synthesis of 4 FAs (14:1n-5c, 16:0, 18:0 and 18:3n-6c) in exponential phase. Within CO2-limited, nitrogen deficiency promoted the synthesis of FAs 14:0, 16:0 and 18:3n-3c, while phosphorus deficiency promoted the synthesis of all 6 FAs in exponential phase. δ13CFAs of H. akashiwo within CO2-limited showed the valley values and were significantly greater than those within CO2-unlimited. Furthermore, δ13CFAs of stationary phase were greater than those of exponential phase. δ13C14:1n-5c in nitrogen deficiency were the highest of the three nutrient groups within CO2-unlimited. This may point out that δ13CFAs could become an indicator of marine phytoplankton blooms. Overall, the present study may provide a novel approach to investigate the physiology and lipid metabolism of H. akashiwo blooms by using stable isotope ratios coupled with FAs profiles.

Geographical distributions and human exposure of organophosphate esters in college library dust from Chinese cities.

Organophosphate esters (OPEs) in indoor dust were closely related to human health. However, OPE contamination in college library dust remained unknown at present. In this study, OPEs were first investigated in 78 indoor dust samples and 26 field blanks of 26 college libraries from 13 prefecture-level cities across China between October and December 2017. The total OPEs fell in the range of 8706-34872 ng/g, and were dominated by tris(2-chloroisopropyl) phosphate (TCIPP), tris(2-chloroethyl) phosphate (TCEP) and tris(2-butoxyethyl) phosphate (TBOEP). OPEs exhibited geography-specific distributions, with high levels in Beijing, Shanghai and Guangzhou. OPEs significantly correlated with population density and gross domestic product (p < 0.01), indicating the distinct effect of these two indicators on OPE pollution. Analysis of pollution source indicated volatilization and abrasion as main emission pathways of OPEs from OPEs-added products to dust. The daily exposure doses (DEDs) of OPEs via dust ingestion, inhalation and dermal contact were similar for male and female students, ranging from 1.35 to 5.92 ng/kg-bw/day during study time in libraries (25% of day). High DEDs were found in Beijing, shanghai and Guangzhou, indicating high exposure risk of OPEs to college students in large cities. The non-carcinogenic and carcinogenic risks of OPEs to college students were quantitatively evaluated based on the oral reference dose and cancer slope factor of OPEs recently updated by USEPA, and all much lower than the threshold risk values. However, the potential risk may occur if exposure to OPEs is high in other microenvironments over remaining hours of the day.

Geographical origin traceability and species identification of three scallops (Patinopecten yessoensis, Chlamys farreri, and Argopecten irradians) using stable isotope analysis.

Traceability and authenticity is crucial to the food safety of scallop. The present study investigated the possibility of using stable isotope analysis to identify the origins and species of scallops (Patinopecten yessoensis, Chlamys farreri, and Argopecten irradians) in the coastal areas of China. The δ13C and δ15N values of a total of 575 samples from seven sites around China were determined and additional 150 samples were tested by fisher linear discrimination analysis (LDA) to estimate the accuracy of origin identification and species prediction. The results show that the stable C and N isotope composition differed significantly depending on the origin, season and species of scallops. Meanwhile, the LDA shows that 92% of the samples were correctly classified for origin prediction, and an accuracy of 98.3% was obtained for species prediction. This study reveals that stable isotope ratio is an effective technique to trace the geographical origin and identify the species of scallops.

Combined use of fatty acid profile and fatty acid δ13C fingerprinting for origin traceability of scallops (Patinopecten yessoensis, Chlamys farreri, and Argopecten irradians).

The aim of this study was to evaluate the combination of fatty acid profile and fatty acid δ13C fingerprinting to identify the origins of scallops. Fatty acid contents, as well as fatty acid δ13C values of 300 samples of three scallop species (Patinopecten yessoensis, Chlamys farreri, and Argopecten irradians) from seven sites in China were determined. Principal component analysis was performed on datasets to evaluate their performance of classification. Moreover, 75 samples were tested by discrimination analysis to estimate the accuracy of origin prediction. The results show that the accuracy rate of fatty acid profile and fatty acid δ13C fingerprinting for origin prediction was 92% and 85.3%, respectively. The combination of these two methods improved the identification, with an accuracy rate of 100.0%. These results indicate that the combination of fatty acid profile and fatty acid δ13C fingerprinting can be a precise and promising tool for origin traceability of scallops.

Effects of CO2 restriction on growth of Nitzschia closterium: Evidence from stable isotopes and fatty acids.

Algae blooms frequently occur in the coastal areas of China, and pose numbers of adverse effects to marine environment. Nitzschia closterium is one of the algal species associated with algae blooms and was selected as the target algae of this work. This study was the first attempt to investigate the effect of carbon source restriction on the growth of N. closterium during marine phytoplankton blooms. Experiments were implemented in the CO2-restricted (include three nutritional conditions) and CO2-unrestricted systems, respectively. The stable isotope ratios (δ13C and δ15N) and fatty acids (FAs) profiles were measured. Here we hypothesized that the deficient carbon source could lead to the changes of stable isotope ratios and FAs profiles in the N. closterium. The results showed that the δ13C of N. closterium enriched under the CO2 restriction during the culture time (the isotopic difference greater than 27.8‰), whereas depleted under CO2-unrestricted system. Furthermore, within the CO2 restriction, δ15N showed the enrichment trend with increasing culture time under the nitrogen deficiency conditions, where leveled off under the nitrogen non-deficiency conditions. A total of 12 FAs in N. closterium were detected. Within CO2 restriction, FA 20:5n-3c was the predominant congener in all the three conditions. In addition, FA 16:1n-7c was highest in nitrogen deficient, while FA 16:3 was highest in phosphorus deficient condition. Consequently, the deficient carbon sources leaded to inhibit the FA (14:0, 16:0, 16:1n-7c, 16:3, 18:0, 18:3n-3c) synthesis. Overall, the present study provided the new approach to investigate the forming mechanisms of marine phytoplankton blooms by using stable carbon and nitrogen isotope compositions as well as FAs profiles.

Effect of oil spill on compound-specific stable carbon isotope composition of amino acid in Nitzschia closterium and Heterosigma akashiwo.

Marine microalgae, the most important primary producers in marine ecosystems, are susceptible to toxicants and usually selected as the promising organisms for chemical risk testing. The stable carbon isotope ratios (δ13C) of amino acids (AAs) were measured to determine if compound-specific stable isotope analysis could be used to provide insight into the toxic effects of oil spill on the marine microalgae. The water accommodated fractions (WAF) of #180 fuel oil were selected as the toxic targets with different concentrations in acute (96 h) toxic tests. Naphthalene, phenanthrene, anthracene, and fluoranthene were detected as the predominant congeners of polycyclic aromatic hydrocarbons in the WAF, and may be the main toxic components. At the same WAF concentration, the δ13C values of leucine in Nitzschia closterium increased with the culture time, whereas decreased in Heterosigma akashiwo. However, with the increasing WAF concentrations, the δ13C values of glutamic acid exhibited the increasing trend in both of the two kinds of microalgae at the same culture time. The similar phenomenon was also observed for histidine in H. akashiwo, while opposite in N. closterium, but both enriching in δ13C compared to the controlled experiments without the WAF. Under the different culture times and WAF concentrations, the δ13C values of alanine and methionine showed unexpected trend. These findings indicated that the synthesis pathways of AA in microalgae cells were affected by the WAF, thus leading to the carbon isotopic fractionation in AAs. The present study provide a novel approach to explore the toxicity mechanism of primary producers under oil spill stress, and monitor and evaluate the marine ecological risk of oil spill pollution.

Reflection of concentrations of polybrominated diphenyl ethers in health risk assessment: A case study in sediments from the metropolitan river, North China.

As a developed city in North China, Tsingtao is believed to be suffering from the pollution of polybrominated diphenyl ethers (PBDEs) due to the rapid industrialization and urbanization in recent years. In this work, 8 PBDE congeners were detected in sediments from Moshui River, Tsingtao. BDE-209 and sum of 7 low brominated PBDE congeners (∑7PBDEs, excluding BDE-209) ranged from 10.2 × 10-3 to 237 × 10-3 mg kg-1 and from 1.62 × 10-3 to 23.1 × 10-3 mg kg-1 d.w., respectively. PBDE concentrations decreased in the order of midstream > downstream > upstream, attributing to the discrepancies in anthropogenic activities among these areas. Principal component analysis coupled with multiple linear regression (PCA-MLR) revealed that 24.4% of PBDEs were derived from surface runoff of contaminated soils, 58.2% from direct discharge of local sources and 17.4% from atmospheric deposition. The probabilistic health risk assessment of PBDEs was performed by using Monte Carlo simulation. The carcinogenic and non-carcinogenic risks based on total PBDEs were low for children and teens, whilst severe for adults. However, based on bioaccessible PBDEs (in vitro gastrointestinal model), there was no obvious health risk for the three age groups. To the best of our knowledge, the present study was the first attempt to assess the health risk by using bioaccessible PBDEs in sediments.

Effect of oil spill stress on fatty acid stable carbon isotope composition of Ulva pertusa.

Petroleum is one of the most important pollutants in the marine ecosystem, and oil spills have a long-term effect on the marine environment. After an oil spill, petroleum continues to diffuse, flowing to the intertidal zone where it accumulates. Ulva pertusa is the main macroalgae species in the intertidal zone of the ocean, and petroleum is toxic to marine macroalgae. Fatty acids, which are involved in various physiological activities, including metabolism, are indispensable substances in organisms. Thus, an organism's fatty acid composition reflects its physiological state. Because fatty acids are carbon-rich compounds, their stable carbon isotope composition can be measured to assess the state of the organism. In this study, the effects of the water accommodated fraction (WAF) of different concentrations of 180# fuel oil and 0# diesel oil on the chlorophyll a and fatty acid carbon stable isotope composition (δ13CFAs) of U. pertusa were assessed. The fatty acid carbon stable isotope value varied among the different petroleum treatments, and high WAF concentrations significantly inhibited the synthesis of unsaturated fatty acids. Thus, exposure to petroleum products affected the synthesis of fatty acids in U. pertusa and also caused carbon stable isotope fractionation during the fatty acid synthesis process. The results indicate that the saturated fatty acid δ13C16:0 and the unsaturated fatty acid δ13C18:1 can be used as biomarkers to evaluate the degree of petroleum-induced stress in U. pertusa and that carbon stable isotope analysis of U. pertusa can be used as an environmental risk assessment tool in the intertidal zone.

Effects of weathering process on the stable carbon isotope compositions of polycyclic aromatic hydrocarbons of fuel oils and crude oils.

Two fuel oils and two crude oils were subjected to a 60-day weathering simulation experiment, and the effects of weathering on some common parameters for aromatics and aromatic δ13C values were studied. The results show that weathering of all oil samples affected little the DBT/P (dibenzothiophene/phenanthrene) ratio and methylphenanthrene distribution fraction. Four oil samples could be distinguished only by the DBT/P ratio. The effect of weathering on isotopes in polycyclic aromatic hydrocarbons was small. The results show that the types of four oil samples can be distinguished, while Kuwait and Russia crude oils cannot be discriminated from each other totally by double-coordinate two-dimensional maps for aromatic δ13C; all of the oil samples can be distinguished by principal component analysis of δ13C for aromatics, the relationship of DBT/P and PAHs δ13C values. Therefore, the δ13C value of aromatics can be used as an alternative index for the analysis of oil spills.

Cu/Zn superoxide dismutase (SOD) and catalase (CAT) response to crude oil exposure in the polychaete Perinereis aibuhitensis.

Cu/Zn superoxide dismutase (SOD) and catalase (CAT) cDNAs from the polychaete Perinereis aibuhitensis were cloned and characterized in order to investigate the relationship between crude oil exposure and stress response in this worm. The full length of PaSOD was 870 bp and PaCAT was 1967 bp encoding 150 and 506 amino acids, respectively. Gene expression and enzyme activity of Cu/Zn SOD and CAT in response to crude oil contaminated soil (500, 1500, and 3000 mg/kg) were measured. The results showed that expression of the CAT gene and enzyme activity in P. aibuhitensis was positively correlated to the concentration of crude oil and reached a maximum at 15 days of exposure to 3000 mg/kg crude oil. The expression of the SOD gene and enzyme activity of SOD in P. aibuhitensis also increased during exposure to crude oil and reached a maximum at 10 days of exposure to 3000 mg/kg crude oil. These results indicated that SOD and CAT are important for maintaining the balance of cellular metabolism and protecting P. aibuhitensis from crude oil toxicity.

Identification of the geographical origins of sea cucumber (Apostichopus japonicus) in northern China by using stable isotope ratios and fatty acid profiles.

Geographic traceability is an important issue for food quality and safety control of seafood. In this study,δ13C and δ15N values, as well as fatty acid (FA) content of 133 samples of A. japonicus from seven sampling points in northern China Sea were determined to evaluate their applicability in the origin traceability of A. japonicus. Principal component analysis (PCA) and discriminant analysis (DA) were applied to different data sets in order to evaluate their performance in terms of classification or predictive ability. δ13C and δ15N values could effectively discriminate between different origins of A. japonicus. Significant differences in the FA compositions showed the effectiveness of FA composition as a tool for distinguishing between different origins of A. japonicus. The two technologies, combined with multivariate statistical analysis, can be promising methods to discriminate A. japonicus from different geographical areas.