Transition Metal-Free Aromatic C-H, C-N, C-S and C-O Borylation.

Aromatic organoboron compounds are highly valuable building blocks in organic chemistry. They were mainly synthesized through aromatic C-H and C-Het borylation, in which transition metal-catalysis dominate. In the past decade, with increasing attention to sustainable chemistry, numerous transition metal-free C-H and C-Het borylation transformations have been developed and emerged as efficient methods towards the synthesis of aromatic organoboron compounds. This account mainly focuses on recent advances in transition metal-free aromatic C-H, C-N, C-S, and C-O borylation transformations and provides insights to where further developments are required.

Metro travel and perceived COVID-19 infection risks: A case study of Hong Kong.

The COVID-19 pandemic has exerted unprecedented impacts on travel behaviors because of people's increased health precautions and the presence of various COVID-19 containment measures. However, little research has explored whether and how people changed their travel with respect to their perceived local infection risks across space and time. In this article, we relate elasticity and resilience thinking to the changes in metro travel and perceived infection risks at the station or community level over time. Using empirical data from Hong Kong, we measure a metro station's elasticity as the ratio of changes in its average trip length to the COVID-19 cases' footprints around that station. We regard those footprints as a proxy for people's perceived infection risks when making trips to that station. To explore influencing factors on travel in the ups and downs of perceived infection risks, we classify stations based on their elasticity values and examine the association between stations' elasticities and characteristics of stations and their served communities. The findings show that stations varied in elasticity values across space and different surges of the local pandemic. The elasticity of stations can be predicted by socio-demographics and physical attributes of station areas. Stations serving a larger percentage of population with higher education degrees and certain occupations observed more pronounced trip length decrease for the same level of perceived infection risks. The number of parking spaces and retail facilities significantly explained variations in stations' elasticity. The results provide references on crisis management and resilience improvement amid and post COVID-19.

Plasma Manganese Levels and Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study.

Manganese (Mn) intake has been found to be linked with risk of type 2 diabetes. However, the role of Mn in the development of gestational diabetes mellitus (GDM) remains to be investigated. This prospective study included pregnant women from the Tongji Maternal and Child Health Cohort. A total of 2327 participants with plasma specimens before 20 weeks were included. Among the pregnant women, 9.7% (225/2327) were diagnosed with GDM. After adjustment, pregnant women with the third and highest quartile of plasma Mn levels had 1.31-fold (RR, 2.31 [1.48, 3.61]) and 2.35-fold (RR, 3.35 [2.17, 5.17]) increased risk of GDM compared with those with the lowest quartile. A 1 standard deviation increment of ln-transformed plasma Mn levels (0.53 µg/L) was related to elevated risks of GDM with RRs of 1.28 [1.17, 1.40]. The positive associations between Mn and GDM remained consistent in all the subgroups. The weighted quantile sum index was significantly related to GDM (RR, 1.60 [1.37, 1.86]). The contribution of Mn (58.69%) to the metal mixture index was the highest related to GDM. Higher plasma Mn levels were found to be linked with elevated fasting and 2 h post-load blood glucose. This study revealed relationships of higher plasma Mn levels in early pregnancy and increased risk of GDM, suggesting that though essential, excess Mn in the body might be a potential important risk factor for GDM.

Natural attenuation of sulfometuron-methyl in seawater: Kinetics, intermediates, toxicity change and ecological risk assessment.

This research aims to evaluate the environmental feasibility of sulfometuron-methyl (SM) as a growth inhibitor for restricting the growth of Spartina alterniflora. To achieve this purpose, the natural attenuation characteristics, ecological risk, degradation pathway, and comprehensive toxicity changes of SM in seawater were investigated under the simulated marine environmental conditions of Jiaozhou Bay, China. The natural attenuation of SM in seawater followed first-order reaction kinetics with a rate constant (K) of 0.0694 d-1 and a half-life of 9.99 days. When photolysis, hydrolysis, and biodegradation pathways act alone, the rate constants K of SM were 0.0167, 0.0143, and 0.0099 d-1 respectively, indicating that their contributions to the total removal of SM decreased in turn. The calculation results of risk quotient (RQ) showed that the seawater containing 10 mg/L of SM demonstrated a very high risk to marine diatom Skeletonema costatum before and after 21 days of attenuation with RQ values of 24.46 and 6.32, respectively, however, the risk to other marine organisms (fish, crustaceans, and bivalves) decreased from moderate (RQ < 1) to low (RQ < 0.01). Four attenuation products of SM were identified and two degradation pathways of SM in seawater were proposed. Based on the rate of inhibition of bioluminescence, SM in seawater was not harmful to Photobacterium phosphoreum T3, whereas the toxicity of seawater containing SM increased with the extension of attenuation time, suggesting the formation of intermediate products with high aquatic toxicity. According to the toxicity values predicted by ECOSAR, the toxicity of one identified attenuation product was higher than that of SM. To the best of our knowledge, this is the first report on the attenuation characteristics and toxicity changes of SM in seawater. The results indicated that the toxicity of both SM and its degradation products to non-target marine organisms should be considered in evaluating the feasibility of SM in controlling coastal Spartina alterniflora.

Attenuation pathways of erythromycin and biochemical responses related to algal growth and lipid synthesis in a microalga-effluent system.

Microalgal cultivation in municipal wastewater treatment plants (WWTPs) can realize the coupling of wastewater treatment and microalgae energy utilization, however, the residual antibiotics in effluents from WWTPs affect the growth of microalgae. In this study, green alga (Scenedesmus obliquus) cells were inoculated into the effluents to ascertain the attenuation pathways of erythromycin (ERY) and the biochemical responses of microalga in a microalga-effluent system. Results showed that hydrolysis, photolysis, and biodegradation (including bioadsorption) cause the attenuation of ERY in a microalga-effluent system, and the biodegradation (including bioadsorption) has the greatest removal rate (reaching a maximum of 57.87%), followed by hydrolysis (reaching a maximum of 34.13%), and photolysis (less than 5%) after five days. The photosynthetic pigment contents in cells of microalga decreased the most (by 35.66% for chlorophyll a), and the production of ROS was stimulated (by 33.75%) after five-day exposure to ERY at an initial concentration of 100 µg/L. Meanwhile, the activity of ribulose-1,5-biphosphate carboxylase (RuBPCase) decreased by 55.65%, and the activity of acetyl-CoA carboxylase (ACCase) increased by 55.65%. The ROS level, photosynthetic pigment content, and RuBPCase activity were extremely significantly correlated with each other (P < 0.01), indicating that exposure to ERY changed those biochemical responses related to the rate of photosynthesis of microalga, inhibiting the growth thereof. On the other hand, exposure to ERY increased lipid production by microalga through the induced ACCase activity.

Abrupt changes, institutional reactions, and adaptive behaviors: An exploratory study of COVID-19 and related events' impacts on Hong Kong's metro riders.

Abrupt socioeconomic changes have become increasingly commonplace. In face of these, both institutions and individuals must adapt. Against the backdrop of the COVID-19 pandemic, suddenness, scale, and impacts of which are unprecedented as compared to its counterparts in history, we first propose transferable measures and methods that can be used to quantify and geovisualize COVID-19 and subsequent events' impacts on metro riders' travel behaviors. Then we operationalize and implement those measures and methods with empirical data from Hong Kong, a metropolis heavily reliant on transit/metro services. We map out where those impacts were the largest and explores its correlates. We exploit the best publicly available data to assemble probable explanatory variables and to examine quantitatively whether those variables are correlated to the impacts and if so, to what degree. We find that both macro- and meso-level external/internal events following the COVID-19 outbreak significantly influenced of metro riders' behaviors. The numbers of public rental housing residents, public and medical facilities, students' school locations, residents' occupation, and household income significantly predict the impacts. Also, the impacts differ across social groups and locales with different built-environment attributes. This means that to effectively manage those impacts, locale- and group-sensitive interventions are warranted.

Natural attenuation characteristics and comprehensive toxicity changes of C9 aromatics under simulated marine conditions.

Microcosmic experiments were performed under a simulated marine environment to investigate the natural attenuation of C9 aromatics using nine components (propylbenzene, isopropylbenzene, 2-ethyltoluene, 3-ethyltoluene, 4-ethyltoluene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene, and indene). This research aims to assess the contribution of biodegradation and abiotic activity to total attenuation of C9 aromatics and ascertain the changes in the comprehensive toxicity of seawater in the natural environment. The process of natural attenuation indicates the agreement with pseudo-first-order kinetics for all nine components in microcosmic experiments. The half-lives of the nine main compounds in C9 aromatics ranged between 0.34 day and 0.44 day under optimal conditions. The experiments showed that the natural attenuation of nine aromatic hydrocarbons mainly occurred via abiotic processes. Seawater samples significantly inhibited the luminescence of P. phosphoreum (the luminescence inhibition ratio reached 100%) at the beginning of the experiment. In addition, the toxicity declined slowly and continued for 25 days. The attenuation kinetics and changes in toxicity could be applied to explore the natural attenuation of C9 aromatics in the marine environment.

The pathways by which the marine diatom Thalassiosira sp. OUC2 biodegrades p-xylene, combined with a mechanistic analysis at the proteomic level.

A marine diatom, Thalassiosira sp. OUC2, was isolated from natural seawater collected from Daya Bay, China. This diatom degraded 1.25-40 mg L-1p-xylene within five days, at a removal efficiency exceeding 98%. Gas chromatography-mass spectrometer (GC-MS) analysis indicated that p-xylene was converted into 4-methylbenzyl alcohol, p-toluic acid, and p-cresol in the presence of strain OUC2. Meanwhile, proteomic analysis showed that, after exposure to p-xylene, several algal enzymes were significantly upregulated: including monooxygenase, alcohol dehydrogenase, benzaldehyde dehydrogenase, benzoate 1,2-dioxygenase, and catechol 2,3-dioxygenase. Moreover, ecotoxicological tests suggested that the intermediate metabolites were less toxic than the parent compound (p-xylene). Thalassiosira sp. OUC2 may thus be suitable for the remediation of p-xylene-contaminated marine environments.

Toxicity assessment of p-choroaniline on Platymonas subcordiformis and its biodegradation.

The use of p-chloroaniline (PCA) in various aspects leads to its existence and accumulation in the environment. Relevant researches showed that PCA was a prime toxic pollutant that had imposed a serious risk to public health and the environment. This paper investigated the toxicity effects of PCA on Platymonas subcordiformis (P. subcordiformis) and the biodegradation of PCA by the marine microalga. In the toxicity experiments, the EC50 of PCA on P. subcordiformis at 24 h, 48 h, 72 h and 96 h was 41.42, 24.04, 17.15 and 13.05 mg L-1, respectively. The pigment parameters including chlorophyll a, chlorophyll b, carotenoids, photosynthetic O2 release rate, respiration O2 consumption rate and the chlorophyll fluorescence parameters including Fv/Fm, ETR and qP decreased greatly while antioxidant enzyme activities (SOD, CAT) and the chlorophyll fluorescence parameter NPQ increased when P. subcordiformis exposed to PCA compared with the control group. Fv/Fm would be a suitable indicator for assessing the toxicity of PCA in marine environment based on the analysis of Pearson's correlation coefficient and Integrated Biomarker Response (IBR). The degradation assay in P. subcordiformis indicated that the green marine microalga had the ability to remove and degrade PCA, and the order of removal and degradation proportion of PCA was 2 mg L-1 > 5 mg L-1>10 mg L-1. The maximum removal and biodegradation percentage was 54% and 34%, respectively.

Toxicity effects of p-choroaniline on the growth, photosynthesis, respiration capacity and antioxidant enzyme activities of a diatom, Phaeodactylum tricornutu.

The environmental risk issues of p-choroaniline have been concerned by the widespread application and transportation of this important chemical intermediate. The information about the toxicity of p-chloroaniline was mainly concentrated on freshwater organisms while the current knowledge on marine organisms was scarce yet. In this study, acute toxicity and toxic physiology characteristic of p-chloroaniline to Phaeodactylum tricornutum (P. tricornutum) were first determined. In the acute experiments, the effect of the p-choroaniline to P. tricornutum showed time- and dose-dependent response, which the half maximum effective concentration (EC50) at 24 h, 48 h and 96 h was 35.35, 20.10 and 10.00 mgL-1, respectively. Toxic physiology assays in P. tricornutum indicated that the p-choroaniline induced significant changes of photosynthetic pigments (Chl-a, Chl-b, Caro, Chl-a/b and Chl-(a+b)/Caro), Chlorophyll fluorescence parameters (Fv/Fm, ETR, qP and NPQ), rates of photosynthetic O2 release and respiration O2 consumption, and antioxidant enzyme activities (SOD, CAT). The obvious decrease of Fv/Fm, ETR and chl-a in low p-choroaniline treatments (≤ 5.00 mgL-1) compared with the control could be observed, which implied that these parameters could be taken as sensitive indicators for the environmental assessment. Meanwhile, the activities of SOD and CAT significant increase in p-choroaniline stress after 24 h and the extent of the increase has fallen after 96 h. These toxicity data obtained here might provide available basic data for the ecological risk assessment of p-choroaniline pollution.

Kinetic analysis and degradation mechanism for natural attenuation of xylenes under simulated marine conditions.

Microcosm experiments were conducted to examine the attenuation of selected chemicals, i.e. m-xylene (MX), o-xylene (OX) and p-xylene (PX), under simulated marine conditions. Natural attenuation and the contribution of oxidation, photodegradation, biodegradation and volatilization to total attenuation were evaluated. The development of attenuation was in agreement with pseudo-first-order kinetics for all xylenes. The half-lives of MX, OX, and PX under optimal conditions were 0.76, 0.74 and 0.88 days, respectively. Attenuation kinetics were proposed to analyze the natural attenuation of xylenes. The leading attenuation type of MX, OX, and PX was volatilization, and the attenuation rate constants (KV) were 0.5587, 0.6733, and 0.4821 d-1, respectively. Biodegradation of OX (Kb: 0.0003 d-1) was extremely inhibited. The attenuation kinetics presented the attenuation of xylenes in microcosm. The reaction kinetics could be applied to analyze the natural attenuation of chemicals. MX and OX can be converted to one another under certain conditions. Toluene and ethylbenzene were detected for OX in the OP (oxidation and photodegradation) experiment under simulated marine conditions. 4-Methylbenzyl alcohol, p-methyl benzaldehyde and p-toluic acid, as the major intermediates, were identified during the natural attenuation of PX using GC/MS.

Toxicological Assessment of Intermediates in Natural Attenuation of p-Xylene to Marine Microalgae.

The toxic effects of p-xylene, 4-methylbenzyl alcohol, p-methyl benzaldehyde, and p-toluic acid on two marine microalgae (Phaeodactylum tricornutum Bohlin, and Skeletonema costatum) were investigated. p-Xylene was the most toxic to Pha. tricornutum with a 96 h EC50 value of 6.76 mg L-1. Based on the 96 h EC50 values for two microalgae, the toxicity of the four chemicals, in descending order, was: p-xylene, p-methyl benzaldehyde, 4-methylbenzyl alcohol, then p-toluic acid. The results showed that the toxicity of the transformed products of p-xylene was lower than that of p-xylene.

[Optimal gestational weight gain for Chinese urban women].

OBJECTIVE: To examine optimal gestational weight gain(GWG) for Chinese pregnant women. METHODS: A total of 6998 women with singleton and term pregnancy recruited to the Tongji Maternal and Child Health Cohort during January 2013 to May 2016 in Wuhan, Hubei were included. Information on sociodemographic, medical and family history of disease was obtained by questionnaire, body weight and height were measured at the first antenatal care during 8-16 weeks of gestation. Prenatal weight of mothers were measured, and gestational week, mode of delivery, pregnancy complications, gender of newborn, birth weight and length were collected from medical records after delivery. Restricted cubic spline was used to model nonlinear relationships between GWG and the occurrence of small for gestational age(SGA), large for gestational age(LGA), low birth weight(LBW), macrosomia, cesarean, gestational hypertension(GH)and gestational diabetes mellitus(GDM), respectively. The GWG of the lowest risks for adverse pregnant outcomes was regarded as optimal GWG recommended by Tongji(TJ) for pregnant women. The P25-P75 of GWG was defined as the optimal GWG recommended by percentile method. Logistic regression was used to analyze the effect of excessive or insufficient GWG on adverse pregnancy outcomes, while the recommendations of TJ and percentile method were used as references, respectively. RESULTS: (1) The GWG with lower risk of adverse pregnant outcomes based on pre-gravid body mass index(BMI) are 12. 0-17. 0 kg for underweight, 9. 0-14. 0 kg for normal weight and 7. 0-11. 0 kg for overweight, respectively, which are defined as TJ recommendations. The recommended GWG by percentile method are 14. 0-19. 0 kg for underweight, 13. 0-19. 0 kg for normal weight, 10. 8-18. 0 kg for overweight and 9. 0-15. 8 kg for obesity, respectively. (2) Compared to women gain within the TJ recommendations, OR of LGA is 2. 94(95%CI 2. 31-3. 73), macrosomia is 3. 13(95%CI 2. 38-4. 13), cesarean is 1. 53(95%CI 1. 38-1. 71) and GH is 2. 18(95%CI 1. 50-3. 17) for those with excessive GWG, OR of SGA is 1. 82(95%CI 1. 32-2. 53) for those who gain less. The corresponding ORs according to percentile method are 2. 11(95%CI 1. 76-2. 54) for LGA, 2. 16(95%CI 1. 76-2. 65) for macrosomia, 1. 53(95%CI 1. 36-1. 72) for cesarean, 1. 39(95%CI 1. 02-1. 90) for GH and 1. 60(95%CI 1. 29-1. 99) for SGA, respectively. CONCLUSION: The optimal GWG of Chinese pregnant women recommended by the study are 12. 0-17. 0 kg for pre-gravid underweight women, 9. 0-14. 0 kg for normal weight women and 7. 0-11. 0 kg for overweight, respectively.

Maternal dietary pattern characterised by high protein and low carbohydrate intake in pregnancy is associated with a higher risk of gestational diabetes mellitus in Chinese women: a prospective cohort study.

Maternal dietary patterns and macronutrients intake have been shown to affect the development of gestational diabetes mellitus (GDM), but the findings are inconsistent. We aimed to identify maternal dietary patterns and examine their associations with GDM risk, and to evaluate the contributions of macronutrients intake to these associations. We included 2755 Chinese pregnant women from the Tongji Maternal and Child Health Cohort. Dietary intakes were assessed using a validated semi-quantitative FFQ 2 weeks before the diagnosis of GDM. GDM (n 248) was diagnosed based on the results of a 75-g, 2-h oral glucose tolerance test at 24-28 weeks gestation. We derived five different dietary patterns from a principal component analysis. The results showed that high fish-meat-eggs scores, which were positively related to protein intake and inversely related to carbohydrate intake, were associated with a higher risk of GDM (adjusted OR for quartile 4 v. quartile 1: 1·83; 95 % CI 1·21, 2·79; P trend=0·007) and higher plasma glucose levels. In contrast, high rice-wheat-fruits scores, which were positively related to carbohydrate intake and inversely related to protein intake, were associated with lower risk of GDM (adjusted OR for quartile 3 v. quartile 1: 0·54; 95 % CI 0·36, 0·83; P trend=0·010) and lower plasma glucose levels. In addition, dietary protein and carbohydrate intake significantly contributed to the associations between dietary patterns and GDM risk or glucose levels. These findings suggest that a dietary pattern characterised by high protein and low carbohydrate intake in pregnancy was associated with a higher risk of GDM, which may provide important clues for dietary guidance during pregnancy to prevent GDM.

Ecotoxicity of phenol and cresols to aquatic organisms: A review.

With the development of industrial production and continuous demand for chemicals, a large volume of wastewater containing phenols was discharged into the aquatic environment. Moreover, chemical leakage further increased the emission of phenols into aquatic systems. Phenol and its methylated derivative (cresols) were selected due to their extensive use in industry and ecotoxicity to freshwater and marine organisms. This review focused on the ecotoxicity of phenol and m-, o-, and p-cresol on aquatic systems. The mechanism of action of phenols was also discussed. The aim of this literature review was to summarise the knowledge of the behaviour, and toxicity on marine and freshwater organisms, of phenols as well as to try to select a series of sensitive biomarkers suitable for ecotoxicological assessment and environmental monitoring in aquatic environments.

Prenatal NO2 exposure and ultrasound measures of foetal growth: a prospective cohort study in Wuhan, China.

OBJECTIVES: To examine the relationship between prenatal nitrogen dioxide (NO2) exposure and foetal growth in a prospective cohort of 1001 Chinese women. METHODS: The maternal NO2 exposure levels were estimated using land-use regression models based on home address. The biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL) and estimated foetal weight (EFW) were evaluated via ultrasonography. The multiple linear regression model was used to adjust for confounders, and the mixed-effect model was used to assess longitudinal effect. RESULTS: With a 10 µg/m3 increase in NO2 exposure, the BPD, HC, AC, FL and EFW in the second trimester decreased by 0.40 mm (95% CI -0.56 to -0.24), 1.07 mm (95% CI -1.60 to -0.54), 1.02 mm (95% CI -1.57 to -0.48), 0.24 mm (95% CI -0.37 to -0.12) and 7.84 g (95% CI -11.59 to -4.08), respectively; the BPD and HC in the third trimester decreased by 0.26 mm (95% CI -0.50 to -0.02) and 0.71 mm (95% CI -1.37 to -0.06), respectively. The longitudinal analyses showed inverse associations of NO2 exposure with BPD, HC, AC and FL (all p<0.05). The stratified analyses showed that the effects of NO2 on the HC, FL and EFW in the second trimester were stronger among female babies and that the effect of NO2 on EFW in the third trimester was stronger among smoking mothers (all p<0.05). CONCLUSIONS: In this prospective study of Chinese women, maternal NO2 exposure was inversely associated with foetal growth, and the association was stronger among female babies and smoking mothers.

Derivation of predicted no-effect concentration and ecological risk for atrazine better based on reproductive fitness.

Atrazine (ATZ) is an herbicide most commonly used in China and other regions of the world. It is reported toxic to aquatic organisms, and frequently occurs at relatively high concentrations. Currently, ATZ has been proved to affect reproduction of aquatic species at much lower levels. So it is controversial to perform ecological risk assessment using predicted no-effect concentrations (PENCs) derived from traditional endpoints, which fail to provide adequate protection to aquatic organisms. In this study, PNECs of ATZ were derived based on six endpoints of survival, growth, behavior, biochemistry, genetics and reproduction. The PNEC derived from reproductive lesion was 0.044µg ATZ L-1, which was obviously lower than that derived from other endpoints. In addition, a tiered ecological risk assessment was conducted in the Taizi River based on six PNECs derived from six categories of toxicity endpoints. Results of these two methods of ecological risk assessment were consistent with each other, and the risk level of ATZ to aquatic organisms reached highest as taking reproductive fitness into account. The joint probability indicated that severe ecological risk rooting in reproduction might exist 93.9% and 99.9% of surface water in the Taizi River, while 5% threshold (HC5) and 1% threshold (HC1) were set up to protect aquatic organisms, respectively. We hope the present work could provide valuable information to manage and control ATZ pollution.

Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response.

Palbociclib is a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor approved for breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative. We profiled palbociclib in cells either sensitive or resistant to the drug using an ATP/ADP probe-based chemoproteomics platform. Palbociclib only engaged CDK4 or CDK6 in sensitive cells. In resistant cells, no inhibition of CDK4 or CDK6 was observed, although the off-target profiles were similar in both cell types. Prolonged incubation of sensitive cells with the compound (24 h) resulted in the downregulation of additional kinases, including kinases critical for cell cycle progression. This downregulation is consistent with cell cycle arrest caused by palbociclib treatment. Both the direct and indirect targets were also observed in a human tumor xenograft study using the COLO-205 cell line in which phosphorylation of the retinoblastoma protein was tracked as the pharmacodyanamic marker. Together, these results suggest that this probe-based approach could be an important strategy toward predicting patient responsiveness to palbociclib.

ATP Acyl Phosphate Reactivity Reveals Native Conformations of Hsp90 Paralogs and Inhibitor Target Engagement.

Hsp90 is an ATP-dependent chaperone of widespread interest as a drug target. Here, using an LC-MS/MS chemoproteomics platform based on a lysine-reactive ATP acyl phosphate probe, several Hsp90 inhibitors were profiled in native cell lysates. Inhibitor specificities for all four human paralogs of Hsp90 were simultaneously monitored at their endogenous relative abundances. Equipotent inhibition of probe labeling in each paralog occurred at sites both proximal to and distal from bound ATP observed in Hsp90 cocrystal structures, suggesting that the ATP probe is assaying a native conformation not predicted by available structures. Inhibitor profiling against a comprehensive panel of protein kinases and other ATP-binding proteins detected in native cell lysates identified PMS2, a member of the GHKL ATPase superfamily as an off-target of NVP-AUY922 and radicicol. Because of the endogenously high levels of Hsp90 paralogs in typical cell lysates, the measured potency of inhibitors was weaker than published IC50 values. Significant inhibition of Hsp90 required inhibitor concentrations above a threshold where off-target activity was detectable. Direct on- and off-target engagement was measured by profiling lysates derived from cells treated with Hsp90 inhibitors. These studies also assessed the downstream cellular pathway effects of Hsp90 inhibition, including the down regulation of several known Hsp90 client proteins and some previously unknown client proteins. Overall, the ATP probe-based assay methodology enabled a broad characterization of Hsp90 inhibitor activity and specificity in native cell lysates.

Original and improved interspecies correlation estimation models in China for potential application in water quality criteria.

Fluoranthene (FLU) has gained much attention in recent years because of its continuous discharge in natural waters and toxicity to aquatic ecosystems. However, it is difficult to control and manage FLU pollution because of the lack of a rational and scientific water quality criteria (WQC) of FLU. To solve these data gaps, the US EPA established an interspecies correlation estimation (ICE) model, which can be utilized to develop the SSD and HC5 (hazardous concentration, 5th percentile). Moreover, an improved model was developed using a combination of North American ICE models supplemented with China-specific species. In this study, to verify the applicability of the two ICE models, measured acute toxicity data for FLU were obtained from 9 acute toxicity tests using indigenous Chinese aquatic species from different taxonomic levels. Original and improved ICE-based SSD curves, which were generated using 3 surrogate species (Daphnia magna, Oncorhynchus mykiss, and Lepomis macrochirus), were compared with SSD curves based on measured data. The results showed that HC5 was 1.838, 1.062, and 0.570 mg/L for the original ICE, improved ICE, and measured data, respectively. The improved ICE-based HC5 value for FLU was within twofold of the HC5 value based on measure data, while the original ICE-based HC5 value was threefold higher than the HC5 value based on measure data. This indicated that the improved ICE had better predictability in extrapolating data with acceptable deviation than the original ICE. Furthermore, their differences between HC5 derived from two SSD curves were not significant. Generally, the improved ICE model was verified as a valid approach for generating SSDs with limited toxicity data and for deriving WQC for FLU.