MACSPI enables tissue-selective proteomic and interactomic analyses in multicellular organisms.

Multicellular organisms are composed of many tissue types that have distinct morphologies and functions, which are largely driven by specialized proteomes and interactomes. To define the proteome and interactome of a specific type of tissue in an intact animal, we developed a localized proteomics approach called Methionine Analog-based Cell-Specific Proteomics and Interactomics (MACSPI). This method uses the tissue-specific expression of an engineered methionyl-tRNA synthetase to label proteins with a bifunctional amino acid 2-amino-5-diazirinylnonynoic acid in selected cells. We applied MACSPI in Caenorhabditis elegans, a model multicellular organism, to selectively label, capture, and profile the proteomes of the body wall muscle and the nervous system, which led to the identification of tissue-specific proteins. Using the photo-cross-linker, we successfully profiled HSP90 interactors in muscles and neurons and identified tissue-specific interactors and stress-related interactors. Our study demonstrates that MACSPI can be used to profile tissue-specific proteomes and interactomes in intact multicellular organisms.

Photo-ANA enables profiling of host-bacteria protein interactions during infection.

Bacterial pathogens rapidly change and adapt their proteome to cope with the environment in host cells and secrete effector proteins to hijack host targets and ensure their survival and proliferation during infection. Excessive host proteins make it difficult to profile pathogens' proteome dynamics by conventional proteomics. It is even more challenging to map pathogen-host protein-protein interactions in real time, given the low abundance of bacterial effectors and weak and transient interactions in which they may be involved. Here we report a method for selectively labeling bacterial proteomes using a bifunctional amino acid, photo-ANA, equipped with a bio-orthogonal handle and a photoreactive warhead, which enables simultaneous analysis of bacterial proteome reprogramming and pathogen-host protein interactions of Salmonella enterica serovar Typhimurium (S. Typhimurium) during infection. Using photo-ANA, we identified FLOT1/2 as host interactors of S. Typhimurium effector PipB2 in late-stage infection and globally profiled the extensive interactions between host proteins and pathogens during infection.

Identification of antimycin A as a c-Myc degradation accelerator via high-throughput screening.

c-Myc is a critical regulator of cell proliferation and growth. Elevated levels of c-Myc cause transcriptional amplification, leading to various types of cancers. Small molecules that specifically inhibit c-Myc-dependent regulation are potentially invaluable for anticancer therapy. Because c-Myc does not have enzymatic activity or targetable pockets, researchers have attempted to obtain small molecules that inhibit c-Myc cofactors, activate c-Myc repressors, or target epigenetic modifications to regulate the chromatin of c-Myc-addicted cancer without any clinical success. In this study, we screened for c-Myc inhibitors using a cell-dependent assay system in which the expression of c-Myc and its transcriptional activity can be inferred from monomeric Keima and enhanced GFP fluorescence, respectively. We identified one mitochondrial inhibitor, antimycin A, as a hit compound. The compound enhanced the c-Myc phosphorylation of threonine-58, consequently increasing the proteasome-mediated c-Myc degradation. The mechanistic analysis of antimycin A revealed that it enhanced the degradation of c-Myc protein through the activation of glycogen synthetic kinase 3 by reactive oxygen species (ROS) from damaged mitochondria. Furthermore, we found that the inhibition of cell growth by antimycin A was caused by both ROS-dependent and ROS-independent pathways. Interestingly, ROS-dependent growth inhibition occurred only in the presence of c-Myc, which may reflect the representative features of cancer cells. Consistently, the antimycin A sensitivity of cells was correlated to the endogenous c-Myc levels in various cancer cells. Overall, our study provides an effective strategy for identifying c-Myc inhibitors and proposes a novel concept for utilizing ROS inducers for cancer therapy.

Tuning the Pyridine Units in Vinylene-Linked Covalent Organic Frameworks Boosting 2e- Oxygen Reduction Reaction.

The N-doped carbon materials are supposed to be the efficient oxygen reduction reaction (ORR) catalysts with the undefined N-doped carbon ring groups. It is essential to well define the role of the nitrogen atoms of these carbon structures in active behavior. Even though, the covalent organic frameworks (COFs) with precise structures are well developed, but unable to exclude the polar linkages influence. This study presents a series of pyridine-containing COFs linked via nonpolar carbon-carbon double bonds (C = C). Their catalytic activity and selectivity for 2e- ORR are successfully modulated by locating the embedded pyridine nitrogen in the backbones through the linking modes of pyridine moieties within the frameworks. Such phenomena can be attributed to their different binding abilities toward O2, leading to the different binding strength of the intermediate OH* to the catalytic sites, also verified by the theoretical calculation. This work provides us a new insight to design high-efficiency ORR catalysts through the exact location of pyridine nitrogen.

The neglected roles of adjacent natural ecosystems in maintaining bacterial diversity in agroecosystems.

A central aim of community ecology is to understand how local species diversity is shaped. Agricultural activities are reshaping and filtering soil biodiversity and communities; however, ecological processes that structure agricultural communities have often overlooked the role of the regional species pool, mainly owing to the lack of large datasets across several regions. Here, we conducted a soil survey of 941 plots of agricultural and adjacent natural ecosystems (e.g., forest, wetland, grassland, and desert) in 38 regions across diverse climatic and soil gradients to evaluate whether the regional species pool of soil microbes from adjacent natural ecosystems is important in shaping agricultural soil microbial diversity and completeness. Using a framework of multiscales community assembly, we revealed that the regional species pool was an important predictor of agricultural bacterial diversity and explained a unique variation that cannot be predicted by historical legacy, large-scale environmental factors, and local community assembly processes. Moreover, the species pool effects were associated with microbial dormancy potential, where taxa with higher dormancy potential exhibited stronger species pool effects. Bacterial diversity in regions with higher agricultural intensity was more influenced by species pool effects than that in regions with low intensity, indicating that the maintenance of agricultural biodiversity in high-intensity regions strongly depends on species present in the surrounding landscape. Models for community completeness indicated the positive effect of regional species pool, further implying the community unsaturation and increased potential in bacterial diversity of agricultural ecosystems. Overall, our study reveals the indubitable role of regional species pool from adjacent natural ecosystems in predicting bacterial diversity, which has useful implication for biodiversity management and conservation in agricultural systems.

Protocol for CHAMPION study: a prospective study of maximal-cytoreductive therapies for patients with de novo metastatic hormone-sensitive prostate cancer who achieve oligopersistent metastases during systemic treatment with apalutamide plus androgen deprivation therapy.

BACKGROUND: The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. METHODS: CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming's two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. DISCUSSION: The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. TRIAL REGISTRATION: The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.

Carotenoids in maternal and cord blood, breast milk and their association with maternal dietary intake: a longitudinal study in Shanghai, China.

Carotenoids are important bioactive substances in breast milk, the profile of which is seldom studied. This study aimed to explore the profile of carotenoids in breast milk and maternal/cord plasma of healthy mother-neonate pairs in Shanghai, China, and their correlation with dietary intake. Maternal blood, umbilical cord blood and breast milk samples from five lactation stages (colostrum, transitional milk and early-, mid- and late-term mature milk) were collected. Carotenoid levels were analysed by HPLC. Carotenoid levels in breast milk changed as lactation progressed (P < 0·001). ß-Carotene was the primary carotenoid in colostrum. Lutein accounted for approximately 50 % of total carotenoids in transitional milk, mature milk and cord blood. Positive correlations were observed between five carotenoids in umbilical cord blood and maternal blood (P all < 0·001). ß-Carotene levels were also correlated between maternal plasma and three stages of breast milk (r = 0·605, P < 0·001; r = 0·456, P = 0·011, r = 0·446; P = 0·013, respectively). Dietary carotenoid intakes of lactating mothers also differed across lactation stages, although no correlation with breast milk concentrations was found. These findings suggest the importance of exploring the transport mechanism of carotenoids between mothers and infants and help guide the development of formulas for Chinese infants as well as the nutritional diets of lactating mothers.

IL-2 Signaling Couples the MAPK and mTORC1 Axes to Promote T Cell Proliferation and Differentiation in Teleosts.

IL-2 is a pleiotropic cytokine that is critical for T cell immunity. Although the IL-2-mediated regulation of T cell immunity in mammals is relatively well understood, it remains largely unknown whether and how IL-2 regulates T cell immunity in lower vertebrates. To address this knowledge gap, we investigated the role played by IL-2 in the regulation of T cell response, as well as the associated underlying mechanisms in a teleost fish, large yellow croaker (Larimichthys crocea). We found that large yellow croaker (L. crocea) IL-2 (LcIL-2) significantly promoted T cell proliferation both in vivo and in vitro; significantly induced the differentiation of Th1, Th2, regulatory T, and cytotoxic T cells while inhibiting Th17 differentiation; and participated in the elimination of invading pathogenic bacteria. Mechanistically, the binding of LcIL-2 to its heterotrimer receptor complex (LcIL-15Rα/LcIL-2Rß/Lcγc) triggered the conserved JAK-STAT5 pathway, which in turn regulated the expression of genes involved in T cell expansion, differentiation, and biological function. The MAPK and mammalian target of rapamycin complex 1 (mTORC1) axes, which are involved in TCR-mediated signaling, were also required for LcIL-2-mediated T cell response. Collectively, our results demonstrated that fish IL-2 plays a comprehensive regulatory role in T cell response and highlighted the complex and delicate network regulating T cell-driven immune response. We propose that T cell immunity is regulated by the interplay between TCR signaling and cytokine signaling, and that this basic strategy evolved before the emergence of the tetrapod lineage. Our findings provide valuable insights into the regulatory mechanisms underlying T cell response in teleosts.

Molecular cloning of estrogen receptor and its function on vitellogenesis in pompano (Trachinotus ovatus).

Estrogen receptors (ERs) play a critical role in vitellogenesis (Vtgs). However, the contribution of each ER for the regulation of vtgs expression was not analyzed clearly in teleosts. In the present study, three ers isoforms (erα, erß1, and erß2) were cloned in pompano (Trachinotus ovatus). Real-time PCR and enzyme-linked immunosorbent assay (ELISA) was used to detect the effects of 17ß-estradiol (E2) on ERs and Vtgs in the liver of pompano. In vivo injection experiments showed that E2 significantly increased the expressions of ers and vtgs. ER broad spectrum antagonist Fulvestrant significantly attenuated the E2- induced up-regulation of ers and vtgs in a dose-dependent manner. ERα antagonist Methyl-piperidino pyrazole (MPP) significantly attenuated the up-regulation of erα, erß2, vtg-B and vtg-C, and promoted the expressions of erß1 and vtg-A. ERß antagonist Cyclofenil significantly inhibited the expressions of erß1, erß2, vtg-A and vtg-C, and promoted the expressions of erα and vtg-B. In addition, E2 significantly increased the protein level of Vtg, while Fulvestrant, MPP and Cyclofenil significantly inhibited the protein level of Vtg in a dose-dependent manner. Our results indicate that E2 may regulate the expression of each vtg with different subtypes of ERs, and shows a distinct compensatory expression effect on the regulation for ers and vtgs, which provides a theoretical basis for reproductive endocrinology study in pompano.

A study of the spatial distribution characteristics of Chinese surnames.

OBJECTIVES: The spatial distribution of Chinese surnames is diverse and provides rich information about the evolution of human society. This study aims to propose several indices to quantify the spatial distribution characteristics of Chinese common surnames and to explore how these distributions are related to historical evolution. METHODS: This study uses data from China's ID information system covering 1.28 billion people across 362 cities. Based on the location quotient, several new concepts, such as "moderately concentrated cities" and "highly concentrated cities," are defined. Then indices such as range, ununiformity and spatial autocorrelation are proposed and calculated to analyze the spatial characteristics of Chinese common surnames. RESULTS: A significant correlation is observed between the commonness of a surname and its spatial characteristics: the more common the surname, the wider its spatial range, the lower the ununiformity, and the higher the autocorrelation coefficient. These patterns reflect the complex interplay of historical, geographical, and cultural factors influencing surname spatial distribution. CONCLUSIONS: The spatial distribution of Chinese surnames is intricately linked to their historical evolution. Most common surnames, often with deeper historical roots, exhibit wider distributions and lower ununiformity, whereas less common surnames show higher concentrations in specific areas. These quantitative results provide a comprehensive understanding of the evolutionary characteristics of Chinese surnames.

Development and validation of a scoring system to predict the mortality of hospitalized patients with SARS-CoV-2 Omicron: a nationwide, multicentre study.

BACKGROUND: The Omicron variant broke out in China at the end of 2022, causing a considerable number of severe cases and even deaths. The study aimed to identify risk factors for death in patients hospitalized with SARS-CoV-2 Omicron infection and to establish a scoring system for predicting mortality. METHODS: 1817 patients were enrolled at eight hospitals in China from December 2022 to May 2023, including 815 patients in the training group and 1002 patients in the validation group. Forty-six clinical and laboratory features were screened using LASSO regression and multivariable logistic regression. RESULTS: In the training set, 730 patients were discharged and 85 patients died. In the validation set, 918 patients were discharged and 84 patients died. LASSO regression identified age, levels of interleukin (IL) -6, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and D-dimer; neutrophil count, neutrophil-to-lymphocyte ratio (NLR) as associated with mortality. Multivariable logistic regression analysis showed that older age, IL-6, BUN, LDH and D-dimer were significant independent risk factors. Based on these variables, a scoring system was developed with a sensitivity of 83.6% and a specificity of 83.5% in the training group, and a sensitivity of 79.8% and a sensitivity of 83.0% in the validation group. CONCLUSIONS: A scoring system based on age, IL-6, BUN, LDH and D-dime can help clinicians identify patients with poor prognosis early.

Intelligent Fusion of Multi-Source Senses Information for Identifying the Nature of Five Flavors in Chinese Medicine: A Comprehensive Study of Five Classifications.

Objective: To develop a classification model for the five flavors of Chinese medicine using advanced multi-source intelligent sensory information fusion technology. The primary aim is to investigate the feasibility of applying this model to classify and identify the flavors of various Chinese medicines effectively. Methods: We selected 122 representative Chinese medicines, each exhibiting a single distinct flavor (sour, pungent, salty, sweet, bitter), along with 14 common foods. Utilizing the nature and flavors of these decoction pieces specified in Chinese Pharmacopeia (ChP)2020 and the inherent attributes of food components, we obtained valuable data from various sensors, including the PEN3 electronic nose, ASTREE electronic tongue, and SA402B electronic tongue. We then collected single-source data matrices from these sample sensors and a multi-source data matrix that combined the data from all sensors. Using discriminant analysis (DA), principal component analysis-discriminant analysis (PCA-DA), and K-nearest neighbor algorithm (KNN) three kinds of chemometric methods were used to establish five flavors and five-category discrimination models. The results were comprehensively evaluated with the highest correct rate of the model of leave-one-out cross-validation as the index. Results: Upon leave-one-out cross-validation, the correct judgment rate of the five flavors, five-category two-source fusion DA discrimination model (83.8%; ASTREE + SA402B) was significantly higher than the correct judgment rate of the single-source optimal DA and KNN model (73.5%; ASTREE). Following full-sample modeling, the correct judgment rate of the five flavors, five-category three-source fusion DA discrimination model (94.9%; PEN3+ASTREE+SA402B) rose substantially. This was higher than the correct judgment rate of the single-source optimal DA model (77.9%; ASTREE) and slightly higher than the two-source optimal correct judgment rate (89.7%; PEN3 + ASTREE). Conclusions: Compared to single-source identification, multi-source intelligent senses information fusion (MISIF) significantly improved accuracy, providing a new outlook for identifying flavor in Chinese medicine.

Mode of action exploration of reproductive toxicity induced by bisphenol S using human normal ovarian epithelial cells through ERß-MAPK signaling pathway.

BACKGROUND: In the plastics production sector, bisphenol S (BPS) has gained popularity as a replacement for bisphenol A (BPA). However, the mode of action (MOA) of female reproductive toxicity caused by BPS remains unclear and the safety of BPS is controversial. METHODS: Human normal ovarian epithelial cell line, IOSE80, were exposed to BPS at human-relevant levels for short-term exposure at 24 h or 48 h, or for long-term exposure at 28 days, either alone or together with five signaling pathway inhibitors: ICI 18,2780 (estrogen receptor [ER] antagonist), G15 (GPR30 specific inhibitor), U0126 (extracellular regulated protein kinase [ERK] 1/2 inhibitor), SP600125 (c-Jun N-terminal kinase [JNK] inhibitor) or SB203580 (p38 mitogen­activated protein kinase [p38MAPK] inhibitor). MOA through ERß-MAPK signaling pathway interruption was explored, and potential thresholds were estimated by the benchmark dose method. RESULTS: For short-term exposure, BPS exposure at human-relevant levels elevated the ESR2 and MAPK8 mRNA levels, along with the percentage of the G0/G1 phase. For long-term exposure, BPS raised the MAPK1 and EGFR mRNA levels, the ERß, p-ERK, and p-JNK protein levels, and the percentage of the G0/G1 phase, which was partly suppressed by U0126. The benchmark dose lower confidence limit (BMDL) of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM. CONCLUSIONS: The MOA of female reproductive toxicity caused by BPS at human-relevant levels might involve: molecular initiating event (MIE)-BPS binding to ERß receptor, key event (KE)1-the interrupted expression of GnRH, KE2-the activation of JNK (for short-term exposure) and ERK pathway (for long-term exposure), KE3-cell cycle arrest (the increased percentage of the G0/G1 phase), and KE4-interruption of cell proliferation (only for short-term exposure). The BMDL of the percentage of the S phase after 24 h exposure was the lowest among all the BMDLs of a good fit, with BMDL5 of 9.55 µM.

Development and application of the physiologically-based toxicokinetic (PBTK) model for ochratoxin A (OTA) in rats and humans.

Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17 µg/g min-1, 0.46 and 4.108 µg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.

Genotoxic mode of action and threshold exploration of 2-methyl furan under 120-day sub-chronic exposure in male Sprague-Dawley rats.

2-Methylfuran (2-MF) is an important member of the furan family generated during food thermal processing. An in-vivo multiple endpoint genotoxicity assessment system was applied to explore the genotoxic mode of action and threshold of 2-MF. Male Sprague-Dawley rats received 2-MF by oral gavage at doses of 0.16, 0.625, 2.5, and 10 mg/kg.bw/day for 120 days. An additional 15 days were granted for recovery. The Pig-a gene mutation frequency of RET and RBC showed significant increases among the 2-MF groups on day 120. After a 15-day recovery period, the Pig-a gene mutation frequency returned to levels similar to those in the vehicle control. The tail intensity (TI) values of peripheral blood cells at a dose of 10 mg/kg.bw/day significantly increased from day 4 and remained at a high level after the recovery period. No statistical difference was found in the micronucleus frequency of peripheral blood between any 2-MF dose group and the corn oil group at any timepoint. 2-MF may not induce the production of micronuclei, but it could cause DNA breakage. It could not be ruled out that 2-MF may accumulate in vivo and cause gene mutations. Hence, DNA, other than the spindle, may be directly targeted. The mode of action of 2-MF may be that it was metabolized by EPHX1 to more DNA-active metabolites, thus leading to oxidative and direct DNA damage. The point of departure (PoD) of 2-MF-induced genotoxicity was derived as 0.506 mg/kg bw/day.

Spatial accessibility and travel to pharmacy by type in the Detroit region.

BACKGROUND: Community pharmacies are a critical part of the health care provision system. Yet less is understood about the spatial accessibility to pharmacies and how people travel to reach these services. OBJECTIVES: This study compared spatial accessibility and actual travel to different types of pharmacies among selected neighborhoods in the Detroit region. METHODS: Three types of neighborhoods were selected and compared, including two lower income Black urban neighborhoods of high-density and four upper income White suburbs (two of low density and two of high density). Spatial accessibility was computed by pharmacy type and compared among neighborhoods using ANOVA. Pharmacy trips reported in a travel survey were geocoded and linked with community pharmacies in a list generated from ReferenceUSA business data. Destination choices were mapped and the relationship between spatial accessibility and actual distance traveled was examined using ordinary least squares regressions. RESULTS: On average, urban residents in Detroit had higher access to local independent pharmacies (0.74 miles to the nearest one) but relatively lower access to national chains (1.35 miles to the nearest one), which most residents relied on. Urban residents also tended to shop around more for services even among national chains. In fact, they bypassed nearby local independent pharmacies and traveled long distances to use farther pharmacies, primarily national chains. The average trip distance to pharmacy was 2.1 miles for urban residents, but only 1.1 miles and 1.5 miles for residents in high-density suburbs and low-density suburbs, respectively. CONCLUSION: Supposedly good spatial access considering all pharmacies together may mask excessive burden in reaching the pharmacy services needed in low-income minority urban communities, as shown in the case of Detroit. Thus, when mapping pharmacy deserts, it is important to distinguish spatial accessibility among different pharmacy types.

TaCHP encoding C1-domain protein stably enhances wheat yield in saline-alkaline fields.

Overexpression of the zinc finger gene TaCHP stably enhanced wheat yield in saline-alkaline conditions in a multi-year, three-site field trial, and the genetic variations in its promoter contribute to saline-alkaline tolerance of wheat accessions. TaCHP and its tolerant haplotype have great potential for molecular breeding of stress-tolerant wheat.

[Toxicity of bisphenol S on human normal ovarian epithelial cells mediated by ERß-MAPK signaling pathway].

OBJECTIVE: To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERß-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level. METHODS: Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 ß-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 µmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERß and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERß-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits. RESULTS: Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P<0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P<0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P<0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P<0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit. CONCLUSION: Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERß-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.

Pyridazine-Promoted Construction of Vinylene-Linked Covalent Organic Frameworks with Exceptional Capability of Stepwise Water Harvesting.

In this study, we successfully developed two novel vinylene-linked covalent organic frameworks (COFs) using 2-connected 3,6-dimethylpyridazine through Knoevenagel condensation. These COFs featured finely tailored micro-/nano-scale pore sizes, high surface areas and stable non-polar vinylene linkages. Finely resolved powder X-ray diffraction patterns demonstrated highly crystalline structures with a hexagonal lattice in the AA layer stacking. The resulting one-dimensional channels possess strong hydrogen-bond accepting sites arising from the decorated cis-azo/azine units with two pairs of fully exposed lone pair electrons, endowing the as-prepared COFs with exceptional water absorption properties. The g-DZPH-COF exhibited successive steep water uptake steps starting from low relative pressures (P/PSTA=0.1), with the remarkable water uptake capacity of 0.26 g/g at P/PSTA=0.2 (25 °C), which is the optimal value recorded among the reported COFs. Dynamic vapour sorption measurements revealed the fast kinetics of these COFs, even in the cluster formation process. Water uptake and release cycling tests demonstrated their outstanding hydrolytic stability, durability, and adsorption-desorption retention ability.

Mesoporous Vinylene-Linked Covalent Organic Frameworks with Heteroatom-Tuned Crystallinity and Photocatalytic Behaviors.

Owing to its prominent π-delocalization and stability, vinylene linkage holds great merits in the construction of covalent organic frameworks (COFs) with promising semiconducting properties. However, carbon-carbon double bond formation reaction always exhibits relatively low reversibility, unfavorable for the formation of high crystalline frameworks through self-error correction and assembling processes. In this work, we report a heteroatom-tuned strategy to build up a series of two-dimensional (2D) vinylene-linked COFs by Knoevenagel condensation of an electron-deficient methylthiazolyl-based monomer with different triformyl substituted (hetero-)aromatic derivatives. The resulting COFs show high-quality periodic mesoporous structures with high surface areas. Embedding heteroatoms into the backbones enables significantly improving their crystallinity, and finely tailoring their semiconducting structures. Upon visible light stimulation, one of the as-prepared COFs with donor-π-acceptor structure could deliver a nearly seven-fold increase in the catalytic activity of hydrogen generation as compared with the other two. Meanwhile, in combination with high crystallinity and the matched conduction band energy level, such kind of COFs can be able to selectively generate singlet oxygen and superoxide radicals in a high ratio of up to 30:1, allowing for catalyzing aerobic thioanisole oxidation in distinctly tunable activities through the substituent electronic effect of the substrates.