The association between per-/polyfluoroalkyl substances in serum and thyroid function parameters: A cross-sectional study on teenagers living near a Chinese fluorochemical industrial plant.

Thyroid hormones (THs) play an important role in a wide range of crucial biological functions related to growth and development, and thyroid antibodies (TAs) can influence the biosynthesis of THs. Epidemiological studies have indicated that per- and polyfluoroalkyl substances (PFAS) could induce thyroid disruption, but studies on teenagers living in areas with high PFAS exposure are limited. This cross-sectional study focused on 836 teenagers (11- 15 years) living near a Chinese fluorochemical industrial plant. Decreased levels of free thyroxine (FT4, ﹤9.6 pmol/L, abnormal rate = 19.0 %) and elevated levels of free triiodothyronine (FT3, ï¹¥6.15 pmol/L, abnormal rate = 29.8 %) were observed. Correlations of serum PFAS concentrations and TAs/THs were analyzed. Increased PFOA was identified as a risk factor of decreased FT4 by using unadjusted (OR: 11.346; 95 % CI: 6.029, 21.352, p < 0.001) and adjusted (OR: 12.566; 95 % CI: 6.549, 24.115, p < 0.001) logistic regression models. In addition, significantly negative correlations were found between log10 transformed PFOA and FT4 levels using linear (unadjusted: ß = -1.543, 95 % CI: -1.937, -1.148, p < 0.001; adjusted: ß = -1.534, 95 % CI: -1.930, -1.137, p < 0.001) and BKMR models. For abnormal FT3, a significantly positive association between PFHxS and FT3 levels was observed in a regression model (unadjusted: ß = -0.903, 95 % CI: -1.212, -0.595, p < 0.001; adjusted: ß = -0.894, 95 % CI: -1.204, -0.583, p < 0.001), and PFHxS was identified as a risk factor (unadjusted: OR: 4.387; 95 % CI: 2.619, 7.346, p < 0.001; adjusted: OR: 4.527; 95 % CI: 2.665, 7.688, p < 0.001). Sensitivity analyses confirmed the robustness of the above results. This study reported the elevated PFAS exposure and thyroid function of teenagers living near a fluorochemical industrial plant from China.

Identification and predictive analysis for participants at ultra-high risk of psychosis: A comparison of three psychometric diagnostic interviews.

BACKGROUND: An accurate identification of individuals at ultra-high risk (UHR) based on psychometric tools to prospectively identify psychosis as early as possible is required for indicated preventive intervention. The diagnostic comparability of several psychometric tools, including the comprehensive assessment of at risk mental state (CAARMS), the structured interview for psychosis-risk syndrome (SIPS) and the bonn scale for the assessment of basic symptoms (BSABS), is unknown. AIM: To address the psychometric comparability of CAARMS, SIPS and BSABS for subjects who are close relatives of patients with schizophrenia. METHODS: In total, 189 participants aged 18-58 years who were lineal relative by blood and collateral relatives by blood up to the third degree of kinship of patients with schizophrenia were interviewed in the period of May 2017 to January 2019. Relatives of the participants diagnosed schizophrenia were excluded. All the participants were assessed for a UHR state by three psychometric tools (CAARMS, SIPS and BSABS). The psychometric diagnosis results included at risk of psychosis (UHR+), not at risk of psychosis (UHR-) and psychosis. Demographic and clinical characteristics were also measured. The inter-rater agreement was assessed for evaluation of the coherence of the three scales. Transition rates for UHR+ subjects to psychosis within 2 years were also recorded. RESULTS: The overall agreement percentages were 93.12%, 92.06% and 93.65% of CAARMS and SIPS, SIPS and BSABS and CAARMS and BSABS, respectively. The overall agreement percentage of the relative functional impairment of the three groups (UHR+, not at risk of psychosis and psychosis) were 89.24%, 86.36% and 88.12%, respectively. The inter-rater reliability of the CAARMS, SIPS and BSABS total score was 0.90, 0.89 and 0.85. The inter-rater reliability was very good to excellent for all the subscales of these three instruments. For CAARMS, SIPS and BSABS, the kappa coefficient about UHR criteria agreement was 0.87, 0.84 and 0.82, respectively (P < 0.001). The transition rates of UHR+ to psychosis within 2 years were 16.7% (CAARMS), 10.0% (SIPS) and 17.7% (BSABS). CONCLUSION: There is good diagnostic agreement between the CAARMS, SIPS and BSABS towards identification of UHR participants who are close relatives of patients with schizophrenia.

Serum concentrations of per-/polyfluoroalkyl substances and its association with renal function parameters among teenagers near a Chinese fluorochemical industrial plant: A cross-sectional study.

Currently, studies on the association between per-/polyfluoroalkyl substances (PFAS) concentrations and the renal function of residents, especially teenagers, living near fluorochemical industrial plants, are relatively rare, and not all these studies suggested associations. In this cross-sectional study, 775 local teenagers (11-15 years old) were included, and serum concentrations of 18 PFAS were measured. Perfluorooctanoic acid (PFOA) was found to be the dominant PFAS with a concentration of 22.3-3310 ng/mL (mean = 191 ng/mL), accounting for 71.5-99.1% of ΣPFAS. Statistical analyses demonstrated that internal exposure of perfluoroalkyl carboxylic acids (PFCA, C8-C10) was related to the plant. In addition, the prevalence rate of chronic kidney disease (CKD) (35.0%) in the participants was relatively high. A significantly positive association was observed between the increase in PFOA concentration and increasing risk of CKD (OR = 1.741; 95% CI: 1.004, 3.088; p = 0.048) by adjusting for gender, age, body mass index (BMI), and household income. Similar positive correlation was also observed in PFHpA with CKD (OR = 1.628, 95% CI: 1.031, 2.572; p = 0.037). However, no significant correlation was observed for concentrations of other PFAS and CKD (p > 0.05). Furthermore, linear regression analyses demonstrated that none of the PFAS concentrations were significantly correlated with estimated glomerular filtration rate (eGFR) or urine albumin/urine creatinine ratio (ACR) (p > 0.05). However, a significantly negative correlation was observed between PFOA concentration and abnormal ACR (ß = -0.141, 95% CI: -0.283, 0.001; p = 0.048) after stratifying by CKD. Sensitivity analyses further confirmed these results. This cross-sectional study is the first, to our knowledge, to investigate the association between PFAS concentrations and renal function in teenagers living near a Chinese industrial plant. Further prospective and metabonomic studies are needed to interpret the results and clarify the biological mechanisms underlying this association.

A CuS- and BODIPY-loaded nanoscale covalent organic framework for synergetic photodynamic and photothermal therapy.

Herein, we report an inorganic photothermal agent, CuS- and an organic photosensitizer, BODIPY-loaded composite nanoscale COF material via a stepwise post-synthetic modification. The obtained CuS@COF-BDP can be a dual-modal therapeutic agent to highly inhibit MCF-7 tumor cell proliferation due to its efficient singlet oxygen generation and photothermal conversion abilities.

Concentration, spatial distribution, and health risk assessment of PFASs in serum of teenagers, tap water and soil near a Chinese fluorochemical industrial plant.

Discharges released from fluorochemical industrial plants lead to severe contamination of the environment with per- and polyfluoroalkyl substances (PFASs), which may pose risks to human health. In this study, 187 serum samples from teenagers (age = 14 years), 22 tap water samples and 40 soil samples were collected in areas within 0-11 km of a fluorochemical industrial plant in Huantai County, Shandong Province, and concentrations of 18 PFASs were quantified by UPLC-MS/MS. Perfluorooctanoic acid (PFOA) was found to be predominant, concentrations of which ranged from 40.4 to 845 ng/mL in serum, from 2.88 to 19.3 ng/L in tap water, from 4.40 to 189 ng/g in soil, and accounting for 84.1-98.6%, 15.9-79.8%, and 73.8-96.7% of the total PFASs, respectively. Statistical analysis demonstrated that concentrations of perfluorinated carboxylic acids (PFCAs) in soil (C5-C9) and serum (C8-C10) were associated with the industrial plant. And PFOA concentrations in tap water were not relevant to the industrial plant, which were comparable with the non-contaminated area and lower than the threshold value recommended by U.S. EPA (70 ng/mL), indicating that the contribution to the high concentration of serum PFOA of local teenagers by drinking water was limited. Moreover, PFCAs in soil only made a limited contribution to the serum PFCAs of local residents by direct inhalation and dermal exposure, but the potential health risk by the soil via food chain should be paid attention to. Furthermore, health risk assessment demonstrated that high concentrations of PFOA in serum could pose potential health risk to local teenagers. Therefore, effective measures should be taken to attenuate the health risks caused by the industrial plant to local residents, and further epidemiological studies should be carried out in the future.

Immunological characterisation and immunoprotective efficacy of functional domain antigens of botulinum neurotoxin serotype A.

Botulinum neurotoxins (BoNTs) are highly toxic proteins that mediate their effects by binding to neuronal receptors and block the neutralizing ability of therapeutic antibodies. Vaccination is currently the most effective strategy to prevent botulism. In this study, a series of recombinant functional domain antigens of BoNT/A were prepared and identified, and their immunoprotective efficacies were explored and compared. Our results showed that all antigens produced strong humoral immune responses, although their protective effects against the toxin were different. Only the Hc and HN-L antigens produced strong protective effects and afforded complete immunoprotection. In addition, the combined vaccine groups showed that there was no synergistic effect on immune responses after antigen combination, suggesting that the integrity of the toxin antigen or domain is crucial to the immune effects. Studies of the dose-dependent immunoprotective effects further confirmed that the Hc domain antigen afforded more effective protective potency than the HN-L antigen, equivalent to the immune effect of the full-length toxin (Hc + HN-L combination group). Overall, our results demonstrated that the Hc domain elicited a strong protective immune response and also provided basic data and theoretical support for the development of Hc-based BoNT/A subunit vaccine. Therefore, the receptor binding domain Hc is implicated as a promising target antigen of the BoNT/A recombinant subunit vaccine as an alternative to the toxoid vaccine.

Development and evaluation of candidate subunit vaccine and novel antitoxin against botulinum neurotoxin serotype E.

Botulinum neurotoxins (BoNTs) are among the most toxic proteins. Vaccination is an effective strategy to prevent botulism. To generate a vaccine suitable for human use, a recombinant non-His-tagged isoform of the Hc domain of botulinum neurotoxin serotype E (rEHc) was expressed in Escherichia coli and purified by sequential chromatography. The immunogenicity of rEHc was evaluated in mice and dose- and time-dependent immune responses were observed in both antibody titers and protective potency. Then, the pilot-scale expression and purification of rEHc were performed, and its immunological activity was characterized. Our results showed rEHc has good immunogenicity and can elicit strong protective potency against botulinum neurotoxin serotype E (BoNT/E) in mice, indicating that rEHc is an effective botulism vaccine candidate. Further, we developed a novel antitoxin against BoNT/E by purifying F(ab')2 from pepsin-digested serum IgG of rEHc-inoculated horses. The protective effect of the F(ab')2 antitoxin was determined in vitro and in vivo. The results showed that our F(ab')2 antitoxin can prevent botulism in BoNT/E-challenged mice and effectively alleviate the progression of paralysis caused by BoNT/E to achieve therapeutic effects. Therefore, our results provide valuable experimental data for the production of a novel antitoxin, which is a promising candidate for the treatment of BoNT/E-induced botulism.

UiO-68-PT MOF-Based Sensor and Its Mixed Matrix Membrane for Detection of HClO in Water.

As an important type of reactive oxygen species (ROS), hypochloric acid (HClO) is closely linked with our daily life, and its convenient and rapid detection is very significant and imperative. Fluorescent and visual probes are being recognized as powerful and convenient tools for detection of ROS in the environment and living organisms by visualizing and imaging. In this contribution, a new metal-organic framework-based fluorescent probe UiO-68-PT, which was generated from a phenthiazine-decorated benzimidazole bridging dicarboxyl ligand and ZrCl4 under solvothermal conditions via in situ one-pot approach, is reported. The obtained UiO-68-PT features a unique HClO and Vitamin C-triggered reversible redox process, which is accompanied by both visual and fluorescence changes. Therefore, it can be a highly sensitive, specific, and reusable sensor to detect HClO species in water via both visual and fluorogenic observation (turn-on). Furthermore, its mixed membrane material (MMM) was fabricated by the combination of UiO-68-PT and poly(vinyl alcohol), and the obtained hydrophilic MMM can be used as a reversible colorimetric card for visual detection of the HClO in aqueous solution.

CP-25 Attenuates the Activation of CD4+ T Cells Stimulated with Immunoglobulin D in Human.

Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck. Human CD4+ T cells were purified from peripheral blood mononuclear cells using microbeads. T cell viability and proliferation were detected by Cell Counting Kit-8 and CFSE Cell Proliferation Kit. Cytokines secreted by T cells were assessed with the Quantibody Human Inflammation Array. The binding affinity and expression of IgDR on T cells were detected by flow cytometry, and protein expression of IgDR, Lck, and P-Lck were analyzed by western blot. IgD was shown to bind to IgDR on CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394). CP-25 inhibited the IgD-stimulated activation and proliferation of CD4+ T cells, as well as the production of inflammatory cytokines; it was thus suggested that this process might be related to the downregulation of Lck (Tyr394) phosphorylation. These results demonstrate that IgD amplifies the activation of CD4+ T cells, which could be mediated by Lck phosphorylation. Further, CP-25, via its ability to modulate Lck, is a novel potential therapeutic agent for the treatment of human autoimmune diseases.

Effects of immunoglobulin D on expression of IgD receptor and protein tyrosine kinase signaling in human CD4+ T cells / 中国药理学与毒理学杂志

OBJECTIVE To observe whether human CD4 + T cells could be activated by immuno-globulin D (IgD) via IgD receptor(IgDR)-Lck. METHODS Human CD4+ T cells were purified from peripheral blood mononuclear cells (PBMCs) with microbeads. The viability of T cells were detected by CCK-8. The binding affinity and expression of IgDR on T cells were detected by flow cytometry. The protein expression of IgDR, Lck and P-Lck were analyzed by western blot. RESULTS IgD could concentration-dependent bind to IgDR on CD4+ T cells. The expression of IgDR was increased in response to treatment with IgD in a time- dependent and concentration- dependent manner. Stimulating by IgD resulted in enhanced phosphorylation of Lck compared with that in the medium control sample. The expression of Lck was not changed. As inhibitor of PTK, Herbimycin A or A770041, which combined with IgD could significantly inhibit phosphorylation of Lck(Tyr394). The proliferation promoting effect of IgD was blocked by Herbimycin A or A770041. IgD could stimulate CD4+ T cell activation and proliferation through upreg?ulating activating tyrosine residue of Lck (Tyr394) phosphorylation. CONCLUSION These results demon?strate that IgD exaggerates CD4+T cell activities, which may be through promoting Lck phosphorylation.

New limonoids and a dihydrobenzofuran norlignan from the roots of Toona sinensis.

Two new limonoids, toonins A (1) and B (2), and one new dihydrobenzofuran norlignan, toonin C (3), were isolated from the roots of Toona sinensis together with the ten known compounds 4-methoxy-6-(2',4'-dihydroxy-6'-methylphenyl)-pyran-2-one (4), bourjotinolone A (5), proceranone (6), matairesinol (7), 4-hydroxy-3-methoxybenzene-ethanol (8), syringic acid (9), isoscopoletin (10), lyoniresinol (11), aloeemodin (12), and ß-sitosterol (13). Their structures were elucidated on the basis of one- and two-dimensional spectroscopic analysis. Isolation of compounds 4, 6-13 from this plant is reported here for the first time.