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Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid β (Aβ)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aβ amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aβ in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Amyloid-β (Aβ) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aβ peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aβ pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aβ. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aβ plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aβ deposition in novel mouse models and cross-sectional studies using post-mortem human tissue.

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability., (© 2024. The Author(s).)

Background: Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Methods: Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to β-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. Results: S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Conclusions: Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

As one of the deadliest viruses, Ebola virus (EBOV) causes lethal hemorrhagic fevers in humans and nonhuman primates. The suppression of innate immunity leads to robust systemic virus replication of EBOV, leading to enhanced transmission. However, the mechanism of EBOV-host interaction is not fully understood. Here, we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis, which are highly clustered to Jak-STAT signaling. EBOV VP35 and VP30 were found to inhibit type I interferon (IFN) signaling. Moreover, exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1, and suppresses nuclear translocation of STAT1. Using serial truncated mutations of VP35, N-terminal 1-220 amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling. Remarkably, VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus (BDBV) and Marburg virus (MARV), resulting in stable replication to facilitate the pathogenesis. Altogether, this study enriches understanding on EBOV evasion of innate immune response, and provides insights into the interplay between filoviruses and host., Competing Interests: Conflict of interest Prof. Sandra Chiu is an Editorial Board member for Virologica Sinica and was not involved in the editorial review or the decision to publish this article. The authors declare no competing interests., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

A laboratory experiment is conducted to investigate the effects of organic carbon (OC) from riverine and marine sediments on the degradation of ring- 14 C-labeled nonylphenol ( 14 C-NP) by hydrogen peroxide (H 2 O 2 ). Researchers have isolated demineralized OC (DM) before and after oxidation, namely, DM and resistant OC (ROC) fractions, respectively. The structures of DM and ROC are characterized using solid-state 13 C nuclear magnetic resonance. Unstable structures (O-alkyl, OCH 3 /NCH, and COO/NC=O) show a significant and positive correlation with the degradation of 14 C-NP (R 2  > 0.73, p < 0.05), thus suggesting that the NP absorbed in the unstable structures is easily degraded because of the decomposition of unstable components. The stable structures (alkyl C and non-protonated aromatic C [Arom C─C]) exhibit a significant and negative correlation with the degradation of 14 C-NP (R 2  > 0.69, p < 0.05), thus suggesting that the NP absorbed and protected in these resistant structures is minimally degraded. The significant correlations among the degradation kinetic parameters (F rap and F slow ), OC structures (F alip and F arom ), and microporosity further illustrate the important protective roles of OC structures and micropores in the degradation of 14 C-NP by H 2 O 2 (R 2  > 0.69, p < 0.05). The parent NP fraction that desorbed into the aqueous solution or extracted is completely degraded, indicating preferential degradation of the easily desorbed NP. This study provides important insights into the NP degradation mechanism in sediment-water systems, particularly regarding sediment OC structures and microporosity., (© 2023 The Authors. Journal of Environmental Quality © 2023 American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

Enhancing production of protein cargoes delivered by gene therapies can improve efficacy by reducing the amount of vector or simply increasing transgene expression levels. We explored the utility of a 126-amino acid collagen domain (CD) derived from the C1qTNF3 protein as a fusion partner to chaperone secreted proteins, extracellular "decoy receptor" domains, and single-chain variable fragments (scFvs). Fusions to the CD domain result in multimerization and enhanced levels of secretion of numerous fusion proteins while maintaining functionality. Efficient creation of bifunctional proteins using the CD domain is also demonstrated. Recombinant adeno-associated viral vector delivery of the CD with a signal peptide resulted in high-level expression with minimal biological impact as assessed by whole-brain transcriptomics. As a proof-of-concept in vivo study, we evaluated three different anti-amyloid Aβ scFvs (anti-Aβ scFvs), alone or expressed as CD fusions, following viral delivery to neonatal CRND8 mice. The CD fusion increased half-life, expression levels, and improved efficacy for amyloid lowering of a weaker binding anti-Aβ scFv. These studies validate the potential utility of this small CD as a fusion partner for secretory cargoes delivered by gene therapy and demonstrate that it is feasible to use this CD fusion to create biotherapeutic molecules with enhanced avidity or bifunctionality., Competing Interests: T.E.G. is a cofounder of Lacerta Therapeutic and Andante Biologics. The other authors declare no competing interests., (© 2023 The Author(s).)

Introduction: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs., Methods: We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro , ex-vivo and in vivo ., Results: We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and in vivo ., Discussion: Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hossain, Ucar, Monticone, Ran, Majumder, Larter, Luu, Wyczechowska, Heidari, Xu, Shanthalingam, Matossian, Xi, Burow, Collins-Burow, Del Valle, Hicks, Zabaleta, Golde, Osborne and Miele.)

African swine fever virus (ASFV) is a large DNA virus that causes African swine fever (ASF), an acute and hemorrhagic disease in pigs with lethality rates of up to 100%. To date, how ASFV efficiently suppress the innate immune response remains enigmatic. In this study, we identified ASFV cysteine protease pS273R as an antagonist of type I interferon (IFN). Overexpression of pS273R inhibited JAK-STAT signaling triggered by type I IFNs. Mechanistically, pS273R interacted with STAT2 and recruited the E3 ubiquitin ligase DCST1, resulting in K48-linked polyubiquitination at K55 of STAT2 and subsequent proteasome-dependent degradation of STAT2. Furthermore, such a function of pS273R in JAK-STAT signaling is not dependent on its protease activity. These findings suggest that ASFV pS273R is important to evade host innate immunity. IMPORTANCE ASF is an acute disease in domestic pigs caused by infection with ASFV. ASF has become a global threat with devastating economic and ecological consequences. To date, there are no commercially available, safe, and efficacious vaccines to prevent ASFV infection. ASFV has evolved a series of strategies to evade host immune responses, facilitating its replication and transmission. Therefore, understanding the immune evasion mechanism of ASFV is helpful for the development of prevention and control measures for ASF. Here, we identified ASFV cysteine protease pS273R as an antagonist of type I IFNs. ASFV pS273R interacted with STAT2 and mediated degradation of STAT2, a transcription factor downstream of type I IFNs that is responsible for induction of various IFN-stimulated genes. pS273R recruited the E3 ubiquitin ligase DCST1 to enhance K48-linked polyubiquitination of STAT2 at K55 in a manner independent of its protease activity. These findings suggest that pS273R is important for ASFV to escape host innate immunity, which sheds new light on the mechanisms of ASFV immune evasion.

In this study, the role of organic matter structure and microporosity in the adsorption and degradation of radioactive nonylphenol in sediments treated with potassium ferrate solutions was investigated. The demineralized fractions and acid non-hydrolyzable fractions were isolated and characterized via advanced solid-state 13 C nuclear magnetic resonance and CO 2 gas adsorption technology, respectively. Radioactive nonylphenol in the sediments was also fractionated into 14 CO 2 , water-soluble residues, extractable residues, and strongly bound residues after treatment with potassium ferrate. A first-order, two-compartment kinetic model well described the mineralization and degradation kinetics of radioactive nonylphenol in the sediment (R 2  > 0.99). The degradation percentages of spiked nonylphenol were highly negatively correlated with aromatic carbon, aliphatic carbon, and microporosity estimated from acid-non-hydrolyzable fractions in the bulk sediments (R 2  > 0.82, p < 0.01). The percentages of adsorbed parent nonylphenol residues were highly positively correlated with aromatic carbon, aliphatic carbon, and microporosity estimated from acid-non-hydrolyzable fractions in the bulk sediments (R 2  > 0.90, p < 0.01). The parent nonylphenol compound desorbed into the aqueous phase and was completely degraded. This study is the first to demonstrate the important role of aromatic carbon, aliphatic carbon, and microporosity in acid non-hydrolyzable fractions on the degradation of nonylphenol during the potassium ferrate oxidation treatment process., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Aims: NAFLD is a progressive disease without known effective drug treatments. Switch-associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD., Approach and Results: The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte-specific Swap70 knockout and overexpression mice fed a high-fat, high-cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response, and fibrosis. Mechanically, RNA sequencing analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between transforming growth factor β-activated kinase 1 (TAK1) binding protein 1 and TAK1 and sequentially suppressed the phosphorylation of TAK1 and subsequent c-Jun N-terminal kinase/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown., Conclusions: SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

In order to be able to make full use of domain knowledge to improve the performance of skill word extraction, this paper proposes a skill word extraction method based on a combination of deep learning and corpus features. Skill word extraction is transformed into a sequence annotation problem, and based on the basic model of sequence annotation, Bi-LSTM-CRF, corpus features are added to the input layer, and the output of the input layer is connected with the Bi-LSTM output as the input of the CRF layer. The experimental results show timely updating of the question bank, paying attention to the quality of vocational skill identification, and strictly managing the issuance of vocational qualification false certificates., Competing Interests: The authors declared that they have no conflicts of interest regarding this work., (Copyright © 2022 Yeming Wang and Yong Ran.)

ASFV is a large DNA virus that is highly pathogenic in domestic pigs. How this virus is sensed by the innate immune system as well as why it is so virulent remains enigmatic. In this study, we show that the ASFV genome contains AT-rich regions that are recognized by the DNA-directed RNA polymerase III (Pol-III), leading to viral RNA sensor RIG-I-mediated innate immune responses. We further show that ASFV protein I267L inhibits RNA Pol-III-RIG-I-mediated innate antiviral responses. I267L interacts with the E3 ubiquitin ligase Riplet, disrupts Riplet-RIG-I interaction and impairs Riplet-mediated K63-polyubiquitination and activation of RIG-I. I267L-deficient ASFV induces higher levels of interferon-β, and displays compromised replication both in primary macrophages and pigs compared with wild-type ASFV. Furthermore, I267L-deficiency attenuates the virulence and pathogenesis of ASFV in pigs. These findings suggest that ASFV I267L is an important virulence factor by impairing innate immune responses mediated by the RNA Pol-III-RIG-I axis., Competing Interests: The authors have declared that no competing interests exist.

The proinflammatory cytokine IL-1β is a crucial mediator of inflammatory responses. IL-1β-induced signaling is finely regulated by various mechanisms, and its imbalance is involved in a variety of diseases. In this study, we identified FAM177A1, a protein of unknown function, as a negative regulator of IL-1β-induced signaling in human cells. Overexpression of FAM177A1 inhibited IL-1β-triggered activation of NF-κB and transcription of inflammatory genes, whereas knockdown of FAM177A1 showed the opposite effects. Mechanistically, FAM177A1 competitively bound to the E3 ubiquitin ligase TRAF6 and impaired its interaction with the E2-conjugating enzyme Ubc13; therefore, it inhibited TRAF6-mediated polyubiquitination and recruitment of downstream signaling molecules. These findings reveal a function of FAM177A1 and promote our understanding of the regulatory mechanisms of IL-1β-induced inflammatory responses., (Copyright © 2021 by The American Association of Immunologists, Inc.)

African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-γ-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The distribution and bioconcentration of polycyclic aromatic hydrocarbons (PAHs) in water, suspended particulate material (SPM), algae, and zooplankton samples from the Pearl River Delta (PRD), South China, were investigated. The PAHs in the water and SPM samples is significantly associated with chlorophyll a (Chl a), implying the important role of the aquatic productivity on PAH distribution. PAHs in the water or SPM samples were strongly correlated to dissolved organic carbon (DOC) or algal particulate organic carbon (A-POC). Moreover, the log bioconcentration factor (BCF) values (mL g -1 ) of PAHs in both the algae and zooplankton samples were linearly related to their log octanol-water coefficient (Kow) values. However, the slopes of these relationships were negatively correlated with Chl a, attributing to the difference in the dominant plankton species or the non-equilibrium exchange between air-water-biota. The above results indicate the important role of trophic levels on the distribution and bioaccumulation of PAHs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Trafficking of toll-like receptor 3 (TLR3) from the endoplasmic reticulum (ER) to endolysosomes and its subsequent proteolytic cleavage are required for it to sense viral double-stranded RNA (dsRNA) and trigger antiviral response, yet the underlying mechanisms remain enigmatic. We show that the E3 ubiquitin ligase TRIM3 is mainly located in the Golgi apparatus and transported to the early endosomes upon stimulation with the dsRNA analog poly(I:C). TRIM3 mediates K63-linked polyubiquitination of TLR3 at K831, which is enhanced following poly(I:C) stimulation. The polyubiquitinated TLR3 is recognized and sorted by the ESCRT (endosomal sorting complex required for transport) complexes to endolysosomes. Deficiency of TRIM3 impairs TLR3 trafficking from the Golgi apparatus to endosomes and its subsequent activation. Trim3 -/- cells and mice express lower levels of antiviral genes and show lower levels of inflammatory response following poly(I:C) but not lipopolysaccharide (LPS) stimulation. These findings suggest that TRIM3-mediated polyubiquitination of TLR3 represents a feedback-positive regulatory mechanism for TLR3-mediated innate immune and inflammatory responses., Competing Interests: The authors declare no competing interest.

Water-soluble carbon dots (CDs) were synthesized using a one-step hydrothermal treatment of chloroplast dispersions extracted from fresh leaves as a green carbon source. The CD solution showed an emission peak centred at 445 nm when excited at 300 nm. The synthesized CDs were uniform and monodispersed with an average size of 5.6 nm. When adding ferric(III) ions (Fe 3+ ) to the solution of the original CDs, the fluorescence intensity decreased significantly. Based on the linear relationship between fluorescence intensity and concentration of Fe 3+ ions, an effective method for rapid, sensitive and selective Fe 3+ sensing in aqueous solution could be established. Under optimum conditions, the extent of the fluorescence quenching of prepared CDs strongly depended on the Fe 3+ ions over a wide concentration range 1.0-100.0 μM with a detection limit (3σ/k) of 0.3 μM. Furthermore, the quantitative determination of Fe 3+ ions in environmental water samples was realized., (© 2020 John Wiley & Sons, Ltd.)

Notch signaling provides an important cue in the mammalian developmental process. It is a key player in T cell development and function. Notch ligands such as Delta-like ligands (DLL) 1, 3, 4, and JAG1, 2 can impact Notch signaling positively or negatively, by trans -activation or cis -inhibition. Trans and cis interactions are receptor-ligand interaction on two adjacent cells and interaction on the same cell, respectively. The former sends an activation signal and the later, a signal for inhibition of Notch. However, earlier reports suggested that Notch is activated in the absence of Notch ligand-expressing APCs in a purified population of CD4 T cells. Thus, the role of ligands in Notch activation, in a purified population of CD4 T cells, remains obscure. In this study, we demonstrate that mature CD4 T cells are capable of expressing Notch ligands on their surface very early upon activation with soluble antibodies against CD3 and CD28. Moreover, signaling solely through CD28 induces Notch ligand expression and CD3 signaling inhibits ligand expression, in contrast to Notch which is induced by CD3 signaling. Additionally, by using decoys, mimicking the Notch extracellular domain, we demonstrated that DLL1, DLL4, and JAG1, expressed on the T cells, can cis -interact with the Notch receptor and inhibit activation of Notch. Thus, our data indicate a novel mechanism of the regulation of Notch ligand expression on CD4 T cells and its impact on activated Notch., (Copyright © 2020 Mitra, Shanthalingam, Sherman, Singh, Canakci, Torres, Lawlor, Ran, Golde, Miele, Thayumanavan, Minter and Osborne.)

The demineralized fraction (DM), lipid-free fraction (LF), nonhydrolyzable organic carbon fraction (NHC), and black carbon (BC) were isolated from five marine surface sediments, and they were characterized by elemental analysis as well as CO 2 and N 2 adsorption techniques, respectively. The NHC fractions were characterized using advanced solid-state 13 C nuclear magnetic resonance (NMR) and x-ray photoelectron spectroscopy (XPS). Then, the sorption isotherms of phenanthrene (Phen) and nonylphenol (NP) on all of the samples were investigated by a batch technique. The CO 2 micropore volumes were corrected for the outer specific surface areas (SSAs) by using the N 2 -SSA. Significant correlations between the micropore-filling volumes of Phen and NP and the micropore volumes suggested that the micropore-filling mechanism dominated the Phen and NP sorption. Meanwhile, the (O + N)/C atomic ratios were negatively and significantly correlated with the sorption capacities of Phen and NP, indicating that the sedimentary organic matter (SOM) polarity also played a significant role in the sorption process. In addition, a strong linear correlation was demonstrated between the aromatic C and the sorption capacity of Phen for the NHC fractions. This study demonstrates the importance of the micropores, polarity, and aromaticity on the sorption processes of Phen and NP in the sediments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Neonicotinoid insecticides have posed a great threat to non-target organisms, yet the mechanisms underlying their toxicity are not well characterized. Major modes of action (MoAs) of imidacloprid were analyzed in an aquatic insect Chironomus dilutus. Lethal and sublethal outcomes were assessed in the midges after 96-h exposure to imidacloprid. Global transcriptomic profiles were determined using de novo RNA-sequencing to more holistically identify toxicity pathways. Transcriptional 10% biological potency values derived from ranked KEGG pathways and GO terms were 0.02 (0.01-0.08) (mean (95% confidence interval) and 0.05 (0.04-0.06) μg L -1 , respectively, which were more sensitive than those from phenotypic traits (10% lethal concentration: 0.44 (0.23-0.79) μg L -1 ; 10% burrowing behavior concentration: 0.30 (0.22-0.43) μg L -1 ). Major MoAs of imidacloprid in aquatic species were identified as follows: the activation of nicotinic acetylcholine receptors (nAChRs) induced by imidacloprid impaired organisms' nerve system through calcium ion homeostasis imbalance and mitochondrial dysfunction, which posed oxidative stress and DNA damage and eventually caused death of organisms. The current investigation highlighted that imidacloprid affected C. dilutus at environmentally relevant concentrations, and elucidated toxicity pathways derived from gene alteration to individual outcomes, calling for more attention to toxicity of neonicotinoids to aquatic organisms., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Toll-like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL-1β is an important pro-inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin-1 receptor (IL-1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/IL-1R-mediated signaling. Overexpression of RNF152 potentiates IL-1β- and LPS-induced NF-κB activation in an ubiquitination-independent manner, whereas knockdown of RNF152 has the opposite effects. RNF152-deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS-induced lethal endotoxemia. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/IL-1R-mediated signal transduction. Our findings suggest that RNF152-mediated oligomerization of MyD88 is important for TLR/IL-1R-mediated inflammatory response., (© 2020 The Authors.)

Although spores/pollens are so abundant and ubiquitous in the environment, the role of these natural organic matter concerning fate and transport of organic pollutants in the environment is neglected. Lipid-free fractions and sporopollenins were isolated from seven spores/pollens collected from lower and higher biota species and were characterized by elemental analysis, CO 2 adsorption techniques, and advanced solid-state 13 C nuclear magnetic resonance spectroscopy. Then, the sorption isotherms of phenanthrene (Phen) on all the samples were investigated by a batch technique. The sporopollenins were a highly cross-linked polymer including alkyl carbon, poly(methylene) carbon, and aromatic carbon as well as oxygen functionalities; additionally, their sorption capacities ( K oc ) for Phen reached up to 1 170 000 mL/g, suggesting that some of the sporopollenins were good biopolymeric sorbents for the removal of hydrophobic organic contaminants in aquatic media. A highly significant and positive correlation between the sorption capacity of Phen and the aliphaticity of the sporopollenins suggested that their structure was critical to Phen sorption. Meanwhile, the (O + N)/C atomic ratios and polar groups were significantly and negatively correlated with the sorption capacity of Phen, indicating that accessibility also played a significant role in the sorption process. Moreover, variable correlations between the sorption capacities ( K oc ) and the micropore volumes of the spore/pollen fractions were observed. This study sheds light on the importance of the polarity, microporosity, and structure of sporopollenins in the sorption process of Phen.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics., (© 2019 Futch et al.)

STING plays central roles in the innate immune response to pathogens that contain DNA. Sensing cytoplasmic DNA by cyclic GMP-AMP synthase produces cyclic GMP-AMP, which binds to and activates STING and induces STING translocation from the endoplasmic reticulum to the perinuclear microsome. However, this trafficking process has not been fully elucidated yet. In this study, we identified YIPF5 as a positive regulator of STING trafficking. YIPF5 is essential for DNA virus- or intracellular DNA-triggered production of type I IFNs. Consistently, knockdown of YIPF5 impairs cellular antiviral responses to DNA virus. Mechanistically, YIPF5 interacts with both STING and components of COPII, facilitating STING recruitment to COPII in the presence of cytoplasmic dsDNA. Furthermore, knockdown of components of COPII inhibits DNA virus-triggered production of type I IFNs, suggesting that COPII is involved in innate immune responses to DNA viruses. Collectively, our findings demonstrate that YIPF5 positively regulates STING-mediated innate immune responses by recruiting STING to COPII-coated vesicles and facilitating STING trafficking from the endoplasmic reticulum to Golgi, providing important insights into the molecular mechanisms of intracellular DNA-stimulated STING trafficking and activation., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The effects of the chemical structure, surface properties, and micropore of modified black carbon samples (BCs) on the sorption mechanism of hydrophobic organic contaminants (HOCs) are discussed. Activated and oxidized BCs were produced from a shale kerogen at 250-500 °C by chemical activation regents (KOH and ZnCl 2 ) and then by oxidative regents (H 2 O 2 and NaClO). The surface properties (water contact angel, Boehm titration, and cation exchange capacity, CEC), structural properties (advanced solid-state 13 C NMR), micropore properties (CO 2 adsorption), mesopore properties (N 2 adsorption), and sorption and desorption properties of phenanthrene were obtained. The results showed that ZnCl 2 -activated BCs had higher basic surface groups, CEC values, aromatic carbon contents, micropore volumes, and adsorption volumes but exhibited lower acidic surface groups than the KOH-activated BCs did. Micropore modeling and sorption irreversibility indicated that the micropore filling was the main sorption mechanism of phenanthrene. In addition, ZnCl 2 activated and NaClO oxidized BCs showed a nice regression equation between adsorption volumes and micropore volumes (CO 2 - V 0 ) as follows: Q 0 ' = 0.495 V 0 + 6.28( R 2 = 0.98, p < 0.001). Moreover, the contents of nonprotonated aromatic carbon, micropore volumes, and micropore sizes are the critical factors to micropore filling mechanism of phenanthrene on BCs. The size of fused aromatic rings was estimated from the recoupled 1 H- 13 C dipolar dephasing, and the BC structural models at temperatures ranging from 300 to 500 were proposed. This finding improves our understanding of the sorption mechanism of HOCs from the perspectives of chemical structure and micropore properties.

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3., Competing Interests: The authors declare no conflict of interest.

The occurrence and distributions of selected endocrine-disrupting chemicals (EDCs), along with related environmental factors, were investigated in two rivers and six reservoirs in the Pearl River Delta. The vertical profiles of aqueous 4-tert-octylphenol (OP), 4-nonylphenol (NP), and estrone (E1) were constant, with little change in concentration between the surface and the river bottom, while higher aqueous concentrations of bisphenol A (BPA) were found in the bottom layers of the rivers. OP and NP in suspended particulate matter (SPM) were transferred from the surface to the bed layer, ultimately accumulating in the sediment. However, the particulate profiles of BPA and E1 both featured increases from the surface to the bottom layers and attenuation in the river bed. Dissolved oxygen (DO), water temperature, and pH were negatively correlated with the EDC concentrations, and negative relationships between DO and distribution coefficient (K d ) values for OP and NP were found as well. This indicated that these environmental parameters were primarily responsible for the EDC vertical distribution and SPM-water partitioning in the rivers. Positive relationships were observed between chlorophyll a and EDCs in the particulate phase, and the algae/water K d values for EDCs in reservoirs were comparable to the SPM/water and sediment/water K d values from the rivers. These results suggest that algae played an important role in regulating the distribution of EDCs in surface waters. Moreover, relationships between UV absorbance and EDCs revealed that π-π interactions were among the dissolved organic carbon (DOC)-EDC binding mechanisms and that DOC fractions with higher degrees of aromaticity and humification possessed higher affinities towards EDCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Polybrominated diphenyl ethers (PBDEs) were investigated by GC-NCI-MS in sediments collected from the Pearl River Delta (PRD) and Guiyu town, South China. The concentrations of ∑ 39 PBDEs and BDE 209 were in the ranges of 0.31-38.9 ng g -1 and 12.2-488 ng g -1 in the PRD, and 2.57-21,207 ng g -1 and 7.02-66,573 ng g -1 in Guiyu, respectively. The levels of PBDEs in Dongjiang River (DJ), Zhujiang River (ZJ), and Beijiang River (BJ), and Guiyu (GY) followed the order: GY > DJ > ZJ > BJ. The very high PBDE concentration (87,779 ng g -1 ) was detected at G1 sediment in Guiyu compared with those in sediments from other regions around the world. The PBDE mixtures detected were mainly comprised of penta-, octa-, and deca-BDEs, in which deca-BDE was the dominant constituent. The abundant congeners, excluding BDE-209, were BDE-47, BDE-99, and BDE-183, suggesting the diverse use of commercial products containing these congeners in this region. The concentrations of major congeners were significantly correlated with total organic carbon (TOC) contents (p < .01). A good regression between the logarithmic TOC-normalized BDE average concentrations and their log K ow confirmed that the sorption of PBDEs on sediment organic matter governed their spatial distribution, transport, and fate in the sediments. Furthermore, risk quotients (RQs) derived from concentrations of PBDEs in sediments from our study may pose high ecological risks to exposure of benthic organisms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aberrant accumulated self DNA in the cytoplasm under certain pathological conditions, such as virus induced cell death, DNA damage, mitochondria damage, gene mutations, which results in autoimmune diseases. Therefore, the cGAS-MITA pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases. The regulation of cGAS-MITA pathway at MITA-level have been extensively explored and reviewed elsewhere, here we provide a summary and perspective on recent advances in understanding of the cGAS regulation.

The transcription factors IRF3 and NF-κB are required for the expression of many genes involved in antiviral innate immune response, including type I interferons (IFNs) and proinflammatory cytokines. It is well established that TBK1 is an essential kinase engaged downstream of multiple pattern-recognition receptors (PRRs) to mediate IRF3 phosphorylation and activation, whereas the precise mechanisms of TBK1 activation have not been fully elucidated yet. Here, we identified tripartite motif 26 (TRIM26) as an important regulator for RNA virus-triggered innate immune response. Knockdown of TRIM26 impaired virus-triggered IRF3, NF-κB activation, IFN-β induction, and cellular antiviral response. TRIM26 was physically associated with TBK1 independent of viral infection. As an E3 ligase, TRIM26 underwent autoubiquitination upon viral infection. Ubiquitinated TRIM26 subsequently associated with NEMO, thus bridging TBK1-NEMO interaction, which is critical for the recruitment of TBK1 to the VISA signalsome and activation of TBK1. Our findings suggest that TRIM26 is an important regulator of innate immune responses against RNA viruses, which functions by bridging TBK1 to NEMO and mediating the activation of TBK1., (© The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.)

Background: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM., Results: We find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency., Conclusion: These data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase., (© 2015 The Authors.)

The recognition of nucleic acids is a general strategy used by the host to detect invading pathogens. Many studies have established that MITA/STING is a central component in the innate immune response to cytosolic DNA and RNA derived from pathogens. MITA can act both as a direct sensor of cyclic dinucleotides (CDNs) and as an adaptor for the recruitment of downstream signaling components. In both roles, MITA is part of signaling cascades that orchestrate innate immune defenses against various pathogens, including viruses, bacteria and parasites. Here, we highlight recent studies that have uncovered the molecular mechanisms of MITA-mediated signal transduction and regulation, and discuss some notable issues that remain elusive., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Polybrominated diphenyl ethers (PBDEs) were measured in sewage sludge samples collected from major wastewater treatment plants in Guangdong Province, South China. Concentrations of ∑39PBDE (all 39 compounds including tri- to hepta- PBDE congeners except for BDE-209) ranged from 3.6 to 428 ng/g dw with a mean value of 67.4 ng/g dw and a median value of 25.9 ng/g dw, and those of BDE-209 ranged from 9.9 to 5,010 ng/g dw (mean 1,024 ng/g dw and median 824 ng/g dw). The PBDE mixtures detected were mainly comprised of penta-, octa-, and deca-BDEs, with deca-BDE as the dominant constituent. The most abundant congeners, excluding BDE-209, were BDE-47, BDE-99, and BDE-183. Good correlations were found among the concentrations of BDE-47, BDE-99, BDE-100, BDE-138, and BDE-154 (r>0.8). However, poor correlations were found between the concentrations of BDE-209 and all other congeners (r<0.3). This fact suggests that most tri- to hepta-BDEs detected did not originate from decomposition of deca-BDE. The estimated annual emission of ∑allPBDEs, ∑39PBDEs, penta-BDE, octa-BDE, and deca-BDE to the Pearl River Delta environment (PRD), based on the sludge samples analyzed, amounts to 232, 20.2, 5.5, 1.7, and 212 kg per year, implicating sewage sludge as a significant source of PBDEs to the PRD environment.

Detection of viral nucleic acids by pattern recognition receptors initiates type I interferon (IFN) induction and innate antiviral response. The RIG-I-like receptors (RLRs), including RIG-I and MDA5, recognize cytoplasmic viral RNA in most cell types and are critically involved in innate antiviral response. RIG-I and MDA5 are structurally related and mediate similar signaling pathways. While the regulation of RIG-I activity has been extensively investigated, little is known about the regulatory mechanisms of MDA5 activity. Here we identified ribonucleoprotein PTB-binding 1 (RAVER1) as a specific MDA5-interacting protein. RAVER1 was associated with MDA5 upon viral infection. Overexpression of RAVER1 at low dosages enhanced MDA5- but not RIG-I-mediated activation of the IFN-β promoter, whereas knockdown of RAVER1 inhibited MDA5- but not RIG-I-mediated induction of downstream antiviral genes. Mechanistically, overexpression of RAVER1 enhanced the binding of MDA5 to its ligand poly(I:C), whereas knockdown of RAVER1 had opposite effect. Our findings suggest that RAVER1 specifically regulates MDA5 activity, revealing a mechanism of differential regulation of MDA5- and RIG-I-mediated innate antiviral response.

To examine spatial distribution and bioconcentration of PAHs, water and fish samples were collected from Pearl River Delta in summer and spring, respectively. Particulate organic carbon, dissolved organic carbon, biodegradable DOC (BDOC), and chlorophyll a were measured. PAHs were dominated by 2- and 3-ring compounds in the water and SPM samples. Aqueous and solid-phase PAHs, respectively, showed significant correlations with total organic matter (TOC) in SPM or dissolved organic matter (DOC) in the water. The in-situ partitioning coefficients (logK(oc), mL/g) for the samples were observed to be related to logK(ow), implying that the hydrophobicity of PAHs is a critical factor in their distribution. It was also observed that BCF increased with the increasing K(ow) in the viscera of tilapia (logBCF = 0.507logK(ow) - 1.368, r = 0.883). However, most of the observed log BCF values in other different fish tissues at first increased with the increasing of log K(ow), then reached a maximum value when logK(ow) is between 5 and 7, and then decreased when logK(ow) is higher than 7, indicating that the value of BCF may vary due to the diversity of fish species.

The tripartite motif (TRIM)-containing proteins are a family of proteins that have been known to be involved in divergent biological processes, including important roles in immune responses through regulating various signaling pathways. In this study, we identified a member of the TRIM family, TRIM8, as a positive regulator of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β)-triggered NF-κB activation. Overexpression of TRIM8 activated NF-κB and potentiated TNFα- and IL-1β-induced activation of NF-κB, whereas knockdown of TRIM8 had opposite effects. Coimmunoprecipitations indicated that TRIM8 interacted with TGFβ activated kinase 1 (TAK1), a serine/threonine kinase essential for TNFα- and IL-β-induced NF-κB activation. Furthermore, we found that TRIM8 mediated K63-linked polyubiquitination of TAK1 triggered by TNFα and IL-1β. Our findings demonstrate that TRIM8 serves as a critical regulator of TNFα- and IL-1β-induced NF-κB activation by mediating K63-linked polyubiquitination of TAK1.

Transcription factor IRF3-mediated type I interferon induction is essential for antiviral innate immunity. We identified the deSUMOylating enzyme Sentrin/SUMO-specific protease  (SENP) 2 as a negative regulator of virus-triggered IFN-β induction. Overexpression of SENP2 caused IRF3 deSUMOylation, K48-linked ubiquitination, and degradation, whereas depletion of SENP2 had opposite effects. Both the SUMOylation and K48-linked ubiquitination of IRF3 occurred at lysines 70 and 87, and these processes are competitive. The level of virus-triggered IFN-β was markedly up-regulated and viral replication was reduced in SENP2-deficient cells comparing with wild-type controls. Our findings suggest that SENP2 regulates antiviral innate immunity by deSUMOylating IRF3 and conditioning it for ubiquitination and degradation, and provide an example of cross-talk between the ubiquitin and SUMO pathways in innate immunity.

The endocrine-disrupting chemicals (EDCs) was investigated in 28 riverine sediments from the Pearl River system, China and analyzed by an ultrasonication extraction and GC-MS method. The concentrations of 4-tert-octylphenol (OP), 4-nonylphenol (NP), and bisphenol A (BPA) in the sediments were in the ranges of <2.0-210, 107-16198 and <1.7-430 ng/g dw, respectively. The steroid estrogens estrone (E1) and 17β-estradiol (E2) in the sediments ranged from <1.3 to 10.9 ng/gdw and from <0.9 to 2.6 ng/gdw, respectively. The spatial distribution of these chemicals was related to the discharge of domestic and industrial wastewater along the rivers. The positive correlation between EDCs and total organic carbon indicates that sedimentary organic carbon is an important factor in controlling the distributions of EDCs. Compared with other previous studies, the ZR and DR rivers from the PRD were heavily contaminated by APs and BPA., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Sixteen USEPA priority polycyclic aromatic hydrocarbons (PAHs) extracted by Soxhlet extraction (S-PAHs) with dichloromethane and routine accelerated solvent extraction (A-PAHs) with 1:1 toluene/methanol, respectively, were investigated in 24 soil samples from two cities in the center of the Pearl River Delta, South China. Polycyclic aromatic hydrocarbons, methylphenanthrene and perylene, in two soils, two sediments, and an immature oil shale were also sequentially extracted by accelerated solvent extraction (ASE) with each of four different organic solvents for three times. The A-PAHs' concentrations are 2.41 times the S-PAHs' concentrations. For sequential three ASEs, PAHs in the first extract account for 56 to 67% of their total concentrations in the sequential three extractions and toluene displays the best extraction performance among the four solvents. Diagnostic ratios of PAHs in Soxhlet extraction, routine ASE, and sequential ASE with each solvent for a given sample are very similar, suggesting their identical petrogenic and pyrogenic sources in the soils and sediments. But the PAH ratios for the shale have an obvious petrogenic origin. The perylene/5-ring PAH ratios indicate a diagenetic source, especially in the shale and sediments. The correlation analysis shows that A-PAHs/S-PAHs is better associated with the contents of total organic carbon (TOC) than those of black carbon (BC). The above results indicate the significant petrogenic origin of PAHs and the important effect of organic matter on their extraction and distribution in the investigated field soils/sediments.

Objective: To investigate the role of methylation on E-cadherin inactivation in nasopharyngeal carcinoma (NPC) cell line HNE1 and CNE2, as well as evaluate the inhibitory effect of 5-aza-2'-deoxycytidine (5-Aza-dC) on cell abilities of proliferation and invasion., Methods: The expression level of E-cadherin was measured by RT-PCR, Western blot and immunohistochemistry (polymer method), the methyaltion status was analyzed by methylation-specific PCR (MSP), and cell proliferation and invasion were examined by MTT and invasion assay, separately before and after treatment with demethylating agent 5-Aza-dC., Results: The expression level of E-cadherin was down-regulated compared with the normal tissue, simultaneously partially methylated in gene promoter. Treatment with 20 µmol/L 5-Aza-dC increased the expression of E-cadherin and reduced the methylation degree. Moreover, it also significantly suppressed cell growth (27.6% for HNE1 cells and 34.3% for CNE2 cells, P < 0.05) and invasiveness (37.2% for HNE1 cells and 29.7% for CNE2 cells, P < 0.05)., Conclusions: Aberrant methylation around gene promoter region may play an important part in down regulation of E-cadherin in NPC, suggesting a potential therapeutic strategy for demethylating agents such as 5-Aza-dC.

Viral infection causes activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and cellular antiviral response. The mitochondrial outer membrane protein VISA acts as a critical adapter for assembling a virus-induced complex that signals NF-kappaB and IRF3 activation. Using a biochemical purification approach, we identified the WD repeat protein WDR5 as a VISA-associated protein. WDR5 was recruited to VISA in a viral infection dependent manner. Viral infection also caused translocation of WDR5 from the nucleus to mitochondria. Knockdown of WDR5 impaired the formation of virus-induced VISA-associated complex. Consistently, knockdown of WDR5 inhibited virus-triggered activation of IRF3 and NF-kappaB as well as transcription of the IFNB1 gene. These findings suggest that WDR5 is essential in assembling a virus-induced VISA-associated complex and plays an important role in virus-triggered induction of type I IFNs.

Polycyclic aromatic hydrocarbons (PAHs) in two soils, two sediments and an shale from the Pearl River Delta were extracted by sequential accelerated solvent extraction (ASE) with each of four different organic solvents for three times. PAHs in the first extract accounts for more than half of their total contents, and toluene displays the best extraction performance among the four employed solvents. For a given sample the source diagnostic ratios of PAHs in sequential ASE with each solvent are very similar, suggesting the validity of those ratios in source judgement by different extraction methods.

The occurrence and environmental risk of endocrine-disrupting chemicals was investigated in the surface water samples of the Zhujiang and Dongjiang rivers, Pearl River Delta (PRD) of South China. Thirty surface water samples were collected in the dry season and analyzed by using an MSTFA derivation and a GC-MS-SIM method. Concentrations of biphenol A (BPA) ranged from 43.5 to 639.1 ng L( - 1), and concentrations of estrone (E1) and 17beta-estradiol (E2) ranged from <1.5 to 8.2 ng L( - 1) and from <1.1 to 1.7 ng L( - 1), respectively. The spatial distribution of these chemicals was related to the discharge of domestic and industrial wastewater along the rivers. The highly significant correlation among BPA, E1, and dissolved organic carbon (DOC) might be related to their same contamination source and/or their association with colloidal organic carbon of DOC in the river samples. Compared with other studied rivers in the world, the estrogenic contamination in the investigated rivers was high for BPA and moderate for E1. As the average estrogenic activity in E2 activity equivalent (E2eq; 1.16 ng E2eq L( - 1)) for the target BAP, E1, and E2 combined with those for nonyphenol and octylphenol, which were previously reported, exceeds documented effect levels in the investigated river waters for some aquatic species, they may pose a high risk to the local aquatic organisms.

The concentration levels, source, and inventories of polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OCPs) in 55 surface vegetable soils in the watershed of the Pearl River Delta (PRD) were analyzed and compared with those of the surface sediments in the Pearl River Estuary (PRE) and northern South China Sea (SCS). The 16 priority PAHs on US EPA list range from 58 to 3,077 microg/kg (average: 315 microg/kg). The concentrations of DDTs and HCHs range from 3.58 to 831 microg/kg (average: 82.1 microg/kg) and from 0.19 to 42.3 microg/kg (average: 4.42 microg/kg). The ratios of DDT/ (DDD+DDE) are higher than 2 in majority of the soil samples, suggesting that DDT contamination still exists. The PAH ratios suggest that the source of PAHs is petroleum, and combustion of fossil fuel, biomass, and coal. The average concentrations of PAHs and the linear regression slope between PAHs and TOC for the soils and the sediments are quite similar. It was estimated that the soil mass inventories at 0-20 cm depth are 1,292 metric tons for PAHs and 356 metric tons for OCPs in the studied region. The average PAHs inventory per unit area for the soil samples investigated in PRD is about 0.86 time that of surface sediments in the Pearl River Estuary, and about 2.43 times that of surface sediments in the northern South China Sea. PAHs in the soils in PRD have similar source to those of the surface sediments in PRE. All of those may suggest that PAHs in PRE and SCS are probably mainly inputted from the soils in PRD via soil erosion and river transport.