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1.
Huan Jing Ke Xue ; 42(10): 4727-4738, 2021 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-34581115

RESUMO

Shengjin Lake, which serves as an important National Nature Reserve, is suffering from chemical pollution due to rapid industrial and agricultural development in the circumjacent basin. Therefore, 168 anthropogenic toxic chemicals were determined to examine their spatial distribution and identify priority pollutants using a ranking system based on occurrence(O), persistence(P), bioaccumulation(B), ecological risk(E), and human health risk(H). Ecosystem and human health risks were also assessed. The spatial distribution of pollutants indicated that higher concentrations occur in the upper lake area compared to the middle and lower lake areas because of Jiang Dam. According to the derived priority pollutant list, phthalate esters(PAEs), organochlorine pesticides(OCPs), and heavy metals(HMs) are high-priority pollutants; polychlorinated biphenyls(PCBs), polycyclic aromatic hydrocarbons(PAHs), and volatile organic compounds(VOCs) are medium-priority pollutants; and antibiotics(ANTs) are low-priority pollutants. The ecology risk quotient(RQ) of the high-priority pollutants ranged from 4.3 to 15.9, indicating severe ecology risk to the aquatic organism, and higher risks were found in the upper lake areas. Additionally, the human health risk assessment revealed negligible carcinogenic risks associated with high-priority pollutants. The comprehensive ranking system established in this study can be applied to other lake basins by altering the measured concentrations to screen for priority pollutants, offering a scientific foundation for identifying priority control pollutants for watershed management.


Assuntos
Poluentes Ambientais , Hidrocarbonetos Clorados , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , China , Ecossistema , Monitoramento Ambiental , Humanos , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco , Água , Poluentes Químicos da Água/análise
2.
Molecules ; 26(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34577121

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent cause of Parkinson's disease (PD). As a multidomain ROCO protein, LRRK2 is characterized by the presence of both a Ras-of-complex (ROC) GTPase domain and a kinase domain connected through the C-terminal of an ROC domain (COR). The bienzymatic ROC-COR-kinase catalytic triad indicated the potential role of GTPase domain in regulating kinase activity. However, as a functional GTPase, the detailed intrinsic regulation of the ROC activation cycle remains poorly understood. Here, combining extensive molecular dynamics simulations and Markov state models, we disclosed the dynamic structural rearrangement of ROC's homodimer during nucleotide turnover. Our study revealed the coupling between dimerization extent and nucleotide-binding state, indicating a nucleotide-dependent dimerization-based activation scheme adopted by ROC GTPase. Furthermore, inspired by the well-known R1441C/G/H PD-relevant mutations within the ROC domain, we illuminated the potential allosteric molecular mechanism for its pathogenetic effects through enabling faster interconversion between inactive and active states, thus trapping ROC in a prolonged activated state, while the implicated allostery could provide further guidance for identification of regulatory allosteric pockets on the ROC complex. Our investigations illuminated the thermodynamics and kinetics of ROC homodimer during nucleotide-dependent activation for the first time and provided guidance for further exploiting ROC as therapeutic targets for controlling LRRK2 functionality in PD treatment.

3.
Ecotoxicol Environ Saf ; 225: 112733, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34478978

RESUMO

Perfluorohexanoic acid (PFHxA), a widely used emerging alternative for 8-carbon PFAAs, has been detected at a high level in the water environment. While its toxicity and environmental health risk are still largely unknown in aquatic life. The present study aimed to evaluated the possible developmental neurotoxicity induced by PFHxA exposure (0, 0.48, 2.4, and 12 mg/L for 120 h) in the zebrafish embryo. Here, both developmental endpoints, neurotransmitters concentrations, locomotor behavior were analyzed. No significant effects on mortality, malformation rate, and growth delay were detected in the low dose treatment groups except for in the high dose group (12 mg/L). A significant increase in swimming speed were noted in the 0.48 mg/L group. Other changes including neurotransmitters concentrations and green fluorescent protein (GFP) expression in Tg (HuC-GFP) zebrafish larvae were significantly increased in 12 mg/L group. Beyond that, genes related to neurodevelopment were significantly decreased in larvae. Moreover, downregulations of protein expression levels of α1-tubulin, elavl3, and gap43 were identified. These results demonstrate that the PFAAs alternative PFHxA have no significant neurodevelopmental effects on zebrafish larvae under acute low-dose exposure, while, it is important to note that PFHxA perform inhibiting effects on neurotransmitter and central nervous system under a relatively high dose. This in vivo study could provide reliable toxicity information for risk assessments of PFHxA on aquatic ecosystems. CAPSULE: PFHxA have no significant neurodevelopmental effects on zebrafish larvae under acute low-dose exposure, while exposed with relatively high-dose, could induced the alternations of neurotransmitter concentrations as well as the genes involved in the early developmental stages of zebrafish, leading to the impairment of the nervous system in zebrafish larvae.


Assuntos
Fluorcarbonetos , Poluentes Químicos da Água , Animais , Caproatos , Ecossistema , Embrião não Mamífero , Fluorcarbonetos/toxicidade , Larva , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
4.
Nat Commun ; 12(1): 4721, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354057

RESUMO

G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT1 receptor) - a prototypical class A GPCR-activation. Our findings suggest a synergistic transition mechanism for AT1 receptor activation. A key intermediate state is identified in the activation pathway, which possesses a cryptic binding site within the intracellular region of the receptor. Mutation of this cryptic site prevents activation of the downstream G protein signaling and ß-arrestin-mediated pathways by the endogenous AngII octapeptide agonist, suggesting an allosteric regulatory mechanism. Together, these findings provide a deeper understanding of AT1 receptor activation at an atomic level and suggest avenues for the design of allosteric AT1 receptor modulators with a broad range of applications in GPCR biology, biophysics, and medicinal chemistry.


Assuntos
Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/metabolismo , Regulação Alostérica , Sítio Alostérico , Sítios de Ligação/genética , Desenho de Fármacos , Humanos , Cadeias de Markov , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica , Receptor Tipo 1 de Angiotensina/genética , Transdução de Sinais , beta-Arrestinas/metabolismo
5.
Sci Total Environ ; 794: 148700, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34214810

RESUMO

Screening priority pollutants from vast anthropogenic contaminants discharged into aquatic environment is urgent for protecting water quality definitely. The multi-criteria scoring method involved in the occurrence (O), persistence (P), bioaccumulation (B), ecological risk (Eco-T), and human health risk (Hum-T), was established for pollutants prioritization in waters and applied in Dongping Lake, the final impoundment reservoir along the eastern route of China's South-to-North Water Diversion Project (SNWDP). A total of 170 chemicals including heavy metals (HMs), volatile organic chemicals (VOCs), polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), phthalate esters (PAEs), and antibiotics (ANTs) were investigated as the candidates. Accordingly, 42 chemicals including 8 PAEs, 7 OCPs, 7 PCBs, 5 PAHs, 13 HMs, and 2 VOCs were made up the list of priority pollutants for Dongping Lake, suggesting the necessity of routine monitoring high priority groups and revising the existing list. Multiple risk assessment indicated higher ecological and human health risks induced by HMs than by organic pollutants. Spatial distribution of risks stressed the retention of toxic organic chemicals by the lake body and the accumulation of HMs along the transfer route, respectively, thus triggering ecosystem responses and potential effects on the water-receiving areas as expected.


Assuntos
Poluentes Ambientais , Compostos Orgânicos Voláteis , Poluentes Químicos da Água , China , Ecossistema , Monitoramento Ambiental , Humanos , Poluentes Químicos da Água/análise
6.
J Phys Chem B ; 125(25): 6733-6734, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192874
7.
Ecotoxicol Environ Saf ; 221: 112427, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34171688

RESUMO

Lakes in arid northwestern China, as the main pollutant-holding water bodies in the typical ecologically fragile areas, are facing the unknown risk of exposure to antibiotics and antibiotic resistance genes (ARGs). In this study, five ARGs and one mobile genetic element (intI1) and their relation with antibiotics, microbial communities and water quality were investigated in Ebinur Lake Basin, a typical salt-lake of China. Quantitative PCR analysis indicated that ARGs decreasing order in both surface water and sediment was sul1 >sul2 >tetW>ermB>qnrS, which means sulfonamide resistance genes were the main pollution ARGs. Macrolide antibiotics were the predominant antibiotics in the surface water and sediment in winter, while sulfonamides and quinolones accounted for a high proportion in summer. There was a non-corresponding relationship between ARGs and antibiotics. Moreover, the relationship between ARGs and microbial communities were defined. Sulfonamide resistance genes were carried by a greater diversity of potential host bacteria (76 genera) than other ARGs (9 genera). And their positive correlation with intI1 (p < 0.05) which promotes their migration and provides possibility of their co-occurrence in bacterial populations (e.g., Nitrospira). Bacterial genera were the main driver of ARGs distribution pattern in highly saline lake sediment. Environmental factors like salinity, total nitrogen and organic matter could have a certain influence on the occurrence of ARGs by affecting microorganisms. The results systematically show the distribution and propagation characteristics of ARGs in typical inland salt-lakes in China, and preliminarily explored the relationship between ARGs and antibiotics, resistance genes and microorganisms in lakes in ecologically fragile areas.


Assuntos
Resistência Microbiana a Medicamentos/genética , Monitoramento Ambiental , Genes Bacterianos/genética , Lagos/microbiologia , Microbiota/efeitos dos fármacos , Microbiota/genética , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , China , Quinolonas/farmacologia , Sulfonamidas/farmacologia , Qualidade da Água
8.
Environ Pollut ; 286: 117294, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33971472

RESUMO

Benzophenone-type UV filters have been implicated in multiple adverse reproductive outcomes, yet the underlying processes and molecular targets on the female reproductive tract remain largely unknown. Herein, we investigated the effect of dioxybenzone, one of the widely used congeners, and its demethylated (M1) and hydroxylated (M2) metabolites on transcriptome profiles of ICR mice uterus and identified potential cellular targets in human endometrial stromal cells (HESCs) separated from normal endometrium tissues. Dioxybenzone, M1 and M2 (20 mg/kg bw/d) significantly induced transcriptome aberration with the induction of 683, 802, and 878 differentially expressed genes mainly involved in cancer, reproductive system disease and inflammatory disease. Compared to dioxybenzone, M1 and M2 exhibited a transcriptome profile more similar to estradiol in mice uterus, and subsequently promoted thicker endometrial columnar epithelial layer through upregulation of estrogen receptor target genes-Sprr2s. Dioxybenzone, M1 and M2 (0.1 or 1 µM) also exhibited estrogenic disrupting effect via increasing the mRNA expressions and production of the growth factors responsible for epithelial proliferation, including Fgfs and Igf-1 in HESCs. Additionally, the mRNA expressions of several inflammatory cytokines especially IL-1ß in mice uterus and HESCs was significantly upregulated by dioxybenzone and its metabolites. Overall, we revealed that dioxybenzone and its metabolites triggered transcriptome perturbation dually associated with abnormal steroid hormone response and inflammation, both as key determinants to reproductive health risks.


Assuntos
Benzofenonas , Transcriptoma , Animais , Estradiol , Feminino , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR , Útero
9.
Phys Chem Chem Phys ; 23(21): 12204-12215, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008604

RESUMO

Hepatitis C virus (HCV) is a notorious member of the Flaviviridae family of enveloped, positive-strand RNA viruses. Non-structural protein 5A (NS5A) plays a key role in HCV replication and assembly. NS5A is a multi-domain protein which includes an N-terminal amphipathic membrane anchoring alpha helix, a highly structured domain-1, and two intrinsically disordered domains 2-3. The highly structured domain-1 contains a zinc finger (Zf)-site, and binding of zinc stabilizes the overall structure, while ejection of this zinc from the Zf-site destabilizes the overall structure. Therefore, NS5A is an attractive target for anti-HCV therapy by disulfiram, through ejection of zinc from the Zf-site. However, the zinc ejection mechanism is poorly understood. To disclose this mechanism based on three different states, A-state (NS5A protein), B-state (NS5A + Zn), and C-state (NS5A + Zn + disulfiram), we have performed molecular dynamics (MD) simulation in tandem with DFT calculations in the current study. The MD results indicate that disulfiram triggers Zn ejection from the Zf-site predominantly through altering the overall conformation ensemble. On the other hand, the DFT assessment demonstrates that the Zn adopts a tetrahedral configuration at the Zf-site with four Cys residues, which indicates a stable protein structure morphology. Disulfiram binding induces major conformational changes at the Zf-site, introduces new interactions of Cys39 with disulfiram, and further weakens the interaction of this residue with Zn, causing ejection of zinc from the Zf-site. The proposed mechanism elucidates the therapeutic potential of disulfiram and offers theoretical guidance for the advancement of drug candidates.


Assuntos
Antivirais/farmacologia , Dissulfiram/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Zinco/farmacologia , Antivirais/síntese química , Antivirais/química , Teoria da Densidade Funcional , Dissulfiram/química , Humanos , Simulação de Dinâmica Molecular , Zinco/química
10.
J Environ Manage ; 292: 112578, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965685

RESUMO

To investigate the effect of a constructed wetland (CW) with steel slag as the filler on water contaminated by low phosphorus levels, a multistage pond CW system was designed in this study. Low-phosphorus polluted river water was used as the research object. This study explored the effects of using steel slag as a CW filler on phosphorus removal and the total phosphorus (TP) purification effect of the wetland system. The results showed that the TP removal rates in the ecological pond, oxidation pond, surface flow wetlands and submerged plant pond were 5.17%, 8.02%, 21.56%, and 16.31%, respectively. Intermittent increases in phosphorus concentration were observed in the reactors and were caused by the decay of plant tissues, which released pollutants. Because steel slag was added to the filler, the TP concentrations in the effluent of the first- and second-level horizontal subsurface CWs increased by 151.13% and 16.29%, respectively, compared to the influent concentration. The 20th to 40th days of the test run was a period of rapid phosphorus release of the system. The use of steel slag has a potential risk of phosphorus release when applied in CWs used to purify low-phosphorus contaminated water bodies.


Assuntos
Purificação da Água , Áreas Alagadas , Nitrogênio , Fósforo , Rios , Aço , Eliminação de Resíduos Líquidos , Água
11.
Ecotoxicol Environ Saf ; 219: 112292, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34022628

RESUMO

Response of nitrogen removal efficiency and microbial interactions to organic pollution has been a major issue in wastewater treatment system. However, the nitrogen removal efficiency and interactions among microbial community under antibiotics press is still unclear. Thus, the effect of sulfamethoxazole (SMX) on nitrogen removal and microbial responses of IVCWs was investigated through recorded the nitrogen removal efficiency before and after adding SMX and random matrix theory (RMT)-based network analysis. Results showed that better NH4+-N removal (>90%) after a long period of operation were achieved in IVCWs, but NO3--N was accumulated. However, nitrate removal rates were significantly increased after long-term exposure (60 d) to 100 µgL-1 SMX (from 27.35% to 35.57%) with relatively high SMX removal (53.50%). Surprisingly, the ammonia nitrogen removal rate (90.07-92.70%) were not significantly affected by SMX in IVCWs. Moreover, the bacterial richness was decreased and the bacterial community structures were altered by the presence of SMX, especially those of nitrogen-transforming microorganisms. Molecular ecological network analysis suggested that SMX had positive influences on denitrifying bacteria interactions but reduced the network complexity and microbial interactions on whole molecular network, and among-module connections were weakened obviously at SMX.


Assuntos
Desnitrificação/efeitos dos fármacos , Sulfametoxazol/toxicidade , Purificação da Água , Áreas Alagadas , Antibacterianos , Bactérias , Microbiota , Nitrogênio/análise , Águas Residuárias/química
13.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670371

RESUMO

Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design.


Assuntos
Proteína da Polipose Adenomatosa do Colo/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Peptídeos/química , Proteína da Polipose Adenomatosa do Colo/química , Proteína da Polipose Adenomatosa do Colo/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Ligantes , Simulação de Dinâmica Molecular , Metástase Neoplásica , Peptídeos/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Fatores de Troca de Nucleotídeo Guanina Rho/antagonistas & inibidores , Fatores de Troca de Nucleotídeo Guanina Rho/química , Fatores de Troca de Nucleotídeo Guanina Rho/genética
14.
Environ Sci Pollut Res Int ; 28(24): 30841-30857, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33594570

RESUMO

The occurrence, distribution, sources, and ecological risks of organochlorine pesticides in Dongting Lake of China were investigated. The average concentrations of organochlorine pesticides (OCPs) in 22 surface water samples and 14 sediment samples were 90.07 ng/L and 80.65 ng/g dw, respectively. Sixteen types of OCPs, dominated by HCHs, DDTs and heptachlor, were detected in the Dongting Lake. The relationships of OCP residues between Dongting Lake and its tributary rivers have been discussed and the hydraulic connections with the Yangtze River and the Three Gorges Dam (TGD) were also considered. Results showed that the shortage of runoff, earlier dry season, and reduction of sediment deposition extremely deteriorated the hydraulic conditions, magnified the water cycle, and restrained the self-purification of OCPs. The ∑OCPs in surface water were concentrated in the inlets of Yangtze River, Lishui River, Zishui River, Yuanshui River, and Xiangjiang River. Moreover, the ∑OCPs in the outlet of the Yangtze River also maintained a high level, indicating that OCPs posed adverse effects on the Yangtze River. Risk assessments of OCPs in the surface water of Dongting Lake were estimated according to available water quality guidelines and health risk assessment models. The results indicated that OCPs in the surface water of Dongting Lake were safe for aquatic organisms and human health. In addition, sediment quality guidelines (SQGs) were also applied to evaluate the potential ecotoxicological risks of OCPs in sediments. The results presented that contaminants of γ-HCH; o,p'-DDD; and dieldrin in sediment had adverse effects on benthic organisms, indicating that fundamental solutions should be proposed to control OCP contamination in Dongting Lake.


Assuntos
Hidrocarbonetos Clorados , Praguicidas , Poluentes Químicos da Água , China , Monitoramento Ambiental , Sedimentos Geológicos , Humanos , Hidrocarbonetos Clorados/análise , Lagos , Praguicidas/análise , Medição de Risco , Rios , Poluentes Químicos da Água/análise
15.
Adv Protein Chem Struct Biol ; 124: 87-119, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33632471

RESUMO

Protein kinases use ATP to phosphorylate other proteins. Phosphorylation (p) universally orchestrates a fine-tuned network modulating a multitude of biological processes. Moreover, the start of networks, ATP-binding site, has been recognized dual roles to impact protein kinases function: (i) orthosteric inhibition, via being blocked to interference ATP occupying and (ii) allosteric regulation, via being altered first to induce further conformational changes. The above two terminologies are widely used in drug design, which has acquired quite a significant progress in the protein kinases field over the past 2 decades. Most small molecular inhibitors directly compete with ATP to implement orthosteric inhibition, still exhibiting irreplaceable and promising therapeutic effects. Additionally, numerous inhibitors can paradoxically lead protein kinases to hyperphosphorylation, even activation, indicative of the allosteric regulation role of the ATP-binding site. Here, we review the quintessential examples that apply for the dual roles in diverse ways. Our work provides an insight into the molecular mechanisms under the dual roles and will be promisingly instructive for future drug development.


Assuntos
Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Regulação Alostérica , Animais , Sítios de Ligação , Humanos
16.
Ecotoxicol Environ Saf ; 213: 111997, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582416

RESUMO

Antibiotics are widely detected in the water environment, posing a serious threat to the health of humans and animals. The effect of levofloxacin (LOFL) on pollutant removal and the difference in the influence mechanisms at normal and low temperatures in constructed wetlands are worth discussing. A hydroponic culture experiment was designed with Iris pseudacorus L. at low and normal temperatures. LOFL (0-100 µg/L) was added to the systems. The results indicated that the removal of pollutants was affected most by temperature, followed by LOFL concentration. At the same concentration of LOFL, the pollutant removal rate was significantly higher at normal temperature than at low temperature. Low concentrations of LOFL promoted the degradation of pollutants except TN under normal-temperature conditions. Compared with the results at low temperature, the bacterial community richness was higher and the diversity of bacterial communities was lower under normal-temperature conditions. The genera and the function of bacteria were greatly affected by antibiotic concentration, temperature and test time. A series of microorganisms resistant to antibiotics and low temperature were identified in this study. The results will provide valuable information and a reference for our understanding of the ecological effects of LOFL.


Assuntos
Hidroponia , Iris (Planta)/microbiologia , Eliminação de Resíduos Líquidos/métodos , Antibacterianos/metabolismo , Bactérias , Humanos , Iris , Iris (Planta)/metabolismo , Temperatura , Águas Residuárias/química , Águas Residuárias/microbiologia , Áreas Alagadas
17.
Structure ; 29(6): 553-563.e5, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497604

RESUMO

By using 31P NMR, we present evidence that the Rho family GTPase RhoA, similar to Ras GTPases, exists in an equilibrium of conformations when bound to GTP. High-resolution crystal structures of RhoA bound to the GTP analog GMPPNP and to GDP show that they display a similar overall inactive conformation. In contrast to the previously reported crystal structures of GTP analog-bound forms of two RhoA dominantly active mutants (G14V and Q63L), GMPPNP-bound RhoA assumes an open conformation in the Switch I loop with a previously unseen interaction between the γ-phosphate and Pro36, instead of the canonical Thr37. Molecular dynamics simulations found that the oncogenic RhoAG14V mutant displays a reduced flexibility in the Switch regions, consistent with a crystal structure of GDP-bound RhoAG14V. Thus, GDP- and GTP-bound RhoA can present similar inactive conformations, and the molecular dynamics in the Switch regions are likely to have a role in RhoA activation.

18.
ACS Chem Neurosci ; 12(4): 603-612, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33504150

RESUMO

NLRP3-PYD inflammasome activates an inflammatory pathway in response to a wide variety of cell damage or infections. Dysregulated NLRP3 inflammatory signaling has many chronic inflammatory and autoimmune disorders. NLRP3 and ASC have a PYD, a superfamily member of the Death Domain, which plays a key role in inflammatory assembly. The ASC interacts with NLRP3 through a homotypic PYD and recruits the procaspase-1 through a homotypic caspase recruitment domain interaction. Here, we used several computational approaches to reveal the interactions of the NLRP3 and ASC PYD domains that lead to the activation of the inflammasome complex. We have characterized ASC and NLRP3-PYD intermolecular interactions by protein-protein docking, and further molecular dynamics (MD) simulations were conducted to evaluate the stability of NLRP3/ASC-PYD complex. Subsequently, we have identified several residues that stabilize the NLRP3/ASC-PYD complex in different faces (i.e., Face-1 to Face-4). The research framework offers new insights into the molecular mechanisms of inflammasome and apoptosis signaling as well as the ease of the drug discovery process.


Assuntos
Inflamassomos , Domínio Pirina , Proteínas do Citoesqueleto/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ligação Proteica
19.
Environ Sci Pollut Res Int ; 28(2): 1454-1463, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32839911

RESUMO

AbstractHuman activities, particularly in large cities, can lead to pollution caused by micropollutants such as pesticides in water bodies, which have been recognized as serious threats to the environment and human health. The pollution level of six organophosphorus pesticides, three herbicides, and one bactericide in groundwater and the Wenyu River, and their fates in three sewage treatment plants (STPs) and a hospital were investigated in this study. The concentrations of the ten detected pesticides ranged from not detected (ND) to 323.44 ng L-1 in different water samples from Beijing; metalaxyl was detected to have the highest concentration (89.58 ng L-1), and the detection frequencies of atrazine and metalaxyl were 100%. The maximum concentrations of pesticides in the Wenyu River, STPs, and the hospital were 1-2 orders of magnitude higher than those in the groundwater. Good removal efficiencies by the treatment processes were observed for ametryn (100%), while the removal efficiencies for atrazine and omethoate were the lowest in the three STPs (- 9.6% and 12.67%, respectively). Finally, risk quotient (RQ) values of each contaminant were estimated from the maximum values determined for typical urban to assess the ecology and health effects. In the case of environmental toxicity, the highest RQ values (> 1) were obtained for dichlorvos and omethoate. In the case of health toxicity, the RQ values show that the pesticides found in groundwater pose no potential health risks to humans at current concentrations.


Assuntos
Praguicidas , Poluentes Químicos da Água , Pequim , China , Monitoramento Ambiental , Humanos , Praguicidas/análise , Rios , Água , Poluentes Químicos da Água/análise
20.
Environ Technol ; 42(8): 1213-1224, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31446846

RESUMO

The purpose of this study was to investigate the effects of increasing salinity on the performance and microbial community structure in a sequencing batch reactor (SBR) treating low C/N ratio wastewater. The SBR was subjected to a gradual increased salinity from 0 wt% to3.0 wt% under low Chemical Oxygen Demand (COD)/N ratio, operating for 80 days. The study results indicated that high salinity decreased the removal efficiency of ammonium (NH4+-N) from 77.09% (1.0 wt%) to 45.7% (3.0wt%). The organic matter removal are not significantly affected by the high salinity. Non-metric Multi-Dimensional Scaling (NMDS) analysis showed that the gradual increased salinity altered the overall bacterial community structure, and low salinity (1wt%) promoted the bacterial diversity, while high salinity (2 and 3 wt%) significantly decreased the bacterial diversity in low C/N ratio activated sludge system. Further analysis revealed that two genera related to nitrification process (unclassified-Nitrosomonadales and g-Nitrospira) were inhibited, while a genus related to organic removal (Piscicoccus) and three genera related to denitrification (Rodobacteraceae, Denitromonas and Hyphomicrobium) increased significantly at a salinity of 3 wt%. This study provides insights of shifts in the bacteria community under the stress of high salinity in low C/N ratio of activated sludge systems.


Assuntos
Microbiota , Salinidade , Reatores Biológicos , Desnitrificação , Nitrificação , Nitrogênio , Esgotos , Eliminação de Resíduos Líquidos , Águas Residuárias
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