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1.
J Autism Dev Disord ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743119

RESUMO

We systematically reviewed the evidence on the association between maternal folic acid supplementation and the risk of offspring's autism spectrum disorders (ASD). A total of 10 studies with 23 sub-studies (9795 ASD cases) were included. Folic acid supplementation during early pregnancy was associated with a lower risk of offspring's ASD [OR 0.57, 95% CI 0.41-0.78]. The consumption of a daily amount of at least 400 µg folic acid from dietary sources and supplements, was associated with a reduced risk of offspring ASD [OR 0.55, 95% CI 0.36-0.83]. Critical effective maternal folic acid supplementation strategies, such as intake timing and intake dosage, may aid the reduction in the risk of offspring ASD. This meta-analysis provided new insights for the prevention of offspring's ASD.

2.
Waste Manag ; 125: 172-181, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689991

RESUMO

Anaerobic digestion is promising for waste activated sludge (WAS) degradation. However, conventional processes were generally stuck with limited hydrolysis and poor pathogen destruction. Hyperthermophilic digestion at 70 °C has drawn attention in overcoming those issues at a relatively low energy requirement and operating difficulties. In order to illuminate its operation characteristics, a single-stage hyperthermophilic digester was controlled at 70 °C and operated continuously to degrade WAS. 88.7 mL/g VSadded of methane yield could be achieved in the hyperthermophilic system, fourfold higher than that in the mesophilic system. Kinetic analysis revealed that hyperthermophilic digestion was advantageous in converting the non-degradable fraction. Consequently, hydrolysis under the hyperthermophilic condition was able to be significantly improved. Above 10 d was necessary for the hyperthermophilic system to gain such a high methane production. In the case of stability, the organic loading of higher than 10.2 g VS/L/d resulted in increasing limitation from methanogenesis and accumulation of propionic, butyric and valeric acids. In addition to the dominant acetoclastic genus Methanothrix for methane production in the hyperthermophilic system, two hydrogenotrophic methanogens Methanospirillum and Methanothermobacter reached 18.84% and 8.31%, respectively. The genus Coprothermobacter, affiliated with the phylum Firmicutes, made more contribution to protein hydrolysis in the hyperthermophilic digester.


Assuntos
Microbiota , Esgotos , Anaerobiose , Reatores Biológicos , Cinética , Metano
3.
Open Biol ; 11(2): 200306, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33529552

RESUMO

Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system-endogenous cannabinoids, their receptors and associated enzymes-in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg-1, which affected both the eCB system and ASD-like behaviours. In conclusion, a reduced eCB signalling was observed in autistic children and in the ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggested a novel approach to ASD treatment.

4.
Commun Biol ; 4(1): 188, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580152

RESUMO

Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33560841

RESUMO

Transition-metal carbides are important materials in heterogeneous catalysis. It remains challenging yet attractive in nanoscience to construct the active phase of carbide catalysts in a controllable manner and keep a sintering-resistant property in redox reactions, especially hydroprocessing. In this work, an integrated strategy was presented to synthesize stable and well-defined tungsten carbide nanoparticles (NPs) by assembling the metal precursor onto carbon nanotubes (CNTs), wrapping a thin polymeric layer, and following a controlled carburization. The polymer served as a soft carbon source to modulate the metal/carbon ratio in the carbides and introduced amorphous carbons around the carbides to prevent the NPs from sintering. The as-built p-WxC/CNT displayed high stability in the hydrogenolysis of aryl ether C-O bond in guaiacol for more than 150 h. Its activity was more than two and six times higher than those prepared via typical temperature-programmed reduction with gaseous carbon (WxC/CNT-TPR) and carbothermal reduction with intrinsic carbon support (WxC/CNT-CTR), respectively. Our p-WxC/CNT catalyst also achieved high efficiency for selective cleavage of the aryl ether C-O bonds in lignin-derived aromatic ethers, including anisole, dimethoxylphenol, and diphenyl ether, with a robust lifespan.

6.
Chemosphere ; 263: 128047, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297060

RESUMO

Anaerobic digestion is a promising waste-to-energy alternative technology. However, the efficiency upgrading for conventional mesophilic digestion of organic solid waste is always indispensable. Employing hyperthermophilic or thermophilic microbial community is one of the viable upgrading alternatives. Given the unavailability of the superior microbial communities, mesophilic digested sludge was used as inoculum, and instantly controlled at 70 °C and 55 °C for acclimation of hyperthermophilic and thermophilic inocula, respectively. Waste activated sludge was continuously and synchronously fed into two digesters. After one round, thermophilic digester achieved stable biogas production rate at 0.22 L L-1 d-1, with a methane proportion over 60%, whereas fluctuation was observed in the hyperthermophilic digester, and approximately triple time was needed to reach a relatively stable biogas production rate 0.12 L L-1 d-1. Nevertheless, higher hydrolysis ratio 24.4% was observed in the hyperthermophilic digester despite the lower biogas production. Therefore, methanogenesis step limited the whole anaerobic process for the hyperthermophilic digestion, and digestion at 70 °C was appropriate as a pre-fermentation stage to enhanced hydrolysis. The genus Methanothrix proportion in the thermophilic digester gradually decreased, while another acetoclastic genus Methanosarcina ultimately was acclimated to the dominant methanogen. In addition to Methanothrix, hydrogenotrophic archaea became competitive in the hyperthermophilic digester, with Methanothermobacter dominant at 22.6%. The genus Psychrobacter, affiliated to the phylum Proteobacteria could survive better than the others at 70 °C, with a final proportion of 62.5%.


Assuntos
Microbiota , Esgotos , Anaerobiose , Archaea , Reatores Biológicos , Metano , Temperatura
7.
Bioresour Technol ; 321: 124454, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33285502

RESUMO

Hydrothermal pretreatment (HTP) conditions were optimized for continuous mesophilic (MAD) and thermophilic (TAD) anaerobic digestion of high-solid sludge (10-11% total solids). COD solubilization increased with prolonged HTP durations, and became not significant after 210 min. According to the methane production rate and energy consumption, the optimal HTP temperature was determined at 160 °C. Regarding continuous operation without HTP, TAD achieved higher methane yield and volatile solids (VS) reduction, at 0.12 L/g VSadded and 23.9%, respectively. After HTP, methane yield and VS reduction in MAD and TAD were increased by 400% and 191% (MAD), 67% and 72% (TAD), respectively. TAD was limited due to the inhibition from about 2800 mg/L of NH4+-N concentration. The methanogenic activity of MAD was enhanced, whereas TAD displayed a reduced value owing to ammonia inhibition. Ultimately, MAD with HTP and TAD without HTP achieved the higher energy balance, 5.25 and 3.27 kJ/g VS, respectively.

9.
J Sep Sci ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33305452

RESUMO

A rapid method based on continuous-flow microwave-assisted extraction and online single drop microextraction was first developed and applied to the determination of amide herbicides in rice. The present method has the advantages of both continuous-flow microwave-assisted extraction and online single drop microextraction, which combines extraction, separation, preconcentration, and sample introduction in one step. By continuous-flow microwave-assisted extraction, analytes were first extracted from the rice samples using 15% methanol-water, and then concentrated into single drop. The microdrop was retracted into microsyringe and directly analyzed by GC-MS without any filtration or clean-up process. The method greatly simplifies the sample treatment procedure, reduces consumption of toxic organic solvent, and extends the application of single drop microextraction to complex solid samples. Several parameters were optimized by Box-Behnken design. Under optimal experimental conditions, good linearity was observed in the range of 2.0-500.0 µg kg-1 . The limits of detection and quantification were in the range of 0.3-1.5 µg kg-1 and 1.1-5.1 µg kg-1 , respectively. The intra- and inter-day precisions were between 1.9 and 4.8%. The present method was used to the analysis of real rice samples, and the recoveries of analytes were between 80.3 and 102.3% with the relative standard deviations ranging from 1.1% to 6.9%. This article is protected by copyright. All rights reserved.

10.
Cereb Cortex ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33123725

RESUMO

Autism spectrum disorder is an early-onset neurodevelopmental condition. This study aimed to investigate the progressive structural alterations in the autistic brain during early childhood. Structural magnetic resonance imaging scans were examined in a cross-sectional sample of 67 autistic children and 63 demographically matched typically developing (TD) children, aged 2-7 years. Voxel-based morphometry and a general linear model were used to ascertain the effects of diagnosis, age, and a diagnosis-by-age interaction on the gray matter volume. Causal structural covariance network analysis was performed to map the interregional influences of brain structural alterations with increasing age. The autism group showed spatially distributed increases in gray matter volume when controlling for age-related effects, compared with TD children. A significant diagnosis-by-age interaction effect was observed in the fusiform face area (FFA, Fpeak = 13.57) and cerebellum/vermis (Fpeak = 12.73). Compared with TD children, the gray matter development of the FFA in autism displayed altered influences on that of the social brain network regions (false discovery rate corrected, P < 0.05). Our findings indicate the atypical neurodevelopment of the FFA in the autistic brain during early childhood and highlight altered developmental effects of this region on the social brain network.

11.
Molecules ; 25(17)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825257

RESUMO

Two new 12,23-epoxydammarane-type saponins, notoginsenosides NL-I (1) and NL-J (2), were isolated and identified from Panax notoginseng leaves through the combination of various chromatographies and extensive spectroscopic methods, as well as chemical reactions. Among them, notoginsenoside NL-J (2) had a new skeleton. Furthermore, the lipopolysaccharide (LPS)-induced RAW 264.7 macrophage model was used to identify the in vitro anti-inflammatory activity and mechanisms of compounds 1 and 2. Both of them exerted strong inhibition on nitric oxide (NO) productions in a concentration-dependent manner at 1, 10, and 25 µM. Moreover, these two compounds significantly decreased the secretion of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB/p65), and nitric-oxide synthase (iNOS) in LPS-activated RAW 264.7 cells.

12.
Brain Behav ; 10(10): e01796, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32815287

RESUMO

INTRODUCTION: Autism spectrum disorder (ASD) is a complex and prevalent neurodevelopmental disorder characterized by deficits in social communication and social interaction as well as repetitive behaviors. Alterations in function connectivity are widely recognized in recent electroencephalogram (EEG) studies. However, most studies have not reached consistent conclusions, which could be due to the developmental nature and the heterogeneity of ASD. METHODS: Here, EEG coherence analysis was used in a cohort of children with ASD (n = 13) and matched typically developing controls (TD, n = 15) to examine the functional connectivity characteristics in long-distance and short-distance electrode pairs. Subsequently, we explore the association between the connectivity strength of coherence and symptom severity in children with ASD. RESULTS: Compared with TD group, individuals with ASD showed increased coherence in short-distance electrode pairs in the right temporal-parietal region (delta, alpha, beta bands), left temporal-parietal region (all frequency bands), occipital region (theta, alpha, beta bands), right central-parietal region (delta, alpha, beta bands), and the prefrontal region (only beta band). In the long-distance coherence analysis, the ASD group showed increased coherence in bilateral frontal region, temporal region, parietal region, and frontal-occipital region in alpha and beta bands. The strength of such connections was associated with symptom severity. DISCUSSION: Our study indicates that abnormal connectivity patterns in neuroelectrophysiology may be of critical importance to acknowledge the underlying brain mechanism.

13.
Environ Res ; 191: 110035, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32827519

RESUMO

Hyperthermophilic anaerobic digestion, especially at 70 °C, has drawn wide attention. In order to acquire the inoculum and digestion characteristics, batch acclimation and continuous operation experiments were conducted under hyperthermophilic (70 °C), thermophilic (55 °C) and mesophilic (35 °C) conditions, respectively. Archaea at each temperature was successfully enriched from the sole-source waste activated sludge (WAS). Hyperthermophilic digestion achieved higher archaea diversity, close to the Shannon index 2.23 for the thermophilic digestion, but the population were not improved, at a 16S rRNA genes 5.99 × 105 copies mL-1. Hydrogenotrophic methanogens, Methanospirillum and Methanothermobacter, dominated in the hyperthermophilic digester, accounting for 27.15%, while the primary phylum Firmicutes was promoted to 36.31%, with the proteolytic genus Coprothermobacter in Firmicutes at 19.50%. Refractory organic fractions were converted more with a higher digestion temperature, which was demonstrated by the fact that the COD/VS increased to 5.8, 5.2 and 4.2 at 70 °C, 55 °C and 35 °C, respectively, at the end of batch acclimation. In addition, the most solubilization for the dominant fraction protein in the WAS occurred at 70 °C as well. Similar hydrolysis ratio, over 10%, and specific hydrolysis rate, around 0.025 g COD (g VSS·d)-1, were achieved at 70 °C and 55 °C. The higher hydrolysis for hyperthermophilic digestion even resulted in a higher methane yield than that for the mesophilic digestion. Nevertheless, contrary to higher hydrolysis, methanogenesis limited hyperthermophilic digestion in WAS degradation, with an ultimate methane yield 71.2 mL g-1 VSadded, despite an almost complete VFA conversion through the continuous operation.

14.
J Sep Sci ; 43(21): 4058-4066, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32861220

RESUMO

A new extraction method, microwave absorption medium-assisted extraction coupled with reversed-phase dispersive liquid-liquid microextraction, was developed for the determination of triazine herbicides in corn and soybean samples. Triazine herbicides were extracted with hexane and then directly enriched into the ionic liquid phase. The purification of sample and concentration of target analytes were performed simultaneously. The method combines the advantages of nonpolar solvent dynamic microwave extraction and reversed-phase dispersive liquid-liquid microextraction, which could greatly simplify the operation and reduce the whole pretreatment time. The Box-Behnken design was used to the optimization of experimental factors involved in the dynamic microwave-assisted extraction. In the present study, good linearity in the range of 5.00-500.00 µg/kg was obtained. The limits of detection and quantification varying from 1.3 to 4.2 and 4.1 to 13.9 µg/kg were achieved, respectively. The intra- and interday precisions were between 2.7 and 6.9%. The present method was applied to the analysis of corn and soybean samples, and the recoveries of analytes ranged from 80.7 to 106.9% with the relative standard deviations of 2.1-7.8%. The present method shows the potentials of practical applications in the treatment of the complex fatty solid samples.

15.
Neurotox Res ; 38(4): 992-1000, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32719995

RESUMO

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders accompanied by dysregulation of amino acid (AA) metabolism, and for which there are currently no reliable early diagnostic biomarkers. This study evaluated whether specific AAs can serve as biomarkers for screening ASD patients by analyzing the abundance 21 plasma AAs in 70 ASD patients and 70 control subjects by liquid chromatography-tandem mass spectrometry. We found significant differences between the two groups for eight of the AAs-namely, arginine, cysteine, homocysteine, histidine, methionine, serine, tyrosine, and valine. However, only homocysteine level was positively correlated with ASD symptom severity. Arginine, cysteine, histidine, and methionine were used to generate a predictive model in the Fisher discriminant analysis; cross-validation of this model showed that 88.6% of individuals were correctly segregated into ASD and healthy subject groups with a sensitivity of 85.5% and specificity of 92.2%. The area under the receiver operating characteristic curve was 0.959 (0.927-0.991). Thus, detection of a combination of AAs is an effective method for distinguishing ASD patients from healthy subjects, which may be useful for the early diagnosis of ASD.

16.
BMC Pregnancy Childbirth ; 20(1): 404, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664887

RESUMO

BACKGROUND: Humanitarian crises can lead to the rapid change in the health needs of women and newborns, which may give rise to a complex situation that would require various interventions as solutions. This study aimed to examine the health education and promotion patterns, health-seeking behaviour of mothers, and barriers to the use of maternal health services from public health facilities in two rural areas of Yemen. METHODS: We used a qualitative approach. We conducted in-depth interviews and focus group discussions with frontline health professionals and mothers respectively. Nine in-depth interviews were conducted with the health professionals, including 4 health leaders and 5 midwives, and 2 focus group discussions with mothers aged 18-45 years in Abyan and Lahj. Thematic analysis approach was used to analyze the data in Atlas.ti (version 8) Software. RESULTS: Our data showed that health education and promotion activities on maternal health were ad hoc and coverage was poor. Maternal health services were underutilized by women. According to the data from the focus group discussions, the poor quality of services, as indicated by inadequate numbers of female doctors, lack of medical equipment and medicines, and costs of services were barriers to use maternal health services. Moreover, the use of prenatal and postnatal care services was associated with women's' perceived need. However, according to the health professionals, the inadequate human resource, workload, and inadequate funding from government have contributed significantly to the perceived quality of maternal health services provided by public health facilities. Despite the identified barriers, we found that a safe motherhood voucher scheme was instituted in Lahj which facilitated the use of maternal health services by disadvantaged women by removing financial barriers associated with the use of maternal health services. CONCLUSION: This study identified several obstacles, which worked independently or jointly to minimize the delivery and use of health services by rural women. These included, inadequate funding, inadequate human resources, poor quality of health services, and high cost of services. These barriers need to be addressed to improve the use of reproductive health services in Yemen.

17.
Neurosci Bull ; 36(9): 961-971, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32607739

RESUMO

This study aimed to obtain the first national estimate of the prevalence of autism spectrum disorder (ASD) in Chinese children. We targeted the population of 6 to 12-year-old children for this prevalence study by multistage convenient cluster sampling. The Modified Chinese Autism Spectrum Rating Scale was used for the screening process. Of the target population of 142,086 children, 88.5% (n = 125,806) participated in the study. A total of 363 children were confirmed as having ASD. The observed ASD prevalence rate was 0.29% (95% CI: 0.26%-0.32%) for the overall population. After adjustment for response rates, the estimated number of ASD cases was 867 in the target population sample, thereby achieving an estimated prevalence of 0.70% (95% CI: 0.64%-0.74%). The prevalence was significantly higher in boys than in girls (0.95%; 95% CI: 0.87%-1.02% versus 0.30%; 95% CI: 0.26%-0.34%; P < 0.001). Of the 363 confirmed ASD cases, 43.3% were newly diagnosed, and most of those (90.4%) were attending regular schools, and 68.8% of the children with ASD had at least one neuropsychiatric comorbidity. Our findings provide reliable data on the estimated ASD prevalence and comorbidities in Chinese children.

18.
Nature ; 585(7823): 135-140, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610344

RESUMO

Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer1. Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor-chemokine recognition2-4, less is known about endogenous chemokine-induced receptor activation and G-protein coupling. Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. Our results reveal a unique shallow mode of binding between CXCL8 and CXCR2, and also show the interactions between CXCR2 and Gi protein. Further structural analysis of the inactive and active states of CXCR2 reveals a distinct activation process and the competitive small-molecule antagonism of chemokine receptors. In addition, our results provide insights into how a G-protein-coupled receptor is activated by an endogenous protein molecule, which will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles.


Assuntos
Modelos Moleculares , Receptores de Interleucina-8B/química , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Regulação Alostérica , Sítio Alostérico , Quimiocinas/classificação , Quimiocinas/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Humanos , Interleucina-8/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Especificidade por Substrato
19.
Science ; 368(6489): 428-433, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32327598

RESUMO

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.


Assuntos
Cálcio/química , Receptor Tipo 4 de Melanocortina/química , Receptores Acoplados a Proteínas-G/química , Cristalografia por Raios X , AMP Cíclico/química , Humanos , Ligantes , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/farmacologia , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/química , Ligação Proteica , Multimerização Proteica , Estrutura Secundária de Proteína , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/genética , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais
20.
Science ; 368(6496): 1211-1219, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32327601

RESUMO

The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo-electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.


Assuntos
Antituberculosos/química , Parede Celular/enzimologia , Etambutol/química , Mycobacterium tuberculosis/enzimologia , Pentosiltransferases/química , Microscopia Crioeletrônica , Farmacorresistência Bacteriana Múltipla , Conformação Proteica
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