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1.
J Hazard Mater ; 382: 121068, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472469

RESUMO

The plant microbiome represents a crucial pathway for human exposure to environmental antibiotic resistance. However, little information is available regarding the plant associated resistome in human-related environments at a larger scale. Here, by high-throughput quantitative-PCR chip-based array and amplicon sequencing, we characterized antibiotic resistance genes (ARGs) and bacterial communities in plant and soil microbiomes from human highly disturbed peri-urban farmland and less disturbed forest at a watershed scale. A total of 71 ARGs were detected in the phyllosphere, which covered almost all the major recognized classes of antibiotics that are administered commonly to humans and animals. The overall pattern of the plant associated resistome in intensive anthropogenic influenced farmland was significantly different from that of forest environments (PERMANOVA, P < 0.01), indicating that agricultural activities might be important drivers in shaping the plant resistome. A bipartite network analysis suggested that all ARGs detected in the plant microbiome were also present in the soil microbiome. Together, our findings provide a better understanding of the plant resistome and suggest that land use is a key contributor to the composition of ARG profiles in the plant phyllosphere, and that the soil resistome may represent a critical reservoir of plant associated ARGs.

2.
Toxins (Basel) ; 11(11)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671876

RESUMO

Fusarium graminearum causes Fusarium head blight (FHB), a devastating disease of wheat. Salicylic acid (SA) is involved in the resistance of wheat to F. graminearum. Cell wall mannoprotein (CWM) is known to trigger defense responses in plants, but its role in the pathogenicity of F. graminearum remains unclear. Here, we characterized FgCWM1 (FG05_11315), encoding a CWM in F. graminearum. FgCWM1 was highly expressed in wheat spikes by 24 h after initial inoculation and was upregulated by SA. Disruption of FgCWM1 (ΔFgCWM1) reduced mannose and protein accumulation in the fungal cell wall, especially under SA treatment, and resulted in defective fungal cell walls, leading to increased fungal sensitivity to SA. The positive role of FgCWM1 in mannose and protein accumulation was confirmed by its expression in Saccharomyces cerevisiae. Compared with wild type (WT), ΔFgCWM1 exhibited reduced pathogenicity toward wheat, but it produced the same amount of deoxynivalenol both in culture and in spikes. Complementation of ΔFgCWM1 with FgCWM1 restored the WT phenotype. Localization analyses revealed that FgCWM1 was distributed on the cell wall, consistent with its structural role. Thus, FgCWM1 encodes a CWM protein that plays an important role in the cell wall integrity and pathogenicity of F. graminearum.

3.
JCI Insight ; 4(21)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672938

RESUMO

X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3-CD56dim). This phenotype is reminiscent of hypomorphic mutations in MCM4, which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.

4.
Nanoscale ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674617

RESUMO

As a new kind of porous material, zeolitic imidazolate frameworks (ZIF-8) are built from zinc ions and 2-methylimidazolate and possess unique merits including high porosity, good structural regularity and tunability, adjustable surface functionality and intrinsic pH induced biodegradability. These advantages endow ZIF-8 with multiple functionalities and stimuli-responsive controlled release of loaded payloads by endogenous or exogenous means. In this review, we will summarize the recent advancement of ZIF-8 as nanocarriers for the loading of various molecules including chemotherapeutic drugs, photosensitizers, photothermal agents, and proteins to fabricate multifunctional nanocomposites for synergistic cancer therapy. In addition, the challenges and future developments in this area will be highlighted.

5.
Environ Pollut ; : 113463, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31677875

RESUMO

Growing evidence suggests that metallic oxide nanoparticles can pose a severe risk to the health of invertebrates. Previous attention has been mostly paid to the effects of metallic oxide nanoparticles on the survival, growth and physiology of animals. In comparison, the effects on gut microbiota and incidence of antibiotic resistance genes (ARGs) in soil fauna remain poorly understood. We conducted a microcosm study to explore the responses of the non-target soil invertebrate Enchytraeus crypticus gut microbiota and resistomes to copper oxide nanoparticles (CuO NPs) and copper nitrate by using bacterial 16S rRNA gene amplicons sequencing and high throughput quantitative PCR. The results showed that exposure to Cu2+ resulted in higher bioaccumulation (P < 0.05) and lower body weight and reproduction (P < 0.05) of Enchytraeus crypticus than exposure to CuO NPs. Nevertheless, exposure to CuO NPs for 21 days markedly increased the alpha-diversity of the gut microbiota of Enchytraeus crypticus (P < 0.05) and shifted the gut microbial communities, with a significant decline in the relative abundance of the phylum Planctomycetes (from 37.26% to 19.80%, P < 0.05) and a significant elevation in the relative abundance of the phyla Bacteroidetes, Firmicutes and Acidobacteria (P < 0.05). The number of detected ARGs in the Enchytraeus crypticus gut significantly decreased from 45 in the Control treatment to 16 in the Cu(NO3)2 treatment and 20 in the CuO NPs treatment. The abundance of ARGs in the Enchytraeus crypticus gut were also significantly decreased to 38.48% when exposure to Cu(NO3)2 and 44.90% when exposure to CuO NPs (P < 0.05) compared with the controls. These results extend our understanding of the effects of metallic oxide nanoparticles on the gut microbiota and resistome of soil invertebrates.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31679050

RESUMO

This study introduces an effective method to deposit polypyrrole (PPy) on graphite felt (GF) as anode to improve the start-up performance of microbial fuel cells (MFCs). The results of scanning electron microscope (SEM) and electrochemical testing reveal that polypyrrole is able to improve the electrical conductivity and surface roughness, which is beneficial to the microorganism attachment and growth. It shows that microorganisms grow faster on polypyrrole-modified anode than on unmodified anode. It takes ca. 5 days for polypyrrole-modified anode to reach a reproducible voltage platform, while it takes 11 days for unmodified anode. Moreover, the maximum power density of microbial fuel cells with polypyrrole-modified anode was 919 mW m-2, which were 2.3 times of that with unmodified anode. This research revealed that polypyrrole modification can improve the start-up performance of microbial fuel cells. It is considered as a feasible, economical and sustainable anode.

7.
World Neurosurg ; 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31689570

RESUMO

OBJECTIVE: To evaluate the efficiency of a comprehensive treatment strategy for patients with Enneking stage 3 thoracic aggressive vertebral hemangioma (AVH). METHODS: A retrospective analysis of radiographic and clinical outcomes was performed with 17 patients who received treatment for Enneking stage 3 thoracic AVH accompanied by pain and neurologic deficits between January 2010 and February 2015. A visual analog scale (VAS) was used to clinically evaluate the level of pain. Neurological examinations were performed to assess the patients' sensory symptoms, motor deficits, and Frankel grade. RESULTS: The average operative time was 181.8±37.1 minutes, and the average intraoperative blood loss was 1226.5±151.2 (range, 900-1450) ml. All patients underwent preoperative embolization to minimize intraoperative blood loss. All patients experienced immediate pain relief and resolution of their neurological symptoms. All 17 patients achieved Frankel grade D at the final follow-up; moreover, they reported that their pain was relieved (mean VAS 2.82±0.81) (P<0.05) and that their neurological deficits had resolved. No surgery-related complications were noted. No patients exhibited signs of recurrence. CONCLUSION: We recommend a comprehensive treatment strategy for patients with Enneking stage 3 thoracic AVH that includes preoperative embolization, vertebroplasty, posterior decompression and internal fixation. We recommend that absorbable gelatin sponge particles be used for intraoperative embolization prior to the injection of bone cement, which may significantly reduce intraoperative bleeding, the operative time and the occurrence of surgery-related complications.

8.
J Agric Food Chem ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675231

RESUMO

Microbial degradation plays a major role in the dissipation of pendimethalin, and nitroreduction is an initial and detoxicating step. Previously, a pendimethalin nitroreductase, PNR, was identified in Bacillus subtilis Y3. Here, another pendimethalin nitroreductase from strain Y3, LNR, was identified. LNR shares only 40% identity with PNR and reduces the aromatic ring C-6 nitro group of pendimethalin and both nitro groups of trifluralin, butralin, and oryzalin. The catalytic activities against the four dinitroanilines were much higher for LNR than for PNR. lnr deletion significantly reduced the pendimethalin-reduction activity (60% activity loss), while pnr deletion led to only 30% activity loss, indicating that both LNR and PNR were involved in pendimethalin nitroreduction in strain Y3; however, LNR played the major role. This study facilitates the elucidation of pendimethalin catabolism and provides degrading enzyme resources for the removal of dinitroaniline herbicide residues in environment and agricultural products.

9.
Anal Chem ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682106

RESUMO

Surface enhanced Raman spectroscopy (SERS) is an ultrasensitive label-free analytical technique that can provide unique chemical and structural fingerprint information. However, gaining reliable quantitative analysis with SERS remains a huge challenge because of poor reproducibility and the instability of nanostructured SERS active surfaces. Herein, an effective strategy of coating Au nanoparticles (NPs) with ultra-thin and uniform Prussian blue (PB) shell (Au@PB NPs) was developed for quantitative detection of dopamine (DA) concentrations in blood serum and crystal violet (CV) contaminants in lake water. The only intense PB Raman signal at 2155 cm-1 served as an ideal and interference-free internal standard (IS) for correcting fluctuations in the Raman intensities of analytes. Also, the stability of Au@PB NPs was investigated, exhibiting good functionality in strong acid solutions and thermal stability at 100 ℃. This work demonstrates a convenient and fast quantitative SERS technique for detecting analyte concentrations in complex systems and has a great number of potential applications for use in analytical chemistry.

10.
Behav Processes ; : 103997, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31698032

RESUMO

Artificial light at night (ALAN) is a widespread anthropogenic stimulus that can significantly alter nocturnal animals' behavior, from migration to foraging to vocal communication. In the present study, we tested the hypothesis that the mate choice decisions of female serrate-legged small treefrogs (Kurixalus odontotarsus) were influenced by ambient light intensity. Standard two-speaker phonotaxis tests were conducted in a sound attenuating chamber. We set four light conditions (I-IV, from low to high) based on a range of light intensities from the maximum natural light at night (i.e., full moon) to that of the actual calling sites, which had artificial light. Contrary to our prediction, female frogs showed a preference for calls on the bright side in treatment I when they were exposed to identical stimuli. However, females preferred longer calls on the dim side to shorter calls on the bright side in this treatment. In addition, there were no significant effects of choice side, light treatment or their interaction on leave time or choice time. Our results suggest that females are more attracted to mates in bright light under natural nocturnal light conditions, but the preference for longer calls is not altered in serrate-legged small treefrogs.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31704674

RESUMO

Growing evidence suggests that livestock manure used as organic fertilizer in agriculture may lead to potential propagation of antibiotic resistance genes (ARGs) from "farm to fork". However, little is known about the impacts of manure fertilization on the incidence of ARGs in the plant-associated microbiomes (including rhizosphere, endosphere and phyllosphere), which hampers our ability to assess the dissemination of antibiotic resistance in the soil-plant system. Here, we constructed a pot experiment to explore the effects of poultry and cattle manure applications on the shifts of resistome in the plant microbiome of harvested cherry radish. A total of 144 ARGs conferring resistance to eight major classes of antibiotics were detected among all the samples. Rhizosphere and phyllosphere microbiomes harbored significantly higher diversity and abundance of ARGs than root endophytic microbiomes of cherry radish. Manure application significantly increased the abundance of ARGs in the rhizosphere and phyllosphere, but not in the endophytes of root, which is the edible part of cherry radish. Soil and plant microbiomes changed dramatically after manure applications and clustered separately according to different sample types and treatments. Structural equation modelling revealed that bacterial abundance was the most important factor modulating the distribution patterns of soil and plant resistomes after accounting for multiple drivers. Taken together, we provide evidence that the enrichment of resistome in the rhizosphere and phyllosphere of cherry radish is more obvious compared with the endosphere after manure application, suggesting that manure amendment might not enhance the ARGs dissemination into the root of vegetables in the pot experiment.Importance Our study provides important evidence that manure application increased the occurrence of ARGs in the rhizosphere and phyllosphere of cherry radish, compared with the endophytic bacterial microbiota of root, which is the edible part of cherry radish. Our findings suggest that although manure amendment is a significant route of ARGs entering agricultural soils, these manure-derived ARGs may be at low risk of migrating into the endophytes of root vegetables.

12.
BMC Cancer ; 19(1): 1047, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694596

RESUMO

BACKGROUND: The application of laparoscopic liver resection (LLR) has expanded rapidly in recent decades. Although multiple authors have reported LLR shows improved safety and efficacy in treating hepatocellular carcinoma (HCC) compared with open liver resection (OLR), laparoscopic (LMLR) and open (OMLR) major liver resections for HCC treatment remain inadequately evaluated. This work aimed to test the hypothesis that LMLR is safer and more effective than OMLR for HCC. METHODS: Comparative cohort and registry studies on LMLR and OMLR, searched in PubMed, the Science Citation Index, EMBASE, and the Cochrane Library, and published before March 31, 2018, were collected systematically and meta-analyzed. Fixed- and random-effects models were employed for generating pooled estimates. Heterogeneity was assessed by the Q-statistic. RESULTS: Nine studies (1173 patients) were included. Although the pooled data showed operation time was markedly increased for LMLR in comparison with OMLR (weighted mean difference [WMD] 74.1, 95% CI 35.1 to 113.1, P = 0.0002), blood loss was reduced (WMD = - 107.4, 95% CI - 179.0 to - 35.7, P = 0.003), postoperative morbidity was lower (odds ratio [OR] 0.47, 95% CI 0.35 to 0.63, P <  0.0001), and hospital stay was shorter (WMD = - 3.27, 95% CI - 4.72 to - 1.81, P <  0.0001) in the LMLR group. Although 1-year disease-free survival (DFS) was increased in patients administered LMLR (OR = 1.55, 95% CI 1.04 to 2.31, P = 0.03), other 1-, 3-, and 5-year survival outcomes (overall survival [OS] and/or DFS) were comparable in both groups. CONCLUSIONS: Compared with OMLR, LMLR has short-term clinical advantages, including reduced blood loss, lower postsurgical morbidity, and shorter hospital stay in HCC, despite its longer operative time. Long-term oncological outcomes were comparable in both groups.

13.
Pharm Res ; 36(12): 177, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696314

RESUMO

PURPOSE: The in vitro and in vivo pharmacologic assessment of ABP 980 similarity to its reference product is intended to compare the activity of ABP 980 and trastuzumab and support the overall conclusion of similarity based on a comprehensive analytical and functional evaluation. METHODS: This work complements the primary assessment of functional similarity with additional in vitro assays, binding studies, and non-clinical studies including human epidermal growth factor receptor-2 (HER2) kinetic binding, HER2 signaling, HER2 internalization, synergy with docetaxel chemotherapy, FcγR kinetic binding, primary natural killer and monocyte cell binding, antibody-dependent cellular phagocytosis activity, in vivo xenograft studies, and toxicokinetic parameters. RESULTS: The results contribute to the totality of evidence with respect to functional similarity and support that ABP 980 is similar to trastuzumab in all primary and secondary mechanisms of action. CONCLUSIONS: These results also support the scientific justification of extrapolation to all approved indications of trastuzumab given the established functional similarity of the two products and the same mechanisms of action across all conditions of use.

14.
ACS Appl Mater Interfaces ; 11(42): 38973-38981, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31576737

RESUMO

Infrared (IR) detection at room temperature is very important in many fields. Nanoscale wide-spectrum photodetectors covering IR range are still rare, although they are desired in many applications, such as in integrated optoelectronic devices. Here, we report a new kind of photodetector based on p-n heterojunction-type GaAs1-xSbx/InAs core-shell nanowires. The photodetectors demonstrate high response to the lights ranging from visible light (488 nm) to short-wavelength IR (1800 nm) at room temperature under a very low bias voltage of 0.3 V. The high performance of the devices includes an ultralow dark current (32 pA at room temperature), a high response speed (0.45 ms) to 633 nm light, high responsivity to 1310 nm telecommunication light (0.12 A/W), high response even to 1800 nm light (on/off ratio of 2.5), etc. Besides, the devices also show excellent rectifying I-V characteristics (the current rectification ratio being ∼178 in a voltage range of ±0.3 V). These results suggest that the GaAs1-xSbx/InAs core-shell nanowire devices are promising for applications in nanoelectronic devices, optoelectronic devices, and integrated optoelectronic devices.

15.
BMC Cancer ; 19(1): 986, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646977

RESUMO

BACKGROUND: To examine differences in the plasma levels of miRNA-21, - 214, -34a, and -200a in patients with persistent high-risk human papillomavirus (hr-HPV) infection or with cervical lesions of different grades. METHODS: Venous blood was collected from 232 individuals to measure the plasma expression levels of miRNA-21, - 214, -34a, and -200a. The subjects included normal controls and patients with persistent hr-HPV infection, CIN1, CIN2, CIN3, or cervical cancer (n = 42, 31, 19, 54, 71, and 15 patients, respectively). Cervical conization specimens were collected from all the women. To ensure the accuracy of histopathology, three consecutive tissue sections with an identical diagnosis were selected, and dissection samples were taken from them for miRNA detection. Eligible cases met the inclusion criteria based on sample observation using the middle slice of sandwich tissue sections from the pathological tissue in accordance with the diagnosis of CIN1, CIN2 and CIN3 in 8, 29, and 26 cases, respectively. The miRNA-21, - 214, -34a, and -200a expression levels in the paraffin-embedded tissue samples were determined. The percentage of patients with a CIN2+ diagnosis at 30-49 years old was significantly different from that of those diagnosed with CIN1. The incidence of CIN2+ patients exposed to passive smoking was significantly different from that of CIN1- patients. The percentage of CIN2+ patients with three pregnancies was significantly different from that of those with CIN1, and the percentage of CIN2+ subjects with ≥4 pregnancies was significantly different from that of CIN1- patients. The number of CIN2+ patients with two or more induced abortions was significantly different from that of patients with CIN1. The percentage of CIN2+ patients who underwent a caesarean section was significantly different from that of patients with CIN. The percentage of CIN2+ patients with first-degree relatives with cancer was significantly different from that of those with CIN1. Among CIN2+ patients, the percentage with a first sexual encounter at ≤20 years old was significantly different from that of those with CIN1. The percentage of CIN2+ patients with ≥2 sexual partners was significantly different from that of CIN1- patients. RESULTS: The plasma miRNA-214, -34a, and -200a expression levels were decreased in patients with more severe cervical lesions. Plasma miRNA levels in CIN1- patients were significantly different from those in CIN2+ patients. The kappa values for miRNA-21, - 214, -34a and -200a in tissue versus plasma were 0.7122, 0.9998, 0.8986 and 0.7458, respectively. The sensitivity of each biomarker for detecting CIN2 was calculated, and ROC curves of the four miRNA biomarkers were drawn. The AUC of the four plasma miRNAs was greater than 0.5, with the AUC of miRNA-21 being the largest at 0.703. The plasma miRNA expression levels exhibited at least one tie between CIN1 and CIN2. The AUCs for miRNA-21, -34a, -200a and - 214 were 0.613, 0.508, 0.615 and 0.505, respectively. CONCLUSIONS: Changes in plasma miRNA-21, - 214, -34a and -200a levels were associated with cervical lesion severity. The plasma miRNA levels in CIN1- subjects were significantly different from those in CIN2+ subjects. This analysis may help in detection of high-grade cervical lesions.

16.
Med Sci Monit ; 25: 8131-8141, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31663517

RESUMO

BACKGROUND Worldwide, mortality from cervical cancer in women remains high. This study aimed to investigate the expression of long noncoding RNA (lncRNA) TP73-AS1, microRNA-329-3p (miRNA-329-3p), and the SMAD2 gene and their regulatory relationships in human cervical cancer tissue and cervical cancer cell lines. MATERIAL AND METHODS Cervical cancer tissue samples (n=30) and normal control cervical tissues were studied. Cell proliferation and migration were investigated in HeLa and SiHa human cervical cancer cells using the MTT assay, crystal violet staining, wound healing assay, and the transwell assay. Expression of lncRNA TP73-AS1 and the SMAD2 gene were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Enrichment of miR-329-3p was measured using the RNA immunoprecipitation assay (RIPA). Targeting relationships between TP73-AS1, miR-329-3p, and SMAD2 were identified using the dual-luciferase reporter assay. A subcutaneous xenograft model was established, tumor size was measured, and SMAD2 expression was detected using immunohistochemistry. RESULTS LncRNA TP73-AS1 was overexpressed in cervical cancer tissues and cells and was associated with reduced expression of miR-329-3p. Down-regulation of lncRNA TP73-AS1 inhibited cell proliferation, migration and invasion and increased miR-329-3p expression. Expression of SMAD2 down-regulated miR-329-3p and was associated with increased expression of TP73-AS1. LncRNA TP73-AS1 knockdown resulted in miR-329-3p silencing. In tumor xenografts, expression of TP73-AS1 reduced the tumor volume and down-regulated the expression levels of the SMAD2 gene. CONCLUSIONS LncRNA TP73-AS1 promoted proliferation of cervical cancer cell lines by targeting miR-329-3p to regulate the expression of the SMAD2 gene. A regulatory network was formed between lncRNA TP73-AS1, miR-329-3p, and SMAD2.

17.
Nanotechnology ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31658448

RESUMO

Heterojunctions formed by two-dimensional (2D) layered semiconducting materials have been studied extensively in the past several years. These van der Waals (vdW) structures have shown great potential in future electronic and optoelectronic devices. However, the optoelectronic performance of these devices is limited by the indirect band gap of the multilayer materials and low light absorption of single layer materials. Here, we fabricate photodetectors based on heterojunctions composed of n-type multilayer α-Indium Selenide (In2Se3) and p-type Tungsten Diselenide (WSe2) for the first time. The direct band gap of multilayer α-In2Se3 and type-II band alignment of the WSe2/In2Se3 heterojunction enable high optoelectronic performance of the devices at room temperature in the air. Without light illumination, the dark current is effectively suppressed to 10^-13 A under -1 V bias and a high rectification ratio of 7.37×10^3 is observed. Upon laser illumination with the wavelength of 650 nm, the typical heterojunction device exhibits a photocurrent on/off ratio exceeding 1.24×10^5, a maximum photo responsivity of 26 mA/W and short photoresponse time of 2.22 ms. Moreover, the heterojunction photodetectors show obvious light response in the wavelength range from 650 nm to 900 nm. The present 2D vdW heterojunctions composed of direct band gap multilayer materials show great potential in future optoelectronic devices.

18.
Aging (Albany NY) ; 11(19): 8386-8417, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582589

RESUMO

Children with repeated inhalational anesthesia may develop cognitive disorders. This study aimed to investigate the transcriptome-wide response of hippocampus in young mice that had been exposed to multiple sevoflurane in the neonatal period. Mice received 3% sevoflurane for 2 h on postnatal day (PND) 6, 8, and 10, followed by arterial blood gas test on PND 10, behavioral experiments on PND 31-36, and RNA sequencing (RNA-seq) of hippocampus on PND 37. Functional annotation and protein-protein interaction analyses of differentially expressed genes (DEGs) and quantitative reverse transcription polymerase chain reaction (qPCR) were performed. Neonatal sevoflurane exposures induced cognitive and social behavior disorders in young mice. RNA-seq identified a total of 314 DEGs. Several enriched biological processes (ion channels, brain development, learning, and memory) and signaling pathways (oxytocin signaling pathway and glutamatergic, cholinergic, and GABAergic synapses) were highlighted. As hub-proteins, Pten was involved in nervous system development, synapse assembly, learning, memory, and behaviors, Nos3 and Pik3cd in oxytocin signaling pathway, and Cdk16 in exocytosis and phosphorylation. Some top DEGs were validated by qPCR. This study revealed a transcriptome-wide profile in mice hippocampus after multiple neonatal exposures to sevoflurane, promoting better understanding of underlying mechanisms and investigation of preventive strategies.

19.
Chem Res Toxicol ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31566356

RESUMO

MK-8666, a selective GPR40 agonist developed for the treatment of type 2 diabetes mellitus, was discontinued in phase I clinical trials due to liver safety concerns. To address whether chemically reactive metabolites played a causative role in the observed drug induced liver injury (DILI), we characterized the metabolism, covalent binding to proteins, and amino acid targets of MK-8666 in rat and human hepatocytes or cofactor-fortified liver microsomes. MK-8666 was primarily metabolized to an acyl glucuronide in hepatocytes of both species and a taurine conjugate in rat hepatocytes. Similar levels of covalent binding to proteins were observed in rat and human hepatocytes following incubation with [3H]MK-8666. After protease digestion of hepatocyte pellets, amino acid adducts A1, A2, and A3 were identified as transacylated products with lysine, serine, and cysteine residues, respectively. Amino acid adducts A4a-c were identified as glycation adducts resulting from rearrangement of MK-8666-1-O-ß-acyl glucuronide to ring-opened aldehydes which further condensed with lysine residues of proteins into imine adducts. Adducts A1-A3 and A4a-c were detected in rat and human liver microsomes fortified with UDPGA. Adducts A1-A3 were detected in rat and human liver microsomes fortified with CoA and ATP. Additionally, a trace amount of CoA thioester metabolite of MK-8666 and its transacylated GSH adduct were detected in human liver microsomes fortified with CoA, ATP, and GSH. Higher levels of covalent binding to protein were observed when [3H]MK-8666 was incubated in liver microsomes supplemented with CoA and ATP compared to UDPGA. Addition of GSH attenuated levels of CoA thioester-mediated covalent binding by 41-45%. Collectively, these studies indicated that metabolism of the -COOH moiety of MK-8666 can form a reactive acyl glucuronide and an acyl CoA thioester, which covalently modifies proteins and may represent one causative mechanism of the observed DILI.

20.
Drug Des Devel Ther ; 13: 3137-3149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564830

RESUMO

Purpose: Intracellular calcium ([Ca2+]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca2+ signaling. Methods: H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca2+]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed. Results: Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca2+]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX. Conclusion: This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca2+]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

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