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1.
Nat Commun ; 10(1): 3927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

2.
J Clin Lab Anal ; : e22991, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373724

RESUMO

BACKGROUND: Internal quality control (IQC) in clinical laboratories is carried out to monitor analytical stability. Usually, the satisfactory results of the IQC ensure the acceptability of the examination results. Here, we reported that patients' creatinine results are unreliable, although the internal quality control is satisfactory. METHODS: Creatinine levels were analyzed from two quality control materials and twenty patients' specimens using two different lots of reagents. Lot-to-lot comparison was performed. The daily median values of serum creatinine levels of patients were calculated from the test results recorded in our laboratory information system. RESULTS: Although IQC was consistent, serum creatinine concentrations were higher using lot B (median: 153 µmol/L; interquartile range: 122-522 µmol/L) than using lot A (median: 133 µmol/L; interquartile range: 76-508 µmol/L) for 20 patients (P = .001). The Deming linear regression showed a best fit of y = 0.9394 × x + 45.66. R2  = .8919, and mean percentage difference between two lots was 34%. The new lot was considered unacceptable. Likewise, the median serum creatinine level from the 360 patients using lot B was 102 µmol/L, which was significantly higher than the daily medians of patients using lot A (median: 66 µmol/L; range: 61-70 µmol/L) in the previous month. CONCLUSION: The variations in creatinine concentrations proved to be due to different lots of reagents. However, IQC materials tested using both lots of reagent exhibited minimal variation. Therefore, IQC alone is insufficient for assessing laboratory analytical results. This finding prompts us to be vigilant in potential pitfall of interpreting test results based on satisfactory IQC alone.

3.
Sci Total Environ ; 692: 361-370, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31351280

RESUMO

In 2013, the Chinese government announced its first air quality standard for PM2.5 (particulate matter with a diameter < 2.5 µm) which requires annual mean PM2.5 concentration to achieve the World Health Organization (WHO) interim target 1 of 35 µg/m3 nationwide including the most polluted region of Beijing-Tianjin-Hebei (BTH). Here, we explore the future mitigation pathways for the BTH region to investigate the possibility of air quality attainment by 2030 in that region, by developing two energy scenarios (i.e., baseline energy scenario and enhanced energy scenario) and two end-of-pipe scenarios (i.e., business as usual scenario and best available technology scenario) and simulating future air quality for different scenarios using the WRF/CMAQ model. Results showed that without stringent energy and industrial structure adjustment, even the most advanced end-of-pipe technologies did not allow the BTH region to attain the 35 µg/m3 target. Under the most stringent scenario that coupled the enhanced structure adjustment measures and the best available end-of-pipe measures, the emissions of SO2, NOx, PM2.5 and NMVOCs (nonmethane volatile organic compounds) were estimated to be reduced by 85%, 74%, 82% and 72%, respectively, in 2030 over the BTH region. As a result, the simulated annual mean PM2.5 concentrations in Beijing, Tianjin and Hebei could decline to 23, 28 and 28 µg/m3, respectively, all of which achieved the 35 µg/m3 target by 2030. Our study identified a feasible pathway to achieve the 2030 target and highlighted the importance of reshaping the energy and industrial structure of the BTH region for future air pollution mitigation.

4.
Clin Chim Acta ; 495: 507-511, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152696

RESUMO

BACKGROUND: The pneumatic tube system (PTS) is widely established in clinical laboratories. We aimed to evaluate the impacts of PTS on high-sensitivity cardiac troponin T (hs-cTnT) assays. METHODS: The hemolysis distribution of hs-cTnT PTS specimens from emergency department (ED) were determined by hemolysis index (HI). Grouped samples from 15 healthy volunteers were delivered to the laboratory via manual delivery (MD) or PTS. Interference studies were conducted to access the influence of different hemolysis degrees on hs-cTnT assays. RESULTS: 7.26% PTS specimens from ED were hemolyzed in clinic. Compared with MD samples, we found highly elevated free plasma hemoglobin (Hb) in PTS samples. Hs-cTnT was interfered negatively with free Hb (R = -0.625, P < .001), and it was also validated in interference studies (R ≥ -0.820, all P ≤ .001). Clinically significant bias occurred in each hs-cTnT concentration at 100 mg/dl free Hb (Bias≥ - 13.85%, all P < .05). Moreover, bias of hs-cTnT assays at 50 mg/dl free Hb was approaching 10%, especially at 30 ng/l hs-cTnT concentration (Bias: -11.72%, P < .001). CONCLUSIONS: PTS could increase the frequency of specimen hemolysis which might cause false decrease in hs-cTnT assays. Hence, clinicians should be aware of the increased measurement bias in hs-cTnT from hemolyzed PTS samples with free Hb ≥50 mg/dl.

5.
Biomed Res Int ; 2019: 1498034, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214610

RESUMO

Accumulating evidence reveals that the sirtuin family is involved in the pathology of Parkinson's disease (PD). However, the association between the polymorphisms of the sirtuin gene and the risk of PD remains elusive. Here, we investigated the possible association of nine SIRT1 and SIRT2 SNPs with the risk of PD through a clinical case-control study from the Chinese Han population. Our results showed that rs12778366 in the promoter region of SIRT1 and rs2015 in the 3'untranslated region (3'UTR) of the SIRT2 were significantly associated with the risk of PD. Five SNPs related to SIRT1, rs3740051, rs7895833, rs7069102, rs2273773, and rs4746720 and two SNPs related to SIRT2, rs10410544, and rs45592833 did not show an association with PD risk in this study. Moreover, we found that mRNA level of SIRT2 was upregulated, and mRNA level of SIRT1 was downregulated in the peripheral blood of PD patients compared with healthy controls, and we also observed that SNPs rs12778366 and rs2015 influenced the SIRT1 and SIRT2 expression levels, respectively. Further functional assays suggest that rs2015 may affect the expression of SIRT2 by affecting the binding of miR-8061 to the 3'UTR of SIRT2, ultimately contributing to the risk of PD.

6.
Sci Rep ; 9(1): 7361, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089182

RESUMO

Previous studies have suggested a role for Tet1 in the pathogenesis of childhood asthma. However, how Tet1 contributes to asthma remains unknown. Here we used mice deficient for Tet1 in a well-established model of allergic airway inflammation and demonstrated that loss of Tet1 increased disease severity including airway hyperresponsiveness and lung eosinophilia. Increased expression of Muc5ac, Il13, Il33, Il17a, Egfr, and Tff2 were observed in HDM-challenged Tet1-deficient mice compared to Tet1+/+ littermates. Further, transcriptomic analysis of lung RNA followed by pathway and protein network analysis showed that the IFN signaling pathway was significantly upregulated and the aryl hydrocarbon receptor (AhR) pathway was significantly downregulated in HDM-challenged Tet1-/- mice. This transcriptional regulation of the IFN and AhR pathways by Tet1 was also present in human bronchial epithelial cells at base line and following HDM challenges. Genes in these pathways were further associated with changes in DNA methylation, predicted binding of transcriptional factors with relevant functions in their promoters, and the presence of histone marks generated by histone enzymes that are known to interact with Tet1. Collectively, our data suggest that Tet1 inhibits HDM-induced allergic airway inflammation by direct regulation of the IFN and AhR pathways.

7.
Life Sci ; 224: 255-262, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928404

RESUMO

AIM: To understand potential pro-oncological effects of lower dose paclitaxel treatment in cervical cancer cells, we investigated the potential roles of KRT17 on migration and proliferation of cervical cancer cells which might respond to cytoskeletal-based drugs treatments. MATERIALS AND METHODS: We extracted the clinic data of cervical cancer patients from TCGA database to investigate mRNA expression of different keratins. HPV genotypes were identified by reverse transcription PCR. krt17 mRNA and EMT markers were quantified by real-time PCR. krt17 and EMT markers protein were immunoblotted by western blot. Cell viability was detected by CCK8. Cell migration was performed by transwell migration assay. KEY FINDINGS: Our results showed that HPV16 infection correlated with the expression of KRT17 in cervical cancer cell lines. KRT17 knockdown would decrease Snail2 and elevate E-Cadherin to inhibit migration of Caski cells and SiHa cells. Lower dose of paclitaxel promoted SiHa proliferation, it also significantly promoted the migration of Caski cells. Otherwise, colchicine and higher dose of paclitaxel dose-dependently suppressed the proliferation and migration of Caski cells and SiHa cells. Moreover, KRT17 knockdown significantly facilitated cytoskeletal-based drugs to inhibit migration and induce cytotoxicity in cervical cancer cells. SIGNIFICANCE: KRT17 played pivotal oncogenic roles in cell survival, migration and paclitaxel-induced resistance of cervical cancer cells. Thus, KRT17 would serve as a promising target for compromising paclitaxel-induced resistance and metastasis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Queratina-17/metabolismo , Paclitaxel/farmacologia , Neoplasias do Colo do Útero/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Queratina-17/genética , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética
8.
J Cell Mol Med ; 23(6): 4290-4300, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30973211

RESUMO

Impaired autophagic degradation of intracellular lipids is causally linked to the development of non-alcoholic steatohepatitis (NASH). Pharmacological agents that can restore hepatic autophagic flux could therefore have therapeutic potentials for this increasingly prevalent disease. Herein, we investigated the effects of polydatin, a natural precursor of resveratrol, in a murine nutritional model of NASH and a cell line model of steatosis. Results showed that oral administration of polydatin protected against hepatic lipid accumulation and alleviated inflammation and hepatocyte damage in db/db mice fed methionine-choline deficient diet. Polydatin also alleviated palmitic acid-induced lipid accumulation in cultured hepatocytes. In both models, polydatin restored lysosomal function and autophagic flux that were impaired by NASH or steatosis. Mechanistically, polydatin inhibited mTOR signalling and up-regulated the expression and activity of TFEB, a known master regulator of lysosomal function. In conclusion, polydatin ameliorated NASH through restoring autophagic flux. The polydatin-regulated autophagy was associated with inhibition of mTOR pathway and restoration of lysosomal function by TFEB. Our study provided affirmative preclinical evidence to inform future clinical trials for examining the potential anti-NASH effect of polydatin in humans.

9.
J Pain ; 20(7): 771-785, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30639570

RESUMO

We have reported child anxiety sensitivity (Child Anxiety Sensitivity Index [CASI]) predicts chronic postsurgical pain (CPSP). Herein, we evaluated DNA methylation profiles to understand the gene-environment interactions underlying CPSP and CASI, to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI and pain data over 12 months after surgery were collected. DNA from the peripheral blood of evaluable subjects with (n = 16) and without CPSP (n = 40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially DNA methylated positions (DMPs) associated with CPSP and CASI, respectively (P ≤ .05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (P = .00016 for CPSP; P =.0008 for CASI) and dopamine-DARPP32 feedback in cyclic adenosine monophosphate (P = .004 for CPSP and P =.00003 for CASI) signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism, and neurologic diseases (P < 10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP and a basis for future studies in biomarker development and targetable interventions. PERSPECTIVE: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with CPSP and CASI in adolescents undergoing spine surgery. Our findings support GABA hypofunction and the roles of the dopamine-DARPP32 pathway in emotion/reward contributing to behavioral maintenance of pain 10 to 12 months after surgery.

10.
Cell Physiol Biochem ; 51(6): 2732-2745, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562735

RESUMO

BACKGROUND/AIMS: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson's disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. METHODS: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. RESULTS: Here, we demonstrate that miR-486-3p binds to the 3' UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3' UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. CONCLUSION: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.


Assuntos
MicroRNAs/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Sirtuína 2/genética , alfa-Sinucleína/metabolismo , Regiões 3' não Traduzidas , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Biossíntese de Proteínas , Sirtuína 2/metabolismo
11.
Front Hum Neurosci ; 12: 423, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405377

RESUMO

The objective was to investigate the influence of audiovisual training on horizontal sound localization and the underlying neurological mechanisms using a combination of psychoacoustic and electrophysiological (i.e., event-related potential, ERP) measurements on sound localization. Audiovisual stimuli were used in the training group, whilst the control group was trained using auditory stimuli only. Training sessions were undertaken once per day for three consecutive days. Sound localization accuracy was evaluated daily after training, using psychoacoustic tests. ERP responses were measured on the first and last day of tasks. Sound localization was significantly improved in the audiovisual training group when compared to the control group. Moreover, a significantly greater reduction in front-back confusion ratio for both trained and untrained angles was found between pre- and post-test in the audiovisual training group. ERP measurement showed a decrease in N1 amplitude and an increase in P2 amplitude in both groups. However, changes in late components were only found in the audiovisual training group, with an increase in P400 amplitude and decrease in N500 amplitude. These results suggest that the interactive effect of audiovisual localization training is likely to be mediated at a relatively late cognitive processing stage.

12.
Nat Commun ; 9(1): 4410, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30353012

RESUMO

The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TEdeff tumors. Remarkably, TEdeff correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TEdeff in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.

14.
Blood ; 132(21): e24-e34, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30249787

RESUMO

The transforming growth factor beta (TGF-ß) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-ß signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-ß signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-ß signaling. We found that a TGF-ß signal-correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-ß antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-ß signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski -/- HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski -/- HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski -/- hematopoiesis in the absence of transplantation. Similar to SKI-high MDS patient samples, Ski -/- HSCs strikingly upregulated TGF-ß signaling and deregulated expression of spliceosome genes (including Hnrnpk). Moreover, novel single-cell splicing analyses demonstrated that Ski -/- HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21-mediated loss of SKI activates TGF-ß signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.

15.
Oncol Rep ; 40(5): 2997-3005, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226606

RESUMO

Upregulated ß-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression reportedly occurs in many cancers and is correlated with metastasis and poor prognosis. However, the mechanisms by which ST6Gal­I facilitates gastric cancer progression remain poorly understood. Trastuzumab is exclusively used in human epidermal growth factor receptor 2 (HER2)+ gastric cancers; however, most advanced HER2+ gastric cancers develop trastuzumab resistance. Herein, we identified HER2 as an ST6Gal­I substrate and showed that HER2 α2,6 sialylation confers protection against trastuzumab­mediated apoptosis. SGC7901 cancer cell models in which ST6Gal­I was overexpressed or knocked down were constructed, revealing that ST6Gal­I overexpression induced high HER2 sialylation levels and increased cell viability and invasion compared to those in the vector cell line under serum starvation; ST6Gal­I knockdown had the opposite effects. ST6Gal­I overexpression also potentiated cell cycle arrest in the G2/S phase to reduce drug sensitivity. In addition, FACS analysis revealed that high ST6Gal­I levels increased resistance to trastuzumab­induced apoptosis, accompanied by decreased caspase­3 levels. However, the ST6Gal­I knockdown cell line revealed increased caspase­3 levels and evident apoptosis compared with those in the vector cell line. Although ST6Gal­I overexpression increased HER2 sialylation, corresponding to decreased HER2 phosphorylation, high α2,6­sialylation enhanced Akt and ERK phosphorylation levels compared to those in the vector cell line; ST6Gal­I knockdown had the opposite effects. Collectively, these results implicated a functional role of ST6Gal­I in promoting tumor cell progression and trastuzumab resistance.

16.
Nat Cell Biol ; 20(11): 1328, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30190576

RESUMO

In the version of this Article originally published, in ref. 34 the first author's name was spelled incorrectly. The correct reference is: Rodón, L. et al. Active CREB1 promotes a malignant TGFß2 autocrine loop in glioblastoma. Cancer Discov. 10, 1230-1241 (2014). This has now been amended in all online versions of the Article.

17.
Nat Commun ; 9(1): 3658, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30201950

RESUMO

RNA silencing inhibits mRNA translation. While mRNA translation accounts for the majority of cellular energy expenditure, it is unclear if RNA silencing regulates energy homeostasis. Here, we report that hepatic Argonaute 2 (Ago2)-mediated RNA silencing regulates both intrinsic energy production and consumption and disturbs energy metabolism in the pathogenesis of obesity. Ago2 regulates expression of specific miRNAs including miR-802, miR-103/107, and miR-148a/152, causing metabolic disruption, while simultaneously suppressing the expression of genes regulating glucose and lipid metabolism, including Hnf1ß, Cav1, and Ampka1. Liver-specific Ago2-deletion enhances mitochondrial oxidation and ATP consumption associated with mRNA translation, which results in AMPK activation, and improves obesity-associated pathophysiology. Notably, hepatic Ago2-deficiency improves glucose metabolism in conditions of insulin receptor antagonist treatment, high-fat diet challenge, and hepatic AMPKα1-deletion. The regulation of energy metabolism by Ago2 provides a novel paradigm in which RNA silencing plays an integral role in determining basal metabolic activity in obesity-associated sequelae.

18.
J Phys Chem C Nanomater Interfaces ; 122(29): 16756-16764, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258524

RESUMO

The effect of the alkali-metal cation (Li+, Na+, K+, and Cs+) on the non-Nernstian pH shift of the Pt(554) and Pt(533) step-associated voltammetric peak is elucidated over a wide pH window (1-13), through computation and experiment. In conjunction with our previously reported study on Pt(553), the non-Nernstian pH shift of the step-induced peak is found to be independent of the step density and the step orientation. In our prior work, we explained the sharp peak as due to the exchange between adsorbed hydrogen and hydroxyl along the step and the non-Nernstian shift as a result of the adsorption of an alkali-metal cation and its subsequent weakening of hydroxyl adsorption. Our density functional theory results support this same mechanism on Pt(533) and capture the effect of alkali-metal cation identity and alkali cation coverage well, where increasing electrolyte pH and cation concentration leads to increased cation coverage and a greater weakening effect on hydroxide adsorption. This work paints a consistent picture for the mechanism of these effects, expanding our fundamental understanding of the electrode/electrolyte interface and practical ability to control hydrogen and hydroxyl adsorption thermodynamics via the electrolyte composition, important for improving fuel cell and electrolyzer performance.

19.
Nat Cell Biol ; 20(10): 1228, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30089841

RESUMO

In the version of this Article originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Article.

20.
Environ Epigenet ; 4(3): dvy020, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30090644

RESUMO

Exposures to diesel exhaust particles (DEP) from traffic and house dust mite (HDM) allergens significantly increase risks of airway diseases, including asthma. This negative impact of DEP and HDM may in part be mediated by epigenetic mechanisms. Beyond functioning as a mechanical barrier, airway epithelial cells provide the first line of immune defense towards DEP and HDM exposures. To understand the epigenetic responses of airway epithelial cells to these exposures, we exposed human bronchial epithelial cells to DEP and HDM and studied genome-wide 5-methyl-cytosine (5mC) and 5-hydroxy-methylcytosine (5hmC) at base resolution. We found that exposures to DEP and HDM result in elevated TET1 and DNMT1 expression, associated with 5mC and 5hmC changes. Interestingly, over 20% of CpG sites are responsive to both exposures and changes in 5mC at these sites negatively correlated with gene expression differences. These 5mC and 5hmC changes are located in genes and pathways related to oxidative stress responses, epithelial function and immune cell responses and are enriched for binding sites of transcription factors (TFs) involved in these pathways. Histone marks associated with promoters, enhancers and actively transcribed gene bodies were associated with exposure-induced DNA methylation changes. Collectively, our data suggest that exposures to DEP and HDM alter 5mC and 5hmC levels at regulatory regions bound by TFs, which coordinate with histone marks to regulate gene networks of oxidative stress responses, epithelial function and immune cell responses. These observations provide novel insights into the epigenetic mechanisms that mediate the epithelial responses to DEP and HDM in airways.

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