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1.
ACS Sens ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32174111

RESUMO

Although volatile organic compound samples can be detected by gas nanosensors in adsorption principles, extreme concentrations of target gases imply the excessive adsorption, which would lead to a long recovery time and even a shortened lifetime. Herein, we report the observations of the ionization current sensing behavior on the volatile organic compounds in an ionization gas sensor with silicon-based nanostructures. The micro ionization gas sensor consists of a pair of silicon microneedle array electrodes covered by nanolayer structures and a microdischarge gas gap. The dynamic response behaviors of the sensors to the exposure of ethanol, acetone, and 2-chloroethyl ethyl sulfide have been carefully scrutinized. The sensor exhibits sound performances to the high-concentration volatile organic compounds with a fast-recovery property and could generate effective responses well at 36 V, namely, the safety operation voltages. It could be well understood by the Jesse effect where small proportion of impurities in gases could lead to an intensive increase in the overall ionization probability. Besides, the reproducibility, recovery time, sensitivity, and selectivity properties have been systematically characterized.

2.
Theranostics ; 10(8): 3451-3473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32206101

RESUMO

While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their functions and the underlying molecular mechanisms in cancers, particularly in estrogen receptor alpha (ERα)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) in ERα-positive breast cancers due to its high expression and the associated poor prognosis. Methods: ChIP-seq and RNA-seq were employed to identify the chromatin-binding landscape and transcriptional targets of CARM1, respectively, in the presence of estrogen in ERα-positive MCF7 breast cancer cells. High-resolution mass spectrometry analysis of enriched peptides from anti-monomethyl- and anti-asymmetric dimethyl-arginine antibodies in SILAC labeled wild-type and CARM1 knockout cells were performed to globally map CARM1 methylation substrates. Cell viability was measured by MTS and colony formation assay, and cell cycle was measured by FACS analysis. Cell migration and invasion capacities were examined by wound-healing and trans-well assay, respectively. Xenograft assay was used to analyze tumor growth in vivo. Results: CARM1 was found to be predominantly and specifically recruited to ERα-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced genes in response to estrogen treatment. Global mapping of CARM1 substrates revealed that CARM1 methylated a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor-mediated signaling, chromatin organization and chromatin remodeling. A large number of CARM1 substrates were found to be exclusively hypermethylated by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor-domain-containing protein 3 (TDRD3), to CARM1-bound active enhancers to activate estrogen/ERα-target genes. In consistent with its critical role in estrogen/ERα-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERα-positive breast cancer cells in vitro and tumor growth in mice. Conclusions: our study uncovered a "hypermethylation" strategy utilized by enhancer-bound CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.

3.
J Hematol Oncol ; 13(1): 22, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188475

RESUMO

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m6A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m6A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m6A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m6A and 5mC methylation at the multiomic level. Then, we further established m6A/5mC epigenetic module eigengenes by combining hub m6A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.

4.
Chem Biodivers ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32190963

RESUMO

Osteoporosis (OP) is a metabolic bone disease affecting nearly 200 million individuals globally. Morinda Officinalis How (MOH) has long been used as a traditional herbal medicine for the treatment of bone fractures and joint diseases in China. However, it still remains unclear how the compounds in MOH work synergistically for treating OP. In this study, we used prednisolone (PNSL)-induced zebrafish OP model to screen the antiosteoporosis components in MOH. A network pharmacology approach was further proposed to explore the underlying mechanism of MOH on OP. The PNSL-induced zebrafish model validated that two anthraquinones, one iridoid glycoside, and two saccharides exerted antiosteoporotic effect. We constructed the components-targets network, and obtained the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. A total of 26 candidate compounds of MOH and 257 related targets could probably treat OP through regulating osteoclast differentiation and MAPK signaling pathway. Our work developed a strategy to screen the antiosteoporosis components and explore the underlying mechanism of MOH for treating OP at a network pharmacology level.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32184015

RESUMO

Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and ß-endorphin, while lemairamin treatment induced IL-10 and ß-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-ß-endorphin antiserum or µ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/ß-endorphin pathway following α7nAChR activation.

6.
J Neuroinflammation ; 17(1): 75, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32113469

RESUMO

BACKGROUND: Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. METHODS: Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The ß-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. RESULTS: Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected Emax of 90% MPE and ED50 of 6.4 µg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and ß-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and ß-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not ß-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum and specific µ-opioid receptor antagonist CTAP. Lastly, cinobufagin- and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/ß-endorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. CONCLUSIONS: Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent ß-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/ß-endorphin pathway in antinociception.

7.
J Food Sci ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157685

RESUMO

Green tea is widely consumed as a beverage and/or dietary supplement worldwide, resulting in the difficulty to avoid the comedication with ticagrelor for acute coronary syndrome (ACS) patients receiving antiplatelet therapy. This study was designed to investigate the effect of the most abundant content in green tea, tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. Rats were orally treated with either saline or tea polyphenol extracts (TPEs) dissolved in saline once daily for 6 consecutive days. On day 6, after the last dose of saline or TPE, ticagrelor was given to the rats orally or intravenously. Plasma samples were collected for pharmacokinetic analysis. Human liver and intestinal microsomes were then used to investigate the inhibition by TPE, as well as its major constituents on the metabolism of ticagrelor to its two metabolites, AR-C124910XX and AR-C133913XX. Apparent kinetic constants and inhibition potency (IC50 ) for each metabolic pathway of each compound were estimated. Oral study indicated that exposure of ticagrelor and AR-C124910XX was significantly decreased after TPE administration, while no significant differences were observed in pharmacokinetic parameters after intravenous administration of ticagrelor. TPE effectively inhibited the metabolism of ticagrelor in vitro, with epigallocatechin-3-gallate as the major constituent responsible for the observed inhibitory effects in human liver microsomes and intestinal microsomes (IC50 = 4.23 ± 0.18 µM). Caution should be taken for ACS patients receiving ticagrelor therapy with daily drinking of green tea. PRACTICAL APPLICATION: Potential interactions between tea polyphenols and ticagrelor were revealed for the first time. Results can provide suggestions for clinicians to optimize the dosing of ticagrelor while they are in the face of ACS patients receiving ticagrelor therapy, who also take green tea or its related products in their daily life.

9.
Nature ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152607

RESUMO

On average, an approved drug today costs $2-3 billion and takes over ten years to develop1. In part, this is due to expensive and time-consuming wet-lab experiments, poor initial hit compounds, and the high attrition rates in the (pre-)clinical phases. Structure-based virtual screening (SBVS) has the potential to mitigate these problems. With SBVS, the quality of the hits improves with the number of compounds screened2. However, despite the fact that large compound databases exist, the ability to carry out large-scale SBVSs on computer clusters in an accessible, efficient, and flexible manner has remained elusive. Here we designed VirtualFlow, a highly automated and versatile open-source platform with perfect scaling behaviour that is able to prepare and efficiently screen ultra-large ligand libraries of compounds. VirtualFlow is able to use a variety of the most powerful docking programs. Using VirtualFlow, we have prepared the largest and freely available ready-to-dock ligand library available, with over 1.4 billion commercially available molecules. To demonstrate the power of VirtualFlow, we screened over 1 billion compounds and discovered a small molecule inhibitor (iKeap1) that engages KEAP1 with nanomolar affinity (Kd = 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2. We also identified a set of structurally diverse molecules that bind to KEAP1 with submicromolar affinity. This illustrates the potential of VirtualFlow to access vast regions of the chemical space and identify binders with high affinity for target proteins.

10.
Mol Cancer ; 19(1): 55, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164749

RESUMO

After the publication of this work [1], the authors note that there are no figure legends in published paper.

11.
Can J Gastroenterol Hepatol ; 2020: 5143013, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104670

RESUMO

Background and Aim. Upper gastrointestinal bleeding is a threat to patients with gastric varices (GVs). Previous studies have concluded that both transjugular intrahepatic portosystemic shunt (TIPS) and balloon-occluded retrograde transvenous obliteration (BRTO) are effective treatments for patients with GV. We aimed to compare the efficiency and outcomes of these two procedures in GV patients through meta-analysis. Methods: The PubMed, Cochrane Library, EMBASE, and Web of Science databases were searched using the keywords: GV, bleeding, TIPS, and BRTO to identify relevant randomized controlled trials and cohort studies. The overall survival (OS) rate, imminent haemostasis rate, rebleeding rate, technical success rate, procedure complication rate (hepatic encephalopathy and aggravated ascites), and Child-Pugh score were evaluated. Randomized clinical trials and cohort studies comparing TIPS and BRTO for GV due to portal hypertension were included in our meta-analysis. Two independent reviewers performed data extraction and assessed the study quality. A meta-analysis was performed to calculate risk ratios (RRs), mean differences (MDs), and 95% CIs using random effects models. Results: A total of nine studies fulfilled the inclusion criteria. There was a significant difference between TIPS and BRTO in the OS rate (RR, 0.81 (95% CI, 0.66 to 0.98); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90); P=0.03) and rebleeding rate (RR, 2.61 (95% CI, 1.75 to 3.90). Conclusions: In this meta-analysis, BRTO brought more benefits to patients, with a higher OS rate and lower rebleeding rate. BRTO is a feasible method for GVB.

12.
Biochem Biophys Res Commun ; 524(3): 549-554, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32014255

RESUMO

Cisplatin is a main chemotherapeutic drug used to treat non-small-cell lung cancer patients. However, these patients commonly face cisplatin resistance. The roles and underlying mechanisms of gemcitabine, irinotecan, pemetrexed and docetaxel used as single agents or combined with cisplatin for overcoming cisplatin-resistant non-small-cell lung cancer were explored in this study. MTT assays showed that gemcitabine alone exhibited stronger cytotoxicity on cisplatin-resistant A549 cells than irinotecan, pemetrexed and docetaxel. Meanwhile, gemcitabine combined with cisplatin showed a synergistic inhibitory effect on cisplatin-resistant cells. RNA sequencing and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analysis showed that cell cycle signaling pathways and trx-interacting protein were factors in the efficacy of the cotreatment. Flow cytometry and Western blot results showed that when cisplatin-resistant A549 cells were cotreated with gemcitabine and cisplatin, G0/G1 phase arrest occurred, and trx-interacting protein was upregulated. Silencing trx-interacting protein attenuated the response of the resistant cells to the drug combination. A trx-interacting protein agonist together with cisplatin showed an additive cytotoxic effect on the resistant cells compared with cisplatin alone. The gemcitabine and cisplatin combination, compared to gemcitabine or PBS alone, markedly suppressed the growth of cisplatin-resistant A549 tumors in vivo, accompanied by an increase in trx-interacting protein and a decrease in Ki67 expression. Therefore, we concluded that gemcitabine and cisplatin, as an FDA-approved combination, is a viable therapy for cisplatin-resistant non-small-cell lung cancer ex vivo and in vivo.

13.
Biochem Biophys Res Commun ; 524(3): 689-695, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32033747

RESUMO

Dehydration-responsive element binding (DREB) transcription factors activate the expression of downstream functional genes in combination with a dehydration-responsive element (DRE), and thereby improve the resistance of plants to abiotic stresses such as heat. However, the upstream regulatory mechanism of DREB genes under heat is unclear. A DREBA4 subfamily transcription factor (SlDREBA4), which is heat-responsive and improves heat resistance, was isolated from Solanum lycopersicum 'Microtom'. In this study, promoter truncation experiments were performed to verify changes in ß-glucuronidase (GUS) enzyme activity and GUS gene expression levels in transgenic plants with different lengths of promoter fragments under heat and to identify specific regions in the promoter that respond to heat. Our results showed that the GUS reporter gene was constitutively expressed in tissues of the full-length promoter transgenic 'Microtom' plants, with higher expression in conducting tissues of root, stem, and leaf, as well as sepals of flowers and fruits. Under heat treatment, GUS enzyme activity and GUS gene expression levels in tissues of the full-length promoter transgenic plants increased. Promoter deletion analysis identified two positive regulatory regions (-1095 to -730 bp and -162 to -38 bp) responsible for the promoter's response to heat. These results indicated that the heat shock element (HSE) and MYC recognition sequences may cooperate in heat-induced activation of SlDREBA4 promoter.

14.
Int J Mol Sci ; 21(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046328

RESUMO

Antimicrobial peptides (AMPs) have a unique action mechanism that can help to solve global problems in antibiotic resistance. However, their low therapeutic index and poor stability seriously hamper their development as therapeutic agents. In order to overcome these problems, we designed peptides based on the sequence template XXRXXRRzzRRXXRXX-NH2, where X represents a hydrophobic amino acid like Phe (F), Ile (I), and Leu (L), while zz represents Gly-Gly (GG) or d-Pro-Gly (pG). Showing effective antimicrobial activity against Gram-negative bacteria and low toxicity, designed peptides had a tendency to form an α-helical structure in membrane-mimetic environments. Among them, peptide LRpG (X: L, zz: pG) showed the highest geometric mean average treatment index (GMTI = 73.1), better salt, temperature and pH stability, and an additive effect with conventional antibiotics. Peptide LRpG played the role of anti-Gram-negative bacteria through destroying the cell membrane. In addition, peptide LRpG also exhibited an anti-inflammatory activity by effectively neutralizing endotoxin. Briefly, peptide LRpG has the potential to serve as a therapeutic agent to reduce antibiotic resistance owing to its high therapeutic index and great stability.

15.
Biosci Rep ; 40(3)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32065219

RESUMO

OBJECTIVE: Metastasis and chemoresistance indicate treatment fail and progresses in gastric cancer (GC) patients. However, the molecular mechanisms of chemoresistance and metastasis remain unclear in GC. Thus, identifying the biological indicators of chemoresistance and metastasis is particularly important. MATERIALS AND METHODS: We establish a role for miR-492 in GC metastasis and chemoresistance through experiments in vitro and in vivo. RESULTS: We identified miR-492 overexpression in GC specimens and cell lines, the miR-492 expression level was inversely correlated with the prognosis of GC patients. The inhibition of miR-492 suppressed GC cell invasion and enhanced the sensitivity of gastric cancer cells to CDDP treatment. In contrast, miR-492 overexpression significantly stimulated GC cell invasion and contributed to chemoresistance development. In addition, our research results indicated that the inhibition of miR-492 stimulates GC stemness, and the overexpression of miR-492 induces GC stemness. Importantly, our experiments demonstrated that miR-492 inhibitor suppressed tumor formation, and the combination treatment of miR-492 inhibitor and CDDP significantly inhibited tumor growth in vivo. Furthermore, we demonstrated that miR-492 exerts its anticancer role by targeting DNMT3B in GC. CONCLUSIONS: Our results suggested that inhibiting miR-492 is a novel strategy to control tumor metastasis and chemoresistance in GC.

16.
Cell Death Dis ; 11(2): 128, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071296

RESUMO

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

17.
Mol Genet Genomic Med ; : e1184, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32100970

RESUMO

BACKGROUND: Panel-based targeted exome sequencing was used to analyze the genetic and clinical findings of targeted genes in a cohort of northeast Chinese with retinitis pigmentosa. METHODS: A total of 87 subjects, comprising 23 probands and their family members (total patients: 32) with confirmed retinitis pigmentosa were recruited in the study. Panel-based targeted exome sequencing was used to sequence the patients and family members, all subjects with retinitis pigmentosa underwent a complete ophthalmologic examination. RESULTS: Of the 23 probands, the clinical manifestations include night blindness, narrowing of vision, secondary cataracts, choroidal atrophy, color blindness, and high myopia, the average age of onset of night blindness is 12.9 ± 14 (range, 0-65; median, 8). Posterior subcapsular opacities is the most common forms of secondary cataracts (nine cases, 39.1%), and peripheral choroidal atrophy is the most common form of secondary choroidal atrophy (12 cases, 52.2%). Of these probands with complication peripheral choroidal atrophy, there were eight probands (66.7%, 8/12) caused by the pathogenic variation in USH2A gene. A total of 17 genes and 45 variants were detected in 23 probands. Among these genes, the commonest genes were USH2A (40%; 18/45), RP1 (15.6%; 7/45), and EYS (8.9%; 4/45), and the top three genes account for 56.5% (13/23) of diagnostic probands. Among these variants, comprising 22 (48.9%) pathogenic variants, 14 (31%) likely pathogenic variants, and nine (20%) uncertain clinical significance variants, and 22 variants was discovered first time. Most of the mutations associated with RP were missense (53.3%, 24/45), and the remaining mutation types include frameshift (35.6%, 16/45), nonsense (6.7%, 3/45), and spliceSite (4.4%, 2/45). Among the probands with mutations detected, compound heterozygous forms was detected in 13 (56.5%, 13/23) probands, and digenic inheritance (DI) forms was detected in five (21.7%, 5/23) probands. CONCLUSION: Panel-based targeted exome sequencing revealed 23 novel mutations, recognized different combinations forms of variants, and extended the mutational spectrum of retinitis pigmentosa and depicted common variants in northeast China.

18.
Bioresour Technol ; 303: 122930, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32037191

RESUMO

The main aim of this work was to firstly develop a selective oxidation approach for biologically converting 5-hydroxymethylfurfural and furfural into the corresponding furan-based carboxylic acids with recombinant Escherichia coli HMFOMUT. Whole-cells of this recombinant strain harbored good biocatalytic activity in a narrow pH range (pH 6.5-7.0), which had high tolerance toward furfural (up to 50 mM) and 5-hydroxymethylfurfural (up to 150 mM), well-known potential inhibitors against microorganisms. 5-Hydroxymethyl-2-furancarboxylic acid and furoic acid could be obtained at 96.9% and 100% yield from 5-hydroxymethylfurfural (150 mM) and furfural (50 mM) at 30 °C and pH 7.0. The improved substrate tolerance of Escherichia coli HMFOMUT is gaining a great interest to synthesize value-added furan-based carboxylic acids, which has potential industrial applications.


Assuntos
Escherichia coli , Furanos , Biocatálise , Biomassa , Furaldeído
19.
Br J Haematol ; 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103499

RESUMO

About 25% of patients with newly diagnosed acute myeloid leukaemia (AML) have normal cytogenetics and no nucleophosmin 1 (NPM1) mutation or Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD). The prognosis and best therapy for these patients is controversial. We evaluated 158 newly diagnosed adults with this genotype who achieved histological complete remission within two cycles of induction therapy and were assigned to two post-remission strategies with and without an allotransplant. Targeted regional sequencing at diagnosis was performed and data were used to estimate their prognosis, including relapse and survival. In multivariable analyses, having wild-type or mono-allelic mutated CCAAT/enhancer-binding protein alpha (CEBPA) [hazard ratio (HR) 2·39, 95% confidence interval (CI) 1·08-5·30; P = 0·032), mutated NRAS (HR 2·67, 95% CI 1·36-5·25; P = 0·004), mutated colony-stimulating factor 3 receptor (CSF3R) (HR 2·85, 95% CI 1·12-7·27; P = 0·028) and a positive measurable residual disease (MRD)-test after the second consolidation cycle (HR 2·88, 95% CI 1·32-6·30; P = 0·008) were independently correlated with higher cumulative incidence of relapse (CIR). These variables were also significantly associated with worse survival (HR 3·02, 95% CI 1·17-7·78, P = 0·022; HR 3·62, 95% CI 1·51-8·68, P = 0·004; HR 3·14, 95% CI 1·06-9·31, P = 0·039; HR 4·03, 95% CI 1·64-9·89, P = 0·002; respectively). Patients with ≥1 of these adverse-risk variables benefitted from a transplant, whereas the others did not. In conclusion, we identified variables associated with CIR and survival in patients with AML and normal cytogenetics without a NPM1 mutation or FLT3-ITD.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32067738

RESUMO

The Ras homologous (Rho) proteins are a family of small GTPases, which regulate the cytoskeleton and are related to stress fibers and focal adhesion. The Rho-associated protein kinases (ROCK) constitute part of the Rho effectors that regulate cell shape and movement via phosphorylation of the myosin light chain and actin depolymerizing factor/cofilin. ROCK members are widely expressed and play roles in various cell types during vertebrate development and morphogenesis; therefore, ROCK-knockout animals exhibit multiple defects mostly initiated at the embryonic stage. Analyzing the distinct roles of ROCK in cell shape and movement during the embryonic stages using live mammalian models is difficult. Here, we inhibited the Rho/ROCK pathway in zebrafish, which is a small fish that can be conveniently used as a developmental animal model in place of mammals. To inhibit the Rho/ROCK pathway, we designed a dominant-negative ROCK-2 (dnROCK-2) that lacked the kinase domain and was under the control of an upstream activation sequence (UAS). To evaluate the effects of expression of dnROCK-2, transgenic zebrafish lines were generated by mating strains expressing the construct with counterpart strains expressing the Gal4 activator in target tissues. In this study, we crossed the dnROCK-2-expressing line with two such Gal4-expressing lines; (1) SAGFF(LF)73A for expression in the whole body, and (2) Tg(fli1a: Gal4FF)ubs4 for endothelial cell-specific expression. The phenotypes of the fish obtained were observed by fluorescent stereomicroscopy or confocal microscopy. Overexpression of dnROCK-2 in the whole body resulted in an inhibition of development, notably in cephalic formation, at 1-day post-fertilization (dpf). Confocal microscopy revealed that Hensen's zone became unclear in the trunk muscle fibers expressing dnROCK-2. Endothelial cell-specific expression of dnROCK-2 caused abnormalities in cardiovascular formation at 2-dpf. These results suggest that dnROCK-2 can act as a dominant negative construct of the Rho/ROCK pathway to affect regulation of the cytoskeleton. This construct could be a convenient tool to investigate the function of ROCK members in other vertebrate cell types.

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