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1.
Cancer Lett ; 496: 144-155, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039559

RESUMO

CDC20 regulates cell cycle progression by targeting key substrates for destruction, but its role in hepatocellular carcinoma (HCC) tumorigenesis remains to be explored. Here, by using weighted gene co-expression network analysis (WGCNA), we identified CDC20 as a hub gene in HCC. We demonstrated that CDC20 expression is correlated with HIF-1 activity and overall survival (OS) of clinic HCC patients. The activity of HIF-1 is regulated by the stability of HIF-1a subunit, which is hydroxylated by oxygen-dependent prolyl hydroxylase enzymes, the PHDs. In addition, we show that genetic ablation or pharmacological inhibition of CDC20 can accelerate the degradation of HIF-1a and impair VEGF secretion in HCC cells. Mechanistically, we found that CDC20 binds to the destruction-box (D-box) motif present in the PHD3 protein to promote its polyubiquitination and degradation. The depletion of endogenous PHD3 in CDC20 knockdown HCC cells greatly attenuated the decline of HIF-1a protein and restored the secretion of VEGF. In contrast, overexpression of a non-degradable PHD3 mutant significantly inhibited the proliferation of HCC cells both in vitro and in vivo. Collectively, our findings indicate that CDC20 plays a crucial role in the development of HCC by governing PHD3 protein.

2.
Int J Mol Sci ; 21(22)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198267

RESUMO

Foxtail millet (Setaria italica (L.) P. Beauv) is an important food and forage crop because of its health benefits and adaptation to drought stress; however, reports of transcriptomic analysis of genes responding to re-watering after drought stress in foxtail millet are rare. The present study evaluated physiological parameters, such as proline content, p5cs enzyme activity, anti-oxidation enzyme activities, and investigated gene expression patterns using RNA sequencing of the drought-tolerant foxtail millet variety (Jigu 16) treated with drought stress and rehydration. The results indicated that drought stress-responsive genes were related to many multiple metabolic processes, such as photosynthesis, signal transduction, phenylpropanoid biosynthesis, starch and sucrose metabolism, and osmotic adjustment. Furthermore, the Δ1-pyrroline-5-carboxylate synthetase genes, SiP5CS1 and SiP5CS2, were remarkably upregulated in foxtail millet under drought stress conditions. Foxtail millet can also recover well on rehydration after drought stress through gene regulation. Our data demonstrate that recovery on rehydration primarily involves proline metabolism, sugar metabolism, hormone signal transduction, water transport, and detoxification, plus reversal of the expression direction of most drought-responsive genes. Our results provided a detailed description of the comparative transcriptome response of foxtail millet variety Jigu 16 under drought and rehydration environments. Furthermore, we identify SiP5CS2 as an important gene likely involved in the drought tolerance of foxtail millet.

3.
Curr Med Imaging ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33135612

RESUMO

BACKGROUND: In some medical applications (e.g., virtual surgery), standard human organ models are very important and useful. Now that real human body slice image sets have been collected by several countries, it is possible to obtain real standard organ models. INTRODUCTION: Understanding how to abandon the traditional model construction method of Photoshop sketching slice by slice and directly extracting 3D models from volume images has been an interesting and challenging issue. In this paper, we propose a 3D color volume image matting method to segment human body organ models. METHOD: First, we expand the scope of the known area by means of propagation. Next, we perform neighborhood sampling to find the best sampling for voxels in an unknown region and then calculate the preliminary opacity using the sampling results. RESULT: Finally, we obtain the final result by applying local smoothing to the image. CONCLUSION: From the experimental results, we can see that our method is effective for real standard organ model extraction.

4.
Pain Pract ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33150677

RESUMO

INTRODUCTION: Perioperative use of ketamine has been discussed widely in many kinds of surgery. The aim of our study was to evaluate the short-term and long-term benefits and safety of ketamine after breast surgery. METHOD: We performed a quantitative systematic review. We included randomized controlled trials that compared intravenous administration of ketamine to a placebo control group, or compared bupivacaine in combination with ketamine to bupivacaine alone in thoracic paravertebral blocks or pectoral blocks among patients undergoing breast surgery. The primary outcome was postoperative pain intensity. Secondary outcomes included cumulative opioid consumption during the 0- to 24-hour postoperative period, the effect on postmastectomy pain syndrome, the effect on postoperative depression, and the adverse events associated with the use of ketamine. RESULTS: Thirteen randomized controlled trials with 1,182 patients were included for analysis. Compared with placebo, intravenous ketamine was effective in reducing wound pain intensity during the first 6 hours after surgery (weighted mean difference [WMD] -0.83; 95% confidence interval [CI] -1.65, -0.01; P = 0.048) and during the first 24 hours after surgery (WMD -0.65; 95% CI -0.95, -0.35; P < 0.001), and in decreasing opioid consumption (WMD -4.14; 95% CI -8.00, -0.29; P = 0.035) during the first 24 hours after surgery, without increasing the risks for gastrointestinal and central nervous system adverse events. Adding ketamine to bupivacaine in thoracic paravertebral blocks was also effective in reducing postoperative wound pain during the first 6 hours after surgery (WMD -0.59; 95% CI, -1.06, -0.12; P = 0.014) and during the first 24 hours after surgery (WMD -0.90; 95% CI -1.27, -0.53; P < 0.001), and in decreasing opioid consumption (WMD - 4.59; 95% CI -5.76, -3.42; P < 0.001) during the first 24 hours after surgery. Perioperative use of ketamine was associated with improved postoperative depression symptoms (standardized mean difference -0.80; 95% CI - 1.34, -0.27; P = 0.003) and less incidence of postmastectomy pain syndrome (relative risk 0.79; 95% CI 0.63, 0.99; P = 0.043). CONCLUSION: Ketamine is an effective and safe multimodal analgesic in patients undergoing breast surgery, administered both intravenously and when added to bupivacaine in paravertebral blocks. In addition, ketamine showed a long-term benefit for preventing postoperative depression and postmastectomy pain syndrome.

5.
Ann Palliat Med ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33183020

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic gripped the globe. SARS-CoV-2 is highly infectious and is susceptible to all populations. Immunosuppressed patients have greater risk for opportunistic infections. However, the understanding regarding the biological characteristics of SARSCoV-2 in immunosuppressed patients remains unclear. Herein, we present a case of prolonged shedding of SARS-CoV-2 in a liver transplant patient with COVID-19. A 61-year-old male post liver transplant was confirmed COVID-19 infection on day 10 of illness onset. The patient has received immunosuppressive treatment for over 11 years and has a history of hypertension for 10 years. With antiviral treatment and temporary discontinuation of tacrolimus immunosuppression, he had complete clinical symptoms relieve on day 24. However, recurrently positive tests of SARS-CoV-2 RNA were presented on day 35 and on day 39 after two consecutive negative tests. IgG antibody test for SARS-CoV-2 was positive with IgM negative on day 41. The final shedding duration lasted 52 days. Prolonged shedding of SARS-CoV-2 should be a matter of concern and might attribute to long-term immunosuppression. Therefore, dynamic surveillance and prolonged quarantine are required for immunocompromised individuals. Further data should be collected to investigate if there is a universal prolonged shedding window of SARS-CoV-2 in immunosuppressed patients.

6.
Int J Mol Sci ; 21(21)2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33172005

RESUMO

The development of high-throughput sequencing (next-generation sequencing technology (NGS)) and the continuous increase in experimental throughput require the upstream sample processing steps of NGS to be as simple as possible to improve the efficiency of the entire NGS process. The transposition system has fast "cut and paste" and "copy and paste" functions, and has been innovatively applied to the NGS field. For example, the Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-Seq) uses high-throughput sequencing to detect chromatin regions accessible by Tn5 transposase. Linear Amplification via Transposon Insertion (LIANTI) uses Tn5 transposase for linear amplification, haploid typing, and structural variation detection. Not only is it efficient and simple, it effectively shortens the time for NGS sample library construction, realizes large-scale and rapid sequencing, improves sequencing resolution, and can be flexibly modified for more technological innovation.

7.
Sci Rep ; 10(1): 19236, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33159112

RESUMO

The pipeline easily gets corroded in a seawater environment. The oxygen in the seawater is one of major parameters causing the corrosion. In practice, the corrosion due to the oxygen concentration difference, i.e. differential concentration corrosion (DCC), cannot be avoided. However, a one-dimensional DCC model cannot satisfactorily predict the corrosion because the oxygen distribution near the pipe wall is two-dimensional. In this regard, a two-dimensional DCC model was proposed in this study to numerically investigate the distribution of corrosion potential and current in the ionic conductive layer near the pipe wall as well as the overall corrosion current. The results show that DCC plays a significant role in determining the corrosion potential and current. Without considering DCC, a large corrosion potential and current exist at the location with high oxygen concentration near the pipe wall, whereas the occurrence of the low corrosion potential and current corresponds to the location with low oxygen concentration. However, as DCC is considered, at the location with high corrosion potential, cathodic polarization was produced and the corrosion rate decreases; at the location with low corrosion potential, anodic polarization was produced and the corrosion rate increases. In general, the corrosion potential can be homogenized in terms of DCC.

8.
Int J Biol Macromol ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33159946

RESUMO

KL55, KL74, and KL85 capsular polysaccharide (CPS) biosynthesis loci in Acinetobacter baumannii BAL_204, BAL_309, and LUH5543 genomes, respectively, are related and each contains genes for l-Rhap and d-GlcpA synthesis. The CPSs were isolated and studied by sugar analysis, Smith degradation, and 1H and 13C NMR spectroscopy. The K55 and K74 CPSs are built up of branched octasaccharide repeats (K units) containing one residue each of d-GlcpA and d-GlcpNAc and six residues of l-Rhap. The K55 unit differs from the K74 unit in the linkage between D-GlcpA and an l-Rhap residue in the K unit (1 â†’ 3 versus 1 â†’ 2) and linkage between K units. However, most K units in the isolated K74 CPS were modified by ß-elimination of a side-chain α-l-Rhap-(1 â†’ 3)-α-l-Rhap disaccharide from position 4 of GlcA to give 4-deoxy-l-threo-hex-4-enuronic acid (1:~3 ratio of intact and modified units). The K85 CPS has a branched heptasaccharide K unit similar to the K74 unit but with one fewer α-l-Rhap residue in the side chain. In contrast to previous findings on A. baumannii CPSs, each K locus includes fewer glycosyltransferase (Gtr) genes than the number required to form all linkages in the K units. Hence, one Gtr appears to be multifunctional catalysing formation of two 1 â†’ 2 and one 1 â†’ 3 linkages between the l-Rha residues.

9.
J Dairy Sci ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33189294

RESUMO

Reduced-fat foods have become more popular due to their health benefits; however, reducing the fat content of food affects the sensory experience. Therefore, it is necessary to improve the sensory acceptance of reduced-fat foods to that of full-fat equivalents. The aim of this study was to evaluate the effect of adding whey protein microgels (WPM) with an average diameter of 4 µm, or WPM with adsorbed anthocyanins [WPM (Ant)] on the textural and sensory properties of reduced-fat Cheddar cheese (RFC). Reduced-fat Cheddar cheese was prepared in 2 ways: (1) by adding WPM, designated as RFC+M, or (2) by adding WPM (Ant), designated as RFC+M (Ant). For comparison, RFC without fat substitutes and full-fat Cheddar cheese were also prepared. We discovered that the addition of WPM and WPM (Ant) increased the moisture content, fluidity, and meltability of RFC, and reduced its hardness, springiness, and chewiness. The textural and sensory characteristics of RFC were markedly inferior to those of full-fat Cheddar cheese, whereas addition of WPM and WPM (Ant) significantly improved the sensory characteristics of RFC. The WPM and WPM (Ant) showed a high potential as fat substitutes and anthocyanin carriers to effectively improve the acceptance of reduced-fat foods.

10.
Nanomedicine (Lond) ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33179590

RESUMO

Aim: To investigate the effects of the different morphological characteristics of Prussian blue nanoparticles (PB NPs) on their biocompatibility and biosafety. Materials & methods: PB NPs with different sizes, shapes and charges were synthesized and their biosafety and biocompatibility performance were systematically compared in vitro and in vivo. Results: Increased size and positive charge of PB NPs adversely affected cell viability, while improving their peroxidase activity and photothermal conversion efficiency. In vivo analysis demonstrated good biocompatibility of PB NPs, without retention in the organs, but increased size retarded their metabolism. Meanwhile, increased size and positive charge adversely affected hepatic and renal function. Conclusion: This comprehensive exploration of biosafety and biocompatibility provides strong evidences for the use of PB NPs as nanodrug carrier and/or imaging agent.

11.
J Appl Microbiol ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170985

RESUMO

AIMS: To investigate the role of a microbial consortium in influencing of Camellia sinensis growth and rhizosphere bacteria microbial community structure. METHODS AND RESULTS: Based on glasshouse trials, the microbial consortium TCM was selected for a field trial. TCM significantly increased bud density (67.53%), leaf area (31.15%) and hundred-bud weight (22.5%) compared with the control treatment (P < 0.01) during 180 days. Furthermore, TCM-treated soil showed a significant increase (P < 0.05) in organic matter (60.89%), total nitrogen (66.22%), total phosphorus (3.34%), available phosphorus (3.82%), available potassium (9.24%) and 2-3 mm water-stable aggregates (77.93%). Molecular ecological network analysis of the rhizobacteria indicated an increase in modularity and the number of community, connection and nodes after TCM application. Several plant growth-promoting bacteria were categorized as hubs or indicators, such as Haliangium, Catenulispora and Gemmatimonas, and showed intensive connections with other bacteria. CONCLUSIONS: The TCM consortium enhances the effectiveness of soil mineral nutrition, influences the indigenous rhizobacterial community, alters the rhizobacterial network structure in the rhizosphere and promotes the growth of C. sinensis. SIGNIFICANCE AND IMPACT OF THE STUDY: The TCM growth-promoting mechanism was closely related to rhizosphere bacterial diversity, therefore, strengthening rhizobacterial interactions may help promote C. sinensis growth, which could be a sustainable approach for improving C. sinensis growth and health in tea plantations.

12.
Clin Cancer Res ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172898

RESUMO

PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard of care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications. EXPERIMENTAL DESIGN: RNA/DNA sequencing of 54 flash-frozen salivary ACC and reverse-phase protein array (RPPA) in 38 specimens were performed, with validation by western blot and/or immunohistochemistry. Three independent ACC cohorts were used for validation. RESULTS: Both unbiased RNA-seq and RPPA analysis revealed two molecular subtypes; ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH activating mutations and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, EGFR), and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNAseq. Furthermore, immunohistochemical staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggests a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II producing unique therapeutic vulnerabilities for each subtype. CONCLUSIONS: Co-occurrence of multiple actionable protein/pathways alterations in each subtype indicate unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.

13.
Biosci Rep ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169791

RESUMO

Bladder cancer (BC) is the most common tumor of the urinary tract. Increasing evidence showed that long non-coding RNA (lncRNA) is a critical regulator in cancer development and progression. However, the functions of lncRNAs in the development of BC remain mostly undefined. In this study, based on RNA sequence profiles from The Cancer Genome Atlas database, we identified 723 lncRNAs, 157 miRNAs, and 1816 mRNAs aberrantly expressed in BC tissues. A competing endogenous RNA network, including 49 lncRNAs, 17 miRNAs, and 36 mRNAs, was then established. The functional enrichment analyses showed that the mRNAs in the ceRNA network mainly participated in "regulation of transcription" and "pathways in cancer". Moreover, the Cox regression analyses demonstrated that three lncRNAs (AC112721.1, TMPRSS11GP, and ADAMTS9-AS1) could serve as independent risk factors. We established a risk prediction model with these lncRNAs. Kaplan-Meier curve analysis showed that high-risk patients' prognosis was lower than that of low-risk patients (p = 0.001). This study provides novel insights into the lncRNA-mediated ceRNA network and the potential of lncRNAs to be candidate prognostic biomarkers in BC, which could help better understand the pathological changes and pathogenesis of BC and be useful for clinical studies in the future.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33169978

RESUMO

Exploration of a new nonlinear optical (NLO)-active functional motif is important in the rational design of promising infrared (IR) NLO materials. Compared with typical tetrahedral MQ4 (M = IIB, III, IV metals; Q = S, Se) motifs, MQ3 (M = As, Sb) pyramids favor high second-harmonic generation (SHG) efficiency while frequently hindering phase matching (PM) because of excessively large optical anisotropy. The surfactant-thermal method was first adopted to achieve PM in MQ3-containing systems and synthesize mixed covalent-ionic IR NLO materials. Two new thioarsenates of AMnAs3S6 (A = Cs, Rb) exhibiting strong PM SHG efficiencies comparable to commercial AGS and laser-induced damage thresholds of one order higher than AGS were obtained. The [As3S6]3- unit in their structures is an unprecedented NLO-active functional motif, which can be useful in designing new IR NLO compounds with large SHG efficiency. In addition, the surfactant-thermal method provides a new general strategy for synthesizing new IR NLO materials.

15.
Pharmacol Res ; : 105290, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181320

RESUMO

The coronavirus disease 2019 (COVID-19) epidemic has been almost controlled in China under a series of policies, including "early diagnosis and early treatment". This study aimed to explore the association between early treatment with Qingfei Paidu decoction (QFPDD) and favorable clinical outcomes. In this retrospective multicenter study, we included 782 patients (males, 56 %; median age 46) with confirmed COVID-19 from 54 hospitals in nine provinces of China, who were divided into four groups according to the treatment initiation time from the first date of onset of symptoms to the date of starting treatment with QFPDD. The primary outcome was time to recovery; days of viral shedding, duration of hospital stay, and course of the disease were also analyzed. Compared with treatment initiated after 3 weeks, early treatment with QFPDD after less than 1 week, 1-2 weeks, or 2-3 weeks had a higher likelihood of recovery, with adjusted hazard ratio (HR) (95 % confidence interval [CI]) of 3.81 (2.65-5.48), 2.63 (1.86-3.73), and 1.92 (1.34-2.75), respectively. The median course of the disease decreased from 34 days to 24 days, 21 days, and 18 days when treatment was administered early by a week (P < 0.0001). Treatment within a week was related to a decrease by 1-4 days in the median duration of hospital stay compared with late treatment (P<0.0001). In conclusion, early treatment with QFPDD may serve as an effective strategy in controlling the epidemic, as early treatment with QFPDD was associated with favorable outcomes, including faster recovery, shorter time to viral shedding, and a shorter duration of hospital stay. However, further multicenter, prospective studies with a larger sample size should be conducted to confirm the benefits of early treatment with QFPDD.

16.
Nat Chem ; 12(12): 1180-1186, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33219361

RESUMO

Self-assembly is a powerful method to obtain large discrete functional molecular architectures. When using a single building block, self-assembly generally yields symmetrical objects in which all the subunits relate similarly to their neighbours. Here we report the discovery of a family of self-constructing cyclic macromolecules with stable folded conformations of low symmetry, which include some with a prime number (13, 17 and 23) of units, despite being formed from a single component. The formation of these objects amounts to the production of polymers with a perfectly uniform length. Design rules for the spontaneous emergence of such macromolecules include endowing monomers with a strong potential for non-covalent interactions that remain frustrated in competing entropically favoured yet conformationally restrained smaller cycles. The process can also be templated by a guest molecule that itself has an asymmetrical structure, which paves the way to molecular imprinting techniques at the level of single polymer chains.

17.
Food Funct ; 11(11): 10033-10046, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33135040

RESUMO

Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.

18.
Int J Food Microbiol ; 337: 108927, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33152571

RESUMO

Salmonella enterica serovar Enteritidis (S. Enteritidis) presents an excellent capacity to survive in egg white, which is a hostile environment for bacterial growth. To reveal its survival mechanism, this study focuses on the specific gene SEN1393, which has been found to exist only in the genomic sequence of S. Enteritidis. The survival capacity of the deletion mutant strain ΔSEN1393 was proven to be significantly reduced after incubation in egg white. RNA sequencing and RT-qPCR results demonstrate that the expression levels of 19 genes were up-regulated, while the expression levels of 9 genes were down-regulated in egg white. These genes were classified into 6 groups based on their functional categories, namely the sulfate assimilation pathway, arginine biosynthesis, the tricarboxylic acid cycle, the fimbrial protein, the transport and chelation of metal ion, and others (sctT, rhs, and pspG). The strain ΔSEN1393 was deduced to damage FeS cluster enzymes and increase the sulfate and iron requirements, and to reduce bacterial motility and copper homeostasis. Via InterProScan analysis, the gene SEN1393 was speculated to encode a TerB-like and/or DjlA-like protein, and therefore, together with cysJ, possibly reduced the oxidative toxicities resulting from oxyanions such as tellurite, and/or improved CysPUWA conformation to restrain the uptake of the toxic oxyanions. In summary, the gene SEN1393 enabled the higher survival of S. Enteritidis in egg white as compared to other pathogens by regulating the sulfate assimilation pathway.

19.
J Mol Graph Model ; 102: 107795, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33161371

RESUMO

Canonical transient receptor potential channel 5 (TRPC5) plays a key role in the regulation of central nervous system, cardiovascular system, kidney disease, cancer, and could be also involved in liver function, arthritis, diabetes-associated complications and so on. However, evidence of TRPC5 function on cellular or organismic levels is sparse. There is still a need for identifying novel and efficient TRPC5 channel modulators to study TRPC5 function. In this study, based on the hTRPC5 structure obtained by homology modeling and the predicted binding site, we have performed virtual screening of 212,736 compounds from the specs database(http://www.specs.net) to find potential hTRPC5 modulators. Lipinski and Veber rules, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) and PAINS (Pan Assay Interference structures) filters were used to screen the large database. Further, multi-software combination docking, cluster analysis and interaction analysis were used to select 20 potential active candidates with novel skeleton. 4 Hits, bearing appreciable binding affinity with hTRPC5 were selected for 40ns all-atom molecular dynamics (MD) simulations under explicit water conditions. The MD simulation results suggested that the 4 Hits binding induces a slight structural change and stabilizes the hTRPC5 structure. In addition, decomposition free energy demonstrated that residues TRP434, LEU437, MET438, ALA441, ILE484, ILE487, LEU488, LEU491, LEU515, ILE517, LEU518, LEU521, PHE531, THR607, VAL610, ILE611, VAL615 played the critical role on system stability. 4 Hits, as potential modulators of hTRPC5, may be potential leads to develop effective therapeutics hTRPC5-associated diseases.

20.
Appl Microbiol Biotechnol ; 104(24): 10493-10502, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33151367

RESUMO

Indigoidine is a dark-blue natural pigment with application prospect and synthesized from glutamine (Gln) by series of indigoidine synthetases (IndCs). Indigoidine production can be improved by enhancing Gln pool via supplementing Gln directly or converting metabolism glutamate (Glu) to Gln by glutamine synthetase (GlnA). But, Gln is expensive, and excess Gln inhibits indigoidine production of the recombinant strain. Supplementing Glu instead of Gln may improve the productive and economic efficiency of indigoidine, but the local activities and positions of the indigoidine pathway enzymes GlnA, Sc-IndC, and the helper protein of Sc-IndC (IndB) should be well arranged. We identified the Streptomyces chromofuscus ATCC 49982 derived IndC (Sc-IndC) as an more efficient IndC compared to other IndCs applied for constructing indigoidine-producting strains, and designed series of protein scaffold complexes with architectures of PDZ, SH3, and GBD domains (PxSyG1) to arrange the pathway enzymes. The strain recruiting GlnA, Sc-IndC, and IndB on the PDZ, SH3, and GBD domains of scaffold P1S2G1, respectively, was the most efficient. In the strain, the GlnA supplied sufficient local Gln for Sc-IndC from Glu, and the generated Gln was immediately consumed by Sc-IndC to relieve cell growth inhibition caused by Gln. The optimum Glu concentration (6 g/L) for the strain was higher than those of the strains recruiting Sc-IndC on the GBD domain, which was away from the PDZ domain recruiting GlnA. The highest titer of indigoidine was 12 g/L, which was two folds of the control without scaffold (5.8 g/L). The titer is 5 g/L higher than the control without Glu supplemented (6.9 g/L), meaning that 97% of the supplemented Glu was transformed into indigoidine. The batch fermentation with the optimum strain in a 5-L reactor achieved an indigoidine titer of 14 g/L in 60 h. To our knowledge, this was the most efficient indigoidine productivity achieved so far. The optimization strategies by protein scaffold should be applicative to other pathways with complex substrate demands. KEY POINTS: •Protein scaffold systems were designed to arrange the indigoidine synthetic pathway. •The scaffold system improved supplement of Gln for indigoidine production from Glu. •The inhibition caused by excess Gln was relieved by proper designed scaffold. •The yield and titer of indigoidine was improved by arranging the pathway enzymes. Graphical abstract.

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