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1.
Artigo em Inglês | MEDLINE | ID: mdl-31897587

RESUMO

PURPOSE: The role that gut microbiota plays in determining the efficacy of the anti-tumor effect of immune checkpoint inhibitors is gaining increasing attention, and fecal bacterial transplantation has been recognized as a promising strategy for improving or rescuing the effect of immune checkpoint inhibition. However, techniques for the precise monitoring of in vivo bacterial behaviors after transplantation are limited. In this study, we aimed to use metabolic labeling and subsequent positron emission tomography (PET) imaging to track the in vivo behaviors of gut bacteria that are responsible for the efficacy of anti-PD-1 therapy in living mice. METHODS: The antitumor effect of anti-PD-1 blockade was tested in a low-response 4T1 syngeneic mouse model with or without fecal transplantation and with or without broad-spectrum antibiotic imipenem treatment. High-throughput sequencing analyses of 16S rRNA gene amplicons in feces of 4T1 tumor-bearing mice pre- and post-anti-PD-1 treatment were performed. The identified bacteria, Bacteroides fragilis (B. fragilis), were labeled with 64Cu and fluorescence dye by the metabolic labeling of N3 followed by click chemistry. In vivo PET and optical imaging of B. fragilis were performed in mice after oral gavage. RESULTS: The disturbance of gut microbiota reduced the efficacy of anti-PD-1 treatment, and the combination of B. fragilis gavage and PD-1 blockade was beneficial in rescuing the antitumor effect of anti-PD-1 therapy. Metabolic oligosaccharide engineering and biorthogonal click chemistry resulted in successful B. fragilis labeling with 64Cu and fluorescence dye with high in vitro and in vivo stability and no effect on viability. PET imaging successfully detected the in vivo behaviors of B. fragilis after transplantation. CONCLUSION: PET tracking by metabolic labeling is a powerful, noninvasive tool for the real-time tracking and quantitative imaging of gut microbiota. This strategy is clinically translatable and may also be extended to the PET tracking of other functional cells to guide cell-based adoptive therapies.

2.
Ann Surg Oncol ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898102

RESUMO

BACKGROUND: Currently, the number of negative lymph nodes (NLNs) has been paid increasing attention and is considered a prognostic indicator in diverse cancers. Therefore, it is necessary to explore the association between number of NLNs and prognosis in esophageal cancer (EC) patients. METHODS: Our data were obtained from the Surveillance, Epidemiology, and End Results 18 database. The X-tile plot was used to determine the optimal cut-off value of the number of NLNs, and propensity score matching (PSM) was performed according to the results of the X-tile plot. RESULTS: A total of 4777 patients were eligible, and 882 pairs of patients were included after PSM. The result of the X-tile plot revealed an optimal cut-off value of three NLNs. Multivariate Cox regression analysis revealed better EC-specific survival (ECSS) in patients with more than three NLNs (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.59-0.77; p < 0.001) compared with patients with three or fewer NLNs. A subgroup analysis revealed better ECSS in patients with more than three NLNs with one to two (HR 0.57, 95% CI 0.46-0.71; p < 0.001) or three to six (HR 0.68, 95% CI 0.50-0.92; p = 0.012) positive lymph nodes (PLNs). CONCLUSIONS: More than three NLNs is associated with better survival in EC patients, especially when the number of PLNs is one to two or three to six. We confirm that the combination of the number of NLNs and number of PLNs can provide better prognostic guidance for EC.

3.
Cell Death Differ ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907392

RESUMO

Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson's and Alzheimer's diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35's function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events.

4.
Chemistry ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909848

RESUMO

For zeolite catalysts, the regulation of active site and pore structure plays an important role in the enhancement of their catalytic performance. In this work, we proposed a one-pot and organic template-free co-regulation route to straightforwardly synthesize basic mesoporous ZSM-5 zeolites with adjustable alkaline-earth metal species. The synthesis pathway combines two decisive strategies: 1) the seed-induced interface assembly growth method and 2) the acidic co-hydrolysis/condensation of aluminosilicate species and alkaline earth metal (e.g., Mg, Ca, Sr or Ba) sources. It is interesting that the mesoporous structure was self-evolved through particle-attached seed-interfacial crystallization without the assistance of any template. Meanwhile, the incorporation of alkaline-earth metals species is homogenous and highly dispersed in the solid products during the whole crystallization process, and finally generate the superior basicity. Catalysis tests of the as-synthesized samples displayed novel performance in the typical base reaction of Knoevenagel condensation, even for the bulky substrates due to the enhanced diffusion rising from meso/microporous network. This finding opens new possibilities for facile, cost-effective, and environment-friendly synthesis of mesoporous high-silica zeolites with tunable acid/base properties, and deepens our understanding of the particle-attached crystallization.

5.
J Diabetes ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919985

RESUMO

AIMS: To estimate the T2DM incidence with DNA methylation of thioredoxin-interacting protein gene (TXNIP) and its interaction with environmental factors. MATERIALS AND METHODS: This case-control study included 286 incident T2DM cases and 286 non-T2DM controls matched by sex, age, marital status, race, and residence village nested in the Rural Chinese Cohort Study. A conditional logistic regression model was used to estimate the association of DNA methylation at TXNIP with T2DM risk. Also, multifactor dimensionality reduction (MDR) and classification and regression tree (CART) analyses were used to investigate the interaction between TXNIP methylation and environmental risk factors. RESULTS: Methylation levels of all five CpG loci at TXNIP were significantly lower in T2DM than controls (all P < 0.001). With increasing methylation level, risk of T2DM was significantly decreased (odds ratio 95% confidence interval 0.80, 0.69-0.94 for CpG1; 0.80, 0.69-0.93 for CpG2; 0.70, 0.56-0.88 for CpG3; 0.78, 0.66-0.92 for CpG4; and 0.76; 0.60-0.97 for CpG5). Additionally, the essential interactions among TXNIP methylation, obesity, and hypertriglyceridemia were identified by CART and MDR analyses. On logistic regression analysis, the risk of T2DM was reduced with terminal node 5 (CpG3 methylation ≥72%, non-obesity, normal TG level, and CpG4 methylation ≥83%) vs terminal node 1 (CpG3 methylation <72%) (odds ratio 95% confidence interval 0.20, 0.10-0.40). CONCLUSIONS: TXNIP methylation was associated with T2DM incidence in a Chinese population. Interaction between TXNIP methylation and environmental factors may influence T2DM risk and needs more investigation. This article is protected by copyright. All rights reserved.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31922711

RESUMO

In this work, a new type of hybrid energy storage device is constructed by combining the zinc-ion supercapacitor and zinc-air battery in mild electrolyte. The reduced graphene oxide with rich defects, large surface area, and abundant oxygen-containing functional groups is used as active material, which exhibits two kinds of charge storage mechanisms of capacitor and battery simultaneously. Apart from the physical adsorption/desorption of anions on the surface of graphene, the zinc ions in electrolyte will be electrochemically adsorbed/desorbed onto the oxygen-containing groups of graphene during the charge/discharge process, contributing extra capacitance to the device. Moreover, the defects in graphene will further improve the electrochemical performance of the energy storage device via catalyzing the oxygen reduction reaction when exposure to air. Consequently, the synergistic effect leads to a record high capacitance of 370.8 F g-1 at a current density of 0.1 A g-1, which is higher than that of zinc-ion supercapacitors reported previously. Furthermore, the hybrid device exhibits a superior cycling stability with 94.5% of capacitance retention even after 10000 charge/discharge cycles at a high current density of 5 A g-1. Interestingly, the developed hybrid device can be self-charging automatically after the power is exhausted in the ambient atmosphere. Other electrode materials such as carbon nanotube paper is also used to build hybrid device to verify the feasibility of this strategy. This facile, green and convenient strategy provides new insight for developing high performance storage device, showing great application prospect in other hybrid energy storage devices in mild electrolyte.

7.
Cell Death Dis ; 11(1): 22, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924749

RESUMO

Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31913115

RESUMO

Three halophilic archaeal strains, YJ-53T, ZS-5 and DYF38, were isolated from marine solar salterns located in different provinces of China. The three strains formed a single cluster (99.7-99.8 and 97.9-99.2 % similarities, respectively) that was separate from the current two members of Salinigranum (96.7-98.0 and 89.8-92.9 % similarities, respectively) on the basis of 16S rRNA and rpoB' gene sequence comparisons and phylogenetic analysis. Diverse phenotypic characteristics differentiated strains YJ-53T, ZS-5 and DYF38 from Salinigranum rubrum GX10T and Salinigranum salinum YJ-50-S2T. The major polar lipids of isolated strains were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and two major glycolipids chromatographically identical to mannosyl glucosyl diether and sulfated mannosyl glucosyl diether, detected in the current members of Salinigranum. The OrthoANI and in silico DNA-DNA hybridization (DDH) values between the three strains were in the range of 97.7-98.4 % and 80.3-86.1 %, respectively, much higher than the threshold values proposed as species boundaries (average nucleotide identity 95-96 % and in silico DDH 70 %), revealing that the three strains represent one species. Results of comparative OrthoANI and in silico DDH analyses of the strains described in this study with validly described members of the genus Salinigranum supported that strains YJ-53T (=CGMCC 1.12860T=JCM 30238T), ZS-5 (=CGMCC 1.12867=JCM 30240) and DYF38 (=CGMCC 1.13779=JCM 33557) represent a novel species of the genus Salinigranum, for which the name Salinigranum halophilum sp. nov. is proposed.

9.
Anticancer Drugs ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31913196

RESUMO

Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data showed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31859469

RESUMO

All-solid-state batteries are expected to be promising next-generation energy storage systems with increased energy density compared to the state-of-the-art Li-ion batteries. Nonetheless, the electrochemical performances of the all-solid-state batteries are currently limited by the high interfacial resistance between active electrode materials and solid-state electrolytes. In particular, elemental interdiffusion and the formation of interlayers with low ionic conductivity are known to restrict the battery performance. Herein, we apply a nondestructive variable-energy hard X-ray photoemission spectroscopy to detect the elemental chemical states at the interface between the cathode and the solid-state electrolyte, in comparison to the widely used angle-resolved (variable-angle) X-ray photoemission spectroscopy/X-ray absorption spectroscopy methods. The accuracy of variable-energy hard X-ray photoemission spectroscopy is also verified with a focused ion beam and high-resolution transmission electron microscopy. We also show the significant suppression of interdiffusion by building an artificial layer via atomic layer deposition at this interface.

11.
Front Microbiol ; 10: 2658, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798569

RESUMO

The soil-borne, asexual fungus Fusarium oxysporum f.sp. lycopersici (Fol) is the causal agent of tomato wilt disease. Autophagy plays a crucial role in the development and virulence of Fol. The Fol endosomal system is highly dynamic and has been shown to be associated with conidiogenesis and pathogenicity. Rab GTPases and the regulators are highly conserved in regulating autophagy and endocytosis in most eukaryotes. Identification and characterization of additional Rab regulators in fungal pathogens should facilitate the understanding of the autophagy and endocytosis in different filamentous fungi. Here, we have identified and characterized the yeast VPS9 homolog FolVPS9 in Fol. Targeted gene deletion showed that FolVPS9 is important for growth, conidiation and virulence in Fol. Cytological examination revealed that FolVps9 co-localized with FolVps21 (a marker of early endosome) and played a critical role in endocytosis and autophagosome degradation. Pull-down assays showed that FolVps9 interacted with FolVps21, which was also important for development and plant infection in Fol. Yeast two-hybrid, bimolecular fluorescence complementation and co-immunoprecipitation assays revealed that FolVps9 specifically interacts with the GDP-bound form of FolVps21. Furthermore, a constitutively active form of FolVps21 (Q72L) was able to rescue defects of ΔFolvps9 and ΔFolvps21 mutants. In summary, our study provides solid evidence that FolVps9 acts as a FolVps21 guanine nucleotide exchange factor (GEFs) to modulate endocytosis and autophagy, thereby controlling vegetative growth, asexual development and pathogenicity in Fol.

12.
Otol Neurotol ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31821264

RESUMO

BACKGROUND: During skull base tumor surgery, temporomandibular joint (TMJ) dissection is commonly performed. The impact of this procedure on patients' postoperative diet and TMJ function is a matter of concern to surgeons. METHODS: We reviewed the Craniomandibular Index (CMI) for 32 patients (15 men and 17 women) who underwent TMJ dissection during surgery for skull base tumors between August 2015 and May 2018. RESULTS: Fifteen patients underwent removal of the mandibular condyle, and 17 had the condyle preserved. Twenty-one patients mainly underwent infratemporal fossa approach, and 11 underwent extended temporal bone resection. No significant difference between pre- and postoperative diet was observed in any group. Significant differences in CMI index were seen in all groups. The highest score was 0.115 of Dysfunction Index, observed postoperatively in the group that underwent condyle removal. CONCLUSIONS: For skull base tumor surgery, TMJ dissection has no significant impact on postoperative diet. Patients who underwent removal of the mandibular condyle have significantly worse postoperative TMJ function.

13.
Sci Total Environ ; : 135381, 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31810673

RESUMO

Harmful algal blooms (HABs) have been investigated for their catastrophic effects on public health and aquaculture intensively, but the research about HABs effects on the diversity patterns and intrinsic functions of the plankton community based on a species identification with high resolution and accuracy has been scarce. We therefore investigated the shifts of plankton diversity via pyrosequencing during and around a natural dinoflagellate (Prorocentrum donghaiense) bloom and analyzed the effect of P. donghaiense abundance on the operationally-defined resource use efficiency (RUE) of plankton community to test our hypothesis that outbreaks of HABs will reduce RUE of the plankton community via shifting the plankton community structure, species composition in particular. We found that the species diversity of eukaryotic plankton community was significantly decreased during the bloom, as reflected in OTU (operational taxonomic unit) richness, and Pielou's evenness index. Principal coordinates analysis indicated significant difference in plankton community structure between blooming and non-blooming periods. As hypothesized, the species richness was positively correlated to RUE (defined as the ratio of phytoplankton biomass to total phosphorus), and more importantly, the cell density of P. donghaiense exhibited significant negative correlation with RUE. Our results explicitly demonstrated HABs reduce RUE via reducing species richness (corresponding to a less occupancy of the trophic niches), which supports the previously documented notion that niche partitioning enhances RUE (a key ecosystem function). Also, our work provides striking evidence for the relationship between plankton species richness (or diversity) and community function (resource use efficiency) via studying on HABs, a natural but exceptional phenomenon, in addition to revealing a profound consequence of HABs.

14.
Clin Ophthalmol ; 13: 2285-2292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819353

RESUMO

Purpose: To assess adherence, non-persistence, discontinuation, and switching of topical cyclosporine ophthalmic emulsion 0.05% (CYC) and lifitegrast ophthalmic solution 5% (LIF) use in the real world among patients with dry eye disease (DED). Design: Retrospective insurance claims study. Methods: Adult patients with DED and ≥1 prescription claim for CYC or LIF (first claim = index date) in the IBM® MarketScan® databases from July 2016 to February 2018 were identified. Eligible patients had continuous medical and pharmacy benefits in the 12 months pre- and post-index periods, and no prior use of the index medication. The proportion of days covered (PDC), adherence, non-persistence, discontinuation, and switching were examined over the 12-month post-index period. Results: This study included 6537 CYC and 3235 LIF patients. The adherence rate was 5.9% for CYC and 9.7% for LIF; the median PDC was 0.3 for both cohorts. Overall, 70.8% of CYC and 64.4% of LIF patients discontinued treatment with median days to discontinuation of 89 and 29, respectively. Non-persistence was 7.1% for CYC and 6.8% for LIF (median days to discontinuation: 89 and 105). In addition, 5.0% switched from CYC to LIF, and 9.6% switched from LIF to CYC over the post-index period. Conclusion: Over 60% of DED patients discontinued treatment within 12 months of initiation; the median time to discontinuation was 3 months for CYC and 1 month for LIF. Although this analysis did not capture the reasons why patients discontinued treatment, the results demonstrate there likely exists a significant unmet need amongst DED patients.

15.
Org Lett ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31789042

RESUMO

The regioselective synthesis of fullerene bis-adducts remains challenging because it produces large amounts of regioisomers. Novel nontethered cis-1 and cis-2 bis(benzofuro)[60]fullerene derivatives were directly synthesized with high regioselectivity by using chlorofullerene C60Cl6 as a precursor. Their structures were determined via spectroscopic data and single-crystal X-ray analysis. A nucleophilic addition elimination mechanism was proposed to elucidate the formation of highly regioselective cis-1 and cis-2 bis-adducts. The potential application of these bis(benzofuro)[60]fullerene derivatives as stabilizers in propellants was also investigated.

16.
J Hypertens ; 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31790053

RESUMO

BACKGROUND: Epidemiological studies reported an inconsistent association between stage 1 hypertension (SBP 130-139 mmHg or DBP 80-89 mmHg) defined by the 2017 American College of Cardiology/American Heart Association hypertension guidelines and cardiovascular disease (CVD) events. In addition, the proportion of CVD events that could be prevented with effective control of stage 1 hypertension is unknown. OBJECTIVES: To assess the association between stage 1 hypertension and CVD events and estimate the population etiologic fraction. METHODS: PubMed, Embase, and Web of Science databases were searched from 1 January 2017 to 22 September 2019. Normal BP was considered SBP less than 120 mmHg and DBP less than 80 mmHg. Hazard ratios and 95% confidence intervals (95% CIs) were pooled by using a random-effects model. RESULTS: We included 11 articles (16 studies including 3 212 447 participants and 65 945 events) in the analysis. Risk of CVD events was increased with stage 1 hypertension versus normal BP (hazard ratio 1.38, 95% CI 1.28-1.49). On subgroup analyses, stage 1 hypertension was associated with coronary heart disease (CHD) (hazard ratio 1.30, 95% CI 1.20-1.41), stroke (1.39, 1.27-1.52), CVD morbidity (1.42, 1.32-1.53), and CVD mortality (1.34, 1.05-1.71). The population etiologic fraction for the association of CVD events, CHD, stroke, CVD morbidity, and CVD mortality with stage 1 hypertension was 12.90, 10.48, 12.71, 14.03, and 11.69%, respectively. CONCLUSION: Stage 1 hypertension is associated with CVD events, CVD morbidity, CVD mortality, CHD, and stroke. Effective control of stage 1 hypertension could prevent more than 10% of CVD events.

17.
Br J Nutr ; : 1-30, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31791429

RESUMO

Metabolically healthy obesity refers to a subset of obese people with a normal metabolic profile. We aimed to explore the association between metabolically healthy and obesity status and risk of hypertension among Chinese adults from The Rural Chinese Cohort Study. This prospective cohort study enrolled 9137 Chinese adults without hypertension, type 2 diabetes, or treatment for lipid abnormality at baseline (2007-2008) and followed up during 2013-2014. Modified Poisson regression models were used to examine the risk of hypertension by different metabolically healthy and obesity status, estimating relative risks (RRs) and 95% confidence intervals (CIs). During 6 years of follow-up, we identified 1734 new hypertension cases (721 men). After adjusting for age, sex, smoking, and other confounding factors, risk of hypertension was increased with metabolically healthy general obesity (MHGO) defined by body mass index (RR 1.75, 95% CI 1.02-3.00) and metabolically healthy abdominal obesity (MHAO) defined by waist circumference (RR 1.51, 95% CI 1.12-2.04) as compared with metabolically healthy non-obesity. The associations between metabolically healthy and obesity status and hypertension outcome were consistent after stratifying by sex, age, smoking, alcohol drinking, and physical activity. Both MHGO and MHAO were associated with increased risk of hypertension. Obesity control programs should be implemented to prevent or delay the development of hypertension in rural China.

18.
Mol Divers ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792660

RESUMO

The present work describes the in vitro antibacterial evaluation of some new pyrimidine derivatives. Twenty-two target compounds were designed, synthesized and preliminarily explored for their antimicrobial activities. The antimicrobial assay revealed that some target compounds exhibited significantly inhibitory efficiencies toward bacteria and fungal including drug-resistant pathogens. Compound 7c presented the most potent inhibitory activities against Gram-positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924) and the fungus Candida albicans 7535, with an MIC of 2.4 µmol/L. Compound 7c was also the most potent, with MICs of 2.4 or 4.8 µmol/L against four multidrug-resistant, Gram-positive bacterial strains. The toxicity evaluation of the compounds 7c, 10a, 19d and 26b was assessed in human normal liver cells (L02 cells). Molecular docking simulation and analysis suggested that compound 7c has a good interaction with the active cavities of dihydrofolate reductase (DHFR). In vitro enzyme study implied that compound 7c also displayed DHFR inhibition.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31794404

RESUMO

Artificial neural network (ANN) and its variants are favored algorithm in designing cardiac arrhythmia classifier (CAC) for its high accuracy. However, the implementation of ultralow power ANN-CAC is challenging due to the intensive computation. Moreover, the imbalanced MIT-BIH database limits the ANN-CAC performance. Several novel techniques are proposed to address the challenges in the low power implementation. Firstly, continuous-in-time discrete-in-amplitude (CTDA) signal flow is adopted to reduce the multiplication operations. Secondly, conditional grouping scheme (CGS) in combination of biased training (BT) is proposed to handle the imbalanced training samples for better training convergency and evaluation accuracy. Thirdly, arithmetic unit sharing with customized high-performance multiplier improves power efficiency. Verified in FPGA and synthesized in 0.18µm CMOS process, the proposed CTDA ANN-CAC can classify an arrhythmia within 252's at 25MHz clock frequency with average power of 13.34µW for 75bpm heart rate. Evaluated on MIT-BIH database, it shows over 98% classification accuracy, 97% sensitivity, and 94% positive predictivity.

20.
Exp Ther Med ; 18(6): 4811-4819, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31798707

RESUMO

The production of lactate under hypoxic conditions or by cancer cells was reported to promote the M2 polarization of tumor-associated macrophages. However, the exact effect of lactate on macrophages, particularly under hypoxic conditions, has remained largely elusive. In the present study, an in-depth bioinformatics analysis of previously published transcriptome data of macrophages was performed. A total of 6, 101 and 764 upregulated genes were identified in the lactate, hypoxia and hypoxia-lactate groups, respectively, whereas 4, 41 and 588 genes were downregulated in the same respective groups. Furthermore, differentially expressed genes (DEGs) of the hypoxia and hypoxia-lactate groups were significantly enriched in the hypoxia-inducible factor 1 (HIF-1) signaling pathway and the Hedgehog pathway. Upregulation of the mTOR and Hedgehog pathways in the hypoxia-lactate group was identified by gene set enrichment analysis. Furthermore, a set of HIF-1 pathway-associated genes was identified to be positively correlated with hypoxia using weighted gene co-expression network analysis. Lactate was indicated to inhibit the cell cycle in a hypoxia-independent manner. The DEGs of the hypoxia and hypoxia-lactate groups, including C-C motif chemokine receptor type 1 and 5, were enriched in the cytokine-cytokine receptor interaction pathway. In conclusion, under normoxic conditions, lactate exerted a weak effect on macrophages, while the combination of lactate and hypoxia markedly promoted the M2-polarization of macrophages via the HIF-1, Hedgehog and mTOR pathways. Lactate and hypoxia may also contribute to the formation of the spatial structure of tumor niches by inhibiting the proliferation of resident macrophages and by regulating the recruitment of peripheral macrophages.

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