Publications by authors named "Li Zhong"

1,252 Publications

  • Page 1 of 1

Impact of Weaning and Maternal Immune Activation on the Metabolism of Pigs.

Front Mol Biosci 2021 15;8:660764. Epub 2021 Jul 15.

Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States.

Weaning wields environmental, social, and nutritional stresses that are detectable in the blood metabolite levels of the offspring. Prenatal stress in the form of maternal immune activation (MIA) in response to infection, which is associated with health and behavior disorders, also elicits prolonged changes in blood and brain cytokine and metabolite levels of the offspring. The goal of this study was to investigate the effects of weaning and MIA on the offspring's liver function to advance the understanding of the impact of stressors on peripheral and central nervous systems, physiology, and health. Gas chromatography-mass spectrometry analysis was used to compare the level of hepatic metabolites from 22-day-old pigs ( = 48) evenly distributed among weaning (nursed or weaned), viral MIA exposure (yes or no), and sexes. Weaning effects were detected on 38 metabolites at -value < 0.05 (28 metabolites at FDR -value < 0.05), and sex-dependent MIA effects were detected on 11 metabolites. Multiple intermediate and final products of the enriched (FDR -value < 0.05) glycolysis and gluconeogenesis and pentose phosphate pathways were over-abundant in nursed relative to weaned pigs. The enriched pathways confirm the impact of weaning on hepatic metabolic shift, oxidative stress, and inflammation. Higher levels of the glucogenic amino acid histidine are observed in pigs exposed to MIA relative to controls, suggesting that the role of this metabolite in modulating inflammation may supersede the role of this amino acid as an energy source. The lower levels of cholesterol detected in MIA pigs are consistent with hypocholesterolemia profiles detected in individuals with MIA-related behavior disorders. Our findings underline the impact of weaning and MIA stressors on hepatic metabolites that can influence peripheral and central nervous system metabolic products associated with health and behavior disorders.
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http://dx.doi.org/10.3389/fmolb.2021.660764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319725PMC
July 2021

Dileucine ingestion is more effective than leucine in stimulating muscle protein turnover in young males: a double blind randomized controlled trial.

J Appl Physiol (1985) 2021 07 29. Epub 2021 Jul 29.

Department of Kinesiology and Community Health, University of Illinois at Urbana Champaign, Urbana, IL, United States.

Leucine is regarded as an anabolic trigger for the mTORC1 pathway and the stimulation muscle protein synthesis rates. More recently, there has been an interest in underpinning the relevance of BCAA-containing dipeptides and their intact absorption into circulation to regulate muscle anabolic responses. We investigated the effects of dileucine and leucine ingestion on postprandial muscle protein turnover. Ten healthy young men (age: 23±3 y) consumed either 2 g of leucine (LEU) or 2 g of dileucine (DILEU) in a randomized crossover design. The participants underwent repeated blood and muscle biopsy sampling during primed continuous infusions of L-[ring-C]phenylalanine and L-[N]phenylalanine to determine myofibrillar protein synthesis (MPS) and mixed muscle protein breakdown rates (MPB), respectively. LEU and DILEU similarly increased plasma leucine net area under the curve (AUC; P = 0.396). DILEU increased plasma dileucine AUC to a greater extent than LEU (P = 0.013). Phosphorylation of Akt (P = 0.002), rpS6 (P <0.001) and p70S6K (P < 0.001) increased over time in both LEU and DILEU conditions. Phosphorylation of 4E-BP1 (P = 0.229) and eEF2 (P = 0.999) did not change over time irrespective of condition. Cumulative (0-180 min) MPS increased in DILEU (0.075±0.032 %⋅hour), but not in LEU (0.047±0.029 %⋅hour; P=0.023). MPB did not differ between LEU (0.043±0.030 %⋅h) and DILEU conditions (0.051±0.027 %⋅hour; P = 0.659). Our results showed that dileucine ingestion elevated plasma dileucine concentrations and muscle protein turnover by stimulating MPS in young men.
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http://dx.doi.org/10.1152/japplphysiol.00295.2021DOI Listing
July 2021

Early resistance training-mediated stimulation of daily muscle protein synthetic responses to higher habitual protein intake in middle-aged adults.

J Physiol 2021 Jul 28. Epub 2021 Jul 28.

Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Key Points: The ingestion of protein potentiates the stimulation of myofibrillar protein synthesis rates after an acute bout of resistance exercise. Protein supplementation (eating above the protein Recommended Dietary Allowance) during resistance training has been shown to maximize lean mass and strength gains in healthy young and older adults. Here, we assessed contractile, oxidative, and structural protein synthesis in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle-aged adults. We report that the stimulation of myofibrillar, mitochondrial, or collagen protein synthesis rates during 0-3 weeks of resistance training is not further enhanced by a higher protein diet. These results show that moderate protein diets are sufficient to support the skeletal muscle adaptive response during the early phase of a resistance training program.

Abstract: Protein ingestion augments muscle protein synthesis (MPS) rates acutely after resistance exercise and can offset age-related loss in muscle mass. Skeletal muscle contains a variety of protein pools, such as myofibrillar (contractile), mitochondrial (substrate oxidation), and collagen (structural support) proteins, and the sensitivity to nutrition and exercise seems to be dependent on the major protein fraction studied. However, it is unknown how free-living conditions of dietary protein density with habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g·kg ·d ) or high (HIGH: 1.55 ± 0.25 g·kg ·d ) protein intake on daily MPS rates within the myofibrillar (MyoPS), mitochondrial (MitoPS), and collagen (CPS) protein fractions in middle-aged men and women (n = 20, 47 ± 1 y, BMI 28 ± 1 kg·m ) during the early phase (0-3 wks) of a dietary counseling-controlled resistance training program. Participants were loaded with deuterated water, followed by daily maintenance doses throughout the intervention. Muscle biopsies were collected at baseline and after weeks 1, 2, and 3. MyoPS in the HIGH condition remained constant (P = 1.000), but MOD decreased over time (P = 0.023). MitoPS decreased after 0-3 wks when compared to 0-1 wks (P = 0.010) with no effects of protein intake (P = 0.827). A similar decline with no difference between groups (P = 0.323) was also observed for CPS (P = 0.007). Our results demonstrated that additional protein intake above moderate amounts does not potentiate the stimulation of longer-term MPS responses during the early stage of resistance training adaptations in middle-aged adults. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/JP281907DOI Listing
July 2021

Complete mitochondrial genome of (Actinopterygii, Lophiiformes, Ogcocephalidae), from the West Pacific Ocean.

Mitochondrial DNA B Resour 2021 6;6(8):2214-2215. Epub 2021 Jul 6.

Key Laboratory of Marine Eco-Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resources, Qingdao, China.

is a benthic fish living in the deep Pacific Ocean. Here, we described the complete mitochondrial genome of this species, with the sequences about 17,233 bp in length, containing 13 protein-coding genes (PCGs), 22 tRNAs, and two rRNAs. The gene arrangement of this species was identical with others from family Ogcocephalidae. The content of GC and AT for was 45.41% and 54.59%, respectively. Phylogenetic analysis, based on 13 PCGs and two rRNA genes, revealed the close relationship between and other species of Ogcocephalidae, which was consistent with the morphology.
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http://dx.doi.org/10.1080/23802359.2021.1915203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266229PMC
July 2021

Patient Choice and Willingness Toward Gatekeepers as First-Contact Medical Institutions in Chinese Tiered Healthcare Delivery System: A Cross-Sectional Study.

Front Public Health 2021 23;9:665282. Epub 2021 Jun 23.

School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.

Gatekeeping mechanism of primary care institutions (PCIs) is essential in promoting tiered healthcare delivery system in China. However, patients seeking for higher-level institutions instead of gatekeepers as their first contact has persisted in the past decade. This study aims to explain patients' choice and willingness and to provide potential solutions. A survey was conducted among residents who had received medical care within the previous 14 days. Patients' choice and willingness of PCIs for first contact together with influencing factors were analyzed using binary logistic regression. Of 728 sampled patients in Hubei, 55.22% chose PCIs for first contact. Patients who are older, less educated, with lower family income, not living near non-PCIs, with better self-perceived health status, only buying medicines, and living in rural instead of urban area had significantly higher probability of choosing PCIs. As of willingness, over 90% of the patients inclined to have the same choice for their first contact under similar health conditions. Service capability was the primary reason limiting patients' choice of PCIs. The gatekeeper system did not achieve its goal which was 70% of PCIs among all kinds of institutions for first contact. Future measures should aim to improve gate-keepers' capability.
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http://dx.doi.org/10.3389/fpubh.2021.665282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261039PMC
August 2021

A naturally derived small molecule PSM0537 targets the AF1Q-TCF4 interaction to suppress COX2 expression and inhibit cell proliferation and metastasis in osteosarcoma.

Am J Cancer Res 2021 15;11(6):2637-2653. Epub 2021 Jun 15.

Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061, Shaanxi, China.

ALL1 fused gene from chromosome 1q (AF1Q) functions as an oncogene in several types of cancers, but it has not been observed in osteosarcoma. In this study, we revealed that AF1Q was overexpressed in multiple osteosarcoma cell lines, and its expression level increased with the severity of tumor malignancy in osteosarcoma biopsies. AF1Q was coupled with the transcription factor T cell factor 4 (TCF4) to assemble a complex to bind to the promoter of cyclooxygenase 2 () and activate its expression. The individual knockdown of , or in osteosarcoma cell lines significantly decreased cell proliferation and invasion . The tumor xenograft model also indicated that the individual knockdown of , or could inhibit tumor growth and metastasis. On the basis of these promising results, we established an AlphaScreen method to identify the compounds that disrupted the AF1Q-TCF4 interaction in a naturally derived small molecule pool. We discovered a compound called PSM0537, which showed a strong ability to inhibit the AF1Q-TCF4 interaction at a low dose of half-maximal inhibitory concentration (IC) (210.3 ± 15.6 nM). The administration of PSM0537 and could dramatically inhibit cell proliferation, invasion, and metastasis. Collectively, our findings reveal that the AF1Q-TCF4 transcriptional complex controls the expression of and that targeting the AF1Q-TCF4 interaction with PSM0537 could inhibit tumor cell growth and metastasis. Our results provide a new path for chemotherapy of osteosarcoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263654PMC
June 2021

Value of Conventional MRI Texture Analysis in the Differential Diagnosis of Phyllodes Tumors and Fibroadenomas of the Breast.

Breast Care (Basel) 2021 Jun 23;16(3):283-290. Epub 2020 Jun 23.

Department of Radiology, Daping Hospital, Army Medical University, Chongqing, China.

Background: There is substantial overlap in MRI findings between phyllodes tumors (PTs) and fibroadenomas (FAs). Our study was performed to investigate the value of conventional MRI texture analysis in the differential diagnosis of PTs and FAs.

Methods: Preoperative MRI data - including axial T1WI, T2WI (T2WI with fat suppression), dynamic contrast-enhanced (DCE)-T1WI and DCE-T1WI (T1WI post-strengthened for 2 and 7 min, respectively, on DCE-MRI) - of 45 patients with PTs and 67 patients with FAs were retrospectively analyzed. MaZda 4.7 software was used to manually draw the maximum ROIs at the same lesion level of the above MRI images. The optimized feature selection methods included Fisher's coefficient, probability of classification error and average correction coefficient (POE + ACC), and mutual information (MI) as well as a combination of the above 3 methods (F + POE + ACC + MI [FPM]), respectively. The misclassification rates of PTs and FAs were compared between texture analysis and subjective diagnosis by radiologists.

Results: The DCE-T1WI images had the lowest misclassification rate of 10.71% (12/112). The misclassification rate for the radiologists' analysis (31.25%, 35/112) was higher than that of all the texture analysis, and there was a statistically significant difference between the radiologists' misclassification rates and those from the FPM method in terms of the T2WI and DCE-T1WI images (all < 0.05), and for the DCE-T1WI images by using the Fisher and FPM methods (all < 0.05).

Conclusion: Texture analysis of conventional MRI can be used as an assistant tool in providing a certain objective basis for differentiating PTs from FAs.
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http://dx.doi.org/10.1159/000508456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248772PMC
June 2021

Effect of alkali additives on desulfurization of syngas during supercritical water gasification of sewage sludge.

Waste Manag 2021 Jul 8;131:394-402. Epub 2021 Jul 8.

Institute of Energy and Power Engineering, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address:

Amount of HS and SO were generated during the SCWG of sewage sludge. It is essential to reduce the sulfur concentration in syngas for depth utilization of syngas from SCWG of sewage sludge. The syngas desulfurization ability of five additives (KOH, KCO, NaOH, NaCO, AC) were tested and the result indicated that KCO had the best syngas desulfurization effect while KOH could significantly promote the yield of syngas at 450 °C and 4% loading. Increasing KOH and KCO loading to 12% could reduce around 90% of sulfur in syngas comparing to no additives. The XPS analysis results indicated that alkali additives promoted the cyclization and oxidation of unstable sulfur compounds in raw sludge, which can convert it into stable sulfur compounds such as thiophene, sulfone and sulfate. The sulfur in liquid was mainly in the forms of sulfate, and the effect of alkali and AC additive on sulfur in liquid was relatively weak.
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http://dx.doi.org/10.1016/j.wasman.2021.06.029DOI Listing
July 2021

Avermectin induces toxic effects in insect nontarget cells involves DNA damage and its associated programmed cell death.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Jul 8;249:109130. Epub 2021 Jul 8.

Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address:

Avermectin (AVM), is widely applied in the fields of agriculture, possess activities against mites and insects. AVM is generally thought to keep the GABA-related chloride channels open in insect cells. However, AVM induces cytotoxicity in non-neural cells still ambiguous. Here we evaluate the cytotoxicity and other mode of action of AVM in Spodoptera frugiperda (Sf9) cells. Our results showed that AVM suppressed the activity of Sf9 cells and induced programmed cell death. DNA damage of Sf9 cells was detected by alkaline comet assay and PARP. The cleavage of poly ADP-ribose polymerase (PARP) and DNA double-strand breaks demonstrated AVM induced DNA damage in Sf9 cells. In addition, a series of established cytotoxicity tests were conducted to explore the mechanism of AVM toxicity in Sf9 cells. Typical apoptosis changes were occurred including increasing the expression of Bax/Bcl-2 and the activation of caspase-9/-3. Subsequently, Western blotting was used to detected autophagy related proteins including LC3, Beclin1 and p62. We found that AVM upregulated LC3, Beclin1 expression and downregulated p62 expressions. Moreover, we found that AVM induced autophagy may through AMPK/mTOR-mediated autophagy pathway. These results showed that AVM-induced DNA damage and programmed cell death in Sf9 cells.
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http://dx.doi.org/10.1016/j.cbpc.2021.109130DOI Listing
July 2021

Resveratrol Alleviates 27-Hydroxycholesterol-Induced Senescence in Nerve Cells and Affects Zebrafish Locomotor Behavior via Activation of SIRT1-Mediated STAT3 Signaling.

Oxid Med Cell Longev 2021 21;2021:6673343. Epub 2021 Jun 21.

The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Rd., Nanjing 211166, China.

The oxysterol 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator (SERM), which like endogenous estrogen 17-estradiol (E) induces the proliferation of estrogen receptor- (ER-) positive breast cancer cells . However, 27HC differs from E in that it shows adverse effects in the nervous system. Our previous study confirmed that 27HC could induce neural senescence by activating phosphorylated signal transducer and activator of transcription, which E could not. The purpose of the present study is to investigate whether STAT3 acetylation was involved in 27HC-induced neural senescence. Microglia (BV2 cells) and rat pheochromocytoma cells (PC12 cells) were used to explore the effect of resveratrol (REV) on 27HC-induced neural senescence. Senescence-associated -galactosidase (SA--Gal) staining was performed using an SA--Gal Staining Kit in cells and zebrafish larvae. Zebrafish were used to assess the effect of 27HC on locomotor behavior and aging. We found that 27HC could induce senescence in neural cells, and REV, which has been employed as a Sirtuin-1 (SIRT1) agonist, could attenuate 27HC-induced senescence by inhibiting STAT3 signaling via SIRT1. Moreover, in the zebrafish model, REV attenuated 27HC-induced locomotor behavior disorder and aging in the spinal cord of zebrafish larvae, which was also associated with the activation of SIRT1-mediated STAT3 signaling. Our findings unveiled a novel mechanism by which REV alleviates 27HC-induced senescence in neural cells and affects zebrafish locomotor behavior by activating SIRT1-mediated STAT3 signaling.
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http://dx.doi.org/10.1155/2021/6673343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238615PMC
June 2021

Comparison of intramedullary nailing fixation and percutaneous locked plating fixation for the treatment of proximal tibial fractures: A meta-analysis.

J Orthop Surg (Hong Kong) 2021 May-Aug;29(2):23094990211024395

Department of Orthopedic Trauma, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.

Objective: This meta-analysis aimed to systematically compare the clinical outcomes of intramedullary nailing (IMN) fixation and percutaneous locked plating (PLP) fixation in the treatment of proximal tibial fractures.

Methods: We searched PubMed, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wan Fang to select relevant articles up to March 29, 2020 without language limit. Continuous variables were estimated by weighted mean difference (WMD) with a 95% confidence interval (CI) and dichotomous outcomes were calculated by relative risk (RR) with 95% CI. Moreover, heterogeneity analysis was evaluated. Furthermore, publication bias assessment and sensitivity analysis were conducted. Stata 11.0 software was used to perform the statistical analysis.

Results: Ten studies involving 667 cases (321 from IMN fixation group and 346 from PLP fixation group) were included. The type of fractures involved in the included articles was extra-articular proximal tibia fractures. IMN fixation method achieved significantly shorter union time ( = -2.88, 95% : -3.23 to -2.53, < 0.001) and full weight-bearing time ( = -2.81, 95% : -3.64 to -1.97, < 0.001) than PLP fixation method. Meanwhile, IMN fixation resulted in lower risks of infection ( = 0.50, 95% : 0.27 to 0.91, = 0.02) and total complications ( = 0.36, 95% : 0.22 to 0.60, < 0.001) than PLP fixation. No significant differences were found in the incidence of nonunion ( = 0.33), malunion ( = 0.38), and osteofascial compartment syndrome (OCS, = 0.62) between the two groups.

Conclusions: Compared to PLP fixation, IMN fixation had several advantages in treating proximal tibial fractures, including the short time of union and full weight-bearing, as well as a low risk of infection and total complications.
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http://dx.doi.org/10.1177/23094990211024395DOI Listing
July 2021

CFDSONa: An Effective Precursor Reagent for Deuteriodifluoromethylthiolation and Deuteriodifluoromethylation.

Org Lett 2021 Jul 7;23(14):5545-5548. Epub 2021 Jul 7.

Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

Deuteriodifluoromethythio (SCFD) and deuteriodifluoromethyl (CFD) are important functional groups in pharmaceutical and agrochemical compounds, and the introduction of these functional groups remains a challenging. We herein report a robust reagent for deuteriodifluoromethylthiolation and deuteriodifluoromethylation. Its potentials were successfully showcased by deuteriodifluoromethylation and deuteriodifluoromethylthiolation of indoles with high-level deuterium incorporation. The reagent also has potential for deuteriodifluoromethylation and deuteriodifluoromethylthiolation of wide range of other natural or synthetic bioactive molecules.
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http://dx.doi.org/10.1021/acs.orglett.1c01882DOI Listing
July 2021

Multidose pharmacokinetics and safety of a modified, compounded theophylline product in dogs.

J Vet Pharmacol Ther 2021 Jun 26. Epub 2021 Jun 26.

The Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL, 61820, US.

Theophylline is used in canine medicine for the management of chronic bronchitis and bradyarrhythmias, yet no species-validated commercial products are available. This study reports the single-dose and multidose pharmacokinetics and safety of a modified, compounded theophylline (MCT) product readily available from a well-established, USP-compliant compounding pharmacy, which may be a suitable and reliable source for theophylline for dogs. Eleven dogs underwent serial plasma theophylline measurement following 10 mg/kg MCT PO. After a 7 days washout, dogs received 10 mg/kg MCT PO q12h and serial plasma theophylline quantification was repeated after the ninth dose. Dogs were monitored for potential adverse effects. For the nine dogs that completed the study, plasma theophylline concentrations were between 5 and 30 μg/ml for 91 +/- 15% of the dosing interval. There was no significant difference in half-life between single-dose and multidose administration. The most common adverse effects reported were mild and included agitation, excitement, and increased activity. The results of this study support the use of 10 mg/kg MCT administered twice daily as a starting dosage in dogs. This regimen appears safe, achieves appropriate plasma drug concentrations in most dogs, and does not cause significant changes in pharmacokinetic properties at steady state. Because compounded drugs do not undergo consistent testing for identity, quality, strength, purity, and stability, results of research described in reports using compounded products may not be reproducible.
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http://dx.doi.org/10.1111/jvp.12997DOI Listing
June 2021

Risk factors for mortality in critically ill patients with COVID-19: a multicenter retrospective case-control study.

BMC Infect Dis 2021 Jun 24;21(1):602. Epub 2021 Jun 24.

The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510010, China.

Background: Coronavirus disease 2019 (COVID-19) has spread around the world, until now, the number of positive and death cases is still increasing. Therefore, it remains important to identify risk factors for death in critically patients.

Methods: We collected demographic and clinical data on all severe inpatients with COVID-19. We used univariable and multivariable Cox regression methods to determine the independent risk factors related to likelihood of 28-day and 60-day survival, performing survival curve analysis.

Results: Of 325 patients enrolled in the study, Multi-factor Cox analysis showed increasing odds of in-hospital death associated with basic illness (hazard ratio [HR] 6.455, 95% Confidence Interval [CI] 1.658-25.139, P = 0.007), lymphopenia (HR 0.373, 95% CI 0.148-0.944, P = 0.037), higher Sequential Organ Failure Assessment (SOFA) score on admission (HR 1.171, 95% CI 1.013-1.354, P = 0.033) and being critically ill (HR 0.191, 95% CI 0.053-0.687, P = 0.011). Increasing 28-day and 60-day mortality, declining survival time and more serious inflammation and organ failure were associated with lymphocyte count < 0.8 × 109/L, SOFA score > 3, Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 7, PaO2/FiO2 < 200 mmHg, IL-6 > 120 pg/ml, and CRP > 52 mg/L.

Conclusions: Being critically ill and lymphocyte count, SOFA score, APACHE II score, PaO2/FiO2, IL-6, and CRP on admission were associated with poor prognosis in COVID-19 patients.
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http://dx.doi.org/10.1186/s12879-021-06300-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223178PMC
June 2021

Clinical characteristics and risk factors of male exertional heatstroke in patients with myocardial injury: an over 10-year retrospective cohort study.

Int J Hyperthermia 2021 ;38(1):970-975

Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, China.

Background: Heatstrokes are a serious threat to human health, particularly the cardiovascular system. Understanding the clinical features and risk factors related to death in patients with myocardial injury (MI) complicated by heat stroke is crucial.

Method: This study included the baseline data of all patients with severe heatstroke between October 2008 and May 2019.

Results: Of the 162 patients enrolled, 75 (46.3%) were in the MI group and 87 (53.7%) were in the non-MI group. A significant difference was noted in 90-day survival between the two groups even after correction for Age, Acute Physiology, and Chronic Health Evaluation II (APACHE II) scores, Sequential Organ Failure Assessment (SOFA) scores, Glasgow Coma Score (GCS), and activated partial thromboplastin time (before correction ( < .001; after correction,  = .023). Survival analysis showed that the 90-day survival time of patients with MI was shorter than that of patients without MI ( < .001). The area under the receiver operating characteristic (ROC) curve for predicting mortality based on the SOFA score was 92.8% (95% CI 0.847-1.000,  < .001), the optimal cutoff value was 7.5, the sensitivity was 91.7%, and the specificity was 94.6%.

Conclusion: Patients with heatstroke having MI had more severe clinical conditions, 90-day mortality was significantly increased, and the survival time was shortened. A high SOFA score is an independent risk factor for death in patients with heatstroke having MI, with an optimal cutoff value of 7.5, sensitivity of 91.7%, and specificity of 94.6%.
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http://dx.doi.org/10.1080/02656736.2021.1941312DOI Listing
July 2021

Circular RNA mmu_circ_0005019 inhibits fibrosis of cardiac fibroblasts and reverses electrical remodeling of cardiomyocytes.

BMC Cardiovasc Disord 2021 Jun 21;21(1):308. Epub 2021 Jun 21.

Department of Epidemiology, College of Preventive Medicine, Army Medical University (Third Military Medical University), NO. 30 Gaotanyan Street, Chongqing, 400038, People's Republic of China.

Background: Circular RNA (circRNA) have been reported to play important roles in cardiovascular diseases including myocardial infarction and heart failure. However, the role of circRNA in atrial fibrillation (AF) has rarely been investigated. We recently found a circRNA hsa_circ_0099734 was significantly differentially expressed in the AF patients atrial tissues compared to paired control. We aim to investigate the functional role and molecular mechanisms of mmu_circ_0005019 which is the homologous circRNA in mice of hsa_circ_0099734 in AF.

Methods: In order to investigate the effect of mmu_circ_0005019 on the proliferation, migration, differentiation into myofibroblasts and expression of collagen of cardiac fibroblasts, and the effect of mmu_circ_0005019 on the apoptosis and expression of I, I and SK3 of cardiomyocytes, gain- and loss-of-function of cell models were established in mice cardiac fibroblasts and HL-1 atrial myocytes. Dual-luciferase reporter assays and RIP were performed to verify the binding effects between mmu_circ_0005019 and its target microRNA (miRNA).

Results: In cardiac fibroblasts, mmu_circ_0005019 showed inhibitory effects on cell proliferation and migration. In cardiomyocytes, overexpression of mmu_circ_0005019 promoted Kcnd1, Scn5a and Kcnn3 expression. Knockdown of mmu_circ_0005019 inhibited the expression of Kcnd1, Kcnd3, Scn5a and Kcnn3. Mechanistically, mmu_circ_0005019 exerted biological functions by acting as a miR-499-5p sponge to regulate the expression of its target gene Kcnn3.

Conclusions: Our findings highlight mmu_circ_0005019 played a protective role in AF development and might serve as an attractive candidate target for AF treatment.
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http://dx.doi.org/10.1186/s12872-021-02128-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215745PMC
June 2021

Difenoconazole induces oxidative DNA damage and mitochondria mediated apoptosis in SH-SY5Y cells.

Chemosphere 2021 Jun 10;283:131160. Epub 2021 Jun 10.

Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address:

Difenoconazole is one of the most typical triazole fungicides. Difenoconazole is widely used in the field of agricultural production, and its health and safety problems need to be further studied. The main purpose of this paper is to verify the neurotoxicity of Difenoconazole at the cellular level. In this study, SH-SY5Y cell line of human neuroblastoma was used to evaluate its potentially toxic effects and molecular mechanism in vitro. The research indicated that Difenoconazole could reduce cell viability and inhibit cell proliferation, induce DNA damage and accelerate programmed cell death. Further studies showed that Difenoconazole induced DNA double-strand breaks, intracellular generation of ROS, cleaved PARP, mitochondrial membrane potential collapse, induced Cyt c release, and Bax/Bcl-2 ratio increase in SH-SY5Y cells. In conclusion, the cytotoxicity of Difenoconazole revealed its toxic effect on SH-SY5Y cells, and the IC value was 55.41 μM after 24 h exposure. Meanwhile, the genetic toxicity of Difenoconazole has revealed that it can induce DNA damage and apoptosis of SH-SY5Y cells. Through this study, the toxic effects of Difenoconazole on SH-SY5Y cells are further understood, which provides a more scientific basis for its safe use and risk control.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131160DOI Listing
June 2021

The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion.

Front Oncol 2021 31;11:646511. Epub 2021 May 31.

School of Life and Marine Sciences, Shenzhen University, Shenzhen, China.

Object: Clinically, the effective treatment options available to thyroid cancer (THCA) patients are very limited. Elucidating the features of tumor suppressor genes (TSGs) and the corresponding signal transduction cascade may provide clues for the development of new strategies for targeted therapy of THCA. Therefore, this paper aims to explore the mechanism of ZNF24 underlying promoting THCA cell senescence at molecular level.

Methods: We performed RT-PCR and Western Blotting for evaluating associated RNA and protein expression. CCK8, colony forming, wound healing and Transwell chamber assays were conducted to examine THCA cell proliferation, invasion and migration. β-galactosidase staining assay was performed to detect THCA cells senescence. The size and volume of xenotransplanted tumors in nude mice are calculated to asses ZNF24 effect .

Results: Ectopic expression of ZNF24 significantly inhibited the cell viability, colony forming, migration and invasion abilities of THCA cell lines (K1/GLAG-66i and BCPAPi) ( < 0.05). ZNF24 induced BCPAPi cells senescence through regulating Wnt signaling pathway. ZNF24 inhibited Wnt signaling pathway activition by competitively binding β-catenin from LEF1/TCF1-β-catenin complex. In nude mice, both Ectopic expression of ZNF24 and 2,4-Da (the strong β-catenin/Tcf-4 inhibitor) treatment significantly decreased both the size and weight of xenotransplanted tumors when compared with control mice ( < 0.05).

Conclusion: Results obtained and reveal the role of ZNF24 in significantly suppressing THCA tumorigenesis and invasion by regulating Wnt signaling pathway.
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http://dx.doi.org/10.3389/fonc.2021.646511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201406PMC
May 2021

Caveolin-1 mediates soft scaffold-enhanced adipogenesis of human mesenchymal stem cells.

Stem Cell Res Ther 2021 06 14;12(1):347. Epub 2021 Jun 14.

Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Background: Human bone marrow-derived mesenchymal stem cells (hBMSCs) can differentiate into adipocytes upon stimulation and are considered an appropriate cell source for adipose tissue engineering. In addition to biochemical cues, the stiffness of a substrate that cells attach to has also been shown to affect hBMSC differentiation potential. Of note, most current studies are conducted on monolayer cultures which do not directly inform adipose tissue engineering, where 3-dimensional (3D) scaffolds are often used to create proper tissue architecture. In this study, we aim to examine the adipogenic differentiation of hBMSCs within soft or stiff scaffolds and investigate the molecular mechanism mediating the response of hBMSCs to substrate stiffness in 3D culture, specifically the involvement of the integral membrane protein, caveolin-1 (CAV1), known to regulate signaling in MSCs via compartmentalizing and concentrating signaling molecules.

Methods: By adjusting the photo-illumination time, photocrosslinkable gelatin scaffolds with the same polymer concentration but different stiffnesses were created. hBMSCs were seeded within soft and stiff scaffolds, and their response to adipogenic induction under different substrate mechanical conditions was characterized. The functional involvement of CAV1 was assessed by suppressing its expression level using CAV1-specific siRNA.

Results: The soft and stiff scaffolds used in this study had a compressive modulus of ~0.5 kPa and ~23.5 kPa, respectively. hBMSCs showed high viability in both scaffold types, but only spread out in the soft scaffolds. hBMSCs cultured in soft scaffolds displayed significantly higher adipogenesis, as revealed by histology, qRT-PCR, and immunostaining. Interestingly, a lower CAV1 level was observed in hBMSCs in the soft scaffolds, concomitantly accompanied by increased levels of Yes-associated protein (YAP) and decreased YAP phosphorylation, when compared to cells seeded in the stiff scaffolds. Interestingly, reducing CAV1 expression with siRNA was shown to further enhance hBMSC adipogenesis, which may function through activation of the YAP signaling pathway.

Conclusions: Soft biomaterials support superior adipogenesis of encapsulated hBMSCs in 3D culture, which is partially mediated by the CAV1-YAP axis. Suppressing CAV1 expression levels represents a robust method in the promotion of hBMSC adipogenesis.
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http://dx.doi.org/10.1186/s13287-021-02356-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201886PMC
June 2021

Five metastasis-related mRNAs signature predicting the survival of patients with liver hepatocellular carcinoma.

BMC Cancer 2021 Jun 11;21(1):693. Epub 2021 Jun 11.

Department of Interventional Radiology, The Second Clinical College of North Sichuan Medical College, Nan Chong Central Hospital, Nan Chong, 637000, Sichuan, China.

Backgrounds: Liver hepatocellular carcinoma (HCC) is one of the most malignant tumors, of which prognosis is unsatisfactory in most cases and metastatic of HCC often results in poor prognosis. In this study, we aimed to construct a metastasis- related mRNAs prognostic model to increase the accuracy of prediction of HCC prognosis.

Methods: Three hundred seventy-four HCC samples and 50 normal samples were downloaded from The Cancer Genome Atlas (TCGA) database, involving transcriptomic and clinical data. Metastatic-related genes were acquired from HCMBD website at the same time. Two hundred thirty-three samples were randomly divided into train dataset and test dataset with a proportion of 1:1 by using caret package in R. Kaplan-Meier method and univariate Cox regression analysis and lasso regression analysis were performed to obtain metastasis-related mRNAs which played significant roles in prognosis. Then, using multivariate Cox regression analysis, a prognostic prediction model was established. Transcriptome and clinical data were combined to construct a prognostic model and a nomogram for OS evaluation. Functional enrichment in high- and low-risk groups were also analyzed by GSEA. An entire set based on The International Cancer Genome Consortium(ICGC) database was also applied to verify the model. The expression levels of SLC2A1, CDCA8, ATG10 and HOXD9 are higher in tumor samples and lower in normal tissue samples. The expression of TPM1 in clinical sample tissues is just the opposite.

Results: One thousand eight hundred ninety-five metastasis-related mRNAs were screened and 6 mRNAs were associated with prognosis. The overall survival (OS)-related prognostic model based on 5 MRGs (TPM1,SLC2A1, CDCA8, ATG10 and HOXD9) was significantly stratified HCC patients into high- and low-risk groups. The AUC values of the 5-gene prognostic signature at 1 year, 2 years, and 3 years were 0.786,0.786 and 0.777. A risk score based on the signature was a significantly independent prognostic factor (HR = 1.434; 95%CI = 1.275-1.612; P < 0.001) for HCC patients. A nomogram which incorporated the 5-gene signature and clinical features was also built for prognostic prediction. GSEA results that low- and high-risk group had an obviously difference in part of pathways. The value of this model was validated in test dataset and ICGC database.

Conclusion: Metastasis-related mRNAs prognostic model was verified that it had a predictable value on the prognosis of HCC, which could be helpful for gene targeted therapy.
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http://dx.doi.org/10.1186/s12885-021-08431-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194172PMC
June 2021

Maternal phthalate and phthalate alternative metabolites and urinary biomarkers of estrogens and testosterones across pregnancy.

Environ Int 2021 Oct 8;155:106676. Epub 2021 Jun 8.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA. Electronic address:

Background/objectives: Pregnant women are ubiquitously exposed to phthalates from food packaging materials and personal care products. Phthalates alter estrogen and testosterone concentrations in experimental models, but their ability to impact these hormones in human pregnancy is not well characterized.

Methods: We recruited women ages 18-40 into the Illinois Kids Development Study (I-KIDS) in early pregnancy. Participants provided up to 5 first-morning urine samples across pregnancy (8-40 weeks gestation) that we pooled for quantification of 19 phthalate or phthalate alternative metabolites. Either individual (ng/mL) or molar sums (nmol/mL) of metabolites were used as exposure biomarkers. We summed urinary concentrations (ng/mL) of eight major estrogen (SumEstrogens) and two major testosterone (SumTestosterones) metabolites measured at median 13, 28, and 34 weeks gestation. We also estimated the ratio of estrogens-to-androgens. Linear mixed-effects models assessed relationships of phthalates/alternatives as continuous measures or as concentration quartiles with SumEstrogens, SumTestosterones, and the Estrogen/Androgen ratio in 434 women. In our models, we controlled for age, race, education, parity, smoking in the first trimester, pre-pregnancy body mass index, diet quality, conception season, fetal sex, and gestational age at hormone assessment. We also explored whether gestational age at hormone assessment or fetal sex modified these associations. All biomarkers and outcomes were specific gravity-adjusted, and continuous exposures and outcomes were also natural log-transformed.

Results: Most participants were non-Hispanic white (80.9%), college educated (82.2%), and had urinary phthalate/alternative metabolite concentrations similar to those of reproductive-aged U.S. women. Overall, select phthalate metabolites were positively associated with SumEstrogens and SumTestosterones, but negatively associated with the Estrogen/Androgen ratio. For example, SumEstrogens was 5.1% (95%CI: 1.8, 8.5) higher with every 2-fold increase in sum of di(2-ethylhexyl) phthalate metabolites, while SumTestosterones was 7.9% (95%CI: 1.0, 15.3) higher and Estrogen/Androgen ratio was -7.7% (95%CI: -13.6, -1.4) lower with every 2-fold increase in monoethyl phthalate. However, phthalate alternatives were only positively associated with SumEstrogens, which was 2.4% (95%CI: 0.4, 4.5) and 3.2% (95%CI: 0.7, 5.8) higher with every 2-fold increase in sum of di(isononyl) cyclohexane-1,2-dicarboxylate metabolites and sum of di(2-ethylhexyl) terephthalate metabolites, respectively. Gestational age- and fetal sex-specific associations were only consistently observed for associations of phthalates/alternatives with SumEstrogens, where associations were strongest in mid-to-late pregnancy in women carrying females.

Conclusion: Phthalates/alternatives may impact gestational hormones, with potential for gestational age- and fetal sex-specific associations. Whether maternal urinary estrogens and testosterones mediate associations of phthalates/alternatives with pregnancy and fetal outcomes merits further investigation.
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http://dx.doi.org/10.1016/j.envint.2021.106676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292204PMC
October 2021

Agrimol B present in Agrimonia pilosa Ledeb impedes cell cycle progression of cancer cells through G state arrest.

Biomed Pharmacother 2021 Jun 4;141:111795. Epub 2021 Jun 4.

Chinese Medicine Anti-Cancer Evaluation Program, Greg Brown Laboratory, Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, Australia; Department of Endocrisnology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address:

Cancer recurrence poses a significant challenge. At the cellular level, recurrence takes place as a result of reactivation of dormant cancer cells residing at G phase. The aim of the study was to identify compounds that can trap prostate and lung cancer cells in G phase from a new Chinese herb recipe, Astringent recipe, consisting of Radix Paeoniae Alba, Agrimonia pilosa Ledeb, Fructus Mume, Fritillaria thunbergii Miq., Ganoderma Lucidum Karst, and Astragalus membranaceus (Fisch.) Bunge. Astringent recipe impeded cell cycle progression in prostate and lung cancer cells by rounding them up at G phase by flow cytometric analysis of cancer cells stained with Hoechst 33342 and Pyronin Y, respectively, for DNA and RNA. The anti-cancer efficacy of the recipe was found to be attributable to Agrimonia pilosa Ledeb. Further study established that agrimol B, a polyphenol derived from Agrimonia pilosa Ledeb, contributed to the activity of the herb. The action of agrimol B on the cancer cells was likely derived from its effect on c-MYC, SKP2 and p27 by immunoblotting and immunofluorescence. Oral administration of Agrimonia pilosa Ledeb or agrimol B reduced growth of prostate cancer cell xenograft in animal. In conclusion, Agrimol B can enrich for prostate and lung cancer cells in G state and influence key regulators that govern G status.
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http://dx.doi.org/10.1016/j.biopha.2021.111795DOI Listing
June 2021

Clinical Characteristics and Risk Factors Associated With Acute Kidney Injury Inpatient With Exertional Heatstroke: An Over 10-Year Intensive Care Survey.

Front Med (Lausanne) 2021 19;8:678434. Epub 2021 May 19.

The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Exertional heat stroke (EHS) is a life-threatening injury that can lead to acute kidney injury (AKI). The clinical characteristics of and risk factors for EHS complicated with AKI have been poorly documented. A retrospective study with EHS admitted to the intensive care unit (ICU) from January 2008 to June 2019 was performed. Data including baseline clinical information at admission, main organ dysfunction, 90-day mortality and total cost of hospitalization were collected. A total of 187 patients were finally included, of which 82 (43.9%) had AKI. AKI patients had more severe organ injury and higher total hospitalization costs than non-AKI patients. Multivariate logistic analysis showed that lymphocyte, neutrophil, D-dimer and myoglobin (MB) ≥ 1,000 ng/ml were independent risk factors for AKI caused by EHS. In addition, SOFA score [hazard ratio (HR) 4.1, 95% confidence interval (95% CI) 1.6-10.8, = 0.004] and GCS score (HR 3.2, 95% CI 1.2-8.4 = 0.017) were the risk factor for 90-day mortality in patients with EHS complicated with AKI, with an area under the curve (AUC) of 0.920 (95% CI 0.842-0.998, < 0.001) and 0.851 (95% CI 0.739-0.962, < 0.001), respectively. Survival analysis showed that the 90-day mortality in AKI patients was significantly high ( < 0.0001) and the mortality rate of patients with AKI stage 2 was the highest than other stages. EHS complicated with AKI is associated with higher hospitalization costs and poorly clinical outcomes. MB ≥1,000 ng/ml, Inflammation, coagulation were associated with the occurrence and development of AKI. Early treatment strategies based reducing the SOFA and GCS score may be pivotal for improving the prognosis of EHS.
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http://dx.doi.org/10.3389/fmed.2021.678434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170299PMC
May 2021

Data-driven interval credibility constrained quadratic programming model for water quality management under uncertainty.

J Environ Manage 2021 Sep 2;293:112791. Epub 2021 Jun 2.

Department of Civil Engineering, McMaster University, 1280 Main Street West, Hamilton, L8S 4L7, ON, Canada. Electronic address:

Although integrated simulation-optimization modeling can provide a comprehensive and reliable analysis for water quality management (WQM), it is usually not easy to implement in practice. This study proposed a new efficient simulation-optimization modeling approach by leveraging the power of data-driven modeling, to support WQM under various uncertainties. A water quality simulation model is integrated with the optimization model, and then substituted by a series of numerical surrogate models based on inexact linear regression. The transformation can significantly reduce the computational burden and make it possible to implement uncertainty quantification through hybrid inexact programming. The proposed model incorporates interval quadratic programming and credibility constrained programming to deal with nonlinearity and various uncertainties associated with the management system. The proposed approach is applied to a real case study of the Grand River watershed in Canada for controlling phosphorus concentration in river water. The Grand River Simulation Model (GRSM) is employed as the physical simulation model to estimate the total phosphorus concentration in the river. Interval solutions under different confidence levels of violating the effluent standards were obtained, which can be used to generate optimal phosphorus control strategies. The results indicate the proposed data-driven interval credibility constrained quadratic programming (DICCQP) model is able to provide reliable and robust solutions for WQM by considering nonlinearity and various uncertainties while maintaining a high computational efficiency. The proposed new framework can be extended and applied to the other watersheds. The high efficiency of the proposed model makes it possible to solve large-scale complex water quality management and planning problems.
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http://dx.doi.org/10.1016/j.jenvman.2021.112791DOI Listing
September 2021

A new approach for investigating the relative contribution of basal glucose and postprandial glucose to HbA1.

Nutr Diabetes 2021 06 4;11(1):14. Epub 2021 Jun 4.

Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China.

To develop an accurate method for evaluating the relative contributions of basal glucose (BG) and postprandial glucose (PPG) to glycated haemoglobin (HbA1c) in subjects with hyperglycaemia using a Continuous Glucose Monitoring System (CGMS®). The subjects were divided into the normal glucose tolerance (NGT), impaired glucose tolerance (IGT), newly-diagnosed type 2 diabetes (NDDM), and drug-treated type 2 diabetes (T2DM) groups. We evaluated the relative contributions of BG and PPG to HbA1c in patients with hyperglycaemia according to three different baseline values. Subjects (n = 490) were grouped as follows: 92 NGT, 36 IGT, 131 NDDM, and 231 T2DM. The relative contributions of PPG to HbA1c were calculated using baseline values of 6.1 mmol/L, 5.6 mmol/L, and the 24-h glucose curve of the NGT group. The relative contribution of PPG to HbA1c decreased progressively from the IGT group to the T2DM group. Compared with the 24-h glucose curve as the baseline, the relative contribution of PPG was overestimated in 9.04% and 1.76% of the subjects when 6.1 mmol/L and 5.6 mmol/L were used as baselines, respectively (P < 0.01), in T2DM patients. The 24-h glucose curve of NGT is more suitable for studying the relative contributions of BG and PPG to HbA1c and it is more precise, as it considers physiological fluctuations in NGT after meals. However, 5.6 mmol/L can be used when the 24-h glucose curve for NGT is unavailable; using 6.1 mmol/L as a baseline value may overestimate the contribution to the HbA1c. There is no unified standard for assessing the contributions of basal glucose (BG) and postprandial glucose (PPG) to HbA1c. The 24-h glucose curve of NGT is more suitable for studying the relative contributions of BG and PPG to HbA1c, as it considers physiological fluctuations in NGT after meals. However, 5.6 mmol/L can be used when the 24-h glucose curve for NGT is unavailable; using 6.1 mmol/L as a baseline value may overestimate the contribution to the HbA1c.
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http://dx.doi.org/10.1038/s41387-021-00156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178390PMC
June 2021

An alternative domain-swapped structure of the Pyrococcus horikoshii PolII mini-intein.

Sci Rep 2021 Jun 3;11(1):11680. Epub 2021 Jun 3.

Department of Chemistry, College of the Holy Cross, 1 College Street, Worcester, MA, USA.

Protein splicing is a post-translational process by which an intein catalyzes its own excision from flanking polypeptides, or exteins, concomitant with extein ligation. Many inteins have nested homing endonuclease domains that facilitate their propagation into intein-less alleles, whereas other inteins lack the homing endonuclease (HEN) and are called mini-inteins. The mini-intein that interrupts the DNA PolII of Pyrococcus horikoshii has a linker region in place of the HEN domain that is shorter than the linker in a closely related intein from Pyrococcus abyssi. The P. horikoshii PolII intein requires a higher temperature for catalytic activity and is more stable to digestion by the thermostable protease thermolysin, suggesting that it is more rigid than the P. abyssi intein. We solved a crystal structure of the intein precursor that revealed a domain-swapped dimer. Inteins found as domain swapped dimers have been shown to promote intein-mediated protein alternative splicing, but the solved P. horikoshii PolII intein structure has an active site unlikely to be catalytically competent.
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http://dx.doi.org/10.1038/s41598-021-91090-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175363PMC
June 2021

GCSENet: A GCN, CNN and SENet ensemble model for microRNA-disease association prediction.

PLoS Comput Biol 2021 Jun 3;17(6):e1009048. Epub 2021 Jun 3.

Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Solna, Sweden.

Recently, an increasing number of studies have demonstrated that miRNAs are involved in human diseases, indicating that miRNAs might be a potential pathogenic factor for various diseases. Therefore, figuring out the relationship between miRNAs and diseases plays a critical role in not only the development of new drugs, but also the formulation of individualized diagnosis and treatment. As the prediction of miRNA-disease association via biological experiments is expensive and time-consuming, computational methods have a positive effect on revealing the association. In this study, a novel prediction model integrating GCN, CNN and Squeeze-and-Excitation Networks (GCSENet) was constructed for the identification of miRNA-disease association. The model first captured features by GCN based on a heterogeneous graph including diseases, genes and miRNAs. Then, considering the different effects of genes on each type of miRNA and disease, as well as the different effects of the miRNA-gene and disease-gene relationships on miRNA-disease association, a feature weight was set and a combination of miRNA-gene and disease-gene associations was added as feature input for the convolution operation in CNN. Furthermore, the squeeze and excitation blocks of SENet were applied to determine the importance of each feature channel and enhance useful features by means of the attention mechanism, thus achieving a satisfactory prediction of miRNA-disease association. The proposed method was compared against other state-of-the-art methods. It achieved an AUROC score of 95.02% and an AUPR score of 95.55% in a 10-fold cross-validation, which led to the finding that the proposed method is superior to these popular methods on most of the performance evaluation indexes.
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http://dx.doi.org/10.1371/journal.pcbi.1009048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205154PMC
June 2021

Pharmacokinetics of a cytosine arabinoside subcutaneous protocol in dogs with meningoencephalomyelitis of unknown aetiology.

J Vet Pharmacol Ther 2021 May 26. Epub 2021 May 26.

The Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, Illinois, USA.

Cytosine arabinoside (CA) is a commonly used treatment for dogs with meningoencephalomyelitis of unknown aetiology (MUE) with various proposed protocols, many requiring 24 hours (h) of hospitalization or two visits within 24 h. This is a unidirectional study evaluating the pharmacokinetics of a CA subcutaneous (SC) protocol and a standard constant rate infusion (CRI) protocol in 8 dogs with MUE. Dogs received the CRI (200 mg/m IV over 24 h), followed by a SC protocol (50 mg/m every 2 h for 4 treatments) four weeks later. Plasma CA concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS). Median peak CA concentration for the SC protocol (3.40 µg/ml, range 1.60-9.70 µg/ml) was significantly higher than the CRI (1.09 µg/ml, range 0.77-1.67 µg/ml; p = .02). Median concentration at 1h and 8h following initiation of treatment was significantly higher for the SC protocol (CA 2.28 µg/ml, range 0.97-2.67; CA 1.83 µg/ml, range 0.77-2.84) compared to the CRI (CA1 0.01 µg/ml, range 0-0.45; CA 0.74 µg/ml, range 0.67-1.11; p = .01). While the PK properties of CA when administered as a CRI has been previously investigated, this study demonstrated that CA when administered via repeated 50 mg/m injections every 2 h over an 8-h period, provided sustained plasma levels above its therapeutic target and for a significantly longer duration of time than did a standard CRI protocol.
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http://dx.doi.org/10.1111/jvp.12980DOI Listing
May 2021

Effects of hypertension on the outcomes of COVID-19: a multicentre retrospective cohort study.

Ann Med 2021 12;53(1):770-776

Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Southern Medical University, Guangzhou, China.

Hypertension is thought to be a contributor to mortality in coronavirus disease 2019 patients; however, limited clinical data on the outcomes of COVID-19 in patients with hypertension are available. This study was designed to confirm whether hypertension affects the outcomes of COVID-19. A total of 983 patients with COVID-19 (female, 48%; male, 52%) were enrolled. Significantly higher odds of 60-day mortality ( = .017) were observed in the hypertensive group. In the hypertensive group, even after adjustment in multivariate analysis, the subgroup of patients 70 years old and older had higher 28-day mortality and total 60-day mortality rates than the other age subgroups (both < .05). A total of 297 (89%) COVID-19 patients with hypertension survived, and 35 (11%) died. In addition, compared with hypertensive patients who survived COVID-19, non-survivors had more pre-existing conditions, including cardiovascular diseases and stroke, higher blood pressure on admission, more severe inflammation, and more liver and kidney damage. Hypertension does not affect the outcome of COVID-19, which is different than the conclusions drawn in other studies. However, the 28-day mortality and total 60-day mortality rates of hypertensive patients (age ≥ 70) with COVID-19 were significantly elevated, and compared with the group of survivors, non-surviving COVID-19 patients with hypertension were older, had more basic diseases and had a more severe clinical condition.
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http://dx.doi.org/10.1080/07853890.2021.1931957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183539PMC
December 2021

The Effects of Macrophage Phenotype on Osteogenic Differentiation of MSCs in the Presence of Polyethylene Particles.

Biomedicines 2021 May 1;9(5). Epub 2021 May 1.

Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA.

Wear debris generated from the bearing surfaces of joint arthroplasties leads to acute and chronic inflammation, which is strongly associated with implant failure. Macrophages derived from monocytes recruited to the local tissues have a significant impact on bone healing and regeneration. Macrophages can adopt various functional phenotypes. While M1 macrophages are pro-inflammatory, M2 macrophages express factors important for tissue repair. Here, we established a 3D co-culture system to investigate how the immune system influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in the presence of micron-sized particles. This system allowed for the simulation of an inflammatory reaction via the addition of Lipopolysaccharide-contaminated polyethylene particles (cPE) and the characterization of bone formation using micro-CT and gene and protein expression. Co-cultures of MSCs with M2 macrophages in the presence of cPE in a 3D environment resulted in the increased expression of osteogenic markers, suggesting facilitation of bone formation. In this model, the upregulation of M2 macrophage expression of immune-associated genes and cytokines contributes to enhanced bone formation by MSCs. This study elucidates how the immune system modulates bone healing in response to an inflammatory stimulus using a unique 3D culture system.
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http://dx.doi.org/10.3390/biomedicines9050499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147332PMC
May 2021
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