Publications by authors named "Liang Ye"

267 Publications

B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway.

Cell Death Differ 2022 Jun 16. Epub 2022 Jun 16.

Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.

Podocyte injury is a hallmark of glomerular diseases; however, the underlying mechanisms remain unclear. B7-1 is increased in injured podocytes, but its intrinsic role is controversial. The clinical data here revealed the intimate correlation of urinary B7-1 with severity of glomerular injury. Through transcriptomic and biological assays in B7-1 transgenic and adriamycin nephropathy models, we identified B7-1 is a key mediator in podocyte injury and glomerulosclerosis through a series of signal transmission to β-catenin. Using LC-MS/MS, Hsp90ab1, a conserved molecular chaperone, was distinguished to be an anchor for transmitting signals from B7-1 to β-catenin. Molecular docking and subsequent mutant analysis further identified the residue K69 in the N terminal domain of Hsp90ab1 was the key binding site for B7-1 to activate LRP5/β-catenin pathway. The interaction and biological functions of B7-1-Hsp90ab1-LRP5 complex were further demonstrated in vitro and in vivo. We also found B7-1 is a novel downstream target of β-catenin. Our results indicate an intercrossed network of B7-1, which collectively induces podocyte injury and glomerulosclerosis. Our study provides an important clue to improve the therapeutic strategies to target B7-1.
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http://dx.doi.org/10.1038/s41418-022-01026-8DOI Listing
June 2022

9-Cyclopropylmethoxy-dihydrotetrabenazine and its stereoisomers as vesicular monoamine transporter-2 inhibitors.

Future Med Chem 2022 Jul 31;14(13):991-1003. Epub 2022 May 31.

School of Pharmacy, Key Laboratory of Molecular Pharmacology & Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System & Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.

To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with H-H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition  and pharmacokinetics in rats were evaluated. Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2, 3, 11b)-13a] showed the highest potential VMAT2 binding activity ( = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.
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http://dx.doi.org/10.4155/fmc-2021-0331DOI Listing
July 2022

TP73-AS1 as a predictor of clinicopathological parameters and prognosis in human malignancies: a meta and bioinformatics analysis.

BMC Cancer 2022 May 25;22(1):581. Epub 2022 May 25.

Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China.

Background: Long non-coding RNA P73 antisense RNA 1 T (non-protein coding), also known as Lnc RNA TP73-AS1, is dysregulated in various tumors but the correlation between its expression and clinicopathological parameters and/or prognoses in cancer patients is inconclusive. Here, we performed a meta-analysis to evaluate the prognostic value of Lnc RNA TP73-AS1 for malignancies.

Methods: We systematically searched four online databases including PubMed, the Web of Science, Embase, and the Cochrane Library for eligible articles published up to June 29/2020. Odds ratios (ORs) and Pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to assess the association of TP73-AS1 expression with prognostic and clinicopathological parameters. We further validated TP73-AS1 expression in various malignancies and its potential prognostic value using the GEPIA online database. We predicted potential biological processes and relevant signal mechanisms through the public databases.

Results: A total of 26 studies examining 14 cancers were analyzed to evaluate the relationship between TP73-AS1 expression, clinicopathological features and prognostic indicators. The results indicated that TP73-AS1 expression markedly correlates with TNM stage (OR = 3.27,95% CI:2.43-4.39, P < 0.00001), tumor size (OR = 3.00, 95%CI:2.08-4.35, P < 0.00001), lymph node metastasis (OR = 2.77, 95%CI:1.42-5.38,P < 0.00001) and distant metastasis (OR = 4.50,95%CI:2. 62-7.73,P < 0.00001). No correlation with age (OR = 1.12,95%CI:0.77-1.64, P > 0.05), gender (OR = 1.08, 95%CI:0.84-1.38, P > 0.05) or differentiation (OR = 1.39, 95%CI:0.71-2.70, P = 0.340) was observed. TP73-AS1 overexpression was a biomarker of poor Overall survival(OS)(HR = 1.85,95%CI:1.53-2.22, P < 0.00001) and Disease-Free-Survival (DFS) (HR = 1.57,95%CI:1.03-2.42, P < 0.05). Dysregulated TP73-AS1 expression and its prognostic value in various cancers was validated based on The Cancer Genome Atlas (TCGA). Further biological function predictions indicated that TP73-AS1 was involved in pro-oncogenic signaling.

Conclusions: The upregulation of Lnc RNA TP73-AS1 was related to detrimental clinicopathological parameters and can be considered an indicator of poor prognosis for cancer malignancies.
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http://dx.doi.org/10.1186/s12885-022-09658-2DOI Listing
May 2022

Obstructive sleep apnea aggravates neuroinflammation and pyroptosis in early brain injury following subarachnoid hemorrhage via ASC/HIF-1α pathway.

Neural Regen Res 2022 Nov;17(11):2537-2543

Department of Respiration, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.

Obstructive sleep apnea can worsen the prognosis of subarachnoid hemorrhage. However, the underlying mechanism remains unclear. In this study, we established a mouse model of subarachnoid hemorrhage using the endovascular perforation method and exposed the mice to intermittent hypoxia for 8 hours daily for 2 consecutive days to simulate sleep apnea. We found that sleep apnea aggravated brain edema, increased hippocampal neuron apoptosis, and worsened neurological function in this mouse model of subarachnoid hemorrhage. Then, we established an in vitro HT-22 cell model of hemin-induced subarachnoid hemorrhage/intermittent hypoxia and found that the cells died, and lactate dehydrogenase release increased, after 48 hours. We further investigated the underlying mechanism and found that sleep apnea increased the expression of hippocampal neuroinflammatory factors interleukin-1β, interleukin-18, interleukin-6, nuclear factor κB, pyroptosis-related protein caspase-1, pro-caspase-1, and NLRP3, promoted the proliferation of astrocytes, and increased the expression of hypoxia-inducible factor 1α and apoptosis-associated speck-like protein containing a CARD, which are the key proteins in the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway. We also found that knockdown of hypoxia-inducible factor 1α expression in vitro greatly reduced the damage to HY22 cells. These findings suggest that sleep apnea aggravates early brain injury after subarachnoid hemorrhage by aggravating neuroinflammation and pyroptosis, at least in part through the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway.
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http://dx.doi.org/10.4103/1673-5374.339000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120669PMC
November 2022

Spatiotemporal changes of local hemodynamics and plaque components during atherosclerotic progression in rabbit.

Comput Methods Programs Biomed 2022 Jun 13;220:106814. Epub 2022 Apr 13.

Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Chinese Education Ministry, School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China; School of Engineering Medicine, Beihang University, Beijing, China. Electronic address:

Background And Objective: Recent evidence demonstrates that the atherogenic process is discontinuous. Our goal is to study changes of plaque components and local hemodynamics during atherosclerotic progression.

Methods: The histological and immunohistochemical staining of high-fat diet rabbit aorta were evaluated at 0, 8, 10 and 12 weeks, respectively. In addition, the blood flow and LDL transport were simulated at the above four time points.

Results: The plaque thickness at different characteristic regions increased at different rates. The collagen continued to increase, while the elastin, fibronectin, macrophages and smooth muscle cells increased first and then decreased. The relative surface LDL concentration decreased at 8 weeks, and then it increased first and decreased slightly. Meanwhile, the hemodynamic environment became better firstly at 8 weeks, then got slightly worse and lastly improved again.

Conclusions: The local hemodynamics and plaque components vary nonlinearly during atherosclerotic progression in rabbit aorta.
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http://dx.doi.org/10.1016/j.cmpb.2022.106814DOI Listing
June 2022

LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

Front Pharmacol 2022 11;13:853993. Epub 2022 Apr 11.

School of Pharmacy, Binzhou Medical University, Yantai, China.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect two machineries: proteasome and lysosome-promoted autophagy. Using TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.
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http://dx.doi.org/10.3389/fphar.2022.853993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037595PMC
April 2022

Chrysin Ameliorates Influenza Virus Infection in the Upper Airways by Repressing Virus-Induced Cell Cycle Arrest and Mitochondria-Dependent Apoptosis.

Front Immunol 2022 31;13:872958. Epub 2022 Mar 31.

Department of Pharmacy, Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.

Chrysin has been proven to possess antiviral properties, but the precise underlying anti-influenza mechanism and its anti-influenza efficacy are largely unclear. In this study, we investigated the involvement of chrysin in the blockade of cell cycle and apoptosis in distinct cell lines subjected to two H1N1 influenza A virus (IAV) strains, as well as its anti-IAV activity . Here, we found an early unidentified finding that chrysin strongly impeded IAV replication through a mechanism that was autonomous of innate antiviral immune activation and viral protein interaction. Surprisingly, chrysin can suppress IAV-induced cell cycle arrest in the G0/G1 phase by downregulating the expression levels of P53 and P21 while promoting Cyclin D1/CDK4 and Cyclin E1/CDK2 activation. Furthermore, chrysin dramatically inhibited the IAV-triggered mitochondrial apoptotic pathway by altering the balance of Bax/Bcl-xl and reducing caspase-9 and caspase-3 activation. Accumulated reactive oxygen species (ROS) reduction may contribute to the inhibitory role of chrysin in cell cycle arrest and apoptosis following IAV infection. Notably, chrysin preferably inhibited IAV replication in the upper respiratory tract, indicating that it might be a promising drug for restraining the spread of respiratory viruses.
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http://dx.doi.org/10.3389/fimmu.2022.872958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009290PMC
April 2022

Degradation of long-chain n-alkanes by a novel thermal-tolerant Rhodococcus strain.

Arch Microbiol 2022 Apr 13;204(5):259. Epub 2022 Apr 13.

State Key Laboratory of Microbial Resources, Institute of Microbiology, CAS, Beijing, 100101, China.

A novel bacterial strain, CH91, was isolated from a high-temperature oil reservoir. Morphological characterization, phylogenetic analyses of 16S rRNA gene sequence and genome relatedness indicated that the strain is a potential new species in the genus Rhodococcus. Strain CH91 could grow in the temperature range of 25-50 °C (optimally at 37 °C) and utilize a broad range of long-chain n-alkanes from hexadecane to hexatriacontane. The utilization of the n-alkanes mixture of strain CH91 revealed that the degradation rate was correlated to the length of the carbon chain. Two novel alkB genes encoding alkane 1-monooxygenase were found in the genome of this strain. The protein sequences of both alkane 1-monooxygenases showed a remarkable phylogenetic distance to other reported AlkB protein sequences. These results would help broaden our knowledge about alkane degradation by Rhodocuccus and its potential ecological role. The ability of the strain in the long-chain alkane degradation and thermal tolerance could also be further exploited for bioremediation of oil contaminations and microbial enhanced oil recovery.
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http://dx.doi.org/10.1007/s00203-022-02872-3DOI Listing
April 2022

Development and Validation of a Nomogram for Predicting Postoperative Distant Metastasis in Patients with Cervical Cancer.

Med Sci Monit 2022 Apr 12;28:e933379. Epub 2022 Apr 12.

Department of Gynaecology, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, Guangdong, China (mainland).

BACKGROUND Cervical cancer is the fourth most commonly diagnosed malignant neoplasm among women worldwide. Despite improvements in treatment, the rate of postoperative metastasis remains a problem. Nomograms have been used to predict risk of tumor metastasis. We designed a nomogram to predict postoperative distant metastasis among cervical cancer patients, based on the SEER database, and estimated the performance of the nomogram by internal and external validations. MATERIAL AND METHODS We included 6421 participants and divided them into training (n=4495) and testing (n=1926) sets. Multivariate logistic regression was used to explore predictors. The nomogram's predictive value was assessed by internal (testing set) and external (561 Chinese patients) validations. The receiver operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) value was calculated to evaluate the nomogram's discrimination. The nomogram's calibration was assessed via the Hosmer-Lemeshow test and calibration curve. RESULTS Histologic type, T stage, treatment, tumor size, and positive lymph node were identified as independent predictors of postoperative distant metastasis in surgical patients (P<0.05). The developed nomogram had an AUC of 0.866 (95% CI: 0.844 to 0.888). The AUC and the chi-square for the Hosmer-Lemeshow test of the nomogram were 0.847 (95% CI: 0.807 to 0.888) and 11.292, respectively, (P>0.05) in the internal validation, and were 0.626 (95% CI: 0.548 to 0.704) and 316.53, respectively, (P<0.05) in the external validation. CONCLUSIONS Our nomogram showed a good predictive performance for postoperative distant metastasis in cervical cancer patients based on the SEER database. It remains to be determined if it is applicable to other populations.
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http://dx.doi.org/10.12659/MSM.933379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014871PMC
April 2022

The Effect of Timing of Mandibular Distraction Osteogenesis on Weight Velocity in Infants Affected by Severe Robin Sequence.

Children (Basel) 2022 Feb 28;9(3). Epub 2022 Feb 28.

Department of Rehabilitation Medicine, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.

Background: Impaired weight gain is prevalent in Robin Sequence (RS) newborns. Although mandibular distraction osteogenesis (MDO) has been proven to improve oral feeding, its impact on postoperative weight gain remains unclear. The purpose of this study is to explore whether MDO can help RS babies reach a normal weight, as well as the effect of MDO timing on weight velocity.

Methods: One hundred infants with severe RS and one hundred with normal controls met the inclusion criteria for the study. Included patients underwent MDO. Weights at different timing points were recorded and analyzed and compared to normal controls.

Results: After the distractor removal weights of patients undergoing MDO at <1 month and 1-2 months were close to the normal control (6.81 ± 0.93 kg versus 7.18 ± 0.61 kg, = 0.012, and 6.82 ± 0.98 kg versus 7.37 ± 0.75 kg, = 0.033, respectively), the weights of patients undergoing MDO at 2-3 months and 3-4 months still lagged behind (7.56 ± 1.29 kg versus 8.20 ± 0.61 kg, = 0.000206 and 7.36 ± 1.05 kg versus 8.25 ± 0.77 kg, = 0.004, respectively). The weights of all RS infants undergoing MDO showed no significant difference compared to the controls when they aged to 1 year (9.34 ± 0.99 kg versus 9.55 ± 0.45 kg, = 0.254 for MDO at <1 month; 9.12 ± 0.91 kg versus 9.33 ± 0.46 kg, = 0.100 for MDO at 1 to 2 months; 9.38 ± 0.29 kg versus 9.83 ± 0.53 kg, = 0.098 for MDO at 2 to 3 months; and 9.38 ± 0.29 kg versus 9.83 ± 0.53 kg, = 0.098 for MDO at 3 to 4 months).

Conclusion: The MDO procedure helped patients with severe RS to reach a normal weight; and MDO intervention was recommended at an early stage for early weight gain.
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http://dx.doi.org/10.3390/children9030319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8947281PMC
February 2022

Improving the treatment of Parkinson's disease: Structure-based development of novel 5-HT receptor antagonists/inverse agonists.

Eur J Med Chem 2022 Apr 2;234:114246. Epub 2022 Mar 2.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China. Electronic address:

Pimavanserin is a selective 5-HT receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7-1∼7-37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7-16 exhibited 50-fold higher 5-HT receptor antagonist activity (IC = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC = 2.1 vs 50 nM) than pimavanserin. Moreover, 7-16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7-16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7-16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.
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http://dx.doi.org/10.1016/j.ejmech.2022.114246DOI Listing
April 2022

The anterior cingulate cortex directly enhances auditory cortical responses in air-puffing-facilitated flight behavior.

Cell Rep 2022 03;38(10):110506

Department of Neuroscience, City University of Hong Kong, Kowloon Tong, 0000 Hong Kong SAR, P.R. China; City University of Hong Kong Shenzhen Research Institute, Shenzhen 518507, P.R. China. Electronic address:

For survival, animals encode prominent events in complex environments, which modulates their defense behavior. Here, we design a paradigm that assesses how a mild aversive cue (i.e., mild air puff) interacts with sound-evoked flight behavior in mice. We find that air puffing facilitates sound-evoked flight behavior by enhancing the auditory responses of auditory cortical neurons. We then find that the anterior part of the anterior cingulate cortex (ACC) encodes the valence of air puffing and modulates the auditory cortex through anatomical examination, physiological recordings, and optogenetic/chemogenetic manipulations. Activating ACC projections to the auditory cortex simulates the facilitating effect of air puffing, whereas inhibiting the ACC or its projections to the auditory cortex neutralizes this facilitating effect. These findings show that the ACC regulates sound-evoked flight behavior by potentiating neuronal responses in the auditory cortex.
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http://dx.doi.org/10.1016/j.celrep.2022.110506DOI Listing
March 2022

Carboxymethyl chitin or chitosan for osteoinduction effect on the human periodontal ligament stem cells.

Dent Mater J 2022 May 4;41(3):392-401. Epub 2022 Mar 4.

Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration.

Human periodontal ligament stem cells (hPDLSCs) are seeding cells for tissue-engineered treatment of alveolar bone regeneration. To elucidate carboxymethyl chitosan (CMCTS) and carboxymethyl chitin (CMCT) effect on osteogenic differentiation, hPDLSCs were isolated and treated with CMCTS or CMCT. Cell viability and multiplication capacity were measured. The expression of classic osteogenic related molecules, including Alkaline Phosphatase (ALP), Phosphoprotein 1 (OPN), RUNX family transcription factor 2 (Runx2) and Osteocalcin (OCN), were determined. Mineralization levels were detected by Alizarin Red staining. Results showed that both CMCTS and CMCT treatment had the maximal promoting ability for hPDLSCs viability below the concentration of 100 μg/mL, while CMCTS improved hPDLSCs mineralization significantly. CMCTS induced multiple-factor high expression, including ALP, Runx2, OPN and OCN, whereas slightly osteoinductive bioactivity of CMCT was mainly due to ALP. Therefore, CMCTS had a more significant advantage for osteoinductive differentiation of hPDLSCs than CMCT, which may be a promising material for periodontal regeneration.
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http://dx.doi.org/10.4012/dmj.2021-250DOI Listing
May 2022

Adsorption of Cu by UV aged polystyrene in aqueous solution.

Ecotoxicol Environ Saf 2022 Mar 10;232:113292. Epub 2022 Feb 10.

College of Environmental Sciences, Sichuan Agricultural University, 211 Huimin Road, Chengdu 611130, China. Electronic address:

Microplastics are the critical carriers of heavy metals in the environment. Thus, investigating the adsorption mechanisms between the microplastics and heavy metals is helpful to understand the migration and transformation pattern of the heavy metals in the environment. The adsorption of microplastics towards heavy metals can be largely affected by natural aging (e.g., UV-aging), environmental pH, and salinity. In this study, the adsorption of polystyrene (PS) towards Cu and the effects of UV-aging, environment pH, and salinity on the adsorption were systematically investigated. The results show that the adsorption capacity of PS towards Cu increased with the UV-aging time, as UV-aging increased the microcracks and oxygen-containing functional groups on the surface of the PS. Adsorption kinetics data followed the pseudo-second-order model, indicating that the interaction between PS and Cu is chemical adsorption. Adsorption isotherms data could be well-described by both the Langmuir and Freundlich models, indicating that the adsorption was multilayer adsorption. As the solution pH and salinity can influence the surface charge of the PS, they could also affect the performance of the PS on Cu adsorption. High pH facilitated the adsorption of PS towards Cu, while high salinity (above 1‰) inhibited the adsorption.
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http://dx.doi.org/10.1016/j.ecoenv.2022.113292DOI Listing
March 2022

Exosomes derived from the blood of patients with sepsis regulate apoptosis and aerobic glycolysis in human myocardial cells via the hsa‑miR‑1262/SLC2A1 signaling pathway.

Mol Med Rep 2022 04 9;25(4). Epub 2022 Feb 9.

Trauma Emergency Center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China.

Myocardial injury occurs in the majority of patients with sepsis and is associated with early mortality. MicroRNAs (miRs) transported by exosomes have been implicated in numerous diseases, such as tumors, acute myocardial infarction and cardiovascular disease. Human serum albumin (hsa)‑miR‑1262 has been shown to serve a role in sepsis; however, its role in exosomes isolated from patients with sepsis and septic myocardial injury remains unclear. In the present study, serum exosomes were isolated via ultracentrifugation. Solute carrier family 2 member 1 (SLC2A1), an essential mediator in energy metabolism, was silenced and overexpressed in the human myocardial AC16 cell line using lentiviral plasmids containing either SLC2A1‑targeting short interfering RNAs or SLC2A1 cDNA, respectively. Cell apoptosis was analyzed using flow cytometry, and the extracellular acidification rate and oxygen consumption rate of AC16 cells were determined using an XFe24 Extracellular Flux Analyzer. Furthermore, the dual‑luciferase reporter assay was used to evaluate the interaction between hsa‑miR‑1262 and SLC2A1. Finally, reverse transcription‑quantitative PCR and western blotting were used to evaluate gene and protein expression levels, respectively. Exosomes isolated from the blood of patients with sepsis (Sepsis‑exo) markedly reduced aerobic glycolysis activity, but significantly promoted the apoptosis of human AC16 cells in a time‑dependent manner. Moreover, Sepsis‑exo significantly increased hsa‑miR‑1262 expression levels, but significantly decreased SLC2A1 mRNA expression levels in a time‑dependent manner. Bioinformatics analysis indicated that hsa‑miR‑1262 bound to the 3' untranslated region of SLC2A1 to negatively regulate its expression. The silencing of SLC2A1 promoted apoptosis and suppressed glycolysis in AC16 cells, whereas SLC2A1 overexpression resulted in the opposite effects. Therefore, the present study demonstrated that exosomes derived from patients with sepsis may inhibit glycolysis and promote the apoptosis of human myocardial cells through exosomal hsa‑miR‑1262 via its target SLC2A1. These findings highlighted the importance of the hsa‑miR‑1262/SLC2A1 signaling pathway in septic myocardial injury and provided novel insights into therapeutic strategies for septic myocardial depression.
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http://dx.doi.org/10.3892/mmr.2022.12635DOI Listing
April 2022

Development of a CAFs-related gene signature to predict survival and drug response in bladder cancer.

Hum Cell 2022 Mar 19;35(2):649-664. Epub 2022 Jan 19.

Department of Urology, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao, 266000, China.

As one of important components of tumor microenvironment, CAFs (cancer-associated fibroblasts) play a vital role in the development and metastasis of bladder cancer. The present study aimed to develop a CAFs-related gene signature to predict the prognosis of patients and the response to chemotherapy and immunotherapy based on research of multidatabase. Expression data and clinical information were obtained from TCGA and GEO databases. Different bioinformatic and statistical methods were combined to construct the robust CAFs-related gene signature for prognosis. The model was explored from four aspects: single-cell source, immune infiltration, correlation with cancer-related genes and pathways, and prediction of drug response. After screening, five genes (BNC2, LAMA2, MFAP5, NID1, and OLFML1) related to CAFs were used for constructing the signature to divide patients into high- and low-risk groups. Patients in low-risk group had better prognosis and multidatabase analysis confirmed the predictive value. The five genes were mainly expressed by fibroblasts and involved in regulation of pathways related with glycolysis, hypoxia, and epithelial-mesenchymal transition (EMT). BNC2, LAMA2, and NID1 were strongly associated with drug sensitivity. Moreover, the immunological status was different between high- and low-risk groups. High-risk patients had poor response to chemotherapy or immunotherapy. The CAFs-related gene signature might help to optimize risk stratification and provide a new insight in individual treatment for bladder cancer.
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http://dx.doi.org/10.1007/s13577-022-00673-wDOI Listing
March 2022

Chronic Intermittent Hypoxia Regulates CaMKII-Dependent MAPK Signaling to Promote the Initiation of Abdominal Aortic Aneurysm.

Oxid Med Cell Longev 2021 21;2021:2502324. Epub 2021 Dec 21.

Department of Respiration, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.

Obstructive sleep apnea (OSA) is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, the effects of OSA on AAA initiation in a murine model of sleep apnea have not been completely studied. In this paper, Apoe C57BL/6 mice infused with angiotensin II (Ang II) were placed in chronic intermittent hypoxia (CIH) condition for inducing OSA-related AAA. CIH significantly promoted the incidence of AAA and inhibited the survival of mice. By performing ultrasonography and elastic Van Gieson staining, CIH was found to be effective in promoting aortic dilation and elastin degradation. Immunohistochemical and zymography results show that CIH upregulated the expression and activity of MMP2 and MMP9 and upregulated MCP1 expression while downregulating -SMA expression. Also, CIH exposure promoted ROS generation, apoptosis, and mitochondria damage in vascular smooth muscle cells (VSMCs), which were measured by ROS assay, TUNEL staining, and transmission electron microscopy. The result of RNA sequencing of mouse aortas displayed that 232 mRNAs were differently expressed between Ang II and Ang II+CIH groups, and CaMKII-dependent p38/Jnk was confirmed as one downstream signaling of CIH. CaMKII-IN-1, an inhibitor of CaMKII, eliminated the effects of CIH on the loss of primary VSMCs. To conclude, a mouse model of OSA-related AAA, which contains the phenotypes of both AAA and OSA, was established in this study. We suggested CIH as a risk factor of AAA initiation through CaMKII-dependent MAPK signaling.
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http://dx.doi.org/10.1155/2021/2502324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714336PMC
March 2022

(+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia.

Front Pharmacol 2021 7;12:770377. Epub 2021 Dec 7.

School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China.

Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired -13e [(+)-13e] and -13e [(-)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using and models (+)-13e displayed high affinity for VMAT2 (K = 1.48 nM) and strongly inhibited [H]DA uptake (IC = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. , (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.
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http://dx.doi.org/10.3389/fphar.2021.770377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689140PMC
December 2021

Noradrenergic terminal short-term potentiation enables modality-selective integration of sensory input and vigilance state.

Sci Adv 2021 Dec 17;7(51):eabk1378. Epub 2021 Dec 17.

Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Recent years have seen compelling demonstrations of the importance of behavioral state on sensory processing and attention. Arousal plays a dominant role in controlling brain-wide neural activity patterns, particularly through modulation by norepinephrine. Noradrenergic brainstem nuclei, including locus coeruleus, can be activated by stimuli of multiple sensory modalities and broadcast modulatory signals via axonal projections throughout the brain. This organization might suggest proportional brain-wide norepinephrine release during states of heightened vigilance. Here, however, we have found that low-intensity, nonarousing visual stimuli enhanced vigilance-dependent noradrenergic signaling locally in visual cortex, revealed using dual-site fiber photometry to monitor noradrenergic Ca responses of astroglia simultaneously in cerebellum and visual cortex and two-photon microscopy to monitor noradrenergic axonal terminal Ca dynamics. Nitric oxide, following -methyl--aspartate receptor activation in neuronal nitric oxide synthase-positive interneurons, mediated transient acceleration of norepinephrine-dependent astroglia Ca activation. These findings reveal a candidate cortical microcircuit for sensory modality-selective modulation of attention.
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http://dx.doi.org/10.1126/sciadv.abk1378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8682997PMC
December 2021

Immunosuppression Induced by Glutamine Deprivation Occurs Activating PD-L1 Transcription in Bladder Cancer.

Front Mol Biosci 2021 5;8:687305. Epub 2021 Nov 5.

Key Laboratory, Department of Urology and Andrology, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China.

Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation and . PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.
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http://dx.doi.org/10.3389/fmolb.2021.687305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602840PMC
November 2021

Metallothionein 1: A New Spotlight on Inflammatory Diseases.

Front Immunol 2021 5;12:739918. Epub 2021 Nov 5.

Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China.

MT1 has been demonstrated to be an essential stress protein in maintaining physiological balance and regulating immune homeostasis. While the immunological involvement of MT1 in central nervous system disorders and cancer has been extensively investigated, mounting evidence suggests that MT1 has a broader role in inflammatory diseases and can shape innate and adaptive immunity. In this review, we will first summarize the biological features of MT1 and the regulators that influence MT1 expression, emphasizing metal, inflammation, and immunosuppressive factors. We will then focus on the immunoregulatory function of MT1 on diverse immune cells and the signaling pathways regulated by MT1. Finally, we will discuss recent advances in our knowledge of the biological role of MT1 in several inflammatory diseases to develop novel therapeutic strategies.
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http://dx.doi.org/10.3389/fimmu.2021.739918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602684PMC
December 2021

Overwintering honeybees maintained dynamic and stable intestinal bacteria.

Sci Rep 2021 11 15;11(1):22233. Epub 2021 Nov 15.

College of Plant Protection, Anhui Agricultural University, Hefei, Anhui Province, China.

Honeybee is an important pollinator for maintaining ecological balance. However, scientist found the bizarre mass death of bees in winter. Meanwhile, some reported that the differences composed of intestinal bacteria between healthy honeybees and CCD honeybees. It is essential that explored dynamic changes to the intestinal bacteria in overwintering honeybees. We collected bee samples before overwintering, during prophase of overwintering, metaphase of overwintering, anaphase of overwintering, telophase of overwintering, and after overwintering. By using high-throughput sequencing targeting the V3-V4 regions of the 16S rDNA, the abundance of the intestinal bacteria were analyzed in overwintering honeybees. A total of 1,373,886 high-quality sequences were acquired and Proteobacteria (85.69%), Firmicutes (10.40%), Actinobacteria (3.66%), and Cyanobacteria (1.87%) were identified as major components of the intestinal bacteria. All core honeybee intestinal bacteria genera, such as Gilliamella, Bartonella, Snodgrassella, Lactobacillus, Frischella, Commensalibacter, and Bifidobacterium were detected. The abundance of Actinobacteria, Bartonella, and Bifidobacterium increased initially and then decreased in winter honeybees. There were no significant differences in the richness and evenness of the microbiota in overwintering honeybees; however, there was a statistically significant difference in the beta diversity of the intestinal bacteria after overwintering compared with that in other groups. Our results suggested that honeybees maintained their intestinal ecosystem balance, and increased the abundance of gut probiotics in response to environmental and nutrition pressures in winter.
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http://dx.doi.org/10.1038/s41598-021-01204-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593070PMC
November 2021

Deviation Analyses of Computer-Assisted, Template-Guided Mandibular Reconstruction With Combined Osteotomy and Reconstruction Pre-Shaped Plate Position Technology: A Comparative Study.

Front Oncol 2021 27;11:719466. Epub 2021 Oct 27.

Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China.

Background: Computer-assisted and template-guided mandibular reconstruction provides higher accuracy and less variation than conventional freehand surgeries. The combined osteotomy and reconstruction pre-shaped plate position (CORPPP) technique is a reliable choice for mandibular reconstruction. This study aimed to evaluate the accuracy of CORPPP-guided fibular flap mandibular reconstruction and analyze the possible causes of the deviations.

Patients And Methods: From June 2015 to December 2016, 28 patients underwent fibular flap mandibular reconstruction. Virtual planning and personalized CORPPP-guided templates were applied in 15 patients while 13 patients received conventional freehand surgeries. Deviations during mandibulectomy and fibular osteotomy, and overall and triaxial deviation of the corresponding mandibular anatomical landmarks were measured by superimposing the pre- and postoperative virtual models.

Results: The deviation of the resection line and resection angle was 1.23 ± 0.98 mm and 4.11° ± 2.60°. The actual length of fibula segments was longer than the designed length in 7 cases (mean: 0.35 ± 0.32 mm) and shorter in 22 cases (mean: 1.53 ± 1.19 mm). In patients without ramus reconstruction, deviations of the ipsilateral condylar head point (Co.), gonion point (Go.), and coracoid process point (Cor.) were 6.71 ± 3.42 mm, 5.38 ± 1.71 mm, and 11.05 ± 3.24 mm in the freehand group and 1.73 ± 1.13 mm, 1.86 ± 0.96 mm, and 2.54 ± 0.50 mm in the CORPPP group, respectively, with significant statistical differences ( < 0.05). In patients with ramus reconstruction, deviations of ipsilateral Co. and Go. were 9.79 ± 4.74 mm . 3.57 ± 1.62 mm ( < 0.05), and 15.17 ± 6.53 mm . 4.36 ± 1.68 mm ( < 0.05) in the freehand group and CORPPP group, respectively.

Conclusion: Mandibular reconstructions employing virtual planning and personalized CORPPP-guided templates show significantly higher predictability, convenience, and accuracy of mandibular reconstruction compared with conventional freehand surgeries. However, more clinical cases were required for further dimensional deviation analysis. The application and exploration of clinical practice would also continuously improve the design of templates.
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http://dx.doi.org/10.3389/fonc.2021.719466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579124PMC
October 2021

hsa-MiR-19a-3p and hsa-MiR-19b-3p Are Associated with Spinal Cord Injury-Induced Neuropathic Pain: Findings from a Genome-Wide MicroRNA Expression Profiling Screen.

Neurotrauma Rep 2021 14;2(1):424-439. Epub 2021 Sep 14.

Department of Rehabilitation Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.

Neuropathic pain in spinal cord injury (SCI) is associated with inflammation in both the peripheral and central nervous system (CNS), which may contribute to the initiation and maintenance of persistent pain. An understanding of factors contributing to neuroinflammation may lead to new therapeutic targets for neuropathic pain. Moreover, novel circulating biomarkers of neuropathic pain may facilitate earlier and more effective treatment. MicroRNAs (miRNAs) are short, non-coding single-stranded RNA that have emerged as important biomarkers and molecular mediators in physiological and pathological conditions. Using a genome-wide miRNA screening approach, we studied differential miRNA expression in plasma from 68 healthy, community-dwelling adults with and without SCI enrolled in ongoing clinical studies. We detected 2367 distinct miRNAs. Of these, 383 miRNAs were differentially expressed in acute SCI or chronic SCI versus no SCI and 71 were differentially expressed in chronic neuropathic pain versus no neuropathic pain. We selected homo sapiens (hsa)-miR-19a-3p and hsa-miR-19b-3p for additional analysis based on -value, fold change, and their known role as regulators of neuropathic pain and neuroinflammation. Both hsa-miR-19a-3p and hsa-miR-19b-3p levels were significantly higher in those with chronic SCI and severe neuropathic pain versus those with chronic SCI and no neuropathic pain. In confirmatory studies, both hsa-miR-19a-3p and hsa-miR-19b-3p have moderate to strong discriminative ability to distinguish between those with and without pain. After adjusting for opioid use, hsa-miR-19b-3p levels were positively associated with pain interference with mood. Because hsa-miR-19 levels have been shown to change in response to exercise, folic acid, and resveratrol, these studies suggest that miRNAs are potential targets of therapeutic interventions.
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http://dx.doi.org/10.1089/neur.2021.0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570675PMC
September 2021

Spatial heterogeneity of immune infiltration predicts the prognosis of nasopharyngeal carcinoma patients.

Oncoimmunology 2021 27;10(1):1976439. Epub 2021 Oct 27.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, P.R, China.

Spatial information on the tumor immune microenvironment is of clinical relevance. Here, we aimed to quantify the spatial heterogeneity of lymphocytes and cancer cells and evaluated its prognostic value in patients with nasopharyngeal carcinoma (NPC). The scanned immunohistochemistry images of 336 NPC patients from two different hospitals were used to generate cell density maps for tumor and immune cells. Then, Getis-Ord hotspot analysis, a spatial statistic method used to describe species biodiversity in ecological habitats, was applied to identify cancer, immune, and immune-cancer hotspots. The results showed that cancer hotspots were not associated with any of the studied clinical outcomes, while immune-cancer hotspots predicted worse overall survival (OS) in the training cohort. In contrast, a high immune hotspot score was significantly associated with better OS (HR 0.41, 95% CI 0.22-0.77, = .006), disease-free survival (DFS) (HR 0.43, 95% CI 0.24-0.75, = .003) and distant metastasis-free survival (DMFS) (HR 0.40, 95% CI 0.20-0.81, = .011) in NPC patients in the training cohort, and similar associations were also evident in the validation cohort. Importantly, multivariate analysis revealed that the immune hotspot score remained an independent prognostic indicator for OS, DFS, and DMFS in both cohorts. We explored the spatial heterogeneity of cancer cells and lymphocytes in the tumor microenvironment of NPC patients using digital pathology and ecological analysis methods and further constructed three spatial scores. Our study demonstrates that spatial variation may aid in the identification of the clinical prognosis of NPC patients, but further investigation is needed.
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http://dx.doi.org/10.1080/2162402X.2021.1976439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555536PMC
January 2022

Interferon-λ Improves the Efficacy of Intranasally or Rectally Administered Influenza Subunit Vaccines by a Thymic Stromal Lymphopoietin-Dependent Mechanism.

Front Immunol 2021 29;12:749325. Epub 2021 Sep 29.

Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany.

Previous work showed that interferon-λ (IFN-λ) can trigger the synthesis of thymic stromal lymphopoietin (TSLP) by specialized epithelial cells in the upper airways of mice, thereby improving the performance of intranasally administered influenza vaccines. Here we demonstrate that protein-only influenza vaccines containing either IFN-λ or TSLP boosted antigen-specific IgG1 and IgA responses and enhanced the resistance of mice to influenza virus challenge, irrespective of whether the vaccines were applied the intranasal or the rectal route. TSLP receptor deficiency negatively influenced vaccine-induced antiviral immunity by impairing the migration of dendritic cells from the airways to the draining lymph nodes of immunized mice, thereby restraining follicular helper T cell and germinal center B cell responses. As previously observed during intranasal vaccination, the adjuvant effect of IFN-λ on a rectally administered influenza vaccine was no longer observed when TSLP receptor-deficient mice were used for immunization, highlighting the central role of the IFN-λ/TSLP axis for vaccine-induced antiviral immunity in the mucosa.
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http://dx.doi.org/10.3389/fimmu.2021.749325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511795PMC
January 2022

Age and Behavior-Dependent Differential miRNAs Expression in the Hypopharyngeal Glands of Honeybees ( L.).

Insects 2021 Aug 26;12(9). Epub 2021 Aug 26.

School of Plant Protection, Anhui Agricultural University, Hefei 230036, China.

This study aims to investigate the expression differences of miRNAs in the hypopharyngeal glands (HPGs) of honeybees at three developmental stages and to explore their regulation functions in the HPGs development. Small RNA sequencing was employed to analyze the miRNA profiles of HPGs in newly-emerged bees (NEB), nurse bees (NB), and forager bees (FB). Results showed that a total of 153 known miRNAs were found in the three stages, and ame-miR-276-3p, ame-miR-375-3p, ame-miR-14-3p, ame-miR-275-3p, and ame-miR-3477-5p were the top five most abundant ones. Furthermore, the expression of 11 miRNAs, 17 miRNAs, and 18 miRNAs were significantly different in NB vs. FB comparison, NB vs. NEB comparison, and in FB vs. NEB comparison, respectively, of which ame-miR-184-3p and ame-miR-252a-5p were downregulated in NB compared with that in both the FB and NEB, while ame-miR-11-3p, ame-miR-281-3p, and ame-miR-31a-5p had lower expression levels in FB compared with that in both the NB and NEB. Bioinformatic analysis showed that the potential target genes of the differentially expressed miRNAs (DEMs) were mainly enriched in several key signaling pathways, including mTOR signaling pathway, MAPK signaling pathway-fly, FoxO signaling pathway, Hippo signaling pathway-fly. Overall, our study characterized the miRNA profiles in the HPGs of honeybees at three different developmental stages and provided a basis for further study of the roles of miRNAs in HPGs development.
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http://dx.doi.org/10.3390/insects12090764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466209PMC
August 2021

Reservoir quality and its controlling diagenetic factors in the Bentiu Formation, Northeastern Muglad Basin, Sudan.

Sci Rep 2021 09 16;11(1):18442. Epub 2021 Sep 16.

School of Earth Sciences, Northeast Petroleum University, Daqing, 163318, China.

The Abu Gabra and Bentiu formations are widely distributed within the interior Muglad Basin. Recently, much attention has been paid to study, evaluate and characterize the Abu Gabra Formation as a proven reservoir in Muglad Basin. However, few studies have been documented on the Bentiu Formation which is the main oil/gas reservoir within the basin. Therefore, 33 core samples of the Great Moga and Keyi oilfields (NE Muglad Basin) were selected to characterize the Bentiu Formation reservoir using sedimentological and petrophysical analyses. The aim of the study is to de-risk exploration activities and improve success rate. Compositional and textural analyses revealed two main facies groups: coarse to-medium grained sandstone (braided channel deposits) and fine grained sandstone (floodplain and crevasse splay channel deposits). The coarse to-medium grained sandstone has porosity and permeability values within the range of 19.6% to 32.0% and 1825.6 mD to 8358.0 mD respectively. On the other hand, the fine grained clay-rich facies displays poor reservoir quality as indicated by porosity and permeability ranging from 1.0 to 6.0% and 2.5 to 10.0 mD respectively. A number of varied processes were identified controlling the reservoir quality of the studies samples. Porosity and permeability were enhanced by the dissolution of feldspars and micas, while presence of detrital clays, kaolinite precipitation, iron oxides precipitation, siderite, quartz overgrowths and pyrite cement played negative role on the reservoir quality. Intensity of the observed quartz overgrowth increases with burial depth. At great depths, a variability in grain contact types are recorded suggesting conditions of moderate to-high compactions. Furthermore, scanning electron microscopy revealed presence of micropores which have the tendency of affecting the fluid flow properties in the Bentiu Formation sandstone. These evidences indicate that the Bentiu Formation petroleum reservoir quality is primarily inhibited by grain size, total clay content, compaction and cementation. Thus, special attention should be paid to these inhibiting factors to reduce risk in petroleum exploration within the area.
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http://dx.doi.org/10.1038/s41598-021-97994-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446010PMC
September 2021

PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes.

Genes Dis 2021 Nov 23;8(6):891-906. Epub 2020 Dec 23.

Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders National Clinical Research Center for Child Health and Disorders (Chongqing) China International Science and Technology Cooperation Base of Child Development and Critical Disorders Children's Hospital of Chongqing Medical University, Chongqing, 400000, PR China.

Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are readily available, robustly reproducible, and physiologically appropriate human cells for clinical applications and research in the cardiovascular field, hiPSC-CMs cultured retain an immature metabolic phenotype that limits their application, and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells (hiPSCs ) differentiation into cardiomyocytes. In this study, we found that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation (OXPHOS) during the cardiac differentiation of hiPSCs. Knocking down PGC-1α by siRNA impaired mitochondrial respiration, while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSC-CMs. Furthermore, we found that estrogen-related receptor α (ERRα) was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs. These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.
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http://dx.doi.org/10.1016/j.gendis.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427271PMC
November 2021

Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network.

Cancers (Basel) 2021 Aug 23;13(16). Epub 2021 Aug 23.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL.
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http://dx.doi.org/10.3390/cancers13164234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394654PMC
August 2021
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