Publications by authors named "Liyang Wang"

72 Publications

Decreased CXCR2 expression on circulating monocytes of colorectal cancer impairs recruitment and induces Re-education of tumor-associated macrophages.

Cancer Lett 2022 Jan 6;529:112-125. Epub 2022 Jan 6.

Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, PR China. Electronic address:

Though circulating monocytes are the main source of tumour-associated macrophages (TAMs), the regulatory mechanisms of their recruitment to tumours and further differentiation remain unclear. In the present study, we observed a significant decrease in CXCR2 expression in classical circulating monocytes of patients with colorectal cancer (CRC), particularly those in the late TNM stage. The percentage of CXCR2 monocytes was negatively associated with systemic inflammatory markers and positively associated with intratumoural immunocyte infiltration. The pro-inflammatory cytokine IFN-γ, which was overexpressed in patients with CRC, down-regulated CXCR2 expression of monocytes/TAMs by promoting GRK-2 expression. In vitro, inhibition of CXCR2 signalling in monocytes led to impaired chemotaxis to the tumour cell line supernatant and lower responsiveness to lipopolysaccharide (LPS) stimulation. Finally, monocytes from patients with CRC with decreased CXCR2 expression showed distinct phenotypes and functions after differentiating into CRC cell line-educated TAMs, including expression of co-stimulatory factors and secretion profile, than those from healthy controls. GRK-2 inhibitor altered the functional characteristics of TAMs. In summary, our findings suggest that CXCR2 expression on circulating monocytes reflects CRC stages and is an important factor determining TAM composition in the tumour microenvironment.
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http://dx.doi.org/10.1016/j.canlet.2022.01.004DOI Listing
January 2022

Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma.

Bioengineered 2021 12;12(2):12598-12611

Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China.

Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both and . In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.
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http://dx.doi.org/10.1080/21655979.2021.2010393DOI Listing
December 2021

Androgen receptor and MYC equilibration centralizes on developmental super-enhancer.

Nat Commun 2021 12 15;12(1):7308. Epub 2021 Dec 15.

Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.

Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. Here, we show that this repression is independent of AR chromatin binding and driven by coactivator redistribution, and through chromatin conformation capture methods show disruption of the interaction between the MYC super-enhancer within the PCAT1 gene and the MYC promoter. Conversely, androgen deprivation in vitro and in vivo increases MYC expression. In parallel, global AR activity is suppressed by MYC overexpression, consistent with coactivator redistribution. These suppressive effects of AR and MYC are mitigated at shared AR/MYC binding sites, which also have markedly higher levels of H3K27 acetylation, indicating enrichment for functional enhancers. These findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.
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http://dx.doi.org/10.1038/s41467-021-27077-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674345PMC
December 2021

Electrospun nanoyarn and exosomes of adipose-derived stem cells for urethral regeneration: Evaluations in vitro and in vivo.

Colloids Surf B Biointerfaces 2022 Jan 15;209(Pt 2):112218. Epub 2021 Nov 15.

The Department of Urology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China; Shanghai Eastern Institute of Urologic Reconstruction, Shanghai 200233, China. Electronic address:

Regeneration of urethral defects has been difficult in the clinic. To address it, the collagen/ poly (L-lactide-co-caprolactone) (P(LLA-CL)) nanoyarn scaffold delivering adipose-derived stem cells' exosomes (ADSC-exos) was fabricated. The multipotential differentiation potential of ADSCs were confirmed by Adipogenic, osteogenic, and chondrogenic differentiation. The 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide assay shows that 50% concentration of ADSC-exos nanoyarn scaffold dramatically enhanced the cell viability of fibroblasts. The ADSC-exos nanoyarn scaffold for human foreskin fibroblasts (HFFs) and human urethral scar fibroblasts (HSFs) shows good biocompatibility: theproduction of inflammatory factors IL-6 and Col 1A1 was less, indicating that ADSC-exos had the minimal inflammatory effect of cells. Besides, the cells on the ADSC-exos nanoyarn scaffold did not appear to contribute to DNA damage in the same way as the normal cell's growth did. The HFFs seeding on the ADSC-exos nanoyarn scaffold shows a typical morphology of extending outwards. Urethral repair with ADSC-exos nanoyarn scaffold did not lead to either a sign of urethral stricture or scar formation after 4 weeks post-surgery. The deposition of collagen was less and the epithelial cells formed multiple layer epithelium. The treatment of ADSC-exos stimulated epithelization and vascularization. And the transition from an inflammatory state to a regenerative state was promoted. The ADSC-exos-treated group did not promote the over-proliferation of fibroblasts and the expression of Collagen I. Therefore, the ADSC-exos nanoyarn scaffold has evident, positive effects on wound healing and tissue fibrosis inhibition.
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http://dx.doi.org/10.1016/j.colsurfb.2021.112218DOI Listing
January 2022

Long non-coding RNA ANRIL mitigates neonatal hypoxic-ischemic brain damage via targeting the miR-378b/ATG3 axis.

Am J Transl Res 2021 15;13(10):11585-11596. Epub 2021 Oct 15.

Department of Epidemiology and Biostatistics, School of Public Health, Jiamusi University Jiamusi 154000, Heilongjiang, China.

Hypoxic-ischemic brain injury (HIBD) is the most common form of brain injury in newborns and is a major burden on society. However, the molecular mechanism of HIBD remains unclear. Long non-coding RNA (lncRNA) has been demonstrated to be a key regulator in brain development and numerous neurological diseases. The present study identified the role and underlying mechanism of lncRNA antisense non-coding RNA in the INK4 locus (ANRIL) in HIBD. The data indicated that ANRIL expression was significantly increased in hypoxia-stressed primary neurons and PC12 cells. Silencing ANRIL aggravated oxygen-glucose deprivation-induced cell injury. Mechanistically, microRNA (miR)-378b was predicted and confirmed as a direct target of ANRIL. A miR-378b inhibitor counteracted the effect of ANRIL on hypoxia-induced cell injury. Furthermore, ANRIL positively regulated autophagy related 3 (ATG3) expression and promoted autophagy through competitively binding to miR-378b. Overall, the present findings suggest that ANRIL exerts its protective effects via binding to miR-378b and upregulating ATG3 expression, suggesting the potential of ANRIL as a protective target for HIBD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581876PMC
October 2021

Heterogeneous nutrient supply promotes maize growth and phosphorus acquisition: additive and compensatory effects of lateral roots and root hairs.

Ann Bot 2021 09;128(4):431-440

Department of Plant Nutrition, College of Resources and Environmental Sciences, Center for Resources, Environment and Food Security, Key Laboratory of Plant-Soil Interactions, Ministry of Education, National Academy of Agriculture Green Development, China Agricultural University, Beijing 100193, PR China.

Background And Aims: Root proliferation is a response to a heterogeneous nutrient distribution. However, the growth of root hairs in response to heterogeneous nutrients and the relationship between root hairs and lateral roots remain unclear. This study aims to understand the effects of heterogeneous nutrients on root hair growth and the trade-off between root hairs and lateral roots in phosphorus (P) acquisition.

Methods: Near-isogenic maize lines, the B73 wild type (WT) and the rth3 root hairless mutant, were grown in rhizoboxes with uniform or localized supply of 40 (low) or 140 (high) mg P kg-1 soil.

Results: Both WT and rth3 had nearly two-fold greater shoot biomass and P content under local than uniform treatment at low P. Significant root proliferation was observed in both WT and rth3 in the nutrient patch, with the WT accompanied by an obvious increase (from 0.7 to 1.2 mm) in root hair length. The root response ratio of rth3 was greater than that of WT at low P, but could not completely compensate for the loss of root hairs. This suggests that plants enhanced P acquisition through complementarity between lateral roots and root hairs, and thus regulated nutrient foraging and shoot growth. The disappearance of WT and rth3 root response differences at high P indicated that the P application reduced the dependence of the plants on specific root traits to obtain nutrients.

Conclusions: In addition to root proliferation, the root response to a nutrient-rich patch was also accompanied by root hair elongation. The genotypes without root hairs increased their investment in lateral roots in a nutrient-rich patch to compensate for the absence of root hairs, suggesting that plants enhanced nutrient acquisition by regulating the trade-off of complementary root traits.
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http://dx.doi.org/10.1093/aob/mcab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414595PMC
September 2021

Androgen receptor splice variant 7 functions independently of the full length receptor in prostate cancer cells.

Cancer Lett 2021 10 10;519:172-184. Epub 2021 Jul 10.

Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA. Electronic address:

One mechanism for reactivation of androgen receptor (AR) activity after androgen deprivation therapy in castration-resistant prostate cancer (CRPC) is expression of splice variants such as ARv7 that delete the ligand binding domain and have constitutive activity. Exogenous overexpressed ARv7 can function as a homodimer or heterodimer with full length AR (ARfl), which is highly expressed with ARv7 in CRPC. However, the extent to which endogenous ARv7 function is dependent on heterodimerization with ARfl remains to be determined. We used double-crosslinking to stabilize AR complexes on chromatin in a CRPC cell line expressing endogenous ARfl and ARv7 (LN95 cells), and established that only trace levels of ARfl were associated with ARv7 on chromatin. Consistent with this result, depletion of ARfl with an AR degrader targeting the AR ligand binding domain did not decrease ARv7 binding to chromatin or its association with HOXB13, but did decrease overall AR transcriptional activity. Comparable results were obtained in CWR22RV1 cells, another CRPC cell line expressing ARfl and ARv7. These results indicate that ARv7 function in CRPC is not dependent on ARfl, and that both contribute independently to overall AR activity.
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http://dx.doi.org/10.1016/j.canlet.2021.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403646PMC
October 2021

An autonomous excavator system for material loading tasks.

Sci Robot 2021 06;6(55)

University of Maryland, College Park, MD 20742, USA.

Excavators are widely used for material handling applications in unstructured environments, including mining and construction. Operating excavators in a real-world environment can be challenging due to extreme conditions-such as rock sliding, ground collapse, or excessive dust-and can result in fatalities and injuries. Here, we present an autonomous excavator system (AES) for material loading tasks. Our system can handle different environments and uses an architecture that combines perception and planning. We fuse multimodal perception sensors, including LiDAR and cameras, along with advanced image enhancement, material and texture classification, and object detection algorithms. We also present hierarchical task and motion planning algorithms that combine learning-based techniques with optimization-based methods and are tightly integrated with the perception modules and the controller modules. We have evaluated AES performance on compact and standard excavators in many complex indoor and outdoor scenarios corresponding to material loading into dump trucks, waste material handling, rock capturing, pile removal, and trenching tasks. We demonstrate that our architecture improves the efficiency and autonomously handles different scenarios. AES has been deployed for real-world operations for long periods and can operate robustly in challenging scenarios. AES achieves 24 hours per intervention, i.e., the system can continuously operate for 24 hours without any human intervention. Moreover, the amount of material handled by AES per hour is closely equivalent to an experienced human operator.
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http://dx.doi.org/10.1126/scirobotics.abc3164DOI Listing
June 2021

Phosphorylation of the androgen receptor at Ser81 is co-sustained by CDK1 and CDK9 and leads to AR-mediated transactivation in prostate cancer.

Mol Oncol 2021 07 3;15(7):1901-1920. Epub 2021 May 3.

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Androgen receptor (AR) is the principal molecule in prostate cancer (PCa) etiology and therapy. AR re-activation still remains a major challenge during treatment of castration-resistant prostate cancer (CRPC) tumors that relapse after castration therapies. Recent reports have indicated the enrichment of Ser81-phosphorylated AR (pS81) in the nucleus of CRPC cells, and CDK1 and CDK9 as the kinases phosphorylating AR at S81. In the current study we showed that pS81 is preferentially localized in the nucleus in both rapid biopsy metastatic CRPC samples and PCa xenografts, and nuclear pS81 localization is correlated with AR transactivation in tumor xenografts. Chromatin immunoprecipitation (ChIP) analysis demonstrated an alignment of S81 phosphorylation and AR-mediated transactivation with the chromatin locus openness. Moreover, pS81-specific ChIP-Seq showed a disproportional occupancy of pS81 on AR-activated promoters, while 3C-ChIP assays further indicated an enrichment of pS81 at the PSA enhancer-promoter loop, a known AR activating hub. In the latter, CDK9 was shown to modulate the transactivation of the AR and RNA Pol II. Indeed, ChIP and re-ChIP assays also confirmed that AR-dependent activation of the PSA enhancer and promoter mediated by pS81 was coupled with activation of Pol II and the pTEFb complex. Mechanistically, we determined that CDK1 and CDK9 sustained the pS81 AR modification in the soluble and chromatin-bound fractions of PCa cells, respectively. Finally, we demonstrated that CDK1 activity was maintained throughout the cell cycle, and that CDK1 inhibitors restored androgen sensitivity in CRPC tumor cells. Based on these findings, CDK1 and CDK9 could be targeted as pS81 kinases in patients with CRPC, either alone or in conjunction with direct AR antagonists.
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http://dx.doi.org/10.1002/1878-0261.12968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253089PMC
July 2021

A Comparative Analysis of Novel Deep Learning and Ensemble Learning Models to Predict the Allergenicity of Food Proteins.

Foods 2021 Apr 9;10(4). Epub 2021 Apr 9.

Key Laboratory of Precision Nutrition and Food Quality, The Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.

Traditional food allergen identification mainly relies on in vivo and in vitro experiments, which often needs a long period and high cost. The artificial intelligence (AI)-driven rapid food allergen identification method has solved the above mentioned some drawbacks and is becoming an efficient auxiliary tool. Aiming to overcome the limitations of lower accuracy of traditional machine learning models in predicting the allergenicity of food proteins, this work proposed to introduce deep learning model-transformer with self-attention mechanism, ensemble learning models (representative as Light Gradient Boosting Machine (LightGBM) eXtreme Gradient Boosting (XGBoost)) to solve the problem. In order to highlight the superiority of the proposed novel method, the study also selected various commonly used machine learning models as the baseline classifiers. The results of 5-fold cross-validation showed that the area under the receiver operating characteristic curve (AUC) of the deep model was the highest (0.9578), which was better than the ensemble learning and baseline algorithms. But the deep model need to be pre-trained, and the training time is the longest. By comparing the characteristics of the transformer model and boosting models, it can be analyzed that, each model has its own advantage, which provides novel clues and inspiration for the rapid prediction of food allergens in the future.
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http://dx.doi.org/10.3390/foods10040809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069377PMC
April 2021

Cross sectional investigation of a COVID-19 outbreak at a London Army barracks: Neutralising antibodies and virus isolation.

Lancet Reg Health Eur 2021 Mar;2:100015

Immunisation and Countermeasures Division, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.

Background: Military personnel in enclosed societies are at increased risk of respiratory infections. We investigated an outbreak of Coronavirus Disease 2019 in a London Army barracks early in the pandemic.

Methods: Army personnel, their families and civilians had nasal and throat swabs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcriptase -polymerase chain reaction (RT-PCR), virus isolation and whole genome sequencing, along with blood samples for SARS-CoV-2 antibodies. All tests were repeated 36 days later.

Findings: During the first visit, 304 (254 Army personnel, 10 family members, 36 civilians, 4 not stated) participated and 24/304 (8%) were SARS-CoV-2 RT-PCR positive. Infectious virus was isolated from 7/24 (29%). Of the 285 who provided a blood sample, 7% (19/285) were antibody positive and 63% (12/19) had neutralising antibodies. Twenty-two (22/34, 64%) individuals with laboratory-confirmed infection were asymptomatic. Nine SARS-CoV-2 RT-PCR positive participants were also antibody positive but those who had neutralising antibodies did not have infectious virus. At the second visit, no new infections were detected, and 13% (25/193) were seropositive, including 52% (13/25) with neutralising antibodies. Risk factors for SARS-CoV-2 antibody positivity included contact with a confirmed case (RR 25.2; 95% CI 14-45), being female (RR 2.5; 95% CI 1.0-6.0) and two-person shared bathroom (RR 2.6; 95% CI 1.1-6.4).

Interpretation: We identified high rates of asymptomatic SARS-CoV-2 infection. Public Health control measures can mitigate spread but virus re-introduction from asymptomatic individuals remains a risk. Most seropositive individuals had neutralising antibodies and infectious virus was not recovered from anyone with neutralising antibodies.

Funding: PHE.
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http://dx.doi.org/10.1016/j.lanepe.2020.100015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834392PMC
March 2021

A Novel Machine Learning Strategy for the Prediction of Antihypertensive Peptides Derived from Food with High Efficiency.

Foods 2021 Mar 6;10(3). Epub 2021 Mar 6.

College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.

Strategies to screen antihypertensive peptides with high throughput and rapid speed will doubtlessly contribute to the treatment of hypertension. Food-derived antihypertensive peptides can reduce blood pressure without side effects. In the present study, a novel model based on the eXtreme Gradient Boosting (XGBoost) algorithm was developed and compared with the dominating machine learning models. To further reflect on the reliability of the method in a real situation, the optimized XGBoost model was utilized to predict the antihypertensive degree of the k-mer peptides cutting from six key proteins in bovine milk, and the peptide-protein docking technology was introduced to verify the findings. The results showed that the XGBoost model achieved outstanding performance, with an accuracy of 86.50% and area under the receiver operating characteristic curve of 94.11%, which were better than the other models. Using the XGBoost model, the prediction of antihypertensive peptides derived from milk protein was consistent with the peptide-protein docking results, and was more efficient. Our results indicate that using the XGBoost algorithm as a novel auxiliary tool is feasible to screen for antihypertensive peptides derived from food, with high throughput and high efficiency.
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http://dx.doi.org/10.3390/foods10030550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999667PMC
March 2021

Cross-sectional observational study of epidemiology of COVID-19 and clinical outcomes of hospitalised patients in North West London during March and April 2020.

BMJ Open 2021 02 18;11(2):e044384. Epub 2021 Feb 18.

Departments of Microbiology, Infectious Diseases, Emergency, Research and Development and Corporate Affairs, London North West University Healthcare NHS Trust, London, UK.

Objective: The aim of this paper is to describe evolution, epidemiology and clinical outcomes of COVID-19 in subjects tested at or admitted to hospitals in North West London.

Design: Observational cohort study.

Setting: London North West Healthcare NHS Trust (LNWH).

Participants: Patients tested and/or admitted for COVID-19 at LNWH during March and April 2020 MAIN OUTCOME MEASURES: Descriptive and analytical epidemiology of demographic and clinical outcomes (intensive care unit (ICU) admission, mechanical ventilation and mortality) of those who tested positive for COVID-19.

Results: The outbreak began in the first week of March 2020 and reached a peak by the end of March and first week of April. In the study period, 6183 tests were performed in on 4981 people. Of the 2086 laboratory confirmed COVID-19 cases, 1901 were admitted to hospital. Older age group, men and those of black or Asian minority ethnic (BAME) group were predominantly affected (p<0.05). These groups also had more severe infection resulting in ICU admission and need for mechanical ventilation (p<0.05). However, in a multivariate analysis, only increasing age was independently associated with increased risk of death (p<0.05). Mortality rate was 26.9% in hospitalised patients.

Conclusion: The findings confirm that men, BAME and older population were most commonly and severely affected groups. Only older age was independently associated with mortality.
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http://dx.doi.org/10.1136/bmjopen-2020-044384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896375PMC
February 2021

Role of key amino acids in the transmembrane domain of the Newcastle disease virus fusion protein.

Biosci Trends 2021 Mar 27;15(1):16-23. Epub 2021 Jan 27.

Department of Virology, School of Public Health, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, China.

Newcastle disease (ND), caused by the Newcastle disease virus (NDV), is transmitted by poultry with severe infectivity and a high fatality rate. The fusion (F) protein on the NDV envelope facilitates the merger of the viral and host cell membranes with the help of the homologous hemagglutinin-neuraminidase protein (HN). The transmembrane (TM) domains of viral fusion proteins are typically required for fusion, but the key amino acids in NDV F TM domains have not been identified. Site-directed mutagenesis was utilized to change the conserved amino acids at 500, 501, 502, 505, 510, 513, 516, 519, and 520 to alanine. It was found that mutants L519 and V520 had an interrupted protein expression, decreased to below 10%, and mutants A500, I505, V513, and V516 had a hypoactive impact on fusion activity, decreased to 85.38%, 67.05%, 55.38% and 51.13% of wt F, respectively. The results indicated that the TM domain plays a vital part in the fusion activity of the NDV F protein.
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http://dx.doi.org/10.5582/bst.2020.03317DOI Listing
March 2021

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine.

Cells 2021 01 11;10(1). Epub 2021 Jan 11.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.
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http://dx.doi.org/10.3390/cells10010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827922PMC
January 2021

An observational cohort study of bacterial co-infection and implications for empirical antibiotic therapy in patients presenting with COVID-19 to hospitals in North West London.

J Antimicrob Chemother 2021 02;76(3):796-803

Department of Microbiology, London North West University Healthcare NHS Trust, London HA1 3UJ, UK.

Objectives: To describe the prevalence and nature of bacterial co-infections in COVID-19 patients within 48 hours of hospital admission and assess the appropriateness of empirical antibiotic treatment they received.

Methods: In this retrospective observational cohort study, we included all adult non-pregnant patients who were admitted to two acute hospitals in North West London in March and April 2020 and confirmed to have COVID-19 infection within 2 days of admission. Results of microbiological specimens taken within 48 hours of admission were reviewed and their clinical significance was assessed. Empirical antibiotic treatment of representative patients was reviewed. Patient age, gender, co-morbidities, inflammatory markers at admission, admission to ICU and 30 day all-cause in-hospital mortality were collected and compared between patients with and without bacterial co-infections.

Results: Of the 1396 COVID-19 patients included, 37 patients (2.7%) had clinically important bacterial co-infection within 48 hours of admission. The majority of patients (36/37 in those with co-infection and 98/100 in selected patients without co-infection) received empirical antibiotic treatment. There was no significant difference in age, gender, pre-existing illnesses, ICU admission or 30 day all-cause mortality in those with and without bacterial co-infection. However, white cell count, neutrophil count and CRP on admission were significantly higher in patients with bacterial co-infections.

Conclusions: We found that bacterial co-infection was infrequent in hospitalized COVID-19 patients within 48 hours of admission. These results suggest that empirical antimicrobial treatment may not be necessary in all patients presenting with COVID-19 infection, although the decision could be guided by high inflammatory markers.
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http://dx.doi.org/10.1093/jac/dkaa475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717240PMC
February 2021

Revisiting China's provincial energy efficiency and its influencing factors.

Energy (Oxf) 2020 Oct 26;208:118361. Epub 2020 Jul 26.

School of Economics and Management, China University of Petroleum, Qingdao 266580, China.

Improving the energy efficiency is a fundamental way to ensure energy security and sustainable development, and is also the requirement of supply-side structural reform of China's energy. This paper uses the DEA-BCC model to estimate China's energy efficiency at the provincial level, analyzes its regional differences from 2006 to 2016, and applies a panel data model to analyze the influencing factors of energy efficiency. It selects labor, capital stock and total energy consumption as inputs and takes real GDP and comprehensive index of environmental pollution as desirable and undesirable outputs, respectively. The results show that (1) energy efficiency when undesirable output is included is generally lower than when undesirable output is excluded; (2) There is a considerable difference in energy efficiency among provinces, and China's energy efficiency, by and large, shows a trend of declining. The energy efficiency of four major regions demonstrates obvious regional differences: coastal region>northeastern region> middle region >western region; (3) The economic development level, technological progress, energy price and urbanization level are positively associated with energy efficiency, while the proportion of secondary industry and the energy consumption structure dominated by coal and oil are negatively correlated with energy efficiency.
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http://dx.doi.org/10.1016/j.energy.2020.118361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382643PMC
October 2020

Prediction of Type 2 Diabetes Risk and Its Effect Evaluation Based on the XGBoost Model.

Healthcare (Basel) 2020 Jul 31;8(3). Epub 2020 Jul 31.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.

In view of the harm of diabetes to the population, we have introduced an ensemble learning algorithm-EXtreme Gradient Boosting (XGBoost) to predict the risk of type 2 diabetes and compared it with Support Vector Machines (SVM), the Random Forest (RF) and K-Nearest Neighbor (K-NN) algorithm in order to improve the prediction effect of existing models. The combination of convenient sampling and snowball sampling in Xicheng District, Beijing was used to conduct a questionnaire survey on the personal data, eating habits, exercise status and family medical history of 380 middle-aged and elderly people. Then, we trained the models and obtained the disease risk index for each sample with 10-fold cross-validation. Experiments were made to compare the commonly used machine learning algorithms mentioned above and we found that XGBoost had the best prediction effect, with an average accuracy of 0.8909 and the area under the receiver's working characteristic curve (AUC) was 0.9182. Therefore, due to the superiority of its architecture, XGBoost has more outstanding prediction accuracy and generalization ability than existing algorithms in predicting the risk of type 2 diabetes, which is conducive to the intelligent prevention and control of diabetes in the future.
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http://dx.doi.org/10.3390/healthcare8030247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551910PMC
July 2020

Corrigendum to "A systematic comparison of exercise training protocols on animal models of cardiovascular capacity" [Life Sci. 217 (2019) 128-140].

Life Sci 2020 Aug 4;254:117757. Epub 2020 Jun 4.

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an 710119, China. Electronic address:

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http://dx.doi.org/10.1016/j.lfs.2020.117757DOI Listing
August 2020

IGRNet: A Deep Learning Model for Non-Invasive, Real-Time Diagnosis of Prediabetes through Electrocardiograms.

Sensors (Basel) 2020 Apr 30;20(9). Epub 2020 Apr 30.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.

The clinical symptoms of prediabetes are mild and easy to overlook, but prediabetes may develop into diabetes if early intervention is not performed. In this study, a deep learning model-referred to as IGRNet-is developed to effectively detect and diagnose prediabetes in a non-invasive, real-time manner using a 12-lead electrocardiogram (ECG) lasting 5 s. After searching for an appropriate activation function, we compared two mainstream deep neural networks (AlexNet and GoogLeNet) and three traditional machine learning algorithms to verify the superiority of our method. The diagnostic accuracy of IGRNet is 0.781, and the area under the receiver operating characteristic curve (AUC) is 0.777 after testing on the independent test set including mixed group. Furthermore, the accuracy and AUC are 0.856 and 0.825, respectively, in the normal-weight-range test set. The experimental results indicate that IGRNet diagnoses prediabetes with high accuracy using ECGs, outperforming existing other machine learning methods; this suggests its potential for application in clinical practice as a non-invasive, prediabetes diagnosis technology.
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http://dx.doi.org/10.3390/s20092556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248708PMC
April 2020

AK-DL: A Shallow Neural Network Model for Diagnosing Actinic Keratosis with Better Performance Than Deep Neural Networks.

Diagnostics (Basel) 2020 Apr 13;10(4). Epub 2020 Apr 13.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Plant Protein and Grain Processing, National Engineering and Technology Research Center for Fruits and Vegetables, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.

Actinic keratosis (AK) is one of the most common precancerous skin lesions, which is easily confused with benign keratosis (BK). At present, the diagnosis of AK mainly depends on histopathological examination, and ignorance can easily occur in the early stage, thus missing the opportunity for treatment. In this study, we designed a shallow convolutional neural network (CNN) named actinic keratosis deep learning (AK-DL) and further developed an intelligent diagnostic system for AK based on the iOS platform. After data preprocessing, the AK-DL model was trained and tested with AK and BK images from dataset HAM10000. We further compared it with mainstream deep CNN models, such as AlexNet, GoogLeNet, and ResNet, as well as traditional medical image processing algorithms. Our results showed that the performance of AK-DL was better than the mainstream deep CNN models and traditional medical image processing algorithms based on the AK dataset. The recognition accuracy of AK-DL was 0.925, the area under the receiver operating characteristic curve (AUC) was 0.887, and the training time was only 123.0 s. An iOS app of intelligent diagnostic system was developed based on the AK-DL model for accurate and automatic diagnosis of AK. Our results indicate that it is better to employ a shallow CNN in the recognition of AK.
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http://dx.doi.org/10.3390/diagnostics10040217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235884PMC
April 2020

All-trans retinoic acid reduces cancer stem cell-like cell-mediated resistance to gefitinib in NSCLC adenocarcinoma cells.

BMC Cancer 2020 Apr 15;20(1):315. Epub 2020 Apr 15.

Department of Biochemistry & Molecular Biology, Sichuan Cancer Insititute, No.55, Section 4, South Renmin Road, Chengdu, 610041, People's Republic of China.

Background: The enrichment of cancer stem cell-like cells (CSCs) has been considered to be responsible for tumor progression after an initial response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung adenocarcinoma (NSCLC/ADC). CSCs with ALDH1A1 /CD44 expression contribute to the TKIs resistance in NSCLC/ADC cells. All-trans retinoic acid (ATRA) has been shown to be a potential targeted therapy against CSCs due to its ability to inhibit ALDH1A1 activity. We therefore investigated whether ATRA could circumvent the resistance to improve the response to gefitinib in NSCLC/ADC cells.

Methods: Treatment of NSCLC/ADC A549 and H1650 cells with gefitinib enriched the gefitinib surviving cells (GSCs). The expression of ALDH1A1 and CD44 and the IC50 values for gefitinib were determined by flow cytometry (FCM) and crystal violet assay in GSCs and ATRA-treated GSCs, respectively. Using DEAB as the positive control, direct inhibitory effect of ATRA on ALDH1A1 activity was determined by ALDEFLUOR assay, RESULTS: GSCs showed higher expression of ALDH1A1 and CD44 and IC50 values for gefitinib than their respective parental cells, suggesting that gefitinib can lead to propagation of CSC-enriched gefitinib-resistant cells. Treatment with ATRA was found to significantly reduce the increased expression of ALDH1A1 and CD44 and the IC50 values for gefitinib in A549GSC and H1650GSC cells, and ATRA could directly inhibit active ALDH1A1 as compared to DEAB.

Conclusion: Our findings suggest that combination treatment with ATRA prevents gefitinib-induced enrichment of ALDH1A1/CD44 CSCs and enhances gefitinib-induced growth inhibition of NSCLC/ADC cells.
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http://dx.doi.org/10.1186/s12885-020-06818-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161137PMC
April 2020

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

Cell Biosci 2020 6;10:55. Epub 2020 Apr 6.

Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Xi'an, 710062 China.

Background: In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis.

Methods: NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation.

Results: Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation.

Conclusions: Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.
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http://dx.doi.org/10.1186/s13578-020-00414-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137450PMC
April 2020

Calcium-dependent Protein Kinases in Malaria Parasite Development and Infection.

Cell Transplant 2020 Jan-Dec;29:963689719884888

National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, Shaanxi Normal University College of Life Sciences, Xi'an, China.

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite's ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite's life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in , , and . Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.
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http://dx.doi.org/10.1177/0963689719884888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444236PMC
February 2021

LncRNA PCAT1 promotes metastasis of endometrial carcinoma through epigenetical downregulation of E-cadherin associated with methyltransferase EZH2.

Life Sci 2020 Feb 9;243:117295. Epub 2020 Jan 9.

Obstetrics and Gynecology Department, Huaian First Affiliated Hospital, Nanjing Medical University, Huaian, 223300 Jiangsu, China. Electronic address:

More than 140 thousands of women suffer from endometrial carcinoma in the worldwide, and over 40 thousand of the patients die before and after in surgery and chemoradiotherapy because of its metastasis. However, its molecular mechanism is much less known compared to other cancers. In this study, we demonstrated that long non-coding RNA PCAT1 is dramatically increased in the tissues and plasma from endometrial carcinoma (EC) (n = 100, all p < 0.001) controlled by its paracancerous tissue, and cell lines including RL-952, HEC-1-B, KLE, Ishikawa, and AN3CA compared to the cells from normal endometrium (all p < 0.001). When lncRNA PCAT1 was knocked-down, the KLE and AN3CA cells exhibited slow capability on proliferation and colony formation in vitro. With the silence of lncRNA PCAT1, the cells were markedly inhibited on migration and invasion in vitro (all p < 0.001), which were confirmed on the EC patient subjects. When expressions of lncRNA PCAT1 were interfered in the cells, expressions of E-cadherin but not N-cadherin and Vimentin were significantly promoted with a strong up-regulation accompanied by nearly completed recoveries on migration and invasion (all p < 0.001). In order to analyze the association of lncRNA PCAT1 and E-cadherin, we silenced the expressions of both genes and unveiled that EC migration and invasion were significantly congested (all p < 0.001). Importantly, we found that the E-cadherin down-regulation caused by lncRNA PCAT1 associates with histone methyltransferase EZH2. When over-expression of EZH2 was applied in the PCAT1 silenced cells, the expression of E-cadherin experienced significant decrease in the cell lines. Reversely, when expression of EZH2 was annulled in the PCAT1 silenced cells, the expression of E-cadherin was significantly boosted in the cells (all p < 0.001). Furthermore, the interaction of lncRNA PCAT1 and EZH2 were approved with immunoprecipitation. Our data demonstrated that the methyltransferase EZH2 related up-regulation of lncRNA PCAT1 along with down-regulation of E-cadherin could be essential in oncogenesis of endometrial carcinoma in both EC cells and patient subjects. These compact data suggest that combination of lncRNA PCAT1, EZH2 and E-cadherin could provide valued information for efficient EC diagnostics, which would propose a potential target for EC treatment with EZH2i on methyltransferation.
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http://dx.doi.org/10.1016/j.lfs.2020.117295DOI Listing
February 2020

Virtual reality and integrated crime scene scanning for immersive and heterogeneous crime scene reconstruction.

Forensic Sci Int 2019 Oct 13;303:109943. Epub 2019 Sep 13.

Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Ministry of Justice, 1347# West Guangfu Road, Shanghai, China. Electronic address:

Crime scene reconstruction plays a significant role in crime solving by helping to determine the course of events. Non-invasive, high-resolution measurement and increased insight are always the goal of forensic crime scene documentation. However, entire crime scenes cannot be effectively reconstructed with traditional methods. In this study, we present a portable system that consists of a laser scanner, two hand-held structured light scanners and a low-cost virtual reality (VR) headset with a mobile power supply to conduct multi-angle and omnidirectional three-dimensional spatial data collection of crime scenes. To demonstrate practical use, a real case has been analysed to verify the feasibility and effectiveness of the system. The system accurately obtains information on decedent injuries, possible injury-inflicting tools and on-site traces. Various types of evidence from the crime scene can be jointly studied by three-dimensional visualization to develop a cohesive story. The data are presented via immersive VR rather than displayed on computer screens. The relationship between evidence chains enables us to achieve a complete crime scene reconstruction, using the specialized knowledge of experts and computer-aided forensic tools to analyse the causes of damage and identify suspects. The use of three- dimensional imaging techniques allows a more insightful survey and several useful analyses, such as accurate measurement, relative blood source location determination and injury-inflicting tool comparison.
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http://dx.doi.org/10.1016/j.forsciint.2019.109943DOI Listing
October 2019

Taurine Protects Retinal Cells and Improves Synaptic Connections in Early Diabetic Rats.

Curr Eye Res 2020 01 22;45(1):52-63. Epub 2019 Aug 22.

Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.

: Taurine has long been thought to be involved in retinal protection from retinal degenerative diseases, but the underlying molecular mechanisms remain unclear. Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR) that precedes and participates in the microcirculatory abnormalities that occur in DR. Our objective was to investigate the role and mechanisms of taurine in early diabetic retinas.: Eight-week-old STZ-induced diabetic rats and control animals were randomly assigned to receive taurine or vehicle by intraperitoneal injection or by intragastric administration. The retinal function and retinal cell counts were evaluated using an electroretinography (ERG) and immunofluorescence microscopy. Plasma amino acids were measured by ion-exchange chromatography (IEC). The expression levels of retinal taurine transporter (Tau-T), mitochondria-dependent apoptosis-associated genes and reactive gliosis markers were studied by western blotting and immunofluorescence. Pre- and post-synaptic markers (PSD95 and mGluR6) in outer plexiform layer (OPL), and the bipolar cell marker protein kinase C alpha (PKCα) were localized by immunofluorescence. Levels of PSD95 and mGluR6 were determined by quantitative western blot.: Taurine significantly prevented the reduction of photopic b-wave amplitude and retinal cone cells and ganglion cells loss and maintained the Bcl-2/Bax ratio balance in diabetic rats. Taurine also prevented the upregulation of glial fibrillary acidic protein (GFAP) and reduced retinal reactive gliosis. Taurine reduced plasma glutamate and tyrosine levels, which were elevated in diabetic rats. Moreover, mGluR6 levels reduction detected by western blot and immunofluorescence in diabetic retinas was inhibited and the displacement of mGluR6 in OPL into the inner nuclear layer (INL) detected by immunofluorescence was reduced by Taurine treatment.: Taurine may protect retinal cells from diabetic attacks by activating Tau-T, reducing retinal reactive gliosis, improving retinal synaptic connections and decreasing retinal cell apoptosis. Thus, taurine treatment may be a novel approach for early DR.
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http://dx.doi.org/10.1080/02713683.2019.1653927DOI Listing
January 2020

The identification of gene signature and critical pathway associated with childhood-onset type 2 diabetes.

PeerJ 2019 6;7:e6343. Epub 2019 Feb 6.

Medical School of Nantong University, Nantong, Jiangsu, China.

In general, type 2 diabetes (T2D) usually occurs in middle-aged and elderly people. However, the incidence of childhood-onset T2D has increased all across the globe. Therefore, it is very important to determine the molecular and genetic mechanisms of childhood-onset T2D. In this study, the dataset GSE9006 was downloaded from the GEO (Gene Expression Omnibus database); it includes 24 healthy children, 43 children with newly diagnosed Type 1 diabetes (T1D), and 12 children with newly diagnosed T2D. These data were used for differentially expressed genes (DGEs) analysis and weighted co-expression network analysis (WGCNA). We identified 192 up-regulated genes and 329 down-regulated genes by performing DEGs analysis. By performing WGGNA, we found that blue module (539 genes) was highly correlated to cyan module (97 genes). Gene ontology (GO) and pathway enrichment analyses were performed to figure out the functions and related pathways of genes, which were identified in the results of DEGs and WGCNA. Genes with conspicuous logFC and in the high correlated modules were input into GeneMANIA, which is a plugin of Cytoscape application. Thus, we constructed the protein-protein interaction (PPI) network (92 nodes and 254 pairs). Eventually, we analyzed the transcription factors and references related to genes with conspicuous logFC or high-degree genes, which were present in both the modules of WGCNA and PPI network. Current research shows that EGR1 and NAMPT can be used as marker genes for childhood-onset T2D. Gestational diabetes and chronic inflammation are risk factors that lead to the development of childhood-onset T2D.
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http://dx.doi.org/10.7717/peerj.6343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368838PMC
February 2019

Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism.

Chirality 2019 03 24;31(3):236-247. Epub 2019 Jan 24.

State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Science, Beijing, People's Republic of China.

The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3 mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk' against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
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http://dx.doi.org/10.1002/chir.23052DOI Listing
March 2019

Dynamics expression of during embryonic early development of .

Cell Biosci 2019 8;9. Epub 2019 Jan 8.

1National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China/CGDB, Shaanxi Normal University College of Life Sciences, Xi'an, 710062 China.

Background: Calcium signaling are conserved from invertebrates to vertebrates and plays critical roles in many molecular mechanisms of embryogenesis and postnatal development. As a critical component of the signaling pathway, the RyR medicated calcium-induced calcium release signaling system, has been well studied along with their regulator FK506-binding protein 12 (FKBP12/Calstabin). Lack of FKBP12 is known to result in lethal cardiac dysfunction in mouse. However, precisely how FKBP12 is regulated and effects calcium signaling in remains largely unknown.

Results: In this study, we identified both temporal and localization changes in expression of a translational and transcriptional regulator of RyR (DmRyR) and FKBP12, through embryonic development. is first expressed at the syncytial blastoderm stage and undergoes increased expression during the cellular blastoderm and early gastrulation stages. At late gastrulation, expression begins to decline until it reaches homeostasis, which it then maintains throughout the rest of development. Throughout these described changes in expression, DmFKBP12 mRNA remain stable, which indicates that protein dynamics are attributed to regulation at the mRNA to protein translation level. In addition to temporal changes in expression, dynamic expression profiles during development also revealed DmFKBP12 localization. Although DmFKBP12 is distributed evenly between the anterior to posterior poles of the blastoderm egg, the protein is expressed more strongly in the cortex of the early gastrula with the highest concentration found in the basement membrane of the cellular blastoderm. Fertilized egg, through the profile as under-membrane cortex distribution concentering onto basement at cellular blastoderm, to the profile as three-gem layer localization in primitive neuronal and digestion architecture of early gastrula. By late gastrulation, DmFKBP12 is no longer identified in the yolk or lumen of duct structures and has relocated to the future brain (suboesophageal and supraesophageal ganglions), ventral nervous system, and muscular system. Throughout these changes in distribution, in situ mRNA monitoring detected equal distribution of mRNA, once again indicating that regulation of occurs at the translational level in development.

Conclusion: As a critical regulator of the DmRyR-FKBP complex, DmFKBP12 expression in fluctuates temporally and geographically with the formation of organ systems. These finding indicate that and RyR associated calcium signaling plays an essential role in the successful development of . Further study on the differences between mammalian RyR-FKBP12 and DmRyR-FKBP12 can be exploited to develop safe pesticides.
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http://dx.doi.org/10.1186/s13578-019-0270-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325743PMC
January 2019
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