Publications by authors named "Fen Wang"

680 Publications

C-H arylation of arenes at room temperature using visible light ruthenium C-H activation.

Chem Sci 2020 Apr 7;11(17):4439-4443. Epub 2020 Apr 7.

School of Chemistry, The University of Manchester Oxford Road Manchester M13 9PL UK

A ruthenium-catalyzed C-H arylation process is described using visible light. Using the readily available catalyst [RuCl(-cymene)], visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.
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http://dx.doi.org/10.1039/d0sc01289kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159458PMC
April 2020

Sestrin protects Drosophila midgut from mercury chloride-induced damage by inhibiting oxidative stress and stimulating intestinal regeneration.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Jun 2;248:109083. Epub 2021 Jun 2.

College of Biological Science and Agriculture, Qiannan Normal University for Nationalities, Duyun 558000, China. Electronic address:

Overproduction of the deleterious reactive oxygen species (ROS) is one of the major causes of mercury, a heavy metal with diverse applications and environmental presence, induced neuronal and gastrointestinal adversities in exposed organism including Drosophila melanogaster. Sestrin, an oxidative stress responsive gene, emerges as a novel player in the management of oxidative stress response. Due to limited information regarding the role of sestrin in mercury-induced gastrointestinal adversities, it was hypothesized that modulation of sestrin may improve the mercury-induced gastrointestinal adversities in Drosophila. Here, we fed Drosophila with 400 μM HgCl and found that sestrin transcriptional level was significantly increased in midguts. Sestrin knockdown in HgCl-exposed midguts decreased survival rates and climbing ability of flies, and inhibited superoxide dismutase and glutathione-S-transferase activities of midgut epithelieum. Meanwhile, sestrin knockdown in midgut aggravated the HgCl-induced disruption of intestinal organization by worsening ROS production and cell apoptosis. Immunohistochemical staining data revealed that sestrin knockdown inhibited intestinal stem cell division in HgCl-exposed midguts. Furthermore, JNK signaling was found to mediated sestrin expression in midgut. Taken together, the study demonstrated that sestrin protects Drosophila midgut from HgCl-induced oxidative damage by inhibiting ROS production and stimulating the tissue regeneration program under regulation of JNK signaling pathway. This work suggests therapeutic implications of sestrin against heavy metal-induced gastrointestinal adversities in mammals.
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http://dx.doi.org/10.1016/j.cbpc.2021.109083DOI Listing
June 2021

Functions and Targets of miR-335 in Cancer.

Onco Targets Ther 2021 20;14:3335-3349. Epub 2021 May 20.

Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

MicroRNAs (miRNAs) are small non-coding RNAs (18~25 nt in length) that act as master regulators of eukaryotic gene expression. They might play an oncogenic or tumor-suppressive role in multiple cancers. In recent decades, several studies have focused on the functions and mechanisms of miR-335 in cancer. The expression level of miR-335 in tissues and cells varies with cancer types, and miR-335 has been proposed as a potential biomarker for the prognosis of cancer. Besides, miR-335 may serve as an oncogene or tumor suppressor via regulating different targets or pathways in tumor initiation, development, and metastasis. Furthermore, miR-335 also influences tumor microenvironment and drug sensitivity. MiR-335 is regulated by various factors such as lncRNAs and microRNAs. In this review, we reveal the functions and targets of miR-335 in various cancers and its potential application as a possible biomarker in prognostic judgment and treatment of malignant tumors.
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http://dx.doi.org/10.2147/OTT.S305098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144171PMC
May 2021

White Matter Fractional Anisotropy Is a Superior Predictor for Cognitive Impairment Than Brain Volumes in Older Adults With Confluent White Matter Hyperintensities.

Front Psychiatry 2021 5;12:633811. Epub 2021 May 5.

Department of Neurology, Innovation Center for Neurological Disorders, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.

Older patients with confluent white matter hyperintensities (WMHs) on magnetic resonance imaging have an increased risk for the onset of vascular cognitive impairment (VCI). This study investigates the predictive effects of the white matter (WM) fractional anisotropy (FA) and brain volumes on cognitive impairment for those with confluent WMHs. This study enrolled 77 participants with confluent WMHs (Fazekas grade 2 or 3), including 44 with VCI-no dementia (VCIND) and 33 with normal cognition (NC). The mean FA of 20 WM tracts was calculated to evaluate the global WM microstructural integrity, and major WM tracts were reconstructed using probabilistic tractography. Voxel-based morphometry was used to calculate brain volumes for the total gray matter (GM), the hippocampus, and the nucleus basalis of Meynert (NbM). All volumetric assays were corrected for total intracranial volume. All regression analyses were adjusted for age, gender, education, and apolipoprotein E (ApoE) gene ε4 status. Logistic regression analysis revealed that the mean FA value for global WM was the only independent risk factor for VCI (z score of FA: OR = 4.649, 95%CI 1.576-13.712, = 0.005). The tract-specific FAs were not associated with the risk of cognitive impairment after controlling the mean FA for global WM. The mean FA value was significantly associated with scores of Mini-Mental State Examination (MMSE) and Auditory Verbal Learning Test. A lower FA was also associated with smaller volumes of total GM, hippocampus, and NbM. However, brain volumes were not found to be directly related to cognitive performances, except for an association between the hippocampal volume and MMSE. In conclusion, the mean FA for global WM microstructural integrity is a superior predictor for cognitive impairment than tract-specific FA and brain volumes in people with confluent WMHs.
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http://dx.doi.org/10.3389/fpsyt.2021.633811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131652PMC
May 2021

Differences in Clinical Manifestations and Tumor Features Between Metastatic Pheochromocytoma/Paraganglioma Patients With and Without Germline SDHB Mutation.

Endocr Pract 2021 Apr 14;27(4):348-353. Epub 2020 Dec 14.

Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Objective: To compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes.

Methods: Clinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients.

Results: SDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01).

Conclusion: Compared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.
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http://dx.doi.org/10.1016/j.eprac.2020.09.015DOI Listing
April 2021

Rhodium-Catalyzed C-H Activation-Based Construction of  Axiall and Centrally Chiral Indenes through Two Discrete Insertions.

Angew Chem Int Ed Engl 2021 May 18. Epub 2021 May 18.

Shandong University, Institute of Frontier and Interdisciplinary Sciences, CHINA.

Reported herein is asymmetric [3+2] annulation of arylnitrones with different classes of alkynes catalyzed by chiral rhodium(III) complexes, with the nitrone acting as an electrophilic directing group. Three classes of chiral indenes/indenones have been effectively constructed, depending on the nature of the substrates. The coupling system features mild reaction conditions, excellent enantioselectivity, and high atom-economy. In particular, the coupling of N -benzylnitrones and different classes of sterically hindered alkynes afforded C-C or C-N atropochiral pentatomic biaryls with a C-centered point-chirality in excellent enantio- and diastereoselectivity (45 examples, average 95.6% ee). These chiral center and axis are disposed in a distal fashion and they are constructed via two distinct migratory insertions that are stereo-determining.
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http://dx.doi.org/10.1002/anie.202105093DOI Listing
May 2021

Transcriptome analysis of ovary tissues from low- and high-yielding Changshun green-shell laying hens.

BMC Genomics 2021 May 14;22(1):349. Epub 2021 May 14.

College of Animal Sciences, Zhejiang University, 310058, Hangzhou, China.

Background: Changshun green-shell laying hens are unique to Guizhou Province, China, and have high egg quality. Improving egg production performance has become an important breeding task, and in recent years, the development of high-throughput sequencing technology provides a fast and exact method for genetic selection. Therefore, we aimed to use this technology to analyze the differences between the ovarian mRNA transcriptome of low and high-yield Changshun green-shell layer hens, identify critical pathways and candidate genes involved in controlling the egg production rate, and provide basic data for layer breeding.

Results: The egg production rates of the low egg production group (LP) and the high egg production group (HP) were 68.00 ± 5.56 % and 93.67 ± 7.09 %, with significant differences between the groups (p < 0.01). Moreover, the egg weight, shell thickness, strength and layer weight of the LP were significantly greater than those of the HP (p < 0.05). More than 41 million clean reads per sample were obtained, and more than 90 % of the clean reads were mapped to the Gallus gallus genome. Further analysis identified 142 differentially expressed genes (DEGs), and among them, 55 were upregulated and 87 were downregulated in the ovaries. KEGG pathway enrichment analysis identified 9 significantly enriched pathways, with the neuroactive ligand-receptor interaction pathway being the most enriched. GO enrichment analysis indicated that the GO term transmembrane receptor protein tyrosine kinase activity, and the DEGs identified in this GO term, including PRLR, NRP1, IL15, BANK1, NTRK1, CCK, and HGF may be associated with crucial roles in the regulation of egg production.

Conclusions: The above-mentioned DEGs may be relevant for the molecular breeding of Changshun green-shell laying hens. Moreover, enrichment analysis indicated that the neuroactive ligand-receptor interaction pathway and receptor protein tyrosine kinases may play crucial roles in the regulation of ovarian function and egg production.
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http://dx.doi.org/10.1186/s12864-021-07688-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122536PMC
May 2021

Conventional bioretention column with Fe-hydrochar for stormwater treatment: Nitrogen removal, nitrogen behaviour and microbial community analysis.

Bioresour Technol 2021 May 5;334:125252. Epub 2021 May 5.

School of Environmental Science and Engineering, Tianjin University, Tianjin 300350, China.

An FeCl-modified rice husk hydrochar ('Fe-hydrochar') was used as the filler in a conventional bioretention column to remove nitrogen from synthetic stormwater. When the ammonia nitrogen (NH-N) and nitrate nitrogen (NO-N) concentrations of the influent were both 20 mg/L, the average removal rates of NH-N and total nitrogen (TN) were approximately 97% and 50%, respectively. Nitrogen was mainly removed by microbial nitrification and denitrification, with 25% of NH-N being adsorbed by the Fe-hydrochar. The remaining NH-N was converted into NO-N by nitrification in the upper layer, and NO-N was mainly converted to nitrogen gas (N) by denitrification in the lower layer. The organic matter released by the Fe-hydrochar was degraded and used as the carbon source for denitrification. The dominant bacteria were Pseudomonas, Rhizobium, and Flavobacterium at the genus level. Pseudomonas and Rhizobium were responsible for heterotrophic nitrification-aerobic denitrification, while Flavobacterium was related to the degradation of organic matter.
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http://dx.doi.org/10.1016/j.biortech.2021.125252DOI Listing
May 2021

sp. nov., a slow-growing scotochromogenic species isolated from sputum.

Int J Syst Evol Microbiol 2021 May;71(5)

National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, PR China.

A slow-growing, scotochromogenic mycobacterial strain (24) was isolated from the sputum of a Chinese male human. Phylogenetic analysis using the 16S rRNA gene assigned strain 24 to the complex, which includes and . The phenotypic characteristics, unique mycolic acid profile and the results of phylogenetic analysis based on and sequences strongly supported the taxonomic status of strain 24 as a representative of a species distinct from the other members of the complex. The genomic G+C content of strain 24 was 65.40mol%. Genomic comparisons showed that strain 24 and ATCC 14470 had an average nucleotide identity (ANI) value of 81.00 % and a DNA-DNA hybridization (DDH) value of 22.80 %, while the ANI and DDH values between strain 24and 49 061 were 80.98 and 22.80 %, respectively. In terms of phylogenetic, phenotypic and chemotaxonomic features, strain 24 is distinguishable from its closest phylogenetic relatives and represents a novel species of the genus , therefore the name sp. nov. is proposed. The type strain is 24 (=CMCC 93559=DSM 105979).
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http://dx.doi.org/10.1099/ijsem.0.004796DOI Listing
May 2021

Prediction of treatment responses to neoadjuvant chemotherapy in breast cancer using contrast-enhanced ultrasound.

Gland Surg 2021 Apr;10(4):1280-1290

Department of Ultrasonography, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Elucidation the efficacy of neoadjuvant chemotherapy (NAC) in breast cancer is important for informing therapeutic decisions. This study aimed at evaluating the potential value of contrast-enhanced ultrasound (CEUS) parameters in predicting breast cancer responses to NAC.

Methods: We performed CEUS examinations before and after two cycles of NAC. Quantitative CEUS parameters [maximum intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (mTT)], tumor diameter, and their changes were measured and compared to histopathological responses, according to the Miller-Payne Grading (MPG) system (score 1, 2, or 3: minor response; score 4 or 5: good response). Prediction models for good response were developed by multiple logistic regression analysis and internally validated through bootstrap analysis. The receiver operating characteristic (ROC) curve was used to evaluate the performance of prediction models.

Results: A total of 143 patients were enrolled in this study among whom 98 (68.5%) achieved a good response and while 45 (31.5%) exhibited a minor response. Several imaging variables including diameter, IMAX, changes in diameter (Δdiameter), IMAX (ΔIMAX) and TTP (ΔTTP) were found to be significantly associated with good therapeutic responses (P<0.05). The areas under the curve (AUC) increased from 0.748 to 0.841 in the multivariate model that combined CEUS parameters and molecular subtypes with a sensitivity and specificity of 0.786, 0.745, respectively. Tumor molecular subtype was the primary predictor of primary endpoint.

Conclusions: CEUS is a potential tool for predicting responses to NAC in locally advanced breast cancer patients. Compared to the other molecular subtypes, triple negative and HER2+/ER- subtypes are more likely to exhibit a good response to NAC.
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http://dx.doi.org/10.21037/gs-20-836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102213PMC
April 2021

Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming.

Aging Cell 2021 Jun 8;20(6):e13375. Epub 2021 May 8.

Department of Neurology, Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Although its pathogenesis remains unclear, a number of studies indicate that microglia-mediated neuroinflammation makes a great contribution to the pathogenesis of PD. Melatonin receptor 1 (MT1) is widely expressed in glia cells and neurons in substantia nigra (SN). Neuronal MT1 is a neuroprotective factor, but it remains largely unknown whether dysfunction of microglial MT1 is involved in the PD pathogenesis. Here, we found that MT1 was reduced in microglia of SN in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Microglial MT1 activation dramatically inhibited lipopolysaccharide (LPS)-induced neuroinflammation, whereas loss of microglial MT1 aggravated it. Metabolic reprogramming of microglia was found to contribute to the anti-inflammatory effects of MT1 activation. LPS-induced excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS) could be reversed by microglial MT1 activation. MT1 positively regulated pyruvate dehydrogenase alpha 1 (PDHA1) expression to enhance OXPHOS and suppress aerobic glycolysis. Furthermore, in LPS-treated microglia, MT1 activation decreased the toxicity of conditioned media to the dopaminergic (DA) cell line MES23.5. Most importantly, the anti-inflammatory effects of MT1 activation were observed in LPS-stimulated mouse model. In general, our study demonstrates that MT1 activation inhibits LPS-induced microglial activation through regulating its metabolic reprogramming, which provides a mechanistic insight for microglial MT1 in anti-inflammation.
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http://dx.doi.org/10.1111/acel.13375DOI Listing
June 2021

Psychometric Evaluation of the Disaster Preparedness Evaluation Tool (DPET) on Emergency Nurses in Mainland China: Two Cross-Sectional Studies.

Disaster Med Public Health Prep 2021 May 5:1-8. Epub 2021 May 5.

School of Nursing, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Background: Emergency nurses play a major role in disaster relief in mainland China, but there is no valid instrument to measure the extent of their disaster preparedness. The Disaster Preparedness Evaluation Tool© is a reliable instrument to assess the disaster preparedness of nurse practitioners. The tool has been translated and validated in Saudi Arabia, Taiwan, China and the United States of America.

Objectives: This study aimed at translating and adapting the Disaster Preparedness Evaluation Tool© (DPET) for emergency nurses in mainland China and determining its psychometric properties.

Design, Settings And Participants: A total of 2 cross-sectional online surveys were conducted in the emergency departments of 26 public grade III-A hospitals in Guangdong, mainland China. In the first study, 633 emergency nurses were recruited from May to August, 2018. In the second study, 205 were recruited in April 2019.

Methods: The instrument was adapted through rigorous forward-backward translation, face validity, and pre-test processes. Exploratory factor and parallel analyses were used in the first study. Confirmatory factor analysis, internal consistency and split-half reliability were used in the second study.

Results: Exploratory factor and parallel analyses extracted a 5-factor solution comprising of 34 items that accounted for 64.06% of the total variance. The fit indices indicated a good model fit. The reliability was good, as indicated by a Cronbach's alpha of 0.97 and a split-half reliability coefficient of 0.97.

Conclusion: The mainland China version of the DPET (DPET-MC) was a reliable and valid instrument and can be used in practice.
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http://dx.doi.org/10.1017/dmp.2021.39DOI Listing
May 2021

Multiomics Analysis Reveals New Insights into the Apple Fruit Quality Decline under High Nitrogen Conditions.

J Agric Food Chem 2021 May 4;69(19):5559-5572. Epub 2021 May 4.

State Key Laboratory of Crop Biology, College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, Shandong, China.

Excessive application of nitrogen (N) fertilizer is common in Chinese apple production. High N reduced the contents of soluble sugar and total flavonoids by 16.05 and 19.01%, respectively, resulting in poor fruit quality. Moreover, high N increased the total N and decreased the total C and C/N ratio of apple fruits. On the basis of the transcriptomic, proteomic, and metabolomic analyses, the global network was revealed. High N inhibited the accumulation of carbohydrates (sucrose, glucose, and trehalose) and flavonoids (rhamnetin-3--rutinoside, rutin, and trihydroxyisoflavone-7--galactoside) in fruits, and more C skeletons were used to synthesize amino acids and their derivatives (especially low C/N ratio, e.g., arginine) to be transferred to N metabolism. This study revealed new insights into the decline in soluble sugar and flavonoids caused by high N, and hub genes (MD07G1172700, MD05G1222800, MD16G1227200, MD01G1174400, and MD02G1207200) and hub proteins (PFK, gapN, and HK) were obtained.
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http://dx.doi.org/10.1021/acs.jafc.1c01548DOI Listing
May 2021

Mechanical Properties of Al Matrix Composite Enhanced by In Situ Formed SiC, MgAlO and MgO via Casting Process.

Materials (Basel) 2021 Apr 2;14(7). Epub 2021 Apr 2.

Shaanxi Key Laboratory of Green Preparation and Functionalization for Inorganic Materials, School of Materials Science and Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.

Al matrix composite, reinforced with the in situ synthesized 3C-SiC, MgAlO and MgO grains, was produced via the casting process using phenolic resin pyrolysis products in flash mode. The contents and microstructure of the composites' fracture characteristics were analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Mechanical properties were tested by universal testing machine. Owing to the strong propulsion formed in turbulent flow in the pyrolysis process, nano-ceramic grains were formed in the resin pyrolysis process and simultaneously were homogeneously scattered in the alloy matrix. Thermodynamic calculation supported that the gas products, as carbon and oxygen sources, had a different chemical activity on in situ growth. In addition, ceramic (3C-SiC, MgAlO and MgO) grains have discrepant contents. Resin pyrolysis in the molten alloy decreased oxide slag but increased pores in the alloy matrix. Tensile strength (142.6 ± 3.5 MPa) had no change due to the cooperative action of increased pores and fine grains; the bending and compression strength was increasing under increased contents of ceramic grains; the maximum bending strength was 378.2 MPa in 1.5% resin-added samples; and the maximum compression strength was 299.4 MPa. Lath-shaped Si was the primary effect factor of mechanical properties. The failure mechanism was controlled by transcrystalline rupture mechanism. We explain that the effects of the ceramic grains formed in the hot process at the condition of the resin exist in mold or other accessory materials. Meanwhile, a novel ceramic-reinforced Al matrix was provided. The organic gas was an excellent source of carbon, nitrogen, and oxygen to in situ ceramic grains in Al alloy.
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http://dx.doi.org/10.3390/ma14071767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038336PMC
April 2021

High Child-Pugh and CRUB65 scores predict mortality of decompensated cirrhosis patients with COVID-19: A 23-center, retrospective study.

Virulence 2021 12;12(1):1199-1208

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

: COVID-19 has rapidly become a major health emergency worldwide. The characteristic, outcome, and risk factor of COVID-19 in patients with decompensated cirrhosis remain unclear.: Medical records were collected from 23 Chinese hospitals. Patients with decompensated cirrhosis and age- and sex-matched non-liver disease patients were enrolled with 1:4 ratio using stratified sampling.: There were more comorbidities with higher Chalson Complication Index (p < 0.001), higher proportion of patients having gastrointestinal bleeding, jaundice, ascites, and diarrhea among those patients (p < 0.05) and in decompensated cirrhosis patients. Mortality (p < 0.05) and the proportion of severe ill (p < 0.001) were significantly high among those patients. Patients in severe ill subgroup had higher mortality (p < 0.001), MELD, and CRUB65 score but lower lymphocytes count. Besides, this subgroup had larger proportion of patients with abnormal (PT), activated partial thromboplatin time (APTT), D-Dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) and Creatinine (Cr) (p < 0.05). Multivariate logistic regression for severity shown that MELD and CRUB65 score reached significance. Higher Child-Pugh and CRUB65 scores were found among non-survival cases and multivariate logistic regression further inferred risk factors for adverse outcome. Receiver Operating Characteristic (ROC) curves also provided remarkable demonstrations for the predictive ability of Child-Pugh and CRUB65 scores.: COVID-19 patients with cirrhosis had larger proportion of more severely disease and higher mortality. MELD and CRUB65 score at hospital admission may predict COVID-19 severity while Child-Pugh and CRUB65 score were highly associated with non-survival among those patients.
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http://dx.doi.org/10.1080/21505594.2021.1909894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078510PMC
December 2021

Incidence of Intracranial Melanoma Progression in the Setting of Positive Extracranial Response to Targeted Therapy and Immunotherapy: An Indication for More Frequent Screening in This Population?

Cureus 2021 Mar 2;13(3):e13648. Epub 2021 Mar 2.

Neurosurgery, University of Kansas Medical Center, Kansas City, USA.

Background and objective The incidence of intracranial metastases from melanoma is on the rise. In this study, we aimed to determine the incidence of intracranial disease progression in patients on BRAF/MEK targeted therapy and immunotherapy in the setting of controlled or improving extracranial disease. Methods This was a single-center, retrospective review that involved patients who underwent stereotactic radiosurgery (SRS) for intracranial metastatic melanoma between January 1, 2014, and December 31, 2018. We focused on BRAF/MEK mutation status and dates of treatment with BRAF/MEK targeted therapy, immunotherapy [ipilimumab (Yervoy), nivolumab (Opdivo), or pembrolizumab (Keytruda)], and combination targeted and immunotherapy. Results A total of 51 patients were enrolled: 36 males and 15 females. The average age of the patients was 58.6 years, and 26 among them were BRAF mutation-positive. Seventeen had prior surgery with SRS as adjuvant therapy. The other 34 had SRS as primary treatment. Forty-two patients had extracranial disease present at the time of SRS. There were 34 patients treated with targeted and immune therapy. Overall, 16 patients (47.1%) demonstrated controlled or improving extracranial disease, and 18 (52.9%) demonstrated progressing extracranial disease at the time of SRS. In the subgroup analysis, patients treated with BRAF/MEK targeted therapy demonstrated a 75% rate of extracranial disease control. The extracranial disease was controlled in 43.75% of patients on immunotherapy with intracranial progression, while it was controlled in 30% of patients on both BRAF/MEK targeted therapy and immunotherapy with intracranial progression. Sixteen patients (47.1%) developed intracranial metastasis in our study while having a stable systemic disease with BRAF/MEK targeted therapy, immunotherapy, or a combination of the two. Conclusion Based on our findings, a systemic response to targeted therapy and immunotherapy does not necessarily parallel intracranial protection.
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http://dx.doi.org/10.7759/cureus.13648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013837PMC
March 2021

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review.

Front Oncol 2021 18;11:642110. Epub 2021 Mar 18.

Division of Medical Oncology, Department of Internal Medicine, University of Kansas Cancer Center, University of Kansas Medical Center, Westwood, KS, United States.

Gut microbiome is proved to affect the activity of immunotherapy in certain tumors. However, little is known if there is universal impact on both the treatment response and adverse effects (AEs) of immune checkpoint inhibitors (ICIs) across multiple solid tumors, and whether such impact can be modulated by common gut microbiome modifiers, such as antibiotics and diet. A systematic search in PubMed followed by stringent manual review were performed to identify clinical cohort studies that evaluated the relevance of gut microbiome to ICIs (response and/or AEs, 12 studies), or association of antibiotics with ICIs (17 studies), or impact of diet on gut microbiome (16 studies). Only original studies published in English before April 1st, 2020 were used. Qualified studies identified in the reference were also included. At the phylum level, patients who had enriched abundance in and almost universally had better response from ICIs, whereas those who were enriched in universally presented with unfavorable outcome. Mixed correlations were observed for in relating to treatment response. Regarding the AEs, correlated to higher incidence whereas were clearly associated with less occurrence. Interestingly, across various solid tumors, majority of the studies suggested a negative association of antibiotic use with clinical response from ICIs, especially within 1-2 month prior to the initiation of ICIs. Finally, we observed a significant correlation of plant-based diet in relating to the enrichment of "ICI-favoring" gut microbiome ( = 0.0476). Gut microbiome may serve as a novel modifiable biomarker for both the treatment response and AEs of ICIs across various solid tumors. Further study is needed to understand the underlying mechanism, minimize the negative impact of antibiotics on ICIs, and gain insight regarding the role of diet so that this important lifestyle factor can be harnessed to improve the therapeutic outcomes of cancer immunotherapy partly through its impact on gut microbiome.
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http://dx.doi.org/10.3389/fonc.2021.642110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012896PMC
March 2021

Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP) Exhibits Direct Antibacterial Activity Against .

Infect Drug Resist 2021 23;14:1199-1208. Epub 2021 Mar 23.

National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People's Republic of China.

Objective: Treatment choices for () infections are very limited, and the prognosis is generally poor. Effective new antibiotics or repurposing existing antibiotics against infection are urgently needed. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a member of the lipophilic weak acid class, is known as an efflux pump inhibitor for . The aim of this study was to determine the inhibitory activity of CCCP as a potential novel antibiotic against .

Methods: A total of 47 reference strains of different mycobacterial species and 60 clinical isolates of were enrolled. In vitro inhibitory activity of CCCP was accessed using microplates alamar blue method with the reference and clinical isolates. The activity of CCCP against intracellular residing within macrophage was also evaluated by intracellular colony numerating assay.

Results: CCCP exhibited good activity against clinical isolates in vitro, the minimum inhibitory concentration (MIC) ranged from 0.47 μg/mL to 3.75 μg/mL, with a MIC of 1.875 μg/mL and MIC of 3.75 μg/mL. At concentrations safe for the cells, CCCP exhibited highly intracellular bactericidal activities against and reference strains, with inhibitory rates of 84.8%±8.8% and 72.5%±13.7%, respectively. CCCP demonstrated bactericidal activity against intracellular that was comparable to clarithromycin, and concentration-dependent antimicrobial activity against in macrophages was observed. In addition, CCCP also exhibited good activities against most reference strains of rapidly growing mycobacterial species.

Conclusion: CCCP could be a potential candidate of novel antimicrobiological agent to treat infection.
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http://dx.doi.org/10.2147/IDR.S303113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001050PMC
March 2021

Structure and function of DEAH-box helicase 32 and its role in cancer.

Oncol Lett 2021 May 16;21(5):382. Epub 2021 Mar 16.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361102, P.R. China.

DEAH-box helicase 32 (DHX32) is an RNA helicase with unique structural characteristics that is involved in numerous biological processes associated with RNA, including ribosome biosynthesis, transcription, mRNA splicing and translation. Increasing evidence suggests that abnormal DHX32 expression contributes to cancer initiation and development, due to dysregulated cell proliferation, differentiation, apoptosis and other processes. In the current review, the discovery, structure and function of DHX32, as well as the association between abnormal DHX32 expression and tumors are discussed. DHX32 expression is downregulated in acute lymphoblastic leukemia, but upregulated in solid tumors, including colorectal and breast cancer. Furthermore, DHX32 expression levels are associated with the pathological and clinical features of the cancer. Therefore, DHX32 may serve as a novel liquid biopsy marker for auxiliary diagnosis and prognosis screening, as well as a possible target for cancer therapy. The molecular mechanism underlying the contribution of DHX32 towards the initiation and development of cancer requires further investigation for the development of anticancer treatments based on manipulating DHX32 expression and function.
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http://dx.doi.org/10.3892/ol.2021.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988694PMC
May 2021

Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model.

Front Aging Neurosci 2021 10;13:650103. Epub 2021 Mar 10.

Jiangsu Key Laboratory of Neuropsychiatric Diseases, Institute of Neuroscience, Soochow University, Suzhou, China.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates β-amyloid accumulation by upregulating the expression of β-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.
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http://dx.doi.org/10.3389/fnagi.2021.650103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987677PMC
March 2021

Advances in intranasal application of stem cells in the treatment of central nervous system diseases.

Stem Cell Res Ther 2021 Mar 24;12(1):210. Epub 2021 Mar 24.

Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.

Stem cells are characterized by their self-renewal and multipotency and have great potential in the therapy of various disorders. However, the blood-brain barrier (BBB) limits the application of stem cells in the therapy of neurological disorders, especially in a noninvasive way. It has been shown that small molecular substances, macromolecular proteins, and even stem cells can bypass the BBB and reach the brain parenchyma following intranasal administration. Here, we review the possible brain-entry routes of transnasal treatment, the cell types, and diseases involved in intranasal stem cell therapy, and discuss its advantages and disadvantages in the treatment of central nervous system diseases, to provide a reference for the application of intranasal stem cell therapy.
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http://dx.doi.org/10.1186/s13287-021-02274-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992869PMC
March 2021

Depression Induced by Chronic Unpredictable Mild Stress Increases Susceptibility to Parkinson's Disease in Mice via Neuroinflammation Mediated by P2X7 Receptor.

ACS Chem Neurosci 2021 04 18;12(7):1262-1272. Epub 2021 Mar 18.

Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.

The relationship between depression and Parkinson's disease (PD) is complicated and still not fully understood. We investigated whether depression increased the susceptibility to PD and whether this resulted from neuroinflammation mediated by purinergic ligand-gated ion channel 7 receptor (P2X7R) of microglia in mice. Depression was induced by a 14-day chronic unpredictable mild stress (CUMS), and PD was induced by 1-day acute injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Before MPTP administration, some mice were given brilliant blue G (BBG), a P2X7R inhibitor. Changes in depression and motor function were assessed by sucrose preference, tail suspension, open field, and rotating rod tests. Differences in P2X7R, caspase-1, NLRP3 inflammasome, interleukin (IL)-1β, tyrosine hydroxylase (TH), and microglial activation among experimental groups were detected by immunofluorescence, immunohistochemistry, western blotting, and ELISA. CUMS-induced depression-like behavior, and MPTP induced PD in mice. CUMS mice had no motor dysfunction, but the dyskinesia and loss of TH-positive neurons in the substantia nigra after MPTP treatment were more serious than with MPTP treatment alone. With behavioral changes, neuroinflammatory markers, such as caspase-1, NLRP3 and IL-1β increased, and microglia were activated as well as expression of P2X7R increased. Additionally, BBG partly reversed the above abnormalities. Summarily, we suggest that CUMS aggravates dyskinesia and death of dopaminergic neurons in an MPTP-PD model via promoting activation of microglia and neuroinflammation, which may be mediated by P2X7R. Inhibition of P2X7R could be a new control strategy for PD associated with depression.
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http://dx.doi.org/10.1021/acschemneuro.1c00095DOI Listing
April 2021

Fatigue correlates with sleep disturbances in Parkinson disease.

Chin Med J (Engl) 2020 Dec 16;134(6):668-674. Epub 2020 Dec 16.

Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.

Background: Many Parkinson disease (PD) patients complain about chronic fatigue and sleep disturbances during the night. The objective of this study is to determine the relationship between fatigue and sleep disturbances by using polysomnography (PSG) in PD patients.

Methods: Two hundred and thirty-two PD patients (152 with mild fatigue and 80 with severe fatigue) were recruited in this study. Demographic information and clinical symptoms were collected. Fatigue severity scale (FSS) was applied to evaluate the severity of fatigue, and PSG was conducted in all PD patients. FSS ≥4 was defined as severe fatigue, and FSS <4 was defined as mild fatigue. Multivariate logistic regression and linear regression models were used to investigate the associations between fatigue and sleep disturbances.

Results: Patients with severe fatigue tended to have a longer duration of disease, higher Unified Parkinson Disease Rating Scale score, more advanced Hoehn and Yahr stage, higher daily levodopa equivalent dose, worse depression, anxiety, and higher daytime sleepiness score. In addition, they had lower percentage of rapid eye movement (REM) sleep (P = 0.009) and were more likely to have REM sleep behavior disorder (RBD) (P = 0.018). Multivariate logistic regression analyses found that the presence of RBD and proportion of REM sleep were the independent predictors for fatigue. After the adjustment of age, sex, duration, body mass index, severity of disease, scores of Hamilton Rating Scale for Depression, Hamilton Anxiety Rating Scale, and other sleep disorders, proportion of REM sleep and degree of REM sleep without atonia in patients with PD were still associated with FSS score.

Conclusion: Considering the association between fatigue, RBD, and the altered sleep architecture, fatigue is a special subtype in PD and more studies should be focused on this debilitating symptom.
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http://dx.doi.org/10.1097/CM9.0000000000001303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990014PMC
December 2020

Effect of potassium on DNA methylation of aldosterone synthase gene.

J Hypertens 2021 05;39(5):1018-1024

Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University.

Background: Aldosterone synthase gene, CYP11B2 is regulated by potassium and angiotensin II (Ang II). We have reported that Ang II could change the DNA methylation status around transcription factor-binding sites and a transcription start site (TSS) and activate expression of CYP11B2. Similar to Ang II, small increases in extracellular potassium levels also increase CYP11B2 mRNA levels.

Methods And Results: Adrenocortical H295R cells were treated with different doses of potassium. Methylation analysis of CYP11B2 promoter region was done by bisulfite sequencing. CYP11B2 mRNA and protein levels, chromatin accessibility, methylation and demethylation activity were estimated. The transcriptional ability of CYP11B2 promoter with or without methylation was assessed. Potassium stimulation caused DNA demethylation around cyclic AMP responsive element binding protein 1 (CREB1) and nuclear receptor subfamily 4 group A (NR4A) family-binding sites and a TSS; demethylation was accompanied by recruitment of CREB1 and NR4A1 and increased chromatin accessibility of the CYP11B2 promoter. DNA methylation activity decreased in the nucleus. DNA demethylation at CpG1 (Ad1), CpG2 (Ad5) and CpG3 were detected within 2 to 4 days after potassium (16 mmol/l) stimulation. The changes reached a maximum level by day 7. DNA at CpG2 (Ad5) and CpG3 was re-methylated to levels that were similar to those of nontreated cells at day 9. Potassium treatment significantly reduced DNA methylation activity at days 7 and 9. DNA demethylation activity was not changed by potassium.

Conclusion: : Potassium induced reversibly DNA demethylation, which switches the phenotype of CYP11B2 expression from an inactive to an active state.
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http://dx.doi.org/10.1097/HJH.0000000000002742DOI Listing
May 2021

Bipolar Distribution of Minimum Inhibitory Concentration of Q203 Across Mycobacterial Species.

Microb Drug Resist 2021 Feb 26. Epub 2021 Feb 26.

Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.

In this study, we conducted an experimental study to evaluate susceptibility of Q203 against , as well as the major pathogenic nontuberculous mycobacterial species. A total of 344 nonduplicate mycobacterium isolates were randomly selected for susceptibility testing. Overall, Q203 exhibited excellent activity against multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) isolates, whereas it showed high minimum inhibitory concentration (MIC) values for all nontuberculous mycobacteria (NTM) isolates tested. The MIC and MIC values were both 0.008 mg/L for MDR- and XDR-TB isolates, respectively. In contrast, the MIC and MIC values of four NTM species were all >16 mg/L. QcrB of , a component of the CytBC1 complex of the respiratory chain targeted by Q230, shared 89.7% amino acid sequence identity with QcrB, 87.9% with that of , and 84.0% with that of , whereas with low sequence identity observed in QcrB sequence of . Notably, the QcrBs of and contained a 10-amino acid insertion in the linker between the eighth and ninth helical region. In conclusion, our data demonstrate the bipolar distribution of Q203 MICs across mycobacterial species. Compared with the high MICs in four clinically relevant mycobacterial species, MDR- and XDR-TB isolates have extremely low MICs, indicating that Q203 is a particularly promising candidate for TB treatment. In addition, the 10-amino acid insertion within QcrBs of and may be a plausible explanation for the natural resistance to Q203 among these two species.
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http://dx.doi.org/10.1089/mdr.2020.0239DOI Listing
February 2021

Near-infrared fluorescence-guided resection of micrometastases derived from esophageal squamous cell carcinoma using a c-Met-targeted probe in a preclinical xenograft model.

J Control Release 2021 Apr 24;332:171-183. Epub 2021 Feb 24.

Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China. Electronic address:

The postoperative survival of esophageal squamous cell carcinoma (eSCC) is notably hindered by cancer recurrence due to difficulty in identifying occult metastases. Cellular mesenchymal-epithelial transition factor (c-Met), which is highly expressed in different cancers, including eSCC, has become a target for the development of imaging probes and therapeutic antibodies. In this study, we synthesized an optical probe (SHRmAb-IR800) containing a near-infrared fluorescence (NIRF) dye and c-Met antibody, which may help in NIRF-guided resection of micrometastases derived from eSCC. Cellular uptake of SHRmAb-IR800 was assessed by flow cytometry and confocal microscopy. In vivo accumulation of SHRmAb-IR800 and the potential application of NIRF-guided surgery were evaluated in eSCC xenograft tumor models. c-Met expression in human eSCC samples and lymph node metastases (LNMs) was analyzed via immunohistochemistry (IHC). Cellular accumulation of SHRmAb-IR800 was higher in c-Met-positive EC109 eSCC cells than in c-Met-negative A2780 cells. Infusion of SHRmAb-IR800 produced higher fluorescence intensity and a higher tumor-to-background ratio (TBR) than the control probe in EC109 subcutaneous tumors (P < 0.05). The TBRs of orthotopic EC109 tumors and LNMs were 3.01 ± 0.17 and 2.77 ± 0.56, respectively. The sensitivity and specificity of NIRF-guided resection of metastases derived from orthotopic cancers were 92.00% and 89.74%, respectively. IHC results demonstrated positive staining in 97.64% (124/127) of eSCC samples and 91.67% (55/60) of LNMs. Notably, increased c-Met expression was observed in LNMs compared to normal lymph nodes (P < 0.0001). Taken together, the results of this study indicated that SHRmAb-IR800 facilitated the resection of micrometastases of eSCC in the xenograft tumor model. This c-Met-targeted probe possesses translational potential in NIRF-guided surgery due to the high positive rate of c-Met protein in human eSCCs.
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http://dx.doi.org/10.1016/j.jconrel.2021.02.019DOI Listing
April 2021

Structural characterization of a novel Schisandra polysaccharides and nutritional intervention in immunotoxicity to PCBs.

Carbohydr Polym 2021 Apr 20;258:117380. Epub 2021 Jan 20.

School of the Environment and Safety Engineering, Jiangsu University, Xuefu Rd. 301, Zhenjiang, 212013 Jiangsu, China.

A new polysaccharide from fruits of Schisandra chinensis (SCPP22) with a molecular weight of 143 ± 0.13 KDa was mainly made up of glucose and galactose. The possible structure of SCPP22 was showed that its main chain was composed of 1,4-α-d-Glup and branch was stretched from O-6 position of 1,4-β-d-Glup. Branches consisted of T-α-d-Galp. Further, SCPP22 could reverse PCB126-induced immunosuppression, significantly enhance body weight and immune organ indices. It also significantly ameliorated oxidative injury to immune organ induced by PCB126, as shown by evaluation of SOD activities, as well as MDA levels in spleen and thymus. SCPP22 strongly stimulated cytokines production by up-regulating mRNA expression of TNF-α, INF-γ and IL-2. Mechanism investigation revealed that recovery effects of SCPP22 in immunosuppression induced by PCB126 are mainly through regulating apoptosis-related proteins expression. Schisandra polysaccharides might be applied in functional food as nutritional intervention ingredient.
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http://dx.doi.org/10.1016/j.carbpol.2020.117380DOI Listing
April 2021

HIV-1LAI Nef blocks the development of hematopoietic stem/progenitor cells into T lymphoid cells.

AIDS 2021 05;35(6):851-860

Department of Clinical Medicine, Nanchang University, Nanchang, Jiangxi, China.

Objective: Despite successful antiviral therapy, the recovery of CD4+ T cells may not be complete in certain HIV-1-infected individuals. In our previous work with humanized mice infected with CXCR4-tropic HIV-1LAI (LAI), viral protein Nef was found the major factor determining rapid loss of both CD4+ T cells and CD4+CD8+ thymocytes but its effect on early T-cell development is unknown. The objective of this study is to investigate the influence of LAI Nef on the development of hematopoietic stem/progenitor cells (HSPCs) into T lymphoid cells.

Design: HSPC-OP9-DL1 cell co-culture and humanized mouse model was used to investigate the objective of our study in vitro and in vivo. RNA-seq was exploited to study the change of gene expression signature after nef expression in HSPCs.

Results: Nef expression in HSPCs was found to block their development into T lymphoid cells both in vitro and in the mice reconstituted with nef-expressing HSPCs derived from human cord blood. More surprisingly, in humanized mice nef expression preferentially suppressed the production of CD4+ T cells. This developmental defect was not the result of CD34+ cell loss. RNA-seq analysis revealed that Nef affected the expression of 176 genes in HSPCs, including those involved in tumor necrosis factor, Toll-like receptor, and nucleotide-binding oligomerization domain-like receptor signaling pathways that are important for hematopoietic cell development.

Conclusion: Our results demonstrate that Nef compromises the development of HSPCs into T lymphoid cells, especially CD4+ T cells. This observation suggests that therapeutics targeting Nef may correct HIV-1-associated hematopoietic abnormalities, especially defects in T-cell development.
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http://dx.doi.org/10.1097/QAD.0000000000002837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048728PMC
May 2021

One-stage partial nitrification and anammox process in a sequencing batch biofilm reactor: Start-up, nitrogen removal performance and bacterial community dynamics in response to temperature.

Sci Total Environ 2021 Jun 1;772:145529. Epub 2021 Feb 1.

School of Environmental Science and Engineering, Tianjin University, Tianjin 300350, China.

A one-stage partial nitrification and anammox (PN/A) process was started up and operated under varying temperatures in a lab-scale sequencing batch biofilm reactor. The start‑up phase took 110 days with an intermittent aeration strategy, and the removal efficiencies of ammonia‑nitrogen and total nitrogen were found to be 92.22% and 76.07%, respectively. The total nitrogen removal efficiency (NRE) increased by 9.49% when temperature decreased from 30 °C to 25 °C, but declined by 83.84% from 25 °C to 20 °C. The PN process was inhibited and subsequently limited the nitrogen removal performance at 20 °C. When temperature returned to 28 °C, the NRE recovered to 67.27%, but it was still lower than the value before the decrease in temperature (79.40%). Microbial community analysis showed that the predominant ammonia oxidation bacteria and anammox bacteria were Nitrosomonas and Candidatus Kuenenia, respectively. Nitrosomonas grew, while the relative abundance of Candidatus Kuenenia increased as temperature decreased and vice versa.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145529DOI Listing
June 2021

Caffeine-Operated Synthetic Modules for Chemogenetic Control of Protein Activities by Life Style.

Adv Sci (Weinh) 2021 Feb 13;8(3):2002148. Epub 2020 Dec 13.

Center for Translational Cancer Research Institute of Biosciences and Technology Texas A&M University Houston TX 77030 USA.

A genetically encoded caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti-caffeine nanobody via cell-based high-throughput screening, permits caffeine-inducible gating of calcium channels, tumor killing via necroptosis, growth factors-independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody-mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike protein. Further rationalized engineering of COSMO leads to 34-217-fold enhancement in caffeine sensitivity (EC = 16.9 nanomolar), which makes it among the most potent CID systems like the FK506 binding protein (FKBP)-FKBP rapamycin binding domain (FRB)-rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life.
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http://dx.doi.org/10.1002/advs.202002148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856909PMC
February 2021