Publications by authors named "Yue Feng"

650 Publications

Elevated glycolysis imparts functional ability to CD8 T cells in HIV infection.

Life Sci Alliance 2021 Nov 21;4(11). Epub 2021 Sep 21.

Deparment of Medicine, University of Toronto, Toronto, Canada

The mechanisms inducing exhaustion of HIV-specific CD8 T cells are not fully understood. Metabolic programming directly influences T-cell differentiation, effector function, and memory. We evaluated metabolic profiles of ex vivo CD8 T cells in HIV-infected individuals. The baseline oxygen consumption rate of CD8 T cells was elevated in all infected individuals and CD8 T cells were working at maximal respiratory capacity. The baseline glycolysis rate was enhanced only during early untreated HIV and in viral controllers, but glycolytic capacity was conserved at all stages of infection. CD8 T-cell mTOR activity was found to be reduced. Enhanced glycolysis was crucial for HIV-specific killing of CD8 T cells. CD8 T-cell cytoplasmic GAPDH content was reduced in HIV, but less in early infection and viral controllers. Thus, CD8 T-cell exhaustion in HIV is characterized by reduced glycolytic activity, enhanced OXPHOS demands, dysregulated mTOR, and reduced cytoplasmic GAPDH. These data provide potential metabolic strategies to reverse CD8 T-cell dysfunction in HIV.
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http://dx.doi.org/10.26508/lsa.202101081DOI Listing
November 2021

The Effector SdjA Is a Bifunctional Enzyme That Distinctly Regulates Phosphoribosyl Ubiquitination.

mBio 2021 Sep 7:e0231621. Epub 2021 Sep 7.

Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.

Legionella pneumophila promotes its survival and replication in phagocytes by actively modulating cellular processes using effectors injected into host cells by its Dot/Icm type IV secretion system. Many of these effectors function to manipulate the ubiquitin network of infected cells, thus contributing to the biogenesis of the -containing vacuole (LCV), which is permissive for bacterial replication. Among these, members of the SidE effector family (SidEs) catalyze ubiquitination of functionally diverse host proteins by a mechanism that is chemically distinct from the canonical three-enzyme cascade. The activity of SidEs is regulated by two mechanisms: reversal of the phosphoribosyl ubiquitination by DupA and DupB and direct inactivation by SidJ, which is a calmodulin-dependent glutamylase. In many L. pneumophila strains, SidJ belongs to a two-member protein family. Its homolog SdjA appears to function differently from SidJ despite the high-level similarity in their primary sequences. Here, we found that SdjA is a bifunctional enzyme that exhibits distinct activities toward members of the SidE family. It inhibits the activity of SdeB and SdeC by glutamylation. Unexpectedly, it also functions as a deglutamylase that reverses SidJ-induced glutamylation on SdeA. Our results reveal that an enzyme can catalyze two completely opposite biochemical reactions, which highlights the distinct regulation of phosphoribosyl ubiquitination by the SidJ effector family. One unique feature of L. pneumophila Dot/Icm effectors is the existence of protein families with members of high-level similarity. Whereas members of some families are functionally redundant, as suggested by their primary sequences, the relationship between SidJ and SdjA, the two members of the SidJ family, has remained mysterious. Despite their sharing 57% identity, cannot complement the defects in virulence displayed by a mutant lacking . SidJ inhibits the activity of the SidE family by a calmodulin (CaM)-dependent glutamylase activity. Here, we found that SdjA is a dual function protein: it is a CaM-dependent glutamylase against SdeB and SdeC but exhibits deglutamylase activity toward SdeA that has been modified by SidJ, indicating that SdjA functions to fine-tune the activity of SidEs. These findings have paved the way for future structural and functional analysis of SdjA, which may reveal novel mechanism for isopeptide bond cleavage and provide insights into the study of protein evolution.
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http://dx.doi.org/10.1128/mBio.02316-21DOI Listing
September 2021

A machine learning-based biological aging prediction and its associations with healthy lifestyles: the Dongfeng-Tongji cohort.

Ann N Y Acad Sci 2021 Sep 3. Epub 2021 Sep 3.

Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

This study aims to establish a biological age (BA) predictor and to investigate the roles of lifestyles on biological aging. The 14,848 participants with the available information of multisystem measurements from the Dongfeng-Tongji cohort were used to estimate BA. We developed a composite BA predictor showing a high correlation with chronological age (CA) (r = 0.82) by using an extreme gradient boosting (XGBoost) algorithm. The average frequency hearing threshold, forced expiratory volume in 1 second (FEV ), gender, systolic blood pressure, and homocysteine ranked as the top five important features for the BA predictor. Two aging indexes, recorded as the AgingAccel (the residual from regressing predicted age on CA) and aging rate (the ratio of predicted age to CA), showed positive associations with the risks of all-cause (HR (95% CI) = 1.12 (1.10-1.14) and 1.08 (1.07-1.10), respectively) and cause-specific (HRs ranged from 1.06 to ∼1.15) mortality. Each 1-point increase in healthy lifestyle score (including normal body mass index, never smoking, moderate alcohol drinking, physically active, and sleep 7-9 h/night) was associated with a 0.21-year decrease in the AgingAccel (95% CI: -0.27 to -0.15) and a 0.4% decrease in the aging rate (95% CI: -0.5% to -0.3%). This study developed a machine learning-based BA predictor in a prospective Chinese cohort. Adherence to healthy lifestyles showed associations with delayed biological aging, which highlights potential preventive interventions.
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http://dx.doi.org/10.1111/nyas.14685DOI Listing
September 2021

Characterization of a Novel Hepatitis C Subtype, 6xj, and Its Consequences for Direct-Acting Antiviral Treatment in Yunnan, China.

Microbiol Spectr 2021 Sep 25;9(1):e0029721. Epub 2021 Aug 25.

Faculty of Life Science and Technology, Kunming University of Science and Technologygrid.218292.2, Kunming, China.

Hepatitis C virus (HCV) has a high rate of genetic variability, with eight genotypes and 91 subtypes. The genetic diversity of HCV genotype 6 (HCV-6) is the highest with 31 subtypes, and this genotype is prevalent in Southeast Asia. In this study, we investigated 160 individuals with chronic hepatitis C in Yunnan Province, China. Using reverse transcription (RT)-PCR and Sanger sequencing, 147 cases were successfully amplified and genotyped as 3b (4.9%), 3a (19.73%), 6n (12.24%), 1b (7.48%), 2a (6.12%), 6a (2.04%), 1a (0.68%), 6v (0.68%), and 6xa (0.68%), with eight sequences remaining unclassified. Subsequently, the eight nearly full-length genomes were successfully amplified and analyzed. The eight complete coding sequences formed a phylogenetic group that was distinct from the previously assigned HCV-6 subtypes and clustered with two previously unnamed HCV-6 sequences. Furthermore, Simplot analysis showed no recombination and the -distance was more than 15% in comparison to the 6a to 6xi subtypes. Taken together, we identified a new HCV-6 subtype, 6xj, which originated approximately in 1775 according to Bayesian analyses. Moreover, all eight individuals received follow-up assessments at 44 weeks from the beginning of their 12-week treatments of sofosbuvir/velpatasvir (after-treatment week 32). One case relapsed at after-treatment week 32. Next-generation sequencing (NGS) was conducted and showed that the treatment failure case had two suspected antiviral resistance mutations, NS5A V28M (a change of V to M at position 28) and NS5B A442V, compared with the baseline. Overall, this newly identified 6xj subtype further confirmed the high diversity of the HCV-6 genotype. The newly identified resistance-associated amino acid substitutions may help inform future clinical treatments. This study investigated the genetic diversity of hepatitis C virus (HCV), particularly in relation to genotype 6, which is prevalent in Yunnan, China, and is often difficult to treat successfully. We identified a new HCV-6 subtype, 6xj, which is an ancient strain. Moreover, all eight individuals with the novel subtype received follow-up assessments at 44 weeks from the beginning of their treatments. One case relapsed after 8 months of withdrawal. NGS was conducted and showed that the isolate from the treatment failure case had two suspected antiviral resistance mutations, NS5A V28M and NS5B A442V, compared with the baseline. Overall, this newly identified 6xj subtype further confirmed the high diversity of the HCV-6 genotype. The newly identified resistance-associated amino acid substitutions may help inform future clinical treatments. We believe that our study makes a significant contribution to the literature based on the results described above.
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http://dx.doi.org/10.1128/Spectrum.00297-21DOI Listing
September 2021

Identification of a newly emerging HIV-1 CRF111_01C comprising CRF01_AE and C in Yunnan, China: Genetic characterization and recombinant history.

Infect Genet Evol 2021 Aug 26;95:105053. Epub 2021 Aug 26.

Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China. Electronic address:

New human immunodeficiency virus (HIV)-1 circulating recombinant forms (CRFs) have recently emerged and disseminated rapidly in China; in total 38 CRFs have been identified thus far. Yunnan province shares its border with Myanmar, and is regarded as a "hotspot" for the occurrence of new HIV-1 recombinations; more than half of novel CRFs reported in China have been first documented in Yunnan province. In the present study, based on the information available on four existing near-full-length genome (NFLG) sequences, combined with data on four other closely related sequences obtained via Basic Local Alignment Search Tool (BLAST) analysis, NFLG/subregion phylogenetic, bootscanning, and time to the most recent common ancestor (TMRCA) analyses were performed. Phylogenetic analysis revealed that the eight strains demonstrated the formation of a distinct monophyletic branch with a bootstrap value of 100%. Strains in this branch were distantly related to all known HIV-1 CRFs; it was temporarily named CRF111_01C. Bootscanning analysis revealed that CRF111_01C consisted of a CRF01_AE backbone and four inserted subtype C segments. Remarkably, CRF111_01C shared six mosaic fragment identities with the previously identified CRF100_01C. Furthermore, CRF111_01C may be deemed a potential second-generation CRF consisting of CRF100_01C and C. Coalescent Bayesian analyses revealed that the TMRCA of CRF111_01C was approximately the period 1999-2002. The emergence of such second-generation recombinants highlights that continuous molecular screening is necessary to carefully monitor the evolutionary dynamics of HIV-1 epidemics.
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http://dx.doi.org/10.1016/j.meegid.2021.105053DOI Listing
August 2021

Hydrogen sulfide molecule adsorbed on doped graphene: a first-principles study.

J Mol Model 2021 Aug 27;27(9):265. Epub 2021 Aug 27.

School of Electrical Engineering and Automation, Harbin Institute of Technology, Harbin, 150001, China.

First principles were used to investigate electronic properties of Au-doped graphene, Ag-doped graphene, and Cu-doped graphene and the effect of adsorption behavior of hydrogen sulfide (HS) molecule on their electronic properties. Doped graphene exhibits interesting electronic properties. The gap value of Ag-doped graphene is 0.29 eV, whereas Au-doped graphene is 0.48 eV which is the largest one in three doped systems, a clear difference of structure and electronic properties among three doped systems absorbing HS molecule. The doped atom and the HS molecule are on the same side of the graphene for Au-doped graphene and Cu-doped graphene, which belong to a kind of bonding orbital hybridization of electron cloud showed from charge difference density plots. However, Ag-doped graphene adsorbed with HS molecule exhibits a kind of antibonding orbital hybridization. With the analysis in this paper, it is beneficial to research HS gas sensors.
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http://dx.doi.org/10.1007/s00894-021-04888-wDOI Listing
August 2021

Phytochemistry, pharmacology, and potential clinical applications of saffron: A review.

J Ethnopharmacol 2021 Aug 23;281:114555. Epub 2021 Aug 23.

Zhejiang Provincial Key Laboratory of Resources Protection and Innovation of Traditional Chinese Medicine, Zhejiang A&F University, Hangzhou, 311300, China; State Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, 311300, China. Electronic address:

Ethnopharmacological Relevance: Saffron, the dried red stigma of the perennial herb Crocus sativus L. (Iridaceae), is one of the most important and expensive spices in the world. It is used as a traditional Chinese medicine with demonstrated effects in promoting blood circulation and suppressing blood stasis, cooling blood detoxification, and relieving depression. It is mainly used for the treatment of depression, irregular menstruation, postpartum thrombosis, and bruises.

Aim Of The Study: This review aims to provide a systematic and up-to-date overview of the phytochemistry, pharmacology, and clinical applications of saffron. We hope it could provide useful references and guidance for the future directions of research on saffron.

Materials And Methods: The online database, such as Web of Science, Google Scholar, Science Direct, PubMed, SpringerLink, Wiley Online Library, SciFinder and Chemical book, and CNKI were used to collect relevant literature. And the classic books about Chinese herbal medicine were also being referenced.

Results: More than 150 chemical compounds, including carotenoids, flavonoids and flavonoid glycosides, monoterpenes and monoterpenoid derivatives, monocyclic aromatic hydrocarbons, amino acids, alkaloids and others, were revealed. The pharmacological activities study of saffron were focused on the antioxidant, anti-inflammatory, antitumor, antidepressant, hypoglycemic, hypolipidemic, memory-enhancing, and so on. Currently, saffron is mainly used for the treatment of diabetes, Alzheimer's disease, depression, anxiety disorders, cardiovascular diseases, learning and memory disorders, cancer, and other conditions.

Conclusions: Phytochemical and pharmacological analyses of saffron have been revealed in recent studies. However, clinical studies have focused mainly on AD, depression and anxiety disorders. Therefore, a large number of clinical trials are needed to study the efficacy of saffron and its major chemical components against other diseases including hypertension, hyperlipidemia, and cancer. Further studies of the mechanism of action and toxicological properties of saffron are also required, especially research to establish an effective dose of saffron and its long-term toxicity in vivo.
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http://dx.doi.org/10.1016/j.jep.2021.114555DOI Listing
August 2021

Insights into the dual functions of AcrIF14 during the inhibition of type I-F CRISPR-Cas surveillance complex.

Nucleic Acids Res 2021 Sep;49(17):10178-10191

Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, 100029 Beijing, China.

CRISPR-Cas systems are bacterial adaptive immune systems, and phages counteract these systems using many approaches such as producing anti-CRISPR (Acr) proteins. Here, we report the structures of both AcrIF14 and its complex with the crRNA-guided surveillance (Csy) complex. Our study demonstrates that apart from interacting with the Csy complex to block the hybridization of target DNA to the crRNA, AcrIF14 also endows the Csy complex with the ability to interact with non-sequence-specific dsDNA as AcrIF9 does. Further structural studies of the Csy-AcrIF14-dsDNA complex and biochemical studies uncover that the PAM recognition loop of the Cas8f subunit of the Csy complex and electropositive patches within the N-terminal domain of AcrIF14 are essential for the non-sequence-specific dsDNA binding to the Csy-AcrIF14 complex, which is different from the mechanism of AcrIF9. Our findings highlight the prevalence of Acr-induced non-specific DNA binding and shed light on future studies into the mechanisms of such Acr proteins.
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http://dx.doi.org/10.1093/nar/gkab738DOI Listing
September 2021

Screening of Anti-Inflammatory Components of Qin Jin Hua Tan Tang by a Multivariate Statistical Analysis Approach for Spectrum-Effect Relationships.

J Anal Methods Chem 2021 13;2021:6348979. Epub 2021 Aug 13.

Institute of Otolaryngology, Institute of Hearing and Speech of Sun Yat-sen University, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510520, China.

Qing Jin Hua Tan Tang (QJHTT) exerts therapeutic effects in patients with chronic obstructive pulmonary disease (COPD) by alleviating inflammation. However, the anti-inflammatory components of QJHTT have not yet been reported. Our study aimed to screen the active anti-inflammatory components of QJHTT using a multivariate statistical analysis approach for spectrum-effect relationships. Different polar fractions of QJHTT were prepared using ethanol, ethyl acetate, and -butanol to analyze the phytochemical components. Phytochemical fingerprints were generated using ultrahigh-performance liquid chromatography. In total, 24 peaks were observed in ten batches of QJHTT extracts. The anti-inflammatory activity was evaluated using a xylene-induced ear-swelling mouse model. Additionally, the spectrum-effect relationship between the relative areas of the 24 peaks and pharmacological activity was investigated using multivariate statistical analysis. The potential anti-inflammatory ingredients obtained from the screening (multivariate statistical analysis) will be validated for their anti-inflammatory effects and mechanisms utilizing a lipopolysaccharide-induced macrophage inflammation model. QJHTT ethanol extract 1 exhibited good anti-inflammatory activity. Peaks 11, 12, 13, 14, and 16, which were closely correlated with anti-inflammatory activity, were identified as meranzin, baicalin, baicalein, chrysin-7-O--D-glucuronide, and wogonoside, respectively. The anti-inflammatory activities of meranzin, baicalin, baicalein, and wogonoside were verified . These four bioactive components significantly inhibited the secretion of inflammatory factors in the lipopolysaccharide-stimulated macrophage cell line. This research successfully screened the QJHTT anti-inflammatory active ingredient group. Meranzin, baicalin, baicalein, chrysin-7-O--D-glucuronide, and wogonoside were predicted to be the anti-inflammatory active ingredient groups of QJHTT.
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http://dx.doi.org/10.1155/2021/6348979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380171PMC
August 2021

Analysis of Hi-C Data for Discovery of Structural Variations in Cancer.

Methods Mol Biol 2022 ;2301:143-161

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Structural variations (SVs) are large genomic rearrangements that can be challenging to identify with current short read sequencing technology due to various confounding factors such as existence of genomic repeats and complex SV structures. Hi-C breakfinder is the first computational tool that utilizes the technology of high-throughput chromatin conformation capture assay (Hi-C) to systematically identify SVs, without being interfered by regular confounding factors. SVs change the spatial distance of genomic regions and cause discontinuous signals in Hi-C, which are difficult to analyze by routine informatics practice. Here we provide step-by-step guidance for how to identify SVs using Hi-C data and how to reconstruct Hi-C maps in the presence of SVs.
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http://dx.doi.org/10.1007/978-1-0716-1390-0_7DOI Listing
January 2022

Identification of Biomarkers for Cervical Cancer Radiotherapy Resistance Based on RNA Sequencing Data.

Front Cell Dev Biol 2021 3;9:724172. Epub 2021 Aug 3.

Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China.

Cervical cancer as a common gynecological malignancy threatens the health and lives of women. Resistance to radiotherapy is the primary cause of treatment failure and is mainly related to difference in the inherent vulnerability of tumors after radiotherapy. Here, we investigated signature genes associated with poor response to radiotherapy by analyzing an independent cervical cancer dataset from the Gene Expression Omnibus, including pre-irradiation and mid-irradiation information. A total of 316 differentially expressed genes were significantly identified. The correlations between these genes were investigated through the Pearson correlation analysis. Subsequently, random forest model was used in determining cancer-related genes, and all genes were ranked by random forest scoring. The top 30 candidate genes were selected for uncovering their biological functions. Functional enrichment analysis revealed that the biological functions chiefly enriched in tumor immune responses, such as cellular defense response, negative regulation of immune system process, T cell activation, neutrophil activation involved in immune response, regulation of antigen processing and presentation, and peptidyl-tyrosine autophosphorylation. Finally, the top 30 genes were screened and analyzed through literature verification. After validation, 10 genes (KLRK1, LCK, KIF20A, CD247, FASLG, CD163, ZAP70, CD8B, ZNF683, and F10) were to our objective. Overall, the present research confirmed that integrated bioinformatics methods can contribute to the understanding of the molecular mechanisms and potential therapeutic targets underlying radiotherapy resistance in cervical cancer.
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http://dx.doi.org/10.3389/fcell.2021.724172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369412PMC
August 2021

The potential utility of [ Ga]Ga-DOTA-FAPI-04 as a novel broad-spectrum oncological and non-oncological imaging agent-comparison with [F]FDG.

Eur J Nucl Med Mol Imaging 2021 Aug 19. Epub 2021 Aug 19.

Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping St, Jiangyang District, Luzhou, 646000, Sichuan, People's Republic of China.

Purpose: This study aimed to compare the detection performance of [ Ga]Ga-DOTA-FAPI-04 and [F]FDG PET/CT in the patients with various oncological and non-oncological lesions.

Methods: A total of 123 patients underwent contemporaneous [ Ga]Ga-DOTA-FAPI-04 and [F]FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, specificity, predictive values, and accuracy of [F]FDG and [ Ga]Ga-DOTA-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the detection efficacy.

Results: The study subjects consisted of 123 patients (69 men and 54 women; mean age 56.11 ± 11.94 years). Among the 102 patients with either newly diagnosed (82 patients) or previously treated solid tumor (20 patients), a total of 88 solid primary malignant tumors in 84/102 patients were detected. Two patients had two primary tumors each and 1 patient had three primary tumors. Among them, 58/102 and 43/102 patients had nodal (376 lesions) and distant metastases (406 lesions), respectively. Eight patients had hematological neoplasm. No malignant oncological diseases were detected in the remaining 13 patients. A total of 145 non-oncological lesions and benign tumors in 52/123 patients were detected incidentally. [ Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a significantly higher uptake and detection rate for the primary (SUVmax 10.98 ± 5.83 vs. 8.36 ± 6.43, p < 0.001; sensitivity 97.67 vs. 84.89%; and accuracy 96.59 vs. 82.95%, X = 0.538, p = 0.021), nodal (SUVmax 10.50 ± 5.98 vs. 8.20 ± 6.29, p = 0.011; sensitivity 97.59 vs. 84.72%; and accuracy 97.34 vs. 84.31%, X = 2.067, p < 0.001), and distant metastatic lesions (SUVmax 9.64 ± 6.45 vs. 6.74 ± 4.83; p < 0.001; sensitivity 98.01 vs. 65.59%; and accuracy 97.04 vs. 65.51%, X = 4.897, p < 0.001) of solid tumor than did [F]FDG PET/CT. [ Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a lower activity (SUVmax: 6.84 ± 4.67 vs. 13.09 ± 7.29, p < 0.001) and detection rate (sensitivity 50.65 vs. 96.75%, and accuracy 51.28 vs. 95.51%, X = 5.166, p < 0.001) for multiple myeloma and lymphoma compared to [F]FDG PET/CT. [ Ga]Ga-DOTA-FAPI-04 and [F]FDG PET/CT PET/CT demonstrated a comparative activity (SUVmax 6.40 ± 3.95 vs. 5.74 ± 15.78, p = 0.729) and detection efficacy (sensitivity 86.52 vs. 72.34%, and accuracy 84.83 vs. 72.41%, X = 9.460, p = 0.007) for non-oncological lesion and benign tumor detection.

Conclusions: Except for myeloma and lymphoma, [ Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior detection efficacy for detecting various primary and metastatic lesions than [F]FDG PET/CT. A comparative detection utility for non-oncological lesion was obtained with both tracers. [ Ga]Ga-DOTA-FAPI-04 could be used as a broad-spectrum tumor and inflammatory imaging agent in the clinical especially for various solid tumors and non-oncological lesions.
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http://dx.doi.org/10.1007/s00259-021-05522-wDOI Listing
August 2021

A broadly neutralizing humanized ACE2-targeting antibody against SARS-CoV-2 variants.

Nat Commun 2021 08 17;12(1):5000. Epub 2021 Aug 17.

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.
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http://dx.doi.org/10.1038/s41467-021-25331-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371079PMC
August 2021

Apoptotic investigation of brain tissue cells in dogs naturally infected by canine distemper virus.

Virol J 2021 08 12;18(1):165. Epub 2021 Aug 12.

School of Life Science and Basic Medicine, Xinxiang University, Xinxiang, 453003, Henan, China.

Background: Canine distemper caused by canine distemper virus that belongs to the Morbillivirus genus of the Paramyxoviridae family is still a global epidemic significant infectious disease, especially in pet dogs in China and serious harm to the development of the dog industry. It has been known that apoptosis caused by the canine distemper virus can show in culture cells, lymphoid tissues, and the cerebellum. However, its occurrence in brain tissue cells remains unclear. To investigate the relationship among canine distemper infecting brain tissues, apoptosis in brain tissue cells, and demyelinating pathogenesis was investigated.

Methods: 16 naturally infected dogs that exhibited clinical signs of CD and tested positive for the anti-CDV monoclonal antibody and six healthy dogs that served as the control, were used in the research. Brain specimens were divided into the cerebrum, brain stem, and cerebellum embedded in paraffin and made the sections respectively. Approximately 5 µm-thick sections were stained by hematoxylin-eosin, methyl green pyronin, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique, and immunohistochemistry. CDV nucleocapsid protein was detected by immune streptavidin-biotinylated peroxidase complex.

Results: Alterations in the brain tissues of CDV-infected dogs involved both various cells and nerve fibers. CDV had varying degrees of cytotropism to all brain tissue cells; apoptosis also occurred in all brain cells, especially in the endothelia of cerebral vessels, astrocytes, oligodendrocytes, and ependymal cells, the more serious infection, the more obvious apoptosis. Serious infections also involved the pyramidal and Purkinje cells. The nervous fibers exhibited demyelinating lesions (showed small multifocal vacuole), and some axonal neuron atrophy gradually disappeared (formed large vacuole).

Conclusions: Apoptosis in brain tissue cells was mainly related to the propagation path and cytotropism of CDV. The apoptosis of astrocytes, oligodendrocytes, and some neurons may play a significant role in the demyelinating pathogenesis in dogs with acute canine distemper. A lot of diverse nervous signs shown in the clinic may be related to different neuron apoptosis.
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http://dx.doi.org/10.1186/s12985-021-01635-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359588PMC
August 2021

A randomized, controlled comparison of a stannous-containing dentifrice for reducing gingival bleeding and balancing the oral microbiome relative to a positive control.

Am J Dent 2021 Aug;34(4):222-227

Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China.

Purpose: To evaluate the effect of a stannous-containing fluoride dentifrice on gingival health and on the composition of the oral microbiome versus a positive control dentifrice over 2 weeks, in a population of healthy adults with self-reported sub-optimal oral health at baseline.

Methods: This was a randomized, controlled, double-blind clinical study. 87 subjects with self-reported sub-optimal oral health at enrollment were randomized to brush twice daily with either an experimental dentifrice (n= 43) or a marketed positive control dentifrice (n= 43), both containing stannous chloride and 0.321% sodium fluoride. All subjects used a soft, manual toothbrush that was provided. The Mazza modification of gingival papillary bleeding Index (Mazza GI) was used to assess gingivitis at baseline and at Week 2. Supragingival plaque was collected for microbiome composition analyses at baseline, Week 1, and Week 2.

Results: 83 subjects completed the study. Baseline means were balanced between the treatment groups (P> 0.34). At Week 2, the positive control dentifrice demonstrated a 63.8% statistically significant (P< 0.0001) reduction relative to baseline for Mazza number of gingival bleeding sites. The experimental stannous containing dentifrice provided a comparable 63.5% gingival bleeding reduction versus baseline. There was no significant (P= 0.96) difference between the two dentifrices for either Mazza GI score or number of bleeding sites measured. The microbiome composition analysis at Week 1 found that 28 gingivitis-associated bacterial genera, including Porphyromonas, Tannerella, and Fusobacterium, were significantly inhibited in both dentifrice groups when compared to baseline, while the relative abundance of genera associated with oral health, such as Rothia, Streptococcus, Haemophilus, and Lautropia, was significantly elevated after treatment. These improvements in the oral ecosystem were sustained at Week 2.

Clinical Significance: An experimental stannous-containing sodium fluoride dentifrice significantly reduced gingival bleeding comparable to a positive control, and both dentifrices promoted a shift in the oral microbiome towards those genera associated with oral health in a subject population with self-reported sub-optimal oral health at baseline.
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August 2021

Cell Membrane-Coated Halloysite Nanotubes for Target-Specific Nanocarrier for Cancer Phototherapy.

Molecules 2021 Jul 25;26(15). Epub 2021 Jul 25.

Department of Materials Science and Engineering, Jinan University, Guangzhou 510632, China.

Naturally-occurring halloysite nanotubes (HNTs) have many advantages for constructing target-specific delivery of phototherapeutic agents. Here, HNTs were labeled with fluorescein isothiocyanate (FITC) and loaded with the type-II photosensitizer indocyanine green (ICG) for phototherapy. HNTs-FITC-ICG was structurally stable due to presence of HNTs as the nanocarrier and protective agent. The nanocarrier was further wrapped with red blood cell membrane (RBCM) to enhance the biocompatibility. The HNTs-FITC-ICG-RBCM nanocarrier show high cytocompatibility and hemocompatibility. Due to the photothermal effect of ICG, a significant temperature rising was achieved by irradiation of the nanocarrier using 808 nm laser. The photothermal temperature rising was used to kill the cancer cells effectively. The HNTs-FITC-ICG-RBCM nanocarrier was further linked with anti-EpCAM to endow it with targeting therapy performance against breast cancer, and the anti-EpCAM-conjugated nanocarrier exhibited significantly tumor-specific accumulation. The RBCM-coated and biocompatible HNTs nanocarrier is a promising candidate for target-specific therapy of cancer.
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http://dx.doi.org/10.3390/molecules26154483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348248PMC
July 2021

PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer.

Cancer Res 2021 Sep 2;81(18):4696-4708. Epub 2021 Aug 2.

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Abnormalities in genetic and epigenetic modifications can lead to drastic changes in gene expression profiles that are associated with various cancer types. Small cell lung cancer (SCLC) is an aggressive and deadly form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen in SCLC cells, we identified paired box protein 9 (PAX9) as an essential factor that is overexpressed in human malignant SCLC tumor samples and is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis. Genome-wide studies revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. In multiple SCLC cell lines, genetic depletion of led to significant induction of a primed-active enhancer transition, resulting in increased expression of a large number of neural differentiation and tumor-suppressive genes. Mechanistically, PAX9 interacted and cofunctioned with the nucleosome remodeling and deacetylase (NuRD) complex at enhancers to repress nearby gene expression, which was reversed by pharmacologic HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivation of primed enhancers may have potential therapeutic efficacy in treating SCLC expressing high levels of PAX9. SIGNIFICANCE: A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448979PMC
September 2021

Synthesis, molecular docking and mosquitocidal efficacy of lawsone and its derivatives against the dengue vector Aedes aegypti L. (Diptera: Culicidae).

Med Chem 2021 Jul 27. Epub 2021 Jul 27.

State Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou 311300, China.

Background: Aedes aegypti is the primary dengue vector, a significant public health problem in many countries. Controlling the growth of Ae. aegypti is the biggest challenge in the mosquito control program, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission.

Objective: To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1-phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis.

Methods: All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects.

Results: Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM).

Conclusion: The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programme.
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http://dx.doi.org/10.2174/1573406417666210727121654DOI Listing
July 2021

F-PEG1-Vinyl Sulfone-Labeled Red Blood Cells as Positron Emission Tomography Agent to Image Intra-Abdominal Bleeding.

Front Med (Lausanne) 2021 5;8:646862. Epub 2021 Jul 5.

Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

F-Labeled blood pool agents (BPAs) have attracted great attention for identifying bleeding sites. However, many BPAs are not sufficiently evaluated partially due to the limitations of labeling methods. In our previous work, we noticed that F-PEG1-vinyl sulfone (F-VS) could efficiently label red blood cells (RBCs) and . However, its application as BPA is not fully evaluated. In this study, we systematically explored the feasibility of using F-VS-labeled RBCs as a positron emission tomography (PET) BPA for intra-abdominal bleeding diagnosis. In brief, we first optimized the labeling conditions, which lead to an 80% labeling yield of RBCs after incubating with F-VS in phosphate-buffered saline (PBS) at 37°C for 20 min. F-VS-labeled RBCs were found to be stable , which could simplify its transportation/storage for applications. In normal rat PET study, the cardiovascular system could be clearly imaged up to 5 h post injection (p.i.). An intra-abdominal hemorrhage rat model demonstrated that the F-VS-labeled RBCs clearly showed the dynamic changes of extravascular radioactivity due to intra-abdominal hemorrhage. Validation in the model of gastrointestinal bleeding clearly demonstrated the great potential of using F-VS-labeled RBCs as a BPA, which could be further evaluated in future studies.
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http://dx.doi.org/10.3389/fmed.2021.646862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287037PMC
July 2021

Closed-loop geometric multi-scale heart-coronary artery model for the numerical calculation of fractional flow reserve.

Comput Methods Programs Biomed 2021 Sep 6;208:106266. Epub 2021 Jul 6.

Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address:

Background And Objectives: Fractional flow reserve (FFR) is considered to be the "gold standard" for the clinical diagnosis of functional myocardial ischemia. With the development of medical imaging and computational fluid dynamics (CFD), noninvasive computation of FFR has been developed. The most representative calculation method is the noninvasive FFR derived from coronary CT angiography (FFR), but it cannot thoroughly simulate the real physiological structure of the cardiovascular system. In this study, we propose a noninvasive closed-loop FFR derived from coronary CT angiography (FFR).

Methods: The closed-loop multi-scale model includes three parts: the heart module, the coronary artery module with microcirculation structure and the systemic circulation module. The proposed structure was formed by coupling a lumped parameter model (0D) with a 3D model, such that the 0D model provides the boundary conditions for the 3D model. We enrolled 100 patients through a prospective multi-center clinical trial and calculated their FFR. Then, we extracted the pressure and flow waveforms of the coronary stenosis vessels through closed-loop geometric multi-scale CFD calculations. We evaluated the accuracy of FFR in diagnosing myocardial ischemia using the clinical measurement of FFR as the standard.

Results: The results of FFR calculation in all patients showed a good correlation between FFR and FFR (r = 0.64, p < 0.05). The AUC (95% CI) of FFR was 0.819 [0.72, 0.91]. The accuracy, specificity, sensitivity, positive predictive value and negative predictive value of FFR were 86%, 95%, 62%, 86% and 83%, respectively.

Conclusions: The closed-loop multi-scale model proposed in this study can simulate the physiological cycle in a more realistic way. FFR is a reliable diagnostic index for myocardial ischemia.
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http://dx.doi.org/10.1016/j.cmpb.2021.106266DOI Listing
September 2021

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis.

Ann Med 2021 12;53(1):1118-1128

Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Circulating white blood cell (WBC) counts have been related to lung function impairment, but causal relationship was not established. We aimed to evaluate independent effects and causal relationships of WBC subtypes with lung function.

Methods: The 19,159 participants from NHANES 2011-2012 ( = 3570), coke-oven workers (COW,  = 1762) and Dongfeng-Tongji (DFTJ,  = 13,827) cohorts were included in the observational studies. The associations between circulating counts of WBC subtypes and prebronchodilator lung function were evaluated by linear regression models and LASSO regression was used to select effective WBC subtypes. Summary statistics for WBC-associated SNPs were extracted from literature, and Mendelian randomization (MR) analysis with inverse-variance weighted (IVW) method was applied to estimate the causal effects of total WBC and subtypes on lung function among 4012 subjects from COW ( = 1126) and DFTJ cohorts ( = 2886).

Results: Total WBC counts were negatively associated with lung function among three populations and their pooled analysis indicated that per 1 × 10 cells/L increase in total WBC was associated with 36.13 (95% CI: 30.35, 41.91) mL and 25.23 (95% CI: 19.97, 30.50) mL decrease in FVC and FEV, respectively. Independent associations with lung function were found for neutrophils, monocytes, eosinophils and basophils (all  < .05), except lymphocytes. Besides, IVW MR analysis showed that genetically predicted total WBC and neutrophil counts were associated with reduced FVC ( = .017 and .021, respectively) and FEV ( = .048 and .043, respectively).

Conclusions: WBC subtypes were independently associated with lower lung function except lymphocytes. Our findings suggest that circulating neutrophils may be causal factors in lung function impairment.KEY MESSAGESWhite blood cell (WBC) subtypes were negatively associated with lung function level except lymphocytes in the observational studies.Associations of WBC subtypes with lung function may be modified by sex and smoking.Mendelian randomization analysis shows that neutrophils may be causal factors in lung function impairment.
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http://dx.doi.org/10.1080/07853890.2021.1948603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280897PMC
December 2021

Recapitulating Zika Virus Infection in Vagina of Tree Shrew .

Front Cell Infect Microbiol 2021 25;11:687338. Epub 2021 Jun 25.

Faculty of Life Science and Technology, Yunnan Provincial Center for Molecular Medicine, Kunming University of Science and Technology, Kunming, China.

Sexual transmission of Zika Virus (ZIKV) elevates the risk of its dissemination in the female reproductive tract and causes a serious threat to the fetus. However, the available animal models are not appropriate to investigate sexual transmission, dynamics of ZIKV infection, replication, and shedding. The use of tree shrew as a small animal model of ZIKV vaginal infection was assessed in this study. A total of 23 sexually mature female tree shrews were infected with ZIKV GZ01 the intravaginal route. There was no significant difference in change of body weight, and the temperature between ZIKV infected and control animals. Viral RNA loads were detected in blood, saliva, urine, and vaginal douching. ZIKV RNA was readily detected in vaginal lavage of 22 animals (95.65%, 22/23) at 1 dpi, and viral load ranged from 104.46 to 107.35 copies/ml, and the peak of viral load appeared at 1 dpi. The expression of key inflammatory genes, such as IL6, 8, CCL5, TNF-a, and CXCL9, was increased in the spleen of ZIKV infected animals. In the current study, female tree shrews have been successfully infected with ZIKV through the vaginal route for the first time. Interestingly, at first, ZIKV replicates at the local site of infection and then spreads throughout the host body to develop a robust systemic infection and mounted a protective immune response. This small animal model is not only valuable for exploring ZIKV sexual transmission and may also help to explain the cause of debilitating manifestations of the fetus .
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http://dx.doi.org/10.3389/fcimb.2021.687338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270636PMC
July 2021

Intraoperative Swept-Source OCT-Based Corneal Topography for Measurement and Analysis of Stromal Surface After Epithelial Removal.

J Refract Surg 2021 Jul 1;37(7):484-492. Epub 2021 Jul 1.

Purpose: To assess intraoperative stromal topography measurements using swept-source optical coherence tomography (OCT)-based topography/tomography after epithelial removal and to analyze the epithelial contribution to the corneal topography and optics.

Methods: This was a prospective series of 22 eyes of 19 patients referred to receive phototherapeutic keratotomy (PTK) for treatment of recurrent corneal erosion and a control group of 22 virgin eyes. Swept-source OCT corneal topography/tomography was obtained immediately before and immediately after mechanical deepithelialization before PTK. Epithelial thickness maps were obtained before the surgery using spectral-domain OCT in the control group and as a reference in the group with anterior basement membrane dystrophy. Topographic and optical characteristics, including the curvature, astigmatism, asphericity, and higher order aberrations of the cornea before and after deepithelialization were compared, and their differences correlated with the measurements derived from the epithelial thickness maps.

Results: Stromal topography measurements after deepithelialization were easily obtained and showed excellent repeatability. Assessment of corneal edema induced by deepithelialization revealed that it did not significantly affect the measured parameters. The stromal surface was steeper by 1.28 diopters, had higher with-the-rule astigmatism by 0.41 diopters, was more prolate, and had more higher order aberrations compared to the intact epithelialized corneal surface. These differences correlated well with the parameters derived from epithelial thickness maps.

Conclusions: Measurement of stromal topography using swept-source OCT immediately after mechanical deepithelialization may be a viable method in therapeutic refractive surgery, where stromal topography-guided ablation is needed. A significant epithelial contribution to anterior corneal topography and optics was confirmed. .
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http://dx.doi.org/10.3928/1081597X-20210405-01DOI Listing
July 2021

Tumor invasive ability of papillary thyroid carcinomas is not conferred by acquired gene mutations.

J Investig Med 2021 Jul 7. Epub 2021 Jul 7.

Department of Ultrasound, First Affiliated Hospital of Dalian Medical University, Dalian, China

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The ability to predict whether a carcinoma would exhibit invasive ability in patients with PTC is important and has clinical implications for the selection of therapeutic strategies. Although several studies have focused on the genetic characterization of invasive cancer cells, the factors critical to the origination of invasive cancer cells are still unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of the tumor invasion phenotype and to investigate the genetic features of invasive cancer cells in patients with PTC. We performed customized 48-gene deep exon sequencing in samples obtained from 88 patients with PTC via fine needle aspiration; the results revealed that no genetic changes were specifically associated with the tumor aggressiveness phenotype. Our results indicate that genetic mutations do not cause indolent PTCs to become invasive.
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http://dx.doi.org/10.1136/jim-2021-001971DOI Listing
July 2021

Unique protein interaction networks define the chromatin remodelling module of the NuRD complex.

FEBS J 2021 Jul 7. Epub 2021 Jul 7.

Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.

The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1 and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodelling module of the nucleosome remodelling and deacetylase (NuRD) complex. To date, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential for defining underlying mechanisms of gene regulation. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS), we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodelling activity into both ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation-prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the nuclear receptor co-repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.
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http://dx.doi.org/10.1111/febs.16112DOI Listing
July 2021

Classification of type 2 diabetes mellitus with or without cognitive impairment from healthy controls using high-order functional connectivity.

Hum Brain Mapp 2021 Oct 2;42(14):4671-4684. Epub 2021 Jul 2.

School of Biomedical Engineering, ShanghaiTech University, Shanghai, China.

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM-related dementia is still less understood. Recent resting-state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM-CI). However, they mainly used a mass-univariate statistical analysis that was not suitable to reveal the altered FC "pattern" in T2DM-CI, due to lower sensitivity. In this study, we proposed to use high-order FC to reveal the abnormal connectomics pattern in T2DM-CI with a multivariate, machine learning-based strategy. We also investigated whether such patterns were different between T2DM-CI and T2DM without cognitive impairment (T2DM-noCI) to better understand T2DM-induced cognitive impairment, on 23 T2DM-CI and 27 T2DM-noCI patients, as well as 50 healthy controls (HCs). We first built the large-scale high-order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM-CI (as well as T2DM-noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM-CI versus HC differentiation, but only 59.62% in T2DM-noCI versus HC classification. We found abnormal high-order FC patterns in T2DM-CI compared to HC, which was different from that in T2DM-noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM-induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM.
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http://dx.doi.org/10.1002/hbm.25575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410559PMC
October 2021

Multifaceted Regulation of MicroRNA Biogenesis: Essential Roles and Functional Integration in Neuronal and Glial Development.

Int J Mol Sci 2021 Jun 23;22(13). Epub 2021 Jun 23.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.

MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.
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http://dx.doi.org/10.3390/ijms22136765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269442PMC
June 2021

Physical activity attenuates the associations of systemic immune-inflammation index with total and cause-specific mortality among middle-aged and older populations.

Sci Rep 2021 06 15;11(1):12532. Epub 2021 Jun 15.

Department of Occupational and Environmental Health, Key Laboratory of Environment & Health, Ministry of Education; State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan, 430030, Hubei, China.

Systemic immune-inflammation index (SII) emerged as a biomarker of chronic inflammation and an independent prognostic factor for many cancers. We aimed to investigate the associations of SII level with total and cause-specific mortality risks in the general populations, and the potential modification effects of lifestyle-related factors on the above associations. In this study, we included 30,521 subjects from the Dongfeng-Tongji (DFTJ) cohort and 25,761 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. Cox proportional hazards regression models were used to estimate the associations of SII with mortality from all-cause, cardiovascular diseases (CVD), cancer and other causes. In the DFTJ cohort, compared to subjects in the low SII subgroup, those within the middle and high SII subgroups had increased risks of total mortality [hazard ratio, HR (95% confidence interval, CI) = 1.12 (1.03-1.22) and 1.26 (1.16-1.36), respectively) and CVD mortality [HR (95%CI) = 1.36 (1.19-1.55) and 1.50 (1.32-1.71), respectively]; those within the high SII subgroup had a higher risk of other causes mortality [HR (95%CI) = 1.28 (1.09-1.49)]. In the NHANES 1999-2014, subjects in the high SII subgroup had higher risks of total, CVD, cancer and other causes mortality [HR (95%CI) = 1.38 (1.27-1.49), 1.33 (1.11-1.59), 1.22 (1.04-1.45) and 1.47 (1.32-1.63), respectively]. For subjects with a high level of SII, physical activity could attenuate a separate 30% and 32% risk of total and CVD mortality in the DFTJ cohort, and a separate 41% and 59% risk of total and CVD mortality in the NHANES 1999-2014. Our study suggested high SII level may increase total and CVD mortality in the general populations and physical activity exerted a beneficial effect on the above associations.
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http://dx.doi.org/10.1038/s41598-021-91324-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206152PMC
June 2021

Selenium mitigated aflatoxin B1-induced cardiotoxicity with potential regulation of 4 selenoproteins and ferroptosis signaling in chicks.

Food Chem Toxicol 2021 Aug 8;154:112320. Epub 2021 Jun 8.

Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China. Electronic address:

The aim of the present study was to explore the underlying mechanism of selenium (Se)-mediated detoxification of aflatoxin B (AFB)-induced cardiotoxicity in chicks. A Se-deficient, corn-soybean meal-basal diet (36 μg Se/kg, BD) and three test diets (BD+1.0 mg AFB/kg, 0.3 mg Se/kg, or 1.0 mg AFB/kg+0.3 mg Se/kg) were used in a 3-wk 2 × 2 factorial design trial (n = 30 chicks/group). Dietary AFB led to induced (P < 0.05) serum creatine kinase and creatine kinase MB isoenzyme activities and heart histopathologic lesions. However, Se deficiency aggravated most of these alterations induced by AFB. Moreover, mRNA levels of two ferroptosis activators (solute carrier family 11 Member 2 and transferrin) were upregulated (P < 0.05) in the AFB-treated groups. Additionally, Se deficiency reduced (P < 0.05) glutathione peroxidase (GPX) 3 and thioredoxin reductase 3 mRNA and GPX activity but increased (P < 0.05) selenoprotein M and selenophosphate synthetase 2 mRNA in the heart in AFB-administered groups. The in vitro study showed that Se alleviated (P < 0.05) AFB-reduced cell viability and induced (P < 0.05) ROS and ferroptosis in H9C2 cardiac cells. It also downregulated (P < 0.05) two ferroptosis activators (long-chain acyl-CoA synthetase 4 and solute carrier family 11 Member 2) in the AFB-treated groups in the H9C2 cells. In conclusion, this study illustrated that Se alleviates AFB-induced cardiotoxicity and cardiomyocyte damage potentially related to the regulation of redox status, 4 selenoproteins, and ferroptosis-related signaling.
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http://dx.doi.org/10.1016/j.fct.2021.112320DOI Listing
August 2021

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics.

Elife 2021 06 9;10. Epub 2021 Jun 9.

Biology Department, University of Massachusetts Amherst, Amherst, United States.

Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1α indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.
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http://dx.doi.org/10.7554/eLife.63972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233041PMC
June 2021
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