Publications by authors named "Yuan Tian"

1,265 Publications

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Quantitative Mammographic Density Measurements and Molecular Subtypes in Chinese Women With Breast Cancer.

JNCI Cancer Spectr 2021 Feb 13;5(1):pkaa092. Epub 2020 Oct 13.

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD, USA.

Background: Studies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the human epidermal growth factor receptor-2 (HER2)-enriched subtype in Chinese breast cancer patients.

Methods: In this study, we reevaluated the MD-subtype association in 1549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were 2-sided.

Results: Compared with women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.04 to 1.38;  = .01), luminal B/HER2+ (OR = 1.22, 95% CI = 1.03 to 1.46;  = .03), and HER2-enriched tumors (OR = 1.30, 95% CI = 1.06 to 1.59;  = .01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (<2 cm). In contrast, the triple-negative subtype was associated with lower nondense volume (OR = 0.82, 95% CI = 0.68 to 0.99;  = .04), and the association was only seen among older women (age 50 years or older).

Conclusion: Although biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.
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http://dx.doi.org/10.1093/jncics/pkaa092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791622PMC
February 2021

A Linkage-specific Sialic Acid Labeling Strategy Reveals Different Site-specific Glycosylation Patterns in SARS-CoV-2 Spike Protein Produced in CHO and HEK Cell Substrates.

Front Chem 2021 24;9:735558. Epub 2021 Sep 24.

Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Baltimore, MD, United States.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus utilizes the extensively glycosylated spike (S) protein protruding from the viral envelope to bind to angiotensin-converting enzyme-related carboxypeptidase (ACE2) as its primary receptor to mediate host-cell entry. Currently, the main recombinant S protein production hosts are Chinese hamster ovary (CHO) and human embryonic kidney (HEK) cells. In this study, a recombinant S protein truncated at the transmembrane domain and engineered to express a C-terminal trimerization motif was transiently produced in CHO and HEK cell suspensions. To further evaluate the sialic acid linkages presenting on S protein, a two-step amidation process, employing dimethylamine and ammonium hydroxide reactions in a solid support system, was developed to differentially modify the sialic acid linkages on the glycans and glycopeptides from the S protein. The process also adds a charge to Asp and Glu which aids in ionization. We used MALDI-TOF and LC-MS/MS with electron-transfer/higher-energy collision dissociation (EThcD) fragmentation to determine global and site-specific N-linked glycosylation patterns. We identified 21 and 19 out of the 22 predicted N-glycosites of the SARS-CoV-2 S proteins produced in CHO and HEK, respectively. It was found that the N-glycosite at 1,158 position (N1158) and at 122, 282 and 1,158 positions (N122, N282 and N1158) were absent on S from CHO and HEK cells, respectively. The structural mapping of glycans of recombinant human S proteins reveals that CHO-Spike exhibits more complex and higher sialylation (α2,3-linked) content while HEK-Spike exhibits more high-mannose and a small amount of α2,3- and α2,6-linked sialic acids. The N74 site represents the most abundant glycosite on both spike proteins. The relatively higher amount of high-mannose abundant sites (N17, N234, N343, N616, N709, N717, N801, and N1134) on HEK-Spike suggests that glycan-shielding may differ among the two constructs. HEK-Spike can also provide different host immune system interaction profiles based on known immune system active lectins. Collectively, these data underscore the importance of characterizing the site-specific glycosylation of recombinant human spike proteins from HEK and CHO cells in order to better understand the impact of the production host on this complex and important protein used in research, diagnostics and vaccines.
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http://dx.doi.org/10.3389/fchem.2021.735558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497748PMC
September 2021

Metabolic network-based identification of plasma markers for non-small cell lung cancer.

Anal Bioanal Chem 2021 Oct 7. Epub 2021 Oct 7.

Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 210009, Jaingsu, China.

Metabolic markers, offering sensitive information on biological dysfunction, play important roles in diagnosing and treating cancers. However, the discovery of effective markers is limited by the lack of well-established metabolite selection approaches. Here, we propose a network-based strategy to uncover the metabolic markers with potential clinical availability for non-small cell lung cancer (NSCLC). First, an integrated mass spectrometry-based untargeted metabolomics was used to profile the plasma samples from 43 NSCLC patients and 43 healthy controls. We found that a series of 39 metabolites were altered significantly. Relying on the human metabolic network assembled from Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we mapped these differential metabolites to the network and constructed an NSCLC-related disease module containing 23 putative metabolic markers. By measuring the PageRank centrality of molecules in this module, we computationally evaluated the network-based importance of the 23 metabolites and demonstrated that the metabolism pathways of aromatic amino acids and long-chain fatty acids provided potential molecular targets of NSCLC (i.e., IL4l1 and ACOT2). Combining network-based ranking and support-vector machine modeling, we further found a panel of eight metabolites (i.e., pyruvate, tryptophan, and palmitic acid) that showed a high capability to differentiate patients from controls (accuracy > 97.7%). In summary, we present a meaningful network method for metabolic marker discovery and have identified eight strong candidate metabolites for NSCLC diagnosis.
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http://dx.doi.org/10.1007/s00216-021-03699-5DOI Listing
October 2021

Rational Design of a Dual-Targeting Natural Toxin-Like Bicyclic Peptide for Selective Bioenergetic Blockage in Cancer Cells.

Bioconjug Chem 2021 Oct 4. Epub 2021 Oct 4.

Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, P. R. China.

Stapled α-helical peptides emerge as one of the attractive peptidomimetics which can efficiently penetrate the cell membrane to access intracellular targets. However, the incorporation of a highly lipophilic cross-link may lead to nonspecific membrane toxicity in certain cases. Here, we report a new class of thioether-tethered bicyclic α-helical peptide to mimic the highly constrained loop-helix structure of natural toxins with the dual-targeting ability for both cell-surface receptors and intracellular targets. The thioether cross-links are introduced to replace the redox-sensitive disulfide bonds in natural toxins via a photoinduced thiol-yne reaction followed by macrolactamization. As a proof of concept, αβ integrin targeting ligand was grafted into one of the macrocycles in the bicyclic scaffold, while a mitochondria-targeting proapoptotic motif was introduced into the other macrocycle stabilized by an , + 7 alkyl thioether cross-link to recapitulate its α-helical conformation. The obtained dual-targeting bicyclic α-helical BIRK peptides showed highly stable α-helical conformation in the presence of denaturants or under high temperature. Notably, BIRK peptides could induce selective cell death in αβ integrin-positive B16F10 cells by interfering with the bioenergetic functions of mitochondria. This work provides a new avenue to design and stabilize α-helical peptides in a highly constrained bicyclic loop-helix scaffold with dual functionality.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00366DOI Listing
October 2021

Significance of CD8 + T cell infiltration related biomarkers and the corresponding prediction model for the prognosis of kidney renal clear cell carcinoma.

Aging (Albany NY) 2021 Oct 4;13(undefined). Epub 2021 Oct 4.

Phase I Clinical Trial Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250012, Shandong, P.R. China.

Cytotoxic T cells expressing cell surface CD8 played a key role in anti-cancer immunotherapy, including kidney renal clear cell carcinoma (KIRC). Here we set out to comprehensively analyze and evaluate the significance of CD8 T cell-related markers for patients with KIRC. We checked immune cell response in KIRC and identified cell type-specific markers and related pathways in the tumor-infiltrating CD8 T (TIL-CD8T) cells. We used these markers to explore their prognostic signatures in TIL-CD8 T by evaluating their prognostic efficacy and group differences at various levels. Through pan-cancer analysis, 12 of 63 up-regulated and 162 of 396 down-regulated genes in CD8+ T cells were found to be significantly correlated with the survival prognosis. Based on our highly integrated multi-platform analyses across multiple datasets, we constructed a 6-gene risk scoring model specific to TIL-CD8T. In this model, high TIL-CD8 sig score was corresponding to a higher incidence frequency of copy number variation and drug sensitivity to sorafenib. Moreover, the prognosis of patients with the same or similar immune checkpoint gene levels could be distinguished from each other by TIL-CD8 sig score.
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http://dx.doi.org/10.18632/aging.203584DOI Listing
October 2021

Potentiates the Antitumor Efficacy of FOLFOX in Colon Cancer.

Front Pharmacol 2021 17;12:725583. Epub 2021 Sep 17.

Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, China.

FOLFOX (oxaliplatin, fluorouracil and calcium folinate) is the first-line chemotherapy regimen for colon cancer therapy in the clinic. It provides superior efficacy than oxaliplatin alone, but the underlying mechanism remains unclear. In the present study, pharmacomicrobiomics integrated with metabolomics was conducted to uncover the role of the gut microbiome behind this. First, study demonstrated that FOLFOX exhibited better efficacy than oxaliplatin alone in colon cancer animal models. Second, 16S rDNA gene sequencing analysis showed that the abundance of () remarkably increased in the FOLFOX treated individuals and positively correlated with the therapeutic effect. Third, further exploration confirmed colonization significantly enhanced the anti-cancer efficacy of FOLFOX. Last, metabolomics analysis suggested dipeptides containing branched-chain amino acid (BCAA) might be responsible for gut bacteria mediated FOLFOX efficacy. In conclusion, our study revealed the key role of in mediating FOLFOX efficacy, and manipulating might serve as a novel strategy for colon cancer therapy.
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http://dx.doi.org/10.3389/fphar.2021.725583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484791PMC
September 2021

Genome-Wide Characterization of Aquaporins (aqps) in Lateolabrax maculatus: Evolution and Expression Patterns During Freshwater Acclimation.

Mar Biotechnol (NY) 2021 Sep 30. Epub 2021 Sep 30.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.

Aquaporin (aqp) proteins are a group of small integral membrane proteins that play crucial roles as pore channels for the transport of water and other small solutes across the cell membrane. In our study, we identified 17 aqp genes from the spotted sea bass (Lateolabrax maculatus) genomic database. Gene organization, motif distribution, and selection pressure analyses were performed to investigate their evolutionary characteristics. The aqp mRNA displayed tissue-specific expression pattern in ten selected tissues of healthy spotted sea bass. To investigate the potential involvement of spotted sea bass aqps in osmoregulation, the expression profiles of aqp genes in gills were examined during freshwater (FW) acclimation using qRT-PCR. The mRNA level of aqp3a was dramatically induced during 1-3 day of the FW transition period (77-fold and 15-fold upregulated on 1 day and 3 day than in the control group), indicating that aqp3a may play an important hypo-osmoregulatory role in spotted sea bass. In addition, the expression levels of aqp1aa, aqp1ab, aqp3b, aqp7, and aqp9b increased to various degrees at 1 day after transferring to FW, suggesting their potential involvement in the FW acclimation process. Our study provides a valuable foundation for future studies aimed at uncovering the specific roles of aqp genes during salinity acclimation in spotted sea bass and other teleost species.
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http://dx.doi.org/10.1007/s10126-021-10057-0DOI Listing
September 2021

Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis.

Bioeng Transl Med 2021 Sep 8;6(3):e10232. Epub 2021 Jun 8.

Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University Sapporo Japan.

Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.
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http://dx.doi.org/10.1002/btm2.10232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459589PMC
September 2021

Prevotella contributes to individual response of FOLFOX in colon cancer.

Clin Transl Med 2021 Sep;11(9):e512

Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing, China.

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http://dx.doi.org/10.1002/ctm2.512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473639PMC
September 2021

Ulmoidol, an unusual nortriterpenoid from Eucommia ulmoides Oliv. Leaves prevents neuroinflammation by targeting the PU.1 transcriptional signaling pathway.

Bioorg Chem 2021 Sep 9;116:105345. Epub 2021 Sep 9.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China. Electronic address:

Chronic neuroinflammation is closely associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). In the current study, 13 anti-neuroinflammatory compounds were isolated from Eucommia ulmoides Oliv. leaves. Among these compounds, trans-sinapaldehyde (6), 3',4',5,7-tetrahydroxy-3-methylflavone (7), and amarusine A (13) were isolated from E. ulmoides leaves for the first time. The ursane-type C-triterpenoid, ulmoidol (ULM, 9), significantly inhibited the production of proinflammatory mediators and reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, ULM inhibited the cluster of differentiation 14 (CD14)/Toll-like receptor 4 (TLR4) signaling pathway and consequently limited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Notably, electrophoretic mobility shift assay (EMSA) and molecular docking analyses indicated that ULM could prevent PU box binding-1 (PU.1) from binding to DNA, suggesting that PU.1 might be a potential ULM target. In conclusion, ULM alleviates neuroinflammatory responses in microglia, which could be partly explained by its targeting of PU.1 and the resulting suppression of the TLR4/MAPK/NF-κB signaling pathways. These results suggested that ULM may have therapeutic potential as an agent for treating neuroinflammation-related neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.105345DOI Listing
September 2021

Metal-organic framework modified by silver nanoparticles for SERS-based determination of sildenafil and pioglitazone hydrochloride.

Mikrochim Acta 2021 Sep 23;188(10):351. Epub 2021 Sep 23.

College of Chemistry, Jilin Province Research Center for Engineering and Technology of Spectral Analytical Instruments, Jilin University, Changchun, 130012, People's Republic of China.

A versatile surface-enhanced Raman scattering (SERS) assay has been established that can realize rapid and sensitive determination of sildenafil (SIL) and pioglitazone hydrochloride (PIO) adulteration in healthcare products. Metal-organic frameworks-silver nanoparticles (MOFs-AgNPs) with SERS activity were successfully prepared via in situ synthesis AgNPs on the MOFs surface. By virtue of the adsorptivity of MOFs, the MOFs-AgNPs could effectively concentrate the drug molecules on the electromagnetic enhancement areas of AgNPs. Moreover, the MOFs-AgNPs substrate exhibited more sensitive SERS activity than classical AgNPs with linear range of 1.0 × 10-1.0 × 10 mol L for SIL and 8.0 × 10-3.0 × 10 mol L for PIO and limit of detection (LOD) of 4.8 × 10 mol L for SIL and 1.4 × 10 mol L for PIO. The designed method realized the determination of SIL and PIO in commercial tablets and healthcare products with recoveries of 93.8-108.0% and 93.0-104.0%, respectively, with relative standard deviation (RSD) of 2.7-4.1% and 2.2-4.2%, respectively. The present system displayed little interference effect on determination. This work provides a multifunctional route for the determination of other drugs via the SERS technology.
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http://dx.doi.org/10.1007/s00604-021-05008-4DOI Listing
September 2021

Platelet lysate functionalized gelatin methacrylate microspheres for improving angiogenesis in endodontic regeneration.

Acta Biomater 2021 Sep 20. Epub 2021 Sep 20.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Chengdu Shiliankangjian Biotechnology Co., Ltd.. Electronic address:

Rapid angiogenesis is one of the challenges in endodontic regeneration. Recently, tailored polymeric microsphere system that loaded pro-angiogenic growth factors (GFs) is promising in facilitating vascularization in dental pulp regeneration. In addition, the synergistic effect of multiple GFs is considered more beneficial, but combination usage of them is rather complex and costly. Herein, we aimed to incorporate human platelet lysate (PL), a natural-derived pool of multiple GFs, into gelatin methacrylate (GelMA) microsphere system (GP), which was further modified by Laponite (GPL), a nanoclay with efficient drug delivery ability. These hybrid microspheres were successfully fabricated by electrostatic microdroplet technique with suitable size range (180∼380 µm). After incorporation of the PL and Laponite with GelMA, the Young's modulus of the hybrid hydrogel increased up to about 3-fold and the swelling and degradation rate decreased simultaneously. The PL-derived GFs continued to release up to 28 days from both the GP and GPL microspheres, while the latter released relatively more slowly. What's more, the released GFs could effectively induce tubule formation of human umbilical endothelial cells (HUVECs) and also promote human dental pulp stem cells (hDPSCs) migration. Additionally, the PL component in the GelMA microspheres significantly improved the proliferation, spreading, and odontogenic differentiation of the encapsulated hDPSCs. As further verified by the subcutaneous implantation results, both of the GP and GPL groups enhanced microvascular formation and pulp-like tissue regeneration. This work demonstrated that PL-incorporating GelMA microsphere system was a promising functional vehicle for promoting vascularized endodontic regeneration. STATEMENT OF SIGNIFICANCE: Polymeric microsphere system loaded with pro-angiogenic growth factors (GFs) shows great promise for regeneration of vascularized dental pulp. Herein, we prepared a functional GelMA microsphere system incorporated with human platelet lysates (PL) and nanoclay Laponite by the electrostatic microdroplet method. The results demonstrated that the GelMA/PL/Laponite microspheres significantly improved the spreading, proliferation, and odontogenic differentiation of the encapsulated hDPSCs compared with pure GelMA microspheres. Moreover, they also enhanced microvascular formation and pulp-like tissue regeneration in vivo. This hybrid microsphere system has great potential to accelerate microvessel formation in regenerated dental pulp and other tissues.
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http://dx.doi.org/10.1016/j.actbio.2021.09.024DOI Listing
September 2021

Effect of prophylactic balloon occlusion of internal iliac artery in pregnancies complicated by placenta previa and accreta.

BMC Pregnancy Childbirth 2021 Sep 21;21(1):640. Epub 2021 Sep 21.

Department of Obstetrics and Gynecology, Ministry of Education, West China Second University Hospital of Sichuan University/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), No. 20, 3rd Section, South Renmin Road, Chengdu, 610041, Sichuan, China.

Background: Placenta previa and accreta are serious obstetric conditions that are associated with a high risk of intraoperative massive hemorrhage, the prophylactic intravascular balloon occlusion technique is increasingly used in managing uncontrolled hemorrhage in cesarean section (CS). We aim to examine the clinical effectiveness of prophylactic balloon occlusion of the internal iliac artery (PBOIIA) during CS in improving maternal outcomes for patients with placenta previa and accreta.

Methods: A total of 420 women with placenta previa and accreta who underwent CS from January 2014 to December 2018 were included retrospectively. Patients were divided into balloon group in which patients had PBOIIA (n = 248) and the control group in which patients did not have PBOIIA (n = 172). Meanwhile, we performed a subgroup analysis in whether taking parallel transverse uterine incision (PTUI) surgery. Information on conditions of patients and newborns, perioperative blood indicators, surgical outcomes were collected.

Results: Median estimated blood loss (mEBL) was 2200 mL in the balloon group and 2150 mL in the control group respectively, there was no significant difference between two-groups comparison (P > 0.05), and the rate of patients with hysterectomy was also has no difference between the two groups (36.3% verus 35.5%, P > 0.05), while there is a significant difference between two groups in the amount of PRBCs transfused [3 (0-31.5) verus 3 (0-39), P <0.05], moreover, the proportion of PRBCS> 8 units in the balloon group is significantly lower than that in control group (11.29% verus 23.26%, P <0.05).. However, the total hospitalization costs (45,624.4 ± 11,061.9 verus 37,523.1 ± 14,662.2, CYN) and surgery costs (19,910.6 ± 2622.6 verus 11,850.5 ± 3146.1, CYN) in balloon group were significantly higher than those in control group (P < 0.05). Subgroup analysis showed PTUI surgery had no significant differences in EBL (P >0.05), but it could significantly decrease hysterectomy rates (P <0.05).

Conclusions: PBOIIA has no significant effect on reducing intraoperative EBL and hysterectomy rate in patients with placenta previa and accreta. and although it could reduce the intraoperative PRBCs in patients with massive hemorrhage, it significantly increases the financial cost for patients. Therefore, PBOIIA should not be routinely recommended to patients with placenta previa and accreta.
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http://dx.doi.org/10.1186/s12884-021-04103-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456564PMC
September 2021

Cox15 is a novel oncogene that required for lung cancer cell proliferation.

Biochem Biophys Res Commun 2021 Nov 14;578:70-76. Epub 2021 Sep 14.

Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. Electronic address:

Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future.
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http://dx.doi.org/10.1016/j.bbrc.2021.09.010DOI Listing
November 2021

Efficacy and safety of neoadjuvant chemoradiotherapy plus apatinib for patients with locally advanced, HER2-negative, Siewert's type II-III adenocarcinoma of esophagogastric junction: a single-arm, open-label, phase II trial.

Am J Transl Res 2021 15;13(8):9015-9023. Epub 2021 Aug 15.

Department of Gastrointestinal Surgery, Fourth Hospital of Hebei Medical University Shijiazhuang, Hebei, China.

This study aimed to investigate the efficacy and safety of concurrent neoadjuvant chemoradiotherapy (CRT) plus apatinib in treating locally advanced, HER2-negative, Siewert's type II-III adenocarcinoma of esophagogastric junction (AEG) patients. Thirty eligible patients were analyzed in this single-arm, open-label, phase II trial. Patients received neoadjuvant regimen as follows: two cycles of apatinib (orally, 250 mg/day on day 1-28), two cycles of capecitabine (orally, 1,000 mg/m twice daily on day 1-14), oxaliplatin (intravenously, 130 mg/m on day 1), and concurrent radiotherapy (a total dose of 45 Gy in 25 fractions) started on day 1 of chemotherapy. Then, surgery was performed within 8-12 weeks after the completion of neoadjuvant therapy. This trial was registered on the ClinicalTrials.gov website (access number: NCT03349866). After neoadjuvant CRT plus apatinib treatment, 18 (60.0%) patients achieved objective response, 29 (96.7%) patients achieved disease control, and 20 (66.7%) patients achieved down-staging. Encouragingly, tumor regression grade (TRG) 0, TRG 1, TRG 2 and TRG 3 were observed in 33.3%, 20.0%, 30.0% and 10.0% patients, respectively; the pathological complete response rate was 33.3%, and the R0 resection rate was 93.3%. Regarding survivals, the 1-year and 2-year progression-free survival rates were 96.7% and 88.1%, respectively. Meanwhile, the 1-year and 2-year overall survival rates were 100.0% and 96.6%, respectively. As to safety, the majority of the adverse events were of mild grade, and the post-operative complications were manageable. In conclusion, neoadjuvant CRT plus apatinib exhibits high efficacy and acceptable tolerance in patients with locally advanced, HER2-negative, Siewert's type II-III AEG.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430131PMC
August 2021

Neoadjuvant intraperitoneal and systemic paclitaxel combined with apatinib and S-1 chemotherapy for conversion therapy in gastric cancer patients with positive exfoliative cytology: a prospective study.

J Gastrointest Oncol 2021 Aug;12(4):1416-1427

The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.

Background: To explore the efficacy and safety of neoadjuvant intraperitoneal and systemic (NIPS) paclitaxel chemotherapy combined with apatinib and S-1 in the treatment of gastric cancer patients with positive exfoliative cytology.

Methods: Patients with gastric cancer (PCY) who were confirmed to have free cancer cells (FCCs) in the abdominal cavity after laparoscopic exploration from April 2018 to August 2019 were enrolled. All patients underwent NIPS chemotherapy using paclitaxel combined with apatinib and S-1 treatment. Laparoscopic exploration was performed after 3 cycles of conversion therapy. The primary study endpoint was the FCC negative rate, and the secondary study endpoints were overall survival time (OS), progression-free survival time (PFS), objective response rate (ORR), disease control rate (DCR), and safety indicators.

Results: Out of 312 advanced gastric cancer patients who underwent laparoscopic exploration, 36 patients with PCY gastric cancer were identified and enrolled in this study. After 3 cycles of conversion therapy, the ORR was 80.56% and the DCR was 94.44%. All patients underwent secondary laparoscopic exploration, and the FCC conversion rate was 77.78%. All patients with negative FCC underwent R0 surgical resection, with a median follow-up time of 11.4 months. The median survival time was 15.5 months, and the 1-year OS was 80.55%. The median PFS was 14.4 months, and the 1-year PFS was 75.00%. Treatment-related grade 3 adverse reactions were mainly leukopenia and neutropenia. No grade 4 adverse reactions were observed. There were no reported deaths related to chemotherapy or surgery in the study cohort.

Conclusions: NIPS with paclitaxel combined with apatinib and S-1 treatment may increase the FCC negative rate of PCY gastric cancer patients.
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http://dx.doi.org/10.21037/jgo-21-375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421905PMC
August 2021

Absolute Quantification of Acylcarnitines Using Integrated Tmt-PP Derivatization-Based LC-MS/MS and Quantitative Analysis of Multi-Components by a Single Marker Strategy.

Anal Chem 2021 09 16;93(38):12973-12980. Epub 2021 Sep 16.

Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P. R. China.

Acylcarnitines (ACs) play important roles in the fatty acid β-oxidation and are considered as diagnostic markers for many diseases. Accurate determination of ACs remains challenging due to their low abundance, high structure diversity, and limited availability of standard compounds. In this study, microwave-assisted Tmt-PP (-[3,5-(dimethylamino)-2,4,6-triazine] benzene-1-sulfonyl piperazine) derivatization was utilized to facilitate the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) determination of ACs. The result indicated that Tmt-PP labeling enables the prediction of the retention time and MS response of ACs and enhances their MS response up to 4 times. The introduction of the microwave during the derivatization procedure greatly improved the reaction efficiency, demonstrated by the shortened reaction time from 90 to 1 min. Furthermore, we applied a strategy named quantitative analysis of multi-components by a single marker (QAMS) for the assay of 26 ACs with only 5 AC standards, solving the standard availability issue to a large extent. The established workflow was applied to discover dysregulated ACs in xenograft colon cancer mice, and the quantification results were highly comparable with traditional methods where there were the corresponding standards for each AC. Our study demonstrated that chemical derivatization-based LC-MS/MS integrated with the QAMS strategy is robust for the identification and quantification of ACs and has great potential in targeted metabolomics study.
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http://dx.doi.org/10.1021/acs.analchem.1c02606DOI Listing
September 2021

Observation of higher-order non-Hermitian skin effect.

Nat Commun 2021 Sep 10;12(1):5377. Epub 2021 Sep 10.

National Laboratory of Solid State Microstructures and Department of Materials Science and Engineering, Nanjing University, Nanjing, China.

Beyond the scope of Hermitian physics, non-Hermiticity fundamentally changes the topological band theory, leading to interesting phenomena, e.g., non-Hermitian skin effect, as confirmed in one-dimensional systems. However, in higher dimensions, these effects remain elusive. Here, we demonstrate the spin-polarized, higher-order non-Hermitian skin effect in two-dimensional acoustic higher-order topological insulators. We find that non-Hermiticity drives wave localizations toward opposite edges upon different spin polarizations. More interestingly, for finite systems with both edges and corners, the higher-order non-Hermitian skin effect leads to wave localizations toward two opposite corners for all the bulk, edge and corner states in a spin-dependent manner. We further show that such a skin effect enables rich wave manipulation by configuring the non-Hermiticity. Our study reveals the intriguing interplay between higher-order topology and non-Hermiticity, which is further enriched by the pseudospin degree of freedom, unveiling a horizon in the study of non-Hermitian physics.
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http://dx.doi.org/10.1038/s41467-021-25716-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433224PMC
September 2021

Genome Structural Variation Landscape and Its Selection Signatures in the Fast-growing Strains of the Pacific Oyster, Crassostrea gigas.

Mar Biotechnol (NY) 2021 Sep 8. Epub 2021 Sep 8.

Key Laboratory of Mariculture (Ocean University of China), Ocean University of China Ministry of Education College of Fisheries, Qingdao, 266003, China.

The Pacific oyster (Crassostrea gigas) genome is highly polymorphic and affluent in structural variations (SVs), a significant source of genetic variation underlying inter-individual differences. Here, we used two genome assemblies and 535 individuals of genome re-sequencing data to construct a comprehensive landscape of structural variations in the Pacific oyster. Through whole-genome alignment, 11,087 short SVs and 11,561 copy number variations (CNVs) were identified. While analysis of re-sequencing data revealed 511,170 short SVs and 979,486 CNVs, a total of 63,100 short SVs and 58,182 CNVs were identified in at least 20 samples and regarded as common variations. Based on the common short SVs, both Fst and Pi ratio statistical methods were employed to detect the selective sweeps between 20 oyster individuals from the fast-growing strain and 20 individuals from their corresponding wild population. A total of 514 overlapped regions (8.76 Mb), containing 746 candidate genes, were identified by both approaches, in addition with 103 genes within 61 common CNVs only detected in the fast-growing strains. The GO enrichment and KEGG pathway analysis indicated that the identified candidate genes were mostly associated with apical part of cell and were significantly enriched in several metabolism-related pathways, including tryptophan metabolism and histidine metabolism. This work provided a comprehensive landscape of SVs and revealed their responses to selection, which will be valuable for further investigations on genome evolution under selection in the oysters.
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http://dx.doi.org/10.1007/s10126-021-10060-5DOI Listing
September 2021

AAGAB is an assembly chaperone regulating AP1 and AP2 clathrin adaptors.

J Cell Sci 2021 Oct 5;134(19). Epub 2021 Oct 5.

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.

Multimeric cargo adaptors such as AP2 play central roles in intracellular membrane trafficking. We recently discovered that the assembly of the AP2 adaptor complex, a key player in clathrin-mediated endocytosis, is a highly organized process controlled by alpha- and gamma-adaptin-binding protein (AAGAB, also known as p34). In this study, we demonstrate that besides AP2, AAGAB also regulates the assembly of AP1, a cargo adaptor involved in clathrin-mediated transport between the trans-Golgi network and the endosome. However, AAGAB is not involved in the formation of other adaptor complexes, including AP3. AAGAB promotes AP1 assembly by binding and stabilizing the γ and σ subunits of AP1, and its mutation abolishes AP1 assembly and disrupts AP1-mediated cargo trafficking. Comparative proteomic analyses indicate that AAGAB mutation massively alters surface protein homeostasis, and its loss-of-function phenotypes reflect the synergistic effects of AP1 and AP2 deficiency. Taken together, these findings establish AAGAB as an assembly chaperone for both AP1 and AP2 adaptors and pave the way for understanding the pathogenesis of AAGAB-linked diseases.
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http://dx.doi.org/10.1242/jcs.258587DOI Listing
October 2021

Huaier polysaccharides suppress triple-negative breast cancer metastasis and epithelial-mesenchymal transition by inducing autophagic degradation of Snail.

Cell Biosci 2021 Sep 4;11(1):170. Epub 2021 Sep 4.

Breast Disease Center, Southwest Hospital, Army Medical University, 30# Gaotanyan street, Chongqing, 400038, China.

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and the targeted therapies are lacking for this type of cancer. We previously demonstrated that Huaier effectively improve 5-year OS and DFS in stage III TNBC patients, and the polysaccharides of Huaier (PS-T) have been identified as the major components of Huaier. However, the mechanisms of anti-tumor action of PS-T is unclear. This study aimed to investigate the effect of PS-T on TNBC cell invasion and migration.

Results: This study showed that PS-T inhibited cell invasion and migration both in vitro and in vivo by inducing autophagy to suppress epithelial-mesenchymal transition (EMT). Autophagy inhibitor LY294002 or knockdown of ATG5 suppressed the inhibitory effects of PS-T. In addition, as a key transcription factor controlling EMT initiation, Snail was found to be degraded by PS-T induced autophagy. In addition, overexpression of Snail reversed the inhibitory effects of PS-T. Furthermore, it was confirmed that the expression of Snail was inversely correlated with LC3 and associated with poor prognosis using immunohistochemistry and TCGA database analysis, respectively.

Conclusions: This study demonstrated that PS-T could inhibit EMT in breast cancer cells by inducing autophagy to degrade Snail protein, thus improving the prognosis of TNBC, offering potential treatment alternatives for TNBC patients.
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http://dx.doi.org/10.1186/s13578-021-00682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417980PMC
September 2021

Visualizing the {110} surface structure of equilibrium-form ZIF-8 crystals by low-dose Cs-corrected TEM.

Nanoscale 2021 Aug 27;13(31):13215-13219. Epub 2021 Jul 27.

State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.

The properties of zeolitic imidazolate framework (ZIF) crystals highly depend on the structures of the low-energy surfaces, such as {110} of ZIF-8. However, the atomic/molecular configurations of the ZIF-8 {110} surfaces remain debated. In this study, the near-atomic-scale characterization of {110} surfaces of ZIF-8 is conducted by low-dose aberration-corrected transmission electron microscopy (TEM). The real-space images with mitigated surface delocalization by minimized spherical aberration of TEM, together with the solvent corrected surface energy calculations, demonstrate that the {110} surfaces of ZIF-8 crystals with an equilibrium-form rhombic morphology have a zigzag-type termination. This study provides experimental evidence to clarify the debated structure of {110} ZIF-8 surfaces and has important implications in understanding the crystal growth and surface related properties of ZIF-8.
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http://dx.doi.org/10.1039/d1nr03829jDOI Listing
August 2021

Urban-Rural Disparities in the Association Between Body Mass Index and Cognitive Impairment in Older Adults: A Cross-Sectional Study in Central China.

J Alzheimers Dis 2021 ;83(4):1741-1752

Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China.

Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas.

Objective: This cross-sectional study investigated the associations between BMI and cognitive impairment among community-dwelling older adults from rural and urban areas.

Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results.

Results: Being underweight in the rural-dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural-dwelling participants aged 65-69 years and 75-79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03-1.83; p < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant.

Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas.
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http://dx.doi.org/10.3233/JAD-210295DOI Listing
January 2021

Three-Dimensional Au/Ag Nanoparticle/Crossed Carbon Nanotube SERS Substrate for the Detection of Mixed Toxic Molecules.

Nanomaterials (Basel) 2021 Aug 9;11(8). Epub 2021 Aug 9.

School of Physics and Electronics, Shandong Normal University, Jinan 250358, China.

Research on engineering "hotspots" in the field of surface-enhanced Raman scattering (SERS) is at the forefront of contributing to the best sensing indicators. Currently, there is still an urgent need to design a high-strength and large-scale electric field distribution method in order to obtain an ideal SERS sensor. Here, we designed a three-dimensional (3D) Au/Ag nanoparticle (NP)/crossed carbon nanotube film SERS substrate. The proposed structure formed by the simple preparation process can perfectly coordinate the interaction between the SERS substrates, lasers, and molecules. The denser "hotspots" can be induced and then distributed in holes enclosed by Au/AgNPs and the gaps between them. This process was verified by numerical simulations. The experimental results show that the proposed SERS substrate possesses an excellent sensitivity of 10 M (rhodamine 6G (R6G)), an enhancement factor of 1.60 × 10, and a good signal reproducibility (the relative standard deviation is ~6.03%). We further use a Au/AgNP/crossed CNT substrate to detect complex solutions composed of toxic molecules, which shows that our proposed SERS substrate has a wide range of application potentials, especially in food safety.
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http://dx.doi.org/10.3390/nano11082026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401542PMC
August 2021

Rational Design of Sulfur-Doped Three-Dimensional TiCT MXene/ZnS Heterostructure as Multifunctional Protective Layer for Dendrite-Free Zinc-Ion Batteries.

ACS Nano 2021 Sep 26;15(9):15259-15273. Epub 2021 Aug 26.

Hefei National Laboratory for Physical Science at Microscale, Department of Chemistry, University of Science and Technology of China, Hefei 230026, P.R. China.

Owing to its high theoretical capacity, appropriate working potential, abundant resource, intrinsic safety, and low cost, zinc (Zn) metal is regarded as one of the most promising anode candidates for aqueous batteries. However, the hazards caused by dendrite growth and side reactions impede its practical applications. Herein, to solve these problems, a protective heterogeneous layer composed of electronic conductive sulfur-doped three-dimensional (3D) MXene and ionic conductive ZnS on Zn anode is designed and constructed. The sulfur doping and the creation of a 3D structure on MXene are simultaneously achieved during the generation of ZnS. The sulfur-doped 3D MXene can effectively homogenize distribution of electric field, decrease local current density, and alleviate volume change. The ZnS can inhibit side reactions, promote uniform Zn distribution, and accelerate Zn migration. Consequently, a stable and dendrite-free Zn anode is achieved with notable cycling stability up to 1600 h and rate performance. The relationship between structure of protective layer and performance of Zn anode is also probed. With the protected Zn anode and freestanding sulfur-doped 3D [email protected] cathode, a high-energy, long cycling life, and high-rate full cell is obtained. This work may provide a direction for the design of practical Zn anodes and other metal-based battery systems.
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http://dx.doi.org/10.1021/acsnano.1c05934DOI Listing
September 2021

mA RNA Methylation Regulator YTHDF1 Correlated With Immune Microenvironment Predicts Clinical Outcomes and Therapeutic Efficacy in Breast Cancer.

Front Med (Lausanne) 2021 9;8:667543. Epub 2021 Aug 9.

Department of Breast Surgery, First Affiliated Hospital of Army Military Medical University, Chongqing, China.

Increasing evidence highlights the roles of N-methyladenosine (mA) and its regulators in oncogenesis. Herein, this study observed the associations of mA regulators with breast cancer. RNA-seq profiles of breast cancer were retrieved from the Cancer Genome Atlas (TCGA) database. The expression of mA regulators was analyzed in tumor and normal tissues. Their expression correlations were analyzed by Spearson test. Overall survival (OS) analysis of these regulators was then presented. Gene set enrichment analysis (GSEA) was performed in high and low YTHDF1 expression groups. The correlations of YTHDF1 expression with immune cells and tumor mutation burden (TMB) were calculated in breast cancer samples. Somatic variation was assessed in high and low YTHDF1 expression groups. Most of mA regulators were abnormally expressed in breast cancer compared to normal tissues. At the mRNA levels, there were closely relationships between them. Among them, YTHDF1 up-regulation was significantly related to undesirable prognosis ( = 0.025). GSEA results showed that high YTHDF1 expression was associated with cancer-related pathways. Furthermore, YTHDF1 expression was significantly correlated with T cells CD4 memory activated, NK cells activated, monocytes, and macrophages. There were higher TMB scores in YTHDF1 up-regulation group than its down-regulation group. Missense mutation and non-sense mutation were the most frequent mutation types. Our findings suggested that dysregulated mA regulator YTHDF1 was predictive of survival outcomes as well as response to immunotherapy of breast cancer, and were closely related to immune microenvironment.
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http://dx.doi.org/10.3389/fmed.2021.667543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380833PMC
August 2021

CpG immunostimulatory oligodeoxynucleotide 1826 as a novel nasal ODN adjuvant enhanced the protective efficacy of the periodontitis gene vaccine in a periodontitis model in SD rats.

BMC Oral Health 2021 08 16;21(1):403. Epub 2021 Aug 16.

Key Laboratory of Oral Disease Research, School of Stomatology, Zunyi Medical University, Zunyi, 563000, China.

Background: We previously demonstrated that nasal administration of periodontitis gene vaccine (pVAX1-HA2-fimA) or pVAX1-HA2-fimA plus IL-15 as adjuvant provoked protective immunity in the periodontal tissue of SD rats. This study evaluated the immune effect of pVAX1-HA2-fimA plus CpG-ODN 1826 as an adjuvant in the SD rat periodontitis models to improve the efficacy of the previously used vaccine.

Methods: Periodontitis was induced in maxillary second molars in SD rats receiving a ligature and infected with Porphyromonas gingivalis. Forty-two SD rats were randomly assigned to six groups: A, control without P. gingivalis; B, P. gingivalis with saline; C, P. gingivalis with pVAX1; D, P. gingivalis with pVAX1-HA2-fimA; E, P. gingivalis with pVAX1-HA2-fimA/IL-15; F, P. gingivalis with pVAX1-HA2-fimA+CpG ODN 1826 (30 µg). The levels of FimA-specific and HA2-specific secretory IgA antibodies in the saliva of rats were measured by ELISA. The levels of COX-2 and RANKL were detected by immunohistochemical assay. Morphometric analysis was used to evaluate alveolar bone loss. Major organs were observed by HE staining.

Results: 30 μg could be the optimal immunization dose for CpG-ODN 1826 and the levels of SIgA antibody were consistently higher in the pVAX1-HA2-fimA+CpG-ODN 1826 (30 µg) group than in the other groups during weeks 1-8 (P < 0.05, except week 1 or 2). Morphometric analysis demonstrated that pVAX1-HA2-fimA+CpG-ODN 1826 (30 µg) significantly reduced alveolar bone loss in ligated maxillary molars in group F compared with groups B-E (P < 0.05). Immunohistochemical assays revealed that the levels of COX-2 and RANKL were significantly lower in group F compared with groups B-E (P < 0.05). HE staining results of the major organs indicated that pVAX1-HA2-fimA with or without CpG-ODN 1826 was not toxic for in vivo use.

Conclusions: These results indicated that CpG-ODN 1826 (30 µg) could be used as an effective and safe mucosal adjuvant for pVAX1-HA2-fimA in SD rats since it could elicit mucosal SIgA responses and modulate COX-2 and RANKL production during weeks 1-8, thereby inhibiting inflammation and decreasing bone loss.
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http://dx.doi.org/10.1186/s12903-021-01763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369760PMC
August 2021

Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows inhibition of DNA-induced phase separation and activation of cGAS.

Nucleic Acids Res 2021 Sep;49(16):9389-9403

Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.

Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor that detects aberrant cytosolic DNA arising from pathogen invasions or genotoxic stresses. Upon binding to DNA, cGAS is activated and catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which induces potent antimicrobial and antitumor responses. Kaposi sarcoma-associated herpesvirus (KSHV) is a human DNA tumor virus that causes Kaposi sarcoma and several other malignancies. We previously reported that KSHV inhibitor of cGAS (KicGAS) encoded by ORF52, inhibits cGAS enzymatic activity, but the underlying mechanisms remained unclear. To define the inhibitory mechanisms, here we performed in-depth biochemical and functional characterizations of KicGAS, and mapped its functional domains. We found KicGAS self-oligomerizes and binds to double stranded DNA cooperatively. This self-oligomerization is essential for its DNA binding and cGAS inhibition. Interestingly, KicGAS forms liquid droplets upon binding to DNA, which requires collective multivalent interactions with DNA mediated by both structured and disordered domains coordinated through the self-oligomerization of KicGAS. We also observed that KicGAS inhibits the DNA-induced phase separation and activation of cGAS. Our findings reveal a novel mechanism by which DNA viruses target the host protein phase separation for suppression of the host sensing of viral nucleic acids.
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http://dx.doi.org/10.1093/nar/gkab689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450086PMC
September 2021

Synthesis of tritium labeled 30-KDa PEG and conjugation to form [ H]Pegbelfermin.

J Labelled Comp Radiopharm 2021 Oct 23;64(12):477-481. Epub 2021 Aug 23.

Discovery Chemistry Platforms-Radiochemistry, Bristol Myers Squibb, Princeton, New Jersey, USA.

Non-alcoholic steatohepatitis (NASH) is the most chronic liver condition in the western population and is fueled by the obesity and type 2 diabetes epidemic. Pegbelfermin (1), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. Radiolabeled Pegbelfermin was needed to access the accumulation of intact drug and metabolized PEG. In an effort to accomplish both goals with one labeled synthesis, the isotopic label was positioned in the PEG. A total of 21 mCi of tritium labeled Pegbelfermin was synthesized having a specific activity of 21.6 Ci/mmol for use in animal studies.
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http://dx.doi.org/10.1002/jlcr.3940DOI Listing
October 2021

Distinct Contributions of Genes and Environment to Visual Size Illusion and the Underlying Neural Mechanism.

Cereb Cortex 2021 Aug 11. Epub 2021 Aug 11.

State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, P.R. China.

As exemplified by the Ebbinghaus illusion, the perceived size of an object can be significantly biased by its surrounding context. The phenomenon is experienced by humans as well as other species, hence likely evolutionarily adaptive. Here, we examined the heritability of the Ebbinghaus illusion using a combination of the classic twin method and multichannel functional near-infrared spectroscopy. Results show that genes account for over 50% of the variance in the strength of the experienced illusion. Interestingly, activations evoked by the Ebbinghaus stimuli in the early visual cortex are explained by genetic factors whereas those in the posterior temporal cortex are explained by environmental factors. In parallel, the feedforward functional connectivity between the occipital cortex and the temporal cortex is modulated by genetic effects whereas the feedback functional connectivity is entirely shaped by environment, despite both being significantly correlated with the strength of the experienced illusion. These findings demonstrate that genetic and environmental factors work in tandem to shape the context-dependent visual size illusion, and shed new light on the links among genes, environment, brain, and subjective experience.
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http://dx.doi.org/10.1093/cercor/bhab262DOI Listing
August 2021
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