Publications by authors named "Xi Rao"

37 Publications

N -methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305.

IUBMB Life 2021 Feb 28;73(2):408-417. Epub 2020 Dec 28.

Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), whether circular RNA (circRNA) is involved in this process remains unknown. In this study, we performed circRNA microarray profile and found an HBV-related circRNA, circ-ARL3 (hsa_circ_0092493). Stable knockdown of circ-ARL3 inhibited the proliferation and invasion of HBV HCC cells. High circ-ARL3 was positively correlated with malignant clinical features and poor prognosis. In terms of mechanism, HBx protein upregulated N -methyladenosine (m A) methyltransferases METTL3 expression, increasing the m A modification of circ-ARL3; then, m A reader YTHDC1 bound to m A-modified of circ-ARL3 and favored its reverse splicing and biogenesis. Furthermore, circ-ARL3 was able to sponge miR-1305, antagonizing the inhibitory effects of miR-1305 on a cohort of target oncogenes, thereby promoting HBV HCC progression. Importantly, depletion of circ-ARL3 significantly retarded HBV HCC cell growth in vivo, whereas this effect was evidently blocked after silencing of miR-1305. Collectively, our data suggest that circ-ARL3 is a critical regulator in HBV-related HCC, targeting the axis of circ-ARL3/miR-1305 may be a promising treatment for HBV HCC patients.
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http://dx.doi.org/10.1002/iub.2438DOI Listing
February 2021

Region-wide comprehensive implementation of roguing infected trees, tree replacement, and insecticide applications successfully controls citrus HLB.

Phytopathology 2020 Dec 23. Epub 2020 Dec 23.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Huanglongbing (HLB) is a devastating citrus disease worldwide. A three-pronged approach to controlling HLB has been suggested, namely, removal of HLB-symptomatic trees, psyllid control, and replacement with HLB-free trees. However, such a strategy did not lead to successful HLB control in many citrus producing regions. We hypothesize this is because of the small-scale or incomprehensive implementation of the program, conversely, a comprehensive implementation of such a strategy at regional level can successfully control HLB. Here we investigated the effects of region-wide comprehensive implementation of this scheme to control HLB in Gannan region, China, with a total planted citrus acreage of over 110,000 ha from 2013-2019. With the region-wide implementation of comprehensive HLB management, overall HLB incidence in Gannan decreased from 19.71% in 2014 to 3.86% in 2019. A partial implementation of such a program (without a comprehensive inoculum removal) at the regional level in Brazil resulted in HLB incidence increasing from 1.89% in 2010 to 19.02% in 2019. A dynamic regression model analyses predicated that in a region-wide comprehensive implementation of such a program, HLB incidence would be controlled to a level of less than 1%. Economic feasibility analyses showed that average net profits were positive for groves that implemented the comprehensive strategy, but negative for groves without such a program over a ten-year period. Overall, the key for the three-pronged program to successfully control HLB control is the large scale (region-wide) and comprehensiveness in implementation. This study provides valuable information to control HLB and other endemic diseases worldwide.
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http://dx.doi.org/10.1094/PHYTO-09-20-0436-RDOI Listing
December 2020

Upregulation of lipid metabolism genes in the breast prior to cancer diagnosis.

NPJ Breast Cancer 2020 6;6:50. Epub 2020 Oct 6.

Susan G. Komen Tissue Bank at the IU Simon Cancer Center, Indianapolis, IN 46202 USA.

Histologically normal tissue adjacent to the tumor can provide insight of the microenvironmental alterations surrounding the cancerous lesion and affecting the progression of the disease. However, little is known about the molecular changes governing cancer initiation in cancer-free breast tissue. Here, we employed laser microdissection and whole-transcriptome profiling of the breast epithelium prior to and post tumor diagnosis to identify the earliest alterations in breast carcinogenesis. Furthermore, a comprehensive analysis of the three tissue compartments (microdissected epithelium, stroma, and adipose tissue) was performed on the breast donated by either healthy subjects or women prior to the clinical manifestation of cancer (labeled "susceptible normal tissue"). Although both susceptible and healthy breast tissues appeared histologically normal, the susceptible breast epithelium displayed a significant upregulation of genes involved in fatty acid uptake/transport (CD36 and AQP7), lipolysis (LIPE), and lipid peroxidation (AKR1C1). Upregulation of lipid metabolism- and fatty acid transport-related genes was observed also in the microdissected susceptible stromal and adipose tissue compartments, respectively, when compared with the matched healthy controls. Moreover, inter-compartmental co-expression analysis showed increased epithelium-adipose tissue crosstalk in the susceptible breasts as compared with healthy controls. Interestingly, reductions in natural killer (NK)-related gene signature and CD45+/CD20+ cell staining were also observed in the stromal compartment of susceptible breasts. Our study yields new insights into the cancer initiation process in the breast. The data suggest that in the early phase of cancer development, metabolic activation of the breast, together with increased epithelium-adipose tissue crosstalk may create a favorable environment for final cell transformation, proliferation, and survival.
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http://dx.doi.org/10.1038/s41523-020-00191-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538898PMC
October 2020

Anemia and perioperative mortality in non-cardiac surgery patients: a secondary analysis based on a single-center retrospective study.

BMC Anesthesiol 2020 05 11;20(1):112. Epub 2020 May 11.

Department of Breast thyroid surgery, Shenzhen Breast Cancer Research and Treatment Research Center, Peking University Shenzhen Hospital, 1120 Lianhua Road, Futian District, Shenzhen, 518000, Guangdong, China.

Background: Evidence regarding the relationship between anemia and perioperative prognosis is controversial. The study was conducted to highlight the specific relationship between anemia and perioperative mortality in non-cardiac surgery patients over 18 years of age.

Methods: This study was a retrospective analysis of the electronic medical records of 90,784 patients at the Singapore General Hospital from January 1, 2012 to October 31, 2016. Multivariate regression, propensity score analysis, doubly robust estimation, and an inverse probability-weighting model was used to ensure the robustness of our findings.

Results: We identified 85,989 patients, of whom75, 163 had none or mild anemia (Hemoglobin>90g/L) and 10,826 had moderate or severe anemia (Hemoglobin≤90g/L). 8,857 patients in each study exposure group had similar propensity scores and were included in the analyses. In the doubly robust model, postoperative 30-day mortality rate was increased by 0.51% (n = 219) in moderate or severe anemia group (Odds Ratio, 1.510; 95% Confidence Interval (CI), 1.049 to 2.174) compared with none or mild anemia group (2.47% vs.1.22%, P<0.001). Moderate or severe anemia was also associated with increased postoperative blood transfusion rates (OR, 5.608; 95% CI, 4.026 to 7.811, P < 0.001). There was no statistical difference in Intensive Care Unit (ICU) admission rate among different anemia groups within 30 days after surgery (P=0.104).

Discussion: In patients undergoing non-cardiac surgery over 18 years old, moderate or severe preoperative anemia would increase the occurrence of postoperative blood transfusion and the risk of death, rather than ICU admission within 30 days after surgery.
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http://dx.doi.org/10.1186/s12871-020-01024-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212669PMC
May 2020

Modulator-Dependent RBPs Changes Alternative Splicing Outcomes in Kidney Cancer.

Front Genet 2020 26;11:265. Epub 2020 Mar 26.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States.

Alternative splicing alterations can contribute to human disease. The ability of an RNA-binding protein to regulate alternative splicing outcomes can be modulated by a variety of genetic and epigenetic mechanisms. In this study, we use a computational framework to investigate the roles of certain genes, termed modulators, on changing RBPs' effect on splicing regulation. A total of 1,040,254 modulator-mediated RBP-splicing interactions were identified, including 137 RBPs, 4,309 splicing events and 2,905 modulator candidates from TCGA-KIRC RNA sequencing data. Modulators function categories were defined according to the correlation changes between RBPs expression and their targets splicing outcomes. QKI, as one of the RBPs influencing the most splicing events, attracted our attention in this study: 2,014 changing triplets were identified, including 1,101 modulators and 187 splicing events. Pathway enrichment analysis showed that QKI splicing targets were enriched in tight junction pathway, endocytosis and MAPK signaling pathways, all of which are highly associated with cancer development and progression. This is the first instance of a comprehensive study on how alternative splicing outcomes changes are associated with different expression level of certain proteins, even though they were regulated by the same RBP. Our work may provide a novel view on understanding alternative splicing mechanisms in kidney cancer.
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http://dx.doi.org/10.3389/fgene.2020.00265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113372PMC
March 2020

Tuning C-C sp2/sp3 ratio of DLC films in FCVA system for biomedical application.

Bioact Mater 2020 Jun 20;5(2):192-200. Epub 2020 Feb 20.

Key Laboratory of Luminescent and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, School of Materials and Energy, Southwest University, Chongqing, 400715, PR China.

Diamond like carbon (DLC) films with different C-C sp2/sp3 ratios were prepared by tuning the N2 flow rate in a filtered cathodic vacuum arc (FCVA) system. The increase of N2 flow rate facilitated the increase of C-C sp2/sp3 ratio (1.09-2.66), the growth of particle size (0.78-1.58 nm) and the improvement of surface roughness. The SBF immersion results, as well as WCAs (77.57°~71.71°), hemolysis rate (0.14-1.00%) and cytotoxicity level (0) demonstrated that the as-fabricated DLC film was promising for biomedical application. As a result of surface charge effect, the apatite layers formed in the SBF increased with the increase of C-C sp2/sp3 ratio until 1.74 and then showed a tiny decrease during 1.74-2.66. A raise of hemolysis and cytotoxicity was observed when sp2/sp3 ratio was increased. Moreover, a decrease of friction coefficient of Si surface induced by increasing sp2/sp3 ratio was respectively evidenced in ambient air and SBF lubrication environments.
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http://dx.doi.org/10.1016/j.bioactmat.2020.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033527PMC
June 2020

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

Oncotarget 2020 Jan 21;11(3):216-236. Epub 2020 Jan 21.

Eli Lilly and Company, Indianapolis, IN, USA.

The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.
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http://dx.doi.org/10.18632/oncotarget.27400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980627PMC
January 2020

Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration.

Cell Death Differ 2020 08 12;27(8):2344-2362. Epub 2020 Feb 12.

Department of Biochemistry and Molecular Biology and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.
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http://dx.doi.org/10.1038/s41418-020-0508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370222PMC
August 2020

AgPO/g-CN nanocomposites for photocatalytic degradating gas phase formaldehyde at continuous flow under 420 nm LED irradiation.

Chemosphere 2020 Apr 25;244:125462. Epub 2019 Nov 25.

Key Laboratory of Luminescent and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, School of Materials and Energy, Southwest University, Chongqing, 400715, PR China; Chongqing Key Laboratory of Soft-Matter Material Chemistry and Function Manufacturing, Southwest University, Chongqing, 400715, PR China. Electronic address:

A series of AgPO/g-CN nanocomposites were synthesized by introducing various small amount of AgPO in g-CN and subsequently employed for decomposing formaldehyde (HCHO) in continuous flow as photocatalysts. The results show that all the AgPO/g-CN nanocomposites could perform a very stable photoactivity for degrading continuously flowing gaseous formaldehyde for at least 600 h. Especially, the HCHO degradation rate reached 22.4% by using 1AP-CN, which was 2.63 times as fast as that of g-CN. Our results reveal that the photoinduced electrons in conduction band (CB) are trapped by O to yield ⋅O, while holes in valence band (VB) directly oxidize -OH and/or water to produce ·OH under visible light irradiation. As a consequence, HCHO is further oxidized to CO and HO by as-generate active species.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125462DOI Listing
April 2020

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

Mol Cancer Ther 2020 02 19;19(2):325-336. Epub 2019 Nov 19.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, -mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in - and -mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a -mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in -mutant models with acquired resistance and . Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0183DOI Listing
February 2020

Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.

Mol Psychiatry 2019 Sep 2. Epub 2019 Sep 2.

Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

Genome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3'UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.
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http://dx.doi.org/10.1038/s41380-019-0508-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050407PMC
September 2019

A Comparison Study of Functional Groups (Amine vs. Thiol) for Immobilizing AuNPs on Zeolite Surface.

Nanomaterials (Basel) 2019 Jul 19;9(7). Epub 2019 Jul 19.

Centre National de la Recherche Scientifique CNRS, Sorbonne Université, Physico-chimie des Electrolytes et Nanosystèmes InterfaciauX, Phenix, F-75005 Paris, France.

Immobilization of gold nanoparticles (AuNPs) on the surface of zeolite has received a great interest due to Au@zeolite's unique characteristics and high performance for catalysis. In this work we studied the grafting of two different functional molecules; one having an amine group (3-aminopropyl)triethoxysilane (APTES) and the second having a thiol group (3-mercaptopropyl)trimethoxysilane (MPTES) on the surface of zeolite using the same wet chemistry method. The modified zeolite surfaces were characterized using zeta potential measurements; diffuse reflectance infrared fourier transform (DRIFT) and X-ray photoelectron spectroscopy (XPS). The results confirmed a successful deposition of both functional groups at the topmost surface of the zeolite. Furthermore; transmission electron microscopy (TEM), ultraviolet-visible (UV-Vis) spectroscopy and XPS results clearly evidenced that APTES provided a better AuNPs immobilization than MPTES as a result of; (1) less active functions obtained after MPTES deposition, and (2) the better attaching ability of thiol to the gold surface.
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http://dx.doi.org/10.3390/nano9071034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669740PMC
July 2019

Synthesis of benzaldehyde with high selectivity using immobilized AuNPs and AuNPs@zeolite in a catalytic microfluidic system.

Lab Chip 2019 09 16;19(17):2866-2873. Epub 2019 Jul 16.

Chimie ParisTech, PSL University, CNRS, Institut de Recherche de Chimie Paris, 75005, Paris, France.

In the present work, gold based catalysts were synthesized and immobilized on the surface of cyclic olefin copolymer (COC) microreactors. The microreactors were subsequently applied in a homemade microfluidic system for synthesizing benzaldehyde by oxidation of benzyl alcohol in water medium. The Au nanoparticles (NPs) immobilized on the inner surface of the microchannel showed a very high selectivity (94%) for benzaldehyde, while zeolite NPs exhibited only an adsorption feature to this reaction. Moreover, the results showed that the AuNP catalytic activity was maintained for at least 9 hours. However, the obtained conversion with AuNPs was only 20%, indicating a relatively low productivity. In comparison, AuNPs assembled on the surface of zeolite NPs (AuNPs@zeolite) and immobilized in the microchannel showed the best catalytic performance, as the highest benzaldehyde selectivity (>99%) with a relatively high benzyl alcohol conversion of 42.4% was achieved under the same conditions. To the best of our knowledge, this is the first example demonstrating the use of AuNP or AuNP@zeolite catalysts in a microsystem performing such high selectivity for benzaldehyde in water medium.
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http://dx.doi.org/10.1039/c9lc00386jDOI Listing
September 2019

Genome-wide association studies of the self-rating of effects of ethanol (SRE).

Addict Biol 2020 03 3;25(2):e12800. Epub 2019 Jul 3.

Department of Psychiatry, University of California, San Diego Medical School, San Diego, California.

The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol problems. We conducted genome-wide association study (GWAS) in the African-American (COGA-AA, N = 1527 from 309 families) and European-American (COGA-EA, N = 4723 from 956 families) subsamples of the Collaborative Studies on the Genetics of Alcoholism (COGA) for two SRE scores: SRE-T (average of first five times of drinking, the period of heaviest drinking, and the most recent 3 months of consumption) and SRE-5 (the first five times of drinking). We then meta-analyzed the two COGA subsamples (COGA-AA + EA). Both SRE-T and SRE-5 were modestly heritable (h : 21%-31%) and genetically correlated with alcohol dependence (AD) and DSM-IV AD criterion count (r : 0.35-0.76). Genome-wide significant associations were observed (SRE-T: chromosomes 6, rs140154945, COGA-EA P = 3.30E-08 and 11, rs10647170, COGA-AA+EA P = 3.53E-09; SRE-5: chromosome13, rs4770359, COGA-AA P = 2.92E-08). Chromosome 11 was replicated in an EA dataset from the National Institute on Alcohol Abuse and Alcoholism intramural program. In silico functional analyses and RNA expression analyses suggest that the chromosome 6 locus is an eQTL for KIF25. Polygenic risk scores derived using the COGA SRE-T and SRE-5 GWAS predicted 0.47% to 2.48% of variances in AD and DSM-IV AD criterion count in independent datasets. This study highlights the genetic contribution of alcohol response phenotypes to the etiology of alcohol use disorders.
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http://dx.doi.org/10.1111/adb.12800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940552PMC
March 2020

KIAA1429 regulates the migration and invasion of hepatocellular carcinoma by altering m6A modification of ID2 mRNA.

Onco Targets Ther 2019 7;12:3421-3428. Epub 2019 May 7.

Department of Endocrinology, Shangrao People's Hospital, Shangrao, JiangXi, China,

Purpose: N6-methyladenosine (m6A), the most abundant mRNA modification in mammals, is involved in various biological processes. KIAA1429 is an important methyltransferase participating in m6A modification. However, the role of KIAA1429 in hepatocellular carcinoma (HCC) is still not well understood. Here, we aimed to investigate the function of KIAA1429 and its corresponding regulation mechanisms in HCC.

Patients And Methods: HCC-related genes were analyzed by clinical and expression data of HCC patients in The Cancer Genome Atlas (TCGA) database. Expression of KIAA1429 was verified by quantitative reverse-transcription PCR, and interference efficiency was obtained using small interfering RNA (siRNA). Cell proliferation, migration, and invasion were assessed by cell counting kit-8 and transwell assays, and the m6A modification was detected by methylated RNA immunoprecipitation-PCR (MeRIP-PCR).

Results: We found a difference in the expression of KIAA1429 between HCC and normal hepatic tissues by analyzing data from the TCGA database. Comparing HCC cell lines (HepG2, Huh-7, HepG2.2.15) with normal hepatic cells (HL-7702), we observed an identically significant difference in KIAA1429 expression. KIAA1429 significantly enhanced proliferation, migration, and invasion of HepG2 cells. Moreover, Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and correlation analysis revealed a significant negative correlation between KIAA1429 and ID2. In the subsequent MeRIP-PCR assay, downregulation of KIAA1429 inhibited m6A modification of ID2 mRNA.

Conclusion: KIAA1429 facilitated migration and invasion of HCC by inhibiting ID2 via upregulating m6A modification of ID2 mRNA.
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http://dx.doi.org/10.2147/OTT.S180954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510231PMC
May 2019

High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction.

J Endocrinol 2019 02;240(2):309-323

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Offspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.
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http://dx.doi.org/10.1530/JOE-18-0493DOI Listing
February 2019

Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration.

Mol Cell Biol 2018 12 28;38(24). Epub 2018 Nov 28.

Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, China

The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.
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http://dx.doi.org/10.1128/MCB.00211-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275188PMC
December 2018

Replication and bioactivation of Ti-based alloy scaffold macroscopically identical to cancellous bone from polymeric template with TiNbZr powders.

J Mech Behav Biomed Mater 2018 12 23;88:296-304. Epub 2018 Aug 23.

Faculty of Materials and Energy, Southwest University, Chongqing 400715, PR China; Chongqing Key Laboratory for Advanced Materials and Technologies of Clean Energy, Southwest University, Chongqing 400715, PR China.

In the present work, a new type of porous Ti-based alloy scaffold with high porosity (about 75%) and interconnected pores in the range of 300-1000 µm was fabricated by polymeric foam replication method with TiNbZr powders. This porous scaffold, which is consisted with major β phase Ti and minor α Ti phase, exhibits a compressive strength of 14.9 MPa and an elastic modulus of 0.21 GPa, resembling the mechanical properties of nature human cancellous bone (σ = 10-50 MPa, E = 0.01-3.0 GPa). To improve its osteogenic potential, a bioactive nanostructural titanate network coating was applied to the scaffold surface using hydrothermal treatment. The bone-like apatite inducing ability of the treated scaffold was systemically assessed using SBF immersion during 3-28 days. The nanostructural titanate network coated on porous TiNbZr scaffold is favorable for apatite nucleation and subsequent growth due to the hydrolysis of titanate. The results suggest that highly porous TiNbZr scaffolds with an appropriate bioactive coating, which was fabricated in this study, could be potentially used for bone tissue engineering application.
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http://dx.doi.org/10.1016/j.jmbbm.2018.08.031DOI Listing
December 2018

Normal Breast-Derived Epithelial Cells with Luminal and Intrinsic Subtype-Enriched Gene Expression Document Interindividual Differences in Their Differentiation Cascade.

Cancer Res 2018 09 11;78(17):5107-5123. Epub 2018 Jul 11.

Departments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.

Cell-type origin is one of the factors that determine molecular features of tumors, but resources to validate this concept are scarce because of technical difficulties in propagating major cell types of adult organs. Previous attempts to generate such resources to study breast cancer have yielded predominantly basal-type cell lines. We have created a panel of immortalized cell lines from core breast biopsies of ancestry-mapped healthy women that form ductal structures similar to normal breast in 3D cultures and expressed markers of major cell types, including the luminal-differentiated cell-enriched ERα-FOXA1-GATA3 transcription factor network. We have also created cell lines from PROCR (CD201)/EpCAM cells that are likely the "normal" counterpart of the claudin-low subtype of breast cancers. RNA-seq and PAM50-intrinsic subtype clustering identified these cell lines as the "normal" counterparts of luminal A, basal, and normal-like subtypes and validated via immunostaining with basal-enriched KRT14 and luminal-enriched KRT19. We further characterized these cell lines by flow cytometry for distribution patterns of stem/basal, luminal-progenitor, mature/differentiated, multipotent PROCR cells, and organogenesis-enriched epithelial/mesenchymal hybrid cells using CD44/CD24, CD49f/EpCAM, CD271/EpCAM, CD201/EpCAM, and ALDEFLUOR assays and E-cadherin/vimentin double staining. These cell lines showed interindividual heterogeneity in stemness/differentiation capabilities and baseline activity of signaling molecules such as NF-κB, AKT2, pERK, and BRD4. These resources can be used to test the emerging concept that genetic variations in regulatory regions contribute to widespread differences in gene expression in "normal" conditions among the general population and can delineate the impact of cell-type origin on tumor progression. In addition to providing a valuable resource for the breast cancer research community to investigate cell-type origin of different subtypes of breast cancer, this study highlights interindividual differences in normal breast, emphasizing the need to use "normal" cells from multiple sources as controls to decipher the effects of cancer-specific genomic aberrations. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125218PMC
September 2018

Catching the therapeutic window of opportunity in early initial-onset Vogt-Koyanagi-Harada uveitis can cure the disease.

Int Ophthalmol 2019 Jun 11;39(6):1419-1425. Epub 2018 Jun 11.

Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Purpose: Vogt-Koyanagi-Harada (VKH) disease is a primary autoimmune granulomatous choroiditis that begins in the choroidal stroma. The aim of this review was to gather a body of evidence for the concept of a window of therapeutic opportunity, defined as a time interval following initial-onset disease during which adequate treatment will substantially modify the disease outcome and possibly even lead to cure, similar to what has been described for rheumatoid arthritis.

Methods: We reviewed the literature and consulted leading experts in VKH disease to determine the consensus for the notion of a therapeutic window of opportunity in VKH disease.

Results: We found a substantial body of evidence in the literature that a therapeutic window of opportunity exists for initial-onset acute uveitis associated with VKH disease. The disease outcome can be substantially improved if dual systemic steroidal and non-steroidal immunosuppressants are given within 2-3 weeks of the onset of initial VKH disease, avoiding evolution to chronic disease and development of "sunset glow fundus." Several studies additionally report series in which the disease could be cured, using such an approach.

Conclusions: There is substantial evidence for a therapeutic window of opportunity in initial-onset acute VKH disease. Timely and adequate treatment led to substantial improvement of disease outcome and prevented chronic evolution and "sunset glow fundus," and very early treatment led to the cure after discontinuation of therapy in several series, likely due to the fact that the choroid is the sole origin of inflammation in VKH disease.
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http://dx.doi.org/10.1007/s10792-018-0949-4DOI Listing
June 2019

Presymptomatic change in microRNAs modulates Tau pathology.

Sci Rep 2018 06 18;8(1):9251. Epub 2018 Jun 18.

Department of Psychological and Brain Sciences, the Linda and Jack Gill Center for Bimolecular Sciences, Indiana University, Bloomington, IN, 47405, USA.

MicroRNAs (miRs) are 18~23 nucleotides long non-coding RNAs that regulate gene expression. To explore whether miR alterations in tauopathy contribute to pathological conditions, we first determined which hippocampal miRs are altered at the presymptomatic and symptomatic stages of tauopathy using rTg4510 mice (Tau mice), a well-characterized tauopathy model. miR-RNA pairing analysis using QIAGEN Ingenuity Pathway Analysis (IPA) revealed 401 genes that can be regulated by 71 miRs altered in Tau hippocampi at the presymptomatic stage. Among several miRs confirmed with real-time qPCR, miR142 (-3p and -5p) in Tau hippocampi were significantly upregulated by two-weeks of age and onward. Transcriptome studies by RNAseq and IPA revealed several overlapping biological and disease associated pathways affected by either Tau or miR142 overexpression, including Signal Transducer and Activator of Transcription 3 (Stat3) and Tumor Necrosis Factor Receptor 2 (Tnfr2) signaling pathways. Similar to what was observed in Tau brains, overexpressing miR142 in wildtype cortical neurons augments mRNA levels of Glial Fibrillary Acidic Protein (Gfap) and Colony Stimulating Factor 1 (Csf1), accompanied by a significant increase in microglia and reactive astrocyte numbers. Taken together, our study suggests that miR alterations by Tau overexpression may contribute to the neuroinflammation observed in Tau brains.
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http://dx.doi.org/10.1038/s41598-018-27527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006352PMC
June 2018

[Correlation between fasting C-peptide and serum uric acid in patients with type 2 diabetes mellitus].

Nan Fang Yi Ke Da Xue Xue Bao 2018 Apr;38(4):490-495

1Department of Endocrinology, Shenzhen Second People's Hospital, Shenzhen 518037, China; 3Shenzhen University Health Science Center, Shenzhen 518060, China. E-mail:

Objective: To explore the relationship between fasting C-peptide (F-CP) and serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM).

Methods: A total of 347 hospitalized patients with T2DM were stratified according to F-CP level to analyze the impact of increased F-CP levels on SUA level and the incidence of hyperuricemia (HUA). The patients with an elevated SUA level (>420 µmol/L) and a normal SUA level (≤420 µmol/L) were compared for general data, fasting C-peptide and other clinical indexes. Pearson or Spearman correlation analysis was used to analyze the correlation of SUA level with F-CP levels and other parameters. The risk factors of elevated SUA were analyzed by binary logistic regression, multiple regression analysis and hierarchical interaction analysis. The ROC curve was used to analyze the independent risk factors of elevated SUA and determine the corresponding cut-off values.

Results: Compared with those with a normal SUA level, patients with elevated SUA had higher body mass index (BMI), waist-to-hip ratio, F-CP, postprandial 2hC peptide (2hP-CP), triglyceride (TG), homocysteine (HCY), serum creatinine (SCr) level (P<0.05), and a greater percentage of drinking (44.8% vs 32.6%, P=0.006), but had significantly lowered levels of HbA1c, high-density lipoprotein (HDL), and estimated glomerular filtration rate (eGFR) (P<0.05). SUA was found to be positively correlated with F-CP, 2hP-CP, BMI, waist-to-hip ratio, diastolic blood pressure, TG, HCY, SCr, smoking and drinking (P<0.05), and was negatively correlated with gender, age, age of disease onset, HbA1c, HDL and eGFR (P<0.05). SUA level and the incidence of hyperuricemia increasea significantly with F-CP level (P<0.05). F-CP was identified as an independent risk factor for elevated SUA, and gender did not affect the relationship between F-CP and SUA. ROC curve analysis showed that a F-CP level >1.260 ng/mL was associated with a significantly increased risk of hyperuricemia in T2DM patients.

Conclusion: F-CP is closely related with SUA and may be an independent risk factor of elevated SUA in patients with T2DM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765660PMC
April 2018

Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis.

Breast Cancer Res 2018 05 2;20(1):35. Epub 2018 May 2.

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

Background: The majority of estrogen receptor-positive (ERα) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown.

Methods: We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses.

Results: Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14/KRT19 and CD49f/EpCAM phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα/PR/HER2 tumors, was associated with poor outcome.

Conclusion: These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα breast cancers.
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http://dx.doi.org/10.1186/s13058-018-0963-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932758PMC
May 2018

Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas.

J Neurooncol 2018 May 12;137(3):469-479. Epub 2018 Jan 12.

Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indianapolis, IN, USA.

Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies.
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http://dx.doi.org/10.1007/s11060-018-2753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924594PMC
May 2018

Activation of AKT-mTOR Signaling Directs Tenogenesis of Mesenchymal Stem Cells.

Stem Cells 2018 04 5;36(4):527-539. Epub 2018 Jan 5.

Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

Tendon repair is a clinical challenge because of the limited understanding on tenogenesis. The synthesis of type I collagen (Collagen I) and other extracellular matrix are essential for tendon differentiation and homeostasis. Current studies on tenogenesis focused mostly on the tenogenic transcriptional factors while the signaling controlling tenogenesis on translational level remains largely unknown. Here, we showed that mechanistic target of rapamycin (mTOR) signaling was activated by protenogenic growth factor, transforming growth factors beta1, and insulin-like growth factor-I. The expression of mTOR was upregulated during tenogenesis of mesenchymal stem cells (MSCs). Moreover, mTOR was downregulated in human tendinopathy tissues and was inactivated upon statin treatment. Both inhibition and depletion of AKT or mTOR significantly reduced type I collagen production and impaired tenogenesis of MSCs. Tendon specific-ablation of mTOR resulted in tendon defect and reduction of Collagen I. However, there is no evident downregulation of tendon associated collagens at the transcription level. Our study demonstrated that AKT-mTOR axis is a key mediator of tendon differentiation and provided a novel therapeutic target for tendinopathy and tendon injuries. Stem Cells 2018;36:527-539.
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http://dx.doi.org/10.1002/stem.2765DOI Listing
April 2018

Roles of alternative splicing in modulating transcriptional regulation.

BMC Syst Biol 2017 Oct 3;11(Suppl 5):89. Epub 2017 Oct 3.

College of Automation, Harbin Engineering University, Harbin, Heilongjiang, 150001, China.

Background: The ability of a transcription factor to regulate its targets is modulated by a variety of genetic and epigenetic mechanisms. Alternative splicing can modulate gene function by adding or removing certain protein domains, and therefore affect the activity of protein. Reverse engineering of gene regulatory networks using gene expression profiles has proven valuable in dissecting the logical relationships among multiple proteins during the transcriptional regulation. However, it is unclear whether alternative splicing of certain proteins affects the activity of other transcription factors.

Results: In order to investigate the roles of alternative splicing during transcriptional regulation, we constructed a statistical model to infer whether the alternative splicing events of modulator proteins can affect the ability of key transcription factors in regulating the expression levels of their transcriptional targets. We tested our strategy in KIRC (Kidney Renal Clear Cell Carcinoma) using the RNA-seq data downloaded from TCGA (the Cancer Genomic Atlas). We identified 828of modulation relationships between the splicing levels of modulator proteins and activity levels of transcription factors. For instance, we found that the activity levels of GR (glucocorticoid receptor) protein, a key transcription factor in kidney, can be influenced by the splicing status of multiple proteins, including TP53, MDM2 (mouse double minute 2 homolog), RBM14 (RNA-binding protein 14) and SLK (STE20 like kinase). The influenced GR-targets are enriched by key cancer-related pathways, including p53 signaling pathway, TR/RXR activation, CAR/RXR activation, G1/S checkpoint regulation pathway, and G2/M DNA damage checkpoint regulation pathway.

Conclusions: Our analysis suggests, for the first time, that exon inclusion levels of certain regulatory proteins can affect the activities of many transcription factors. Such analysis can potentially unravel a novel mechanism of how splicing variation influences the cellular function and provide important insights for how dysregulation of splicing outcome can lead to various diseases.
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http://dx.doi.org/10.1186/s12918-017-0465-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629561PMC
October 2017

Bone-like apatite growth on controllable macroporous titanium scaffolds coated with microporous titania.

J Mech Behav Biomed Mater 2018 01 8;77:225-233. Epub 2017 Sep 8.

School of Materials Science and Engineering and Jiangsu Key Laboratory for Advanced Metallic Materials, Southeast University, Nanjing 211189, China.

In this study, a simple, cost-effective approach of polymeric foam replication was used to produce three-dimensionally macroporous titanium scaffolds with controllable porosities and mechanical properties. Two kinds of porous titanium scaffolds with different porosities (74.7% and 87.6%) and pore sizes (360µm and 750µm) were fabricated. Both of the scaffolds exhibit good compressive strength (24.5MPa and 13.5MPa) with a low elastic modulus (0.23GPa and 0.11GPa), approximating the mechanical properties of nature human cancellous bone (E = 10-50MPa, σ = 0.01-3.0GPa). Thereafter, the scaffolds were surface modified using plasma electrolyte oxidation (PEO) process to gain a bioactive porous titania ceramic coating. The SBF immersion test indicates PEO treated scaffolds show excellent bioactivity as the apatite rapidly nucleates and grows on the scaffold surface during 3-28 days. The results suggest that the highly porous titanium scaffolds with titania bioactive coatings are promising in cancellous bone replacement.
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http://dx.doi.org/10.1016/j.jmbbm.2017.09.014DOI Listing
January 2018

Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice.

J Biol Chem 2017 10 12;292(42):17461-17472. Epub 2017 Sep 12.

From the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907,

Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently up-regulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 up-regulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine the role of Plk1 in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis. Surprisingly, Plk1 overexpression had no apparent phenotypes in the mice. Given that no malignant tumor formation was observed even after a long period of Plk1 overexpression, we reasoned that additional factors are required for tumorigenesis in Plk1-overexpressing mice. Because Plk1 can directly participate in the regulation of the DNA damage response (DDR) pathway, we challenged Plk1-overexpressing mice with ionizing radiation (IR) and found that Plk1-overexpressing mice are much more sensitive to IR than their wild-type littermates. Analysis of tumor development in the Plk1-overexpressing mice indicated a marked decrease in the time required for tumor emergence after IR. At the molecular level, Plk1 overexpression led to reduced phosphorylation of the serine/threonine kinases ATM and Chk2 and of histone H2AX after IR treatment both and Furthermore, RNA-Seq analysis suggested that Plk1 elevation decreases the expression of several DDR genes. We conclude that Plk1 overexpression may contribute to tumor formation by both inducing chromosomal instability and suppressing the DDR pathway.
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http://dx.doi.org/10.1074/jbc.M117.810960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655521PMC
October 2017

Hydrogen-peroxide-modified egg albumen for transparent and flexible resistive switching memory.

Nanotechnology 2017 Oct 2;28(42):425202. Epub 2017 Aug 2.

Institute for Clean Energy and Advanced Materials (ICEAM), Southwest University, Chongqing 400715, People's Republic of China.

Egg albumen is modified by hydrogen peroxide with concentrations of 5%, 10%, 15% and 30% at room temperature. Compared with devices without modification, a memory cell of Ag/10% HO-egg albumen/indium tin oxide exhibits obviously enhanced resistive switching memory behavior with a resistance ratio of 10, self-healing switching endurance for 900 cycles and a prolonged retention time for a 10 s @ 200 mV reading voltage after being bent 10 times. The breakage of massive protein chains occurs followed by the recombination of new protein chain networks due to the oxidation of amidogen and the synthesis of disulfide during the hydrogen peroxide modifying egg albumen. Ions such as Fe, Na, K, which are surrounded by protein chains, are exposed to the outside of protein chains to generate a series of traps during the egg albumen degeneration process. According to the fitting results of the double logarithm I-V curves and the current-sensing atomic force microscopy (CS-AFM) images of the ON and OFF states, the charge transfer from one trap center to its neighboring trap center is responsible for the resistive switching memory phenomena. The results of our work indicate that hydrogen- peroxide-modified egg albumen could open up a new avenue of biomaterial application in nanoelectronic systems.
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http://dx.doi.org/10.1088/1361-6528/aa8397DOI Listing
October 2017

regSNPs-splicing: a tool for prioritizing synonymous single-nucleotide substitution.

Hum Genet 2017 09 8;136(9):1279-1289. Epub 2017 Apr 8.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA.

While synonymous single-nucleotide variants (sSNVs) have largely been unstudied, since they do not alter protein sequence, mounting evidence suggests that they may affect RNA conformation, splicing, and the stability of nascent-mRNAs to promote various diseases. Accurately prioritizing deleterious sSNVs from a pool of neutral ones can significantly improve our ability of selecting functional genetic variants identified from various genome-sequencing projects, and, therefore, advance our understanding of disease etiology. In this study, we develop a computational algorithm to prioritize sSNVs based on their impact on mRNA splicing and protein function. In addition to genomic features that potentially affect splicing regulation, our proposed algorithm also includes dozens structural features that characterize the functions of alternatively spliced exons on protein function. Our systematical evaluation on thousands of sSNVs suggests that several structural features, including intrinsic disorder protein scores, solvent accessible surface areas, protein secondary structures, and known and predicted protein family domains, show significant differences between disease-causing and neutral sSNVs. Our result suggests that the protein structure features offer an added dimension of information while distinguishing disease-causing and neutral synonymous variants. The inclusion of structural features increases the predictive accuracy for functional sSNV prioritization.
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http://dx.doi.org/10.1007/s00439-017-1783-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602096PMC
September 2017