Publications by authors named "Mingyi Wang"

137 Publications

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Science 2021 May 22;372(6543):725-729. Epub 2021 Apr 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
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http://dx.doi.org/10.1126/science.abg2365DOI Listing
May 2021

Age-associated proinflammatory elastic fiber remodeling in large arteries.

Mech Ageing Dev 2021 Apr 8;196:111490. Epub 2021 Apr 8.

Laboratory of Cardiovascular Science, Intramural Research Program, National Institution on Aging, National Institutes of Health, Biomedical Research Center (BRC), 251 Bayview Boulevard, Baltimore, MD, 21224, USA. Electronic address:

Elastic fibers are the main components of the extracellular matrix of the large arterial wall. Elastic fiber remodeling is an intricate process of synthesis and degradation of the core elastin protein and microfibrils accompanied by the assembly and disassembly of accessory proteins. Age-related morphological, structural, and functional proinflammatory remodeling within the elastic fiber has a profound effect upon the integrity, elasticity, calcification, amyloidosis, and stiffness of the large arterial wall. An age-associated increase in arterial stiffness is a major risk factor for the pathogenesis of diseases of the large arteries such as hypertensive and atherosclerotic vasculopathy. This mini review is an update on the key molecular, cellular, functional, and structural mechanisms of elastic fiber proinflammatory remodeling in large arteries with aging. Targeting structural and functional integrity of the elastic fiber may be an effective approach to impede proinflammatory arterial remodeling with advancing age.
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http://dx.doi.org/10.1016/j.mad.2021.111490DOI Listing
April 2021

MDAKRLS: Predicting human microbe-disease association based on Kronecker regularized least squares and similarities.

J Transl Med 2021 02 12;19(1):66. Epub 2021 Feb 12.

School of Control Science and Engineering, Shandong University, Jinan, 250061, China.

Background: Microbes are closely related to human health and diseases. Identification of disease-related microbes is of great significance for revealing the pathological mechanism of human diseases and understanding the interaction mechanisms between microbes and humans, which is also useful for the prevention, diagnosis and treatment of human diseases. Considering the known disease-related microbes are still insufficient, it is necessary to develop effective computational methods and reduce the time and cost of biological experiments.

Methods: In this work, we developed a novel computational method called MDAKRLS to discover potential microbe-disease associations (MDAs) based on the Kronecker regularized least squares. Specifically, we introduced the Hamming interaction profile similarity to measure the similarities of microbes and diseases besides Gaussian interaction profile kernel similarity. In addition, we introduced the Kronecker product to construct two kinds of Kronecker similarities between microbe-disease pairs. Then, we designed the Kronecker regularized least squares with different Kronecker similarities to obtain prediction scores, respectively, and calculated the final prediction scores by integrating the contributions of different similarities.

Results: The AUCs value of global leave-one-out cross-validation and 5-fold cross-validation achieved by MDAKRLS were 0.9327 and 0.9023 ± 0.0015, which were significantly higher than five state-of-the-art methods used for comparison. Comparison results demonstrate that MDAKRLS has faster computing speed under two kinds of frameworks. In addition, case studies of inflammatory bowel disease (IBD) and asthma further showed 19 (IBD), 19 (asthma) of the top 20 prediction disease-related microbes could be verified by previously published biological or medical literature.

Conclusions: All the evaluation results adequately demonstrated that MDAKRLS has an effective and reliable prediction performance. It may be a useful tool to seek disease-related new microbes and help biomedical researchers to carry out follow-up studies.
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http://dx.doi.org/10.1186/s12967-021-02732-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881563PMC
February 2021

Retinal cross-section motion correction in three-dimensional retinal optical coherence tomography.

J Biophotonics 2021 Feb 12:e202000443. Epub 2021 Feb 12.

School of Physics and Telecommunication Engineering, South China Normal University, Guangzhou, China.

Motion correction is an important issue in ophthalmic optical coherence tomography (OCT), and can improve the ability of data sets to reflect the physiological structures of tissues and make visualization and subsequent analysis easier. In this study, we present a novel method to correct the cross-sectional motion artifacts in retinal OCT volumes. Motion along the x-direction (fast-scan direction) is corrected through the normalized cross-correlation algorithm, while axial motion compensation is performed using the polynomial fitting method on the inner segment/outer segment (IS/OS) layer segmented by the shortest path faster algorithm (SPFA). The results of volunteers with central serous chorioretinopathy demonstrate that the proposed method effectively corrects motion artifacts in OCT volumes and may have potential application value in the evaluation of ophthalmic diseases such as diabetic retinopathy, glaucoma and age-related macular degeneration.
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http://dx.doi.org/10.1002/jbio.202000443DOI Listing
February 2021

Role of iodine oxoacids in atmospheric aerosol nucleation.

Science 2021 02 4;371(6529):589-595. Epub 2021 Feb 4.

Department of Chemistry and Cooperative Institute for Research in the Environmental Sciences, University of Colorado Boulder, Boulder, CO 80309, USA.

Iodic acid (HIO) is known to form aerosol particles in coastal marine regions, but predicted nucleation and growth rates are lacking. Using the CERN CLOUD (Cosmics Leaving Outdoor Droplets) chamber, we find that the nucleation rates of HIO particles are rapid, even exceeding sulfuric acid-ammonia rates under similar conditions. We also find that ion-induced nucleation involves IO and the sequential addition of HIO and that it proceeds at the kinetic limit below +10°C. In contrast, neutral nucleation involves the repeated sequential addition of iodous acid (HIO) followed by HIO, showing that HIO plays a key stabilizing role. Freshly formed particles are composed almost entirely of HIO, which drives rapid particle growth at the kinetic limit. Our measurements indicate that iodine oxoacid particle formation can compete with sulfuric acid in pristine regions of the atmosphere.
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http://dx.doi.org/10.1126/science.abe0298DOI Listing
February 2021

Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival.

Nat Commun 2021 02 3;12(1):757. Epub 2021 Feb 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.
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http://dx.doi.org/10.1038/s41467-021-21026-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859411PMC
February 2021

Full-field optical multi-functional angiography based on endogenous hemodynamic characteristics.

J Biophotonics 2021 May 10;14(5):e202000411. Epub 2021 Feb 10.

School of Physics and Optoelectronic Engineering, Foshan University, Foshan, China.

Blood flow functional imaging is widely applied in biological research to provide vascular morphological and statistical parameters. It relies on the absorption difference and is, therefore, easily affected by complex biological structures, and it cannot accommodate abundant functional information. We propose a full-field multi-functional angiography method to classify arteriovenous vessels and to display flow velocity and vascular diameter distribution simultaneously. Unlike previous methods, an under-sampled laser Doppler acquisition mode is used to record the low-coherence speckle, and multi-functional angiography is achieved by modulating the endogenous hemodynamic characteristics from low-coherence speckle. To demonstrate the combination of classified angiography, blood flow velocity measurement, and vascular diameter measurement realized using our method, we performed experiments on the flow phantom and living chicken embryos and generated multi-functional angiograms. The proposed method can be used as a label-free multi-functional angiography technique in which red blood cells provide a strong endogenous source of naturally hemodynamic characteristics.
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http://dx.doi.org/10.1002/jbio.202000411DOI Listing
May 2021

The Roles of Fluid Intelligence and Emotional Intelligence in Affective Decision-Making During the Transition to Early Adolescence.

Front Psychol 2020 16;11:574903. Epub 2020 Dec 16.

CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

The current study mainly explored the influence of fluid intelligence (IQ) and emotional intelligence (EI) on affective decision-making from a developmental perspective, specifically, during the transition from childhood into early adolescence. Meanwhile, their age-related differences in affective decision-making were explored. A total of 198 participants aged 8-12 completed the Iowa Gambling Task (IGT), the Cattell's Culture Fair Intelligence Test and the Trait Emotional Intelligence Questionnaire-Child Form. Based on the net scores of IGT, the development of affective decision-making ability did not increase monotonically with age, and there was a developmental trend of an impaired IGT performance in early adolescence (aged 11-12), especially in the early learning phase (first 40 trials) of the IGT. More importantly, IQ and EI played different roles for children and early adolescents: IQ and EI jointly predicted the IGT performance for 8-10 years old children, whereas only EI contributed to the IGT performance of 11-12 years old early adolescents. The present study extends the evidence how cognitive processing and emotional processing interact in affective decision-making from the developmental perspective. Furthermore, it provides insights of future research and intervention with early adolescents' poor affective decision-making.
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http://dx.doi.org/10.3389/fpsyg.2020.574903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772350PMC
December 2020

Enhanced temporal and spatial resolution in super-resolution covariance imaging algorithm with deconvolution optimization.

J Biophotonics 2021 Feb 16;14(2):e202000292. Epub 2020 Nov 16.

School of Physics and Optoelectronic Engineering, Foshan University, Foshan, Guang dong, China.

Based on the numerical analysis that covariance exhibits superior statistical precision than cumulant and variance, a new SOFI algorithm by calculating the n orders covariance for each pixel is presented with an almost -fold resolution improvement, which can be enhanced to 2 via deconvolution. An optimized deconvolution is also proposed by calculating the (n + 1) order SD associated with each n order covariance pixel, and introducing the results into the deconvolution as a damping factor to suppress noise generation. Moreover, a re-deconvolution of the covariance image with the covariance-equivalent point spread function is used to further increase the final resolution by above 2-fold. Simulated and experimental results show that this algorithm can significantly increase the temporal-spatial resolution of SOFI, meanwhile, preserve the sample's structure. Thus, a resolution of 58 nm is achieved for 20 experimental images, and the corresponding acquisition time is 0.8 seconds.
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http://dx.doi.org/10.1002/jbio.202000292DOI Listing
February 2021

Proinflammation, profibrosis, and arterial aging.

Aging Med (Milton) 2020 Sep 18;3(3):159-168. Epub 2020 Mar 18.

Laboratory of Cardiovascular Science National Institute on Aging National Institutes of Health Baltimore Maryland.

Aging is a major risk factor for quintessential cardiovascular diseases, which are closely related to arterial proinflammation. The age-related alterations of the amount, distribution, and properties of the collagen fibers, such as cross-links and degradation in the arterial wall, are the major sequelae of proinflammation. In the aging arterial wall, collagen types I, II, and III are predominant,  and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule-EGF-VIII, and transforming growth factor-beta 1 (TGF-β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP-2) and activates profibrogenic TGF-β1 signaling, contributing to profibrosis. The age-associated increase in activated MMP-2 cleaves latent TGF-β and subsequently increases TGF-β1 activity leading to collagen deposition in the arterial wall. Furthermore, a blockade of the proinflammatory signaling pathway alleviates the fibrogenic signaling, reduces profibrosis, and prevents arterial stiffening with aging. Thus, age-associated proinflammatory-profibrosis coupling is the underlying molecular mechanism of arterial stiffening with advancing age.
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http://dx.doi.org/10.1002/agm2.12099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574637PMC
September 2020

A Magnesium-Incorporated Nanoporous Titanium Coating for Rapid Osseointegration.

Int J Nanomedicine 2020 8;15:6593-6603. Epub 2020 Sep 8.

Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, People's Republic of China.

Purpose: Micro-arc oxidation (MAO) is a fast and effective method to prepare nanoporous coatings with high biological activity and bonding strength. Simple micro/nano-coatings cannot fully meet the requirements of osteogenesis. To further improve the biological activity of a titanium surface, we successfully added biological magnesium (Mg) to a coating by micro-arc oxidation and evaluated the optimal magnesium concentration in the electrolyte, biocompatibility, cell adhesion, proliferation, and osteogenesis in vitro.

Methods: Nanoporous titanium coatings with different concentrations of magnesium were prepared by micro-arc oxidation and characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). The Mg release ability of the magnesium-incorporated nanoporous titanium coatings was determined by inductively coupled plasma emission spectrometry (ICP-OES). The cytotoxicity of the magnesium-incorporated nanoporous titanium coatings was detected with live/dead double-staining tests. A CCK-8 assay was employed to evaluate cell proliferation, and FITC-phalloidin was used to determine the structure of the cytoskeleton by staining β-actin. Alkaline phosphatase (ALP) activity was evaluated by alizarin red S (ARS) staining to determine the effect of the coatings on osteogenic differentiation in vitro. The mRNA expression of osteogenic differentiation-related markers was measured using qRT-PCR.

Results: EDS analyses revealed the successful addition of magnesium to the microporous coatings. The best magnesium concentration of the electrolyte for preparing the new coating was determined. The results showed that the nano-coatings prepared using the electrolyte with 2 g/L magnesium acetate best promoted the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs).

Conclusion: These results suggest that the new titanium metal coating with a dual effect of promoting bone morphology and supplying the biological ion Mg can be beneficial for rapid osseointegration.
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http://dx.doi.org/10.2147/IJN.S255486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490434PMC
December 2020

bloodstream infections: two cases and review of the literature.

Future Microbiol 2020 07 20;15:981-985. Epub 2020 Aug 20.

Marine College, Shandong University, Weihai 264209, China.

is an emerging and uncommon human pathogen that has been under recognized due to the limitations of phenotypic identification. Here we describe two cases of bacteremia caused by and summarize the results of antimicrobial susceptibility testing according to some previous literatures, which illustrate the importance of identification and treatment of unusual organisms. The most reliable antibiotic treatment options to appear to be metronidazole, amoxicillin-clavulanate, carbapenems, vancomycin, cefoxitin, chloramphenicol and clindamycin.
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http://dx.doi.org/10.2217/fmb-2019-0338DOI Listing
July 2020

SomaticCombiner: improving the performance of somatic variant calling based on evaluation tests and a consensus approach.

Sci Rep 2020 07 30;10(1):12898. Epub 2020 Jul 30.

Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research, Frederick, MD, 20877, USA.

It is challenging to identify somatic variants from high-throughput sequence reads due to tumor heterogeneity, sub-clonality, and sequencing artifacts. In this study, we evaluated the performance of eight primary somatic variant callers and multiple ensemble methods using both real and synthetic whole-genome sequencing, whole-exome sequencing, and deep targeted sequencing datasets with the NA12878 cell line. The test results showed that a simple consensus approach can significantly improve performance even with a limited number of callers and is more robust and stable than machine learning based ensemble approaches. To fully exploit the multi-callers, we also developed a software package, SomaticCombiner, that can combine multiple callers and integrates a new variant allelic frequency (VAF) adaptive majority voting approach, which can maintain sensitive detection for variants with low VAFs.
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http://dx.doi.org/10.1038/s41598-020-69772-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393490PMC
July 2020

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas.

Nat Commun 2020 06 18;11(1):3096. Epub 2020 Jun 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, 20892, USA.

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.
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http://dx.doi.org/10.1038/s41467-020-16546-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303129PMC
June 2020

Photo-oxidation of Aromatic Hydrocarbons Produces Low-Volatility Organic Compounds.

Environ Sci Technol 2020 07 18;54(13):7911-7921. Epub 2020 Jun 18.

Institute for Atmospheric and Environmental Sciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany.

To better understand the role of aromatic hydrocarbons in new-particle formation, we measured the particle-phase abundance and volatility of oxidation products following the reaction of aromatic hydrocarbons with OH radicals. For this we used thermal desorption in an iodide-adduct Time-of-Flight Chemical-Ionization Mass Spectrometer equipped with a Filter Inlet for Gases and AEROsols (FIGAERO-ToF-CIMS). The particle-phase volatility measurements confirm that oxidation products of toluene and naphthalene can contribute to the initial growth of newly formed particles. Toluene-derived (C) oxidation products have a similar volatility distribution to that of α-pinene-derived (C) oxidation products, while naphthalene-derived (C) oxidation products are much less volatile than those from toluene or α-pinene; they are thus stronger contributors to growth. Rapid progression through multiple generations of oxidation is more pronounced in toluene and naphthalene than in α-pinene, resulting in more oxidation but also favoring functional groups with much lower volatility per added oxygen atom, such as hydroxyl and carboxylic groups instead of hydroperoxide groups. Under conditions typical of polluted urban settings, naphthalene may well contribute to nucleation and the growth of the smallest particles, whereas the more abundant alkyl benzenes may overtake naphthalene once the particles have grown beyond the point where the Kelvin effect strongly influences the condensation driving force.
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http://dx.doi.org/10.1021/acs.est.0c02100DOI Listing
July 2020

Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma.

Nat Commun 2020 05 18;11(1):2459. Epub 2020 May 18.

Integrative Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.
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http://dx.doi.org/10.1038/s41467-020-16295-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235245PMC
May 2020

Rapid growth of new atmospheric particles by nitric acid and ammonia condensation.

Nature 2020 05 13;581(7807):184-189. Epub 2020 May 13.

Institute for Ion Physics and Applied Physics, University of Innsbruck, Innsbruck, Austria.

A list of authors and their affiliations appears at the end of the paper New-particle formation is a major contributor to urban smog, but how it occurs in cities is often puzzling. If the growth rates of urban particles are similar to those found in cleaner environments (1-10 nanometres per hour), then existing understanding suggests that new urban particles should be rapidly scavenged by the high concentration of pre-existing particles. Here we show, through experiments performed under atmospheric conditions in the CLOUD chamber at CERN, that below about +5 degrees Celsius, nitric acid and ammonia vapours can condense onto freshly nucleated particles as small as a few nanometres in diameter. Moreover, when it is cold enough (below -15 degrees Celsius), nitric acid and ammonia can nucleate directly through an acid-base stabilization mechanism to form ammonium nitrate particles. Given that these vapours are often one thousand times more abundant than sulfuric acid, the resulting particle growth rates can be extremely high, reaching well above 100 nanometres per hour. However, these high growth rates require the gas-particle ammonium nitrate system to be out of equilibrium in order to sustain gas-phase supersaturations. In view of the strong temperature dependence that we measure for the gas-phase supersaturations, we expect such transient conditions to occur in inhomogeneous urban settings, especially in wintertime, driven by vertical mixing and by strong local sources such as traffic. Even though rapid growth from nitric acid and ammonia condensation may last for only a few minutes, it is nonetheless fast enough to shepherd freshly nucleated particles through the smallest size range where they are most vulnerable to scavenging loss, thus greatly increasing their survival probability. We also expect nitric acid and ammonia nucleation and rapid growth to be important in the relatively clean and cold upper free troposphere, where ammonia can be convected from the continental boundary layer and nitric acid is abundant from electrical storms.
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http://dx.doi.org/10.1038/s41586-020-2270-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334196PMC
May 2020

Analysis of aflatoxin signature mutation in hepatocellular carcinomas from Guatemala: A cross-sectional study (2016-2017).

Health Sci Rep 2020 Jun 6;3(2):e155. Epub 2020 May 6.

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland.

Background And Aims: Guatemala has the highest incidence of hepatocellular carcinoma (HCC) in the Western hemisphere. The major risk factors in Guatemala are not well characterized, but the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) appears to be low, while the prevalence of aflatoxin (AFB) exposure appears to be high. To examine whether AFB may contribute to the elevated incidence of HCC in Guatemala, this study examined the frequency of the AFB-signature mutation in the gene (R249S) as well as other somatic mutations. In addition, we assessed whether the frequency of the mutation differed by sex.

Methods: Formalin-fixed, paraffin-embedded (FFPE) HCC tissues were obtained from three hospitals in Guatemala City between 2016 and 2017. In addition, tumor tissues preserved in RNAlater were also obtained. Sociodemographic and clinical information including HBV and HCV status were collected. Targeted sequencing of was performed in the FFPE samples, and a panel of 253 cancer-related genes was sequenced in the RNAlater samples.

Results: Ninety-one FFPE tissues were examined, from 52 men and 39 women. Median (IQR) age at diagnosis was 62 (51-70). Among those with known HBV and HCV status, two were HBV+ and three were HCV+. Overall, 47% of the HCCs had a mutation. The AFB-signature R249S mutation was present in 24%. No overlap between the R249S mutation and HBV+ was observed in this cohort. Among 18 RNAlater samples examined, 44% had any mutation and 33% had the R249S mutation. Other somatic mutations were identified in known HCC driver genes.

Conclusions: The presence of the R249S mutation in the samples studied suggests that AFB may contribute to the high incidence of HCC in Guatemala. The proportion of HBV+ tumors was low, suggesting that AFB may be associated with HCC in the absence of concomitant HBV infection. Further investigation of AFB and other risk factors for HCC in Guatemala is warranted.
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http://dx.doi.org/10.1002/hsr2.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202218PMC
June 2020

ZO-1 Regulates Intercalated Disc Composition and Atrioventricular Node Conduction.

Circ Res 2020 07 29;127(2):e28-e43. Epub 2020 Apr 29.

From the Departments of Pathology (W.D., H.L.S., Y.L., L.S., C.R.W.), The University of Chicago, IL.

Rationale: ZO-1 (Zona occludens 1), encoded by the tight junction protein 1 () gene, is a regulator of paracellular permeability in epithelia and endothelia. ZO-1 interacts with the actin cytoskeleton, gap, and adherens junction proteins and localizes to intercalated discs in cardiomyocytes. However, the contribution of ZO-1 to cardiac physiology remains poorly defined.

Objective: We aim to determine the role of ZO-1 in cardiac function.

Methods And Results: Inducible cardiomyocyte-specific deletion mice (; ) were generated by crossing the floxed mice and transgenic mice. Tamoxifen-induced loss of ZO-1 led to atrioventricular (AV) block without changes in heart rate, as measured by ECG and ex vivo optical mapping. Mice with tamoxifen-induced conduction system-specific deletion of () developed AV block while tamoxifen-induced conduction system deletion of distal to the AV node () did not demonstrate conduction defects. Western blot and immunostaining analyses of AV nodes showed that ZO-1 loss decreased Cx (connexin) 40 expression and intercalated disc localization. Consistent with the mouse model study, immunohistochemical staining showed that ZO-1 is abundantly expressed in the human AV node and colocalizes with Cx40. Ventricular conduction was not altered despite decreased localization of ZO-1 and Cx43 at the ventricular intercalated disc and modestly decreased left ventricular ejection fraction, suggesting ZO-1 is differentially required for AV node and ventricular conduction.

Conclusions: ZO-1 is a key protein responsible for maintaining appropriate AV node conduction through maintaining gap junction protein localization.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334106PMC
July 2020

Treatment of Extracranial Vertebral Artery Aneurysm with Flow Diversion.

World Neurosurg 2020 06 19;138:328-331. Epub 2020 Mar 19.

Department of Interventional Therapy, The First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address:

Background: Aneurysms of the extracranial vertebral artery are rare, and the treatment options are not standardized. We present a case of an extracranial vertebral artery aneurysm treated with flow diversion.

Case Description: In a 72-year-old woman, computed tomography angiography demonstrated a right extracranial vertebral artery aneurysm. The saccular aneurysm (7.9 × 6.6 mm) was demonstrated on digital subtraction angiography at the V3 segment of the right vertebral artery. A Pipeline embolization device was placed in the diseased parent artery. The patency of the Pipeline embolization device was confirmed at 12-month follow-up.

Conclusions: Flow diversion is a simple and promising treatment option for a V3 segment aneurysm. Postoperative asymptomatic partial in-stent stenosis is tolerable.
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http://dx.doi.org/10.1016/j.wneu.2020.03.064DOI Listing
June 2020

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.

JAMA Oncol 2020 05;6(5):724-734

Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, United Kingdom.

Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.

Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma.

Design, Setting, And Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.

Main Outcomes And Measures: The frequency of rare pathogenic or likely pathogenic genetic variants.

Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53.

Conclusions And Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
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http://dx.doi.org/10.1001/jamaoncol.2020.0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082769PMC
May 2020

Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction.

Circ Res 2020 02 3;126(4):456-470. Epub 2020 Jan 3.

From the Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (Q.H., H.Z., N.G.C., D.W., P.W., E.S., L.F.B., W.W.), University of Washington, Seattle.

Rationale: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood.

Objective: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction.

Methods And Results: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death.

Conclusions: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035202PMC
February 2020

Immune gene expression profiling reveals heterogeneity in luminal breast tumors.

Breast Cancer Res 2019 12 19;21(1):147. Epub 2019 Dec 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.

Methods: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.

Results: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.

Conclusion: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.
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http://dx.doi.org/10.1186/s13058-019-1218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924001PMC
December 2019

Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates.

PLoS One 2019 5;14(12):e0225911. Epub 2019 Dec 5.

Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.

Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications of hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is an important clinical goal. Here, we tested the hypothesis that Discoidin Domain Receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, is a determinant of arterial fibrosis. We report a significant increase in collagen type 1 levels along with collagen and ECM remodeling, degradation of elastic laminae, enhanced fat deposition and calcification in the abdominal aorta in a non-human primate model of high-fat, high-sucrose diet (HFS)-induced metabolic syndrome. These changes were associated with a marked increase in DDR2. Resveratrol attenuated collagen type I deposition and remodeling induced by the HFS diet, with a concomintant reduction in DDR2. Further, in isolated rat vascular adventitial fibroblasts and VSMCs, hyperglycemia increased DDR2 and collagen type I expression via TGF-β1/SMAD2/3, which was attenuated by resveratrol. Notably, gene knockdown and overexpression approaches demonstrated an obligate role for DDR2 in hyperglycemia-induced increase in collagen type I expression in these cells. Together, our observations point to DDR2 as a hitherto unrecognized molecular link between metabolic syndrome and arterial fibrosis, and hence a therapeutic target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225911PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894805PMC
March 2020

ZP1 mutations are associated with empty follicle syndrome: evidence for the existence of an intact oocyte and a zona pellucida in follicles up to the early antral stage. A case report.

Hum Reprod 2019 11;34(11):2201-2207

Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, No. 88 Xiangya Road, Changsha 410008, China.

Empty follicle syndrome (EFS) is the complete failure to retrieve oocytes after ovarian stimulation. Although LHCGR and ZP3 were identified as causative genes, it is still unclear what happens to these patients' oocytes, and the pathogenesis of EFS remains obscure. Here, we identified six novel ZP1 mutations associated with EFS and female infertility that was inherited recessively in five unrelated families. Studies in CHO-K1 cells showed that these mutations resulted in either degradation or truncation of ZP1 protein. Immunohistochemistry using ovarian serial sections demonstrated that all preantral follicles had normal architecture, but with a thin ZP, lacking ZP1, surrounding the growing oocytes. The antral follicles were also defective in normal cumulus-oocyte complex organisation, leading us to speculate that the lack of ZP1 might lead to oocyte degeneration or increased fragility of the oocyte during follicular puncture, ultimately resulting in EFS. To our knowledge, this is the first study that presents morphological evidence showing normal preantral folliculogenesis with abnormal ZP assembly in EFS patients. Our data provides a better understanding of the biological functions of ZP1 in human ZP assembly and folliculogenesis and gives new insights into the pathogenesis of EFS and possible therapeutic developments.
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http://dx.doi.org/10.1093/humrep/dez174DOI Listing
November 2019

Molecular Composition and Volatility of Nucleated Particles from α-Pinene Oxidation between -50 °C and +25 °C.

Environ Sci Technol 2019 Nov 8;53(21):12357-12365. Epub 2019 Oct 8.

Department of Applied Physics , University of Eastern Finland , PO Box 1627, 70211 Kuopio , Finland.

We use a real-time temperature-programmed desorption chemical-ionization mass spectrometer (FIGAERO-CIMS) to measure particle-phase composition and volatility of nucleated particles, studying pure α-pinene oxidation over a wide temperature range (-50 °C to +25 °C) in the CLOUD chamber at CERN. Highly oxygenated organic molecules are much more abundant in particles formed at higher temperatures, shifting the compounds toward higher O/C and lower intrinsic (300 K) volatility. We find that pure biogenic nucleation and growth depends only weakly on temperature. This is because the positive temperature dependence of degree of oxidation (and polarity) and the negative temperature dependence of volatility counteract each other. Unlike prior work that relied on estimated volatility, we directly measure volatility via calibrated temperature-programmed desorption. Our particle-phase measurements are consistent with gas-phase results and indicate that during new-particle formation from α-pinene oxidation, gas-phase chemistry directly determines the properties of materials in the condensed phase. We now have consistency between measured gas-phase product concentrations, product volatility, measured and modeled growth rates, and the particle composition over most temperatures found in the troposphere.
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http://dx.doi.org/10.1021/acs.est.9b03265DOI Listing
November 2019

Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma.

Sci Rep 2019 07 9;9(1):9916. Epub 2019 Jul 9.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, 20892.

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.
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http://dx.doi.org/10.1038/s41598-019-46137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617453PMC
July 2019

De Novo Aneurysm Formation After Wingspan Stenting of Intracranial Carotid Stenosis: Computational Hemodynamic Analysis.

World Neurosurg 2019 Jun 13;126:212-215. Epub 2019 Mar 13.

Department of Interventional Neuroradiology, the First Affiliated Hospital of Dalian Medical University, Dalian, China.

Background: The pathophysiology of de novo aneurysm after stenting is poorly understood. Hemodynamic effects may play an important role. We report and discuss the hemodynamic analysis of de novo aneurysm after intracranial stenting.

Case Description: A 51-year-old female underwent angioplasty and coiling for stenosis associated with an aneurysm of the left intracranial carotid artery. Six years later, the follow-up digital subtraction angiography demonstrated a de novo aneurysm at the proximal tine of the Wingspan stent. Computational fluid dynamics simulations showed that stenting for intracranial stenosis resulted in higher oscillatory shear index and lower time-averaged wall shear stress in the neck region of de novo aneurysm.

Conclusions: The hemodynamic change after stenting may lead to formation of a de novo aneurysm. After an initial injury that might result from the tine on the endothelial cells, stenting could produce high oscillatory shear index and low time-averaged wall shear stress near the tine, thus potentially inducing de novo aneurysm formation.
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http://dx.doi.org/10.1016/j.wneu.2019.03.035DOI Listing
June 2019