Publications by authors named "Aleksandar Milosavljevic"

112 Publications

Surface Chemistry of Gold Nanoparticles Produced by Laser Ablation in Pure and Saline Water.

Langmuir 2021 May 3;37(19):5783-5794. Epub 2021 May 3.

Université Claude Bernard Lyon 1, UMR5306 CNRS, Institut Lumière Matière, University of Lyon, F-69622 Villeurbanne, France.

Pulsed laser ablation in liquid (PLAL) is a powerful method for producing nanoparticle colloids with a long-term stability despite the absence of stabilizing organic agents. The colloid stability involves different reactivities and chemical equilibria with complex ionic-specific effects at the nanoparticle/solvent interface which must be strongly influenced by their chemical composition. In this work, the surface composition of PLAL-produced gold nanoparticles in alkaline and saline (NaBr) water is investigated by X-ray photoelectron spectroscopy on free-flying nanoparticles, exempt from any substrate or radiation damage artifact. The Au 4f photoelectron spectra with a depth profiling investigation are used to evaluate the degree of nanoparticle surface oxidation. In alkaline water, the results preclude any surface oxidation contrary to the case of nanoparticles produced in NaBr solution. In addition, the analysis of Br 3d core-level photoelectron spectra agrees with a clear signature of Br on the nanoparticle surface, which is confirmed by a specific valence band feature. This experimental study is supported by DFT calculations, evaluating the energy balance of halide adsorption on different configurations of gold surfaces including oxidation or adsorbed salts.
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http://dx.doi.org/10.1021/acs.langmuir.1c00092DOI Listing
May 2021

Testicular germ cell tumors arise in the absence of sex-specific differentiation.

Development 2021 May 26;148(9). Epub 2021 Apr 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

In response to signals from the embryonic testis, the germ cell intrinsic factor NANOS2 coordinates a transcriptional program necessary for the differentiation of pluripotent-like primordial germ cells toward a unipotent spermatogonial stem cell fate. Emerging evidence indicates that genetic risk factors contribute to testicular germ cell tumor initiation by disrupting sex-specific differentiation. Here, using the 129.MOLF-Chr19 mouse model of testicular teratomas and a NANOS2 reporter allele, we report that the developmental phenotypes required for tumorigenesis, including failure to enter mitotic arrest, retention of pluripotency and delayed sex-specific differentiation, were exclusive to a subpopulation of germ cells failing to express NANOS2. Single-cell RNA sequencing revealed that embryonic day 15.5 NANOS2-deficient germ cells and embryonal carcinoma cells developed a transcriptional profile enriched for MYC signaling, NODAL signaling and primed pluripotency. Moreover, lineage-tracing experiments demonstrated that embryonal carcinoma cells arose exclusively from germ cells failing to express NANOS2. Our results indicate that NANOS2 is the nexus through which several genetic risk factors influence tumor susceptibility. We propose that, in the absence of sex specification, signals native to the developing testis drive germ cell transformation.
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http://dx.doi.org/10.1242/dev.197111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126408PMC
May 2021

CTD: An information-theoretic algorithm to interpret sets of metabolomic and transcriptomic perturbations in the context of graphical models.

PLoS Comput Biol 2021 01 29;17(1):e1008550. Epub 2021 Jan 29.

Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, Texas, United States of America.

We consider the following general family of algorithmic problems that arises in transcriptomics, metabolomics and other fields: given a weighted graph G and a subset of its nodes S, find subsets of S that show significant connectedness within G. A specific solution to this problem may be defined by devising a scoring function, the Maximum Clique problem being a classic example, where S includes all nodes in G and where the score is defined by the size of the largest subset of S fully connected within G. Major practical obstacles for the plethora of algorithms addressing this type of problem include computational efficiency and, particularly for more complex scores which take edge weights into account, the computational cost of permutation testing, a statistical procedure required to obtain a bound on the p-value for a connectedness score. To address these problems, we developed CTD, "Connect the Dots", a fast algorithm based on data compression that detects highly connected subsets within S. CTD provides information-theoretic upper bounds on p-values when S contains a small fraction of nodes in G without requiring computationally costly permutation testing. We apply the CTD algorithm to interpret multi-metabolite perturbations due to inborn errors of metabolism and multi-transcript perturbations associated with breast cancer in the context of disease-specific Gaussian Markov Random Field networks learned directly from respective molecular profiling data.
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http://dx.doi.org/10.1371/journal.pcbi.1008550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875364PMC
January 2021

The lived experience of performing a periodontal treatment in the context of general dentistry.

BDJ Open 2021 Jan 28;7(1). Epub 2021 Jan 28.

Department of Oral Diagnostics, Faculty of Odontology, Malmö University, SE-205 06, Malmö, Sweden.

Aim: To describe what characterises the lived experience of performing a periodontal treatment in the context of general dentistry.

Materials And Methods: Three dental hygienists from general dentistry in Sweden, were purposively selected as participants and interviewed. The participants described a situation in which they had performed a periodontal treatment. The descriptions were analysed using the descriptive phenomenological psychological method.

Results: The general meaning structure of the lived experience of performing a periodontal treatment comprised five constituents, (a) an established treatment routine, (b) importance of oral hygiene, (c) self-awareness and motivation of the patient, (d) support and doubt, and (e) mechanical infection control. The periodontal treatment is perceived as being set prior to its commencement and as following established routines, in which the patients' oral hygiene is experienced as a crucial part. The patients' self-awareness and a supportive clinician are seen as important factors in motivating the patient towards positive behavioural change, although there is a presence of doubt in patients' ability to maintain this positive change. Mechanical infection control is perceived as successful but sometimes difficult to perform.

Conclusions: Important, patient-related, factors are constituting the phenomenon of performing a periodontal treatment but an experience that the pre-existing standardised workflow influences patient management was also present.
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http://dx.doi.org/10.1038/s41405-021-00059-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843605PMC
January 2021

Unravelling molecular interactions in uracil clusters by XPS measurements assisted by ab initio and tight-binding simulations.

Sci Rep 2020 08 4;10(1):13081. Epub 2020 Aug 4.

Normandie Univ., ENSICAEN, UNICAEN, CEA, CNRS, CIMAP, 14000, Caen, France.

The C, N and O 1s XPS spectra of uracil clusters in the gas phase have been measured. A new bottom-up approach, which relies on computational simulations starting from the crystallographic structure of uracil, has been adopted to interpret the measured spectra. This approach sheds light on the different molecular interactions (H-bond, π-stacking, dispersion interactions) at work in the cluster and provides a good understanding of the observed XPS chemical shifts with respect to the isolated molecule in terms of intramolecular and intermolecular screening occurring after the core-hole ionization. The proposed bottom-up approach, reasonably expensive in terms of computational resources, has been validated by finite-temperature molecular dynamics simulations of clusters composed of up to fifty molecules.
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http://dx.doi.org/10.1038/s41598-020-69947-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403593PMC
August 2020

Histoepigenetic analysis of the mesothelin network within pancreatic ductal adenocarcinoma cells reveals regulation of retinoic acid receptor gamma and AKT by mesothelin.

Oncogenesis 2020 Jul 2;9(7):62. Epub 2020 Jul 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

To enable computational analysis of regulatory networks within the cancer cell in its natural tumor microenvironment, we develop a two-stage histoepigenetic analysis method. The first stage involves iterative computational deconvolution to estimate sample-specific cancer-cell intrinsic expression of a gene of interest. The second stage places the gene within a network module. We validate the method in simulation experiments, show improved performance relative to differential expression analysis from bulk samples, and apply it to illuminate the role of the mesothelin (MSLN) network in pancreatic ductal adenocarcinoma (PDAC). The network analysis and subsequent experimental validation in a panel of PDAC cell lines suggests AKT activation by MSLN through two known activators, retinoic acid receptor gamma (RARG) and tyrosine kinase non receptor 2 (TNK2). Taken together, these results demonstrate the potential of histoepigenetic analysis to reveal cancer-cell specific molecular interactions directly from patient tumor profiles.
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http://dx.doi.org/10.1038/s41389-020-00245-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332500PMC
July 2020

Giant left anterior descending artery aneurysm.

Postepy Kardiol Interwencyjnej 2020 Mar 3;16(1):112-113. Epub 2020 Apr 3.

Department of Surgery, Medical Faculty, University of Novi Sad, Novi Sad, Serbia.

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http://dx.doi.org/10.5114/aic.2020.93919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189127PMC
March 2020

Oxygen K-shell spectroscopy of isolated progressively solvated peptide.

Phys Chem Chem Phys 2020 Jun 29;22(23):12909-12917. Epub 2020 Apr 29.

SOLEIL, l'Orme des Merisiers, St Aubin, BP48, 91192 Gif sur Yvette Cedex, France.

Gas-phase near-edge X-ray-absorption fine structure (NEXAFS) action spectroscopy around the oxygen K-edge and mass spectrometry were employed to probe isolated substance P (SP) molecular ions, both bare and progressively solvated with 4 and 11 water molecules. Detailed mass spectra of bare and hydrated precursors are presented for the resonant photon energy of 532 eV that corresponds to O1s →π* core excitation, triggering resonant Auger decay and fragmentation from the ionized radical molecular system. The fragmentation pattern of doubly protonated SP hydrated with 4 water molecules clearly shows a series of abundant doubly charged backbone fragments, as well as triply charged precursor with small neutral losses, all preserving full water cluster. This is drastically different from the collisional induced dissociation of the hydrated peptide where the water loss is a dominant relaxation process. Moreover, the action NEXAFS obtained from several resolved small backbone fragments revealed increased fragmentation of hydrated SP relative to the bare one, due to a resonant O1s excitation of the attached water molecules. Such unexpected result inspires further experimental developments to investigate possible nonlocal energy transfer from the solvent to the biomolecules within the first solvation shell. The experiment is supported by molecular dynamics and DFT calculations to estimate the intensity of the resonant X-ray absorption of bare and hydrated SP around peptide and water O1s excitation region.
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http://dx.doi.org/10.1039/d0cp00994fDOI Listing
June 2020

Polymorphic presentation of an acute aortic syndrome.

J Card Surg 2020 May 15;35(5):1110-1111. Epub 2020 Apr 15.

Clinic for Cardiovascular Surgery, Institute of cardiovascular diseases Vojvodina, Sremska Kamenica, Serbia.

We describe a case of a patient with acute aortic syndrome referred to an emergent surgery. Aortic dissection presented with all-in-one imaging and pathologic entities: aortic dissection with intimal flap and true/false lumen, intramural hematoma and penetrating aortic ulcer. Usually, only one of these entities is present in a single patient, but it is possible that one entity evolve into or coexist with another. Extended hemiarch replacement was performed and the patient was discharged in a good condition.
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http://dx.doi.org/10.1111/jocs.14546DOI Listing
May 2020

Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells.

Cell Rep 2020 02;30(7):2065-2074.e4

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.
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http://dx.doi.org/10.1016/j.celrep.2020.01.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148092PMC
February 2020

Application of deep learning in aquatic bioassessment: Towards automated identification of non-biting midges.

Sci Total Environ 2020 Apr 14;711:135160. Epub 2019 Nov 14.

University of Duisburg-Essen, Aquatic Ecosystem Research, 45117 Essen, Germany.

Morphological species identification is often a difficult, expensive, and time-consuming process which hinders the ability for reliable biomonitoring of aquatic ecosystems. An alternative approach is to automate the whole process, accelerating the identification process. Here, we demonstrate an automatic machine-based identification approach for non-biting midges (Diptera: Chironomidae) using Convolutional Neural Networks (CNNs) as a means of increasing taxonomic resolution of biomonitoring data at a minimal cost. Chironomidae were used to build the automatic identifier, as a family of insects that are abundant and ecologically important, yet difficult and time-consuming to accurately identify. The approach was tested with 10 morphologically very similar species from the same genus or subfamilies, comprising 1846 specimens from the South Morava river basin, Serbia. Three CNN models were built utilizing either species, genus, or subfamily data. After training the artificial neural network, images that the network had not seen during the training phase achieved an accuracy of 99.5% for species-level identification, while at the genus and subfamily level all images were correctly assigned (100% accuracy). Gradient-weighted Class Activation Mapping (Grad-CAM) visualized the mentum, ventromental plates, mandibles, submentum, and postoccipital margin to be morphologically important features for CNN classification. Thus, the CNN approach was a highly accurate solution for chironomid identification of aquatic macroinvertebrates opening a new avenue for implementation of artificial intelligence and deep learning methodology in the biomonitoring world. This approach also provides a means to overcome the gap in bioassessment for developing countries where widespread use techniques for routine monitoring are currently limited.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135160DOI Listing
April 2020

Guidelines for cell-type heterogeneity quantification based on a comparative analysis of reference-free DNA methylation deconvolution software.

BMC Bioinformatics 2020 Jan 13;21(1):16. Epub 2020 Jan 13.

Laboratory TIMC-IMAG, UMR 5525, Univ. Grenoble Alpes, CNRS, F-38700, Grenoble, France.

Background: Cell-type heterogeneity of tumors is a key factor in tumor progression and response to chemotherapy. Tumor cell-type heterogeneity, defined as the proportion of the various cell-types in a tumor, can be inferred from DNA methylation of surgical specimens. However, confounding factors known to associate with methylation values, such as age and sex, complicate accurate inference of cell-type proportions. While reference-free algorithms have been developed to infer cell-type proportions from DNA methylation, a comparative evaluation of the performance of these methods is still lacking.

Results: Here we use simulations to evaluate several computational pipelines based on the software packages MeDeCom, EDec, and RefFreeEWAS. We identify that accounting for confounders, feature selection, and the choice of the number of estimated cell types are critical steps for inferring cell-type proportions. We find that removal of methylation probes which are correlated with confounder variables reduces the error of inference by 30-35%, and that selection of cell-type informative probes has similar effect. We show that Cattell's rule based on the scree plot is a powerful tool to determine the number of cell-types. Once the pre-processing steps are achieved, the three deconvolution methods provide comparable results. We observe that all the algorithms' performance improves when inter-sample variation of cell-type proportions is large or when the number of available samples is large. We find that under specific circumstances the methods are sensitive to the initialization method, suggesting that averaging different solutions or optimizing initialization is an avenue for future research.

Conclusion: Based on the lessons learned, to facilitate pipeline validation and catalyze further pipeline improvement by the community, we develop a benchmark pipeline for inference of cell-type proportions and implement it in the R package medepir.
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http://dx.doi.org/10.1186/s12859-019-3307-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958785PMC
January 2020

Anthocyanins Protect Hepatocytes against CCl-Induced Acute Liver Injury in Rats by Inhibiting Pro-inflammatory mediators, Polyamine Catabolism, Lipocalin-2, and Excessive Proliferation of Kupffer Cells.

Antioxidants (Basel) 2019 Oct 4;8(10). Epub 2019 Oct 4.

Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000 Niš, Serbia.

This study examined the hepatoprotective and anti-inflammatory effects of anthocyanins from Vaccinim myrtillus (bilberry) fruit extract on the acute liver failure caused by carbon tetrachloride-CCl (3 mL/kg, i.p.). The preventive treatment of the bilberry extract (200 mg anthocyanins/kg, orally, 7 days) prior to the exposure to the CCl resulted in an evident decrease in markers of liver damage (glutamate dehydrogenase, sorbitol dehydrogenase, malate dehydrogenase), and reduced pro-oxidative (conjugated dienes, lipid hydroperoxide, thiobarbituric acid reactive substances, advanced oxidation protein products, NADPH oxidase, hydrogen peroxide, oxidized glutathione), and pro-inflammatory markers (tumor necrosis factor-alpha, interleukin-6, nitrite, myeloperoxidase, inducible nitric oxide synthase, cyclooxygenase-2, CD68, lipocalin-2), and also caused a significant decrease in the dissipation of the liver antioxidative defence capacities (reduced glutathione, glutathione S-transferase, and quinone reductase) in comparison to the results detected in the animals treated with CCl exclusively. The administration of the anthocyanins prevented the arginine metabolism's diversion towards the citrulline, decreased the catabolism of polyamines (the activity of putrescine oxidase and spermine oxidase), and significantly reduced the excessive activation and hyperplasia of the Kupffer cells. There was also an absence of necrosis, in regard to the toxic effect of CCl alone. The hepatoprotective mechanisms of bilberry extract are based on the inhibition of pro-oxidative mediators, strong anti-inflammatory properties, inducing of hepatic phase II antioxidant enzymes (glutathione S-transferase, quinone reductase) and reduced glutathione, hypoplasia of Kupffer cells, and a decrease in the catabolism of polyamines.
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http://dx.doi.org/10.3390/antiox8100451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826396PMC
October 2019

Full-dimensional theoretical description of vibrationally resolved valence-shell photoionization of HO.

Struct Dyn 2019 Sep 11;6(5):054101. Epub 2019 Sep 11.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai 980-8577, Japan.

We have performed a full-dimensional theoretical study of vibrationally resolved photoelectron emission from the valence shell of the water molecule by using an extension of the static-exchange density functional theory that accounts for ionization as well as for vibrational motion in the symmetric stretching, antisymmetric stretching, and bending modes. At variance with previous studies performed in centrosymmetric molecules, where vibrationally resolved spectra are mostly dominated by the symmetric stretching mode, in the present case, all three modes contribute to the calculated spectra, including intermode couplings. We have found that diffraction of the ejected electron by the various atomic centers is barely visible in the ratios between vibrationally resolved photoelectron spectra corresponding to different vibrational states of the remaining HO cation (the so-called -ratios), in contrast to the prominent oscillations observed in K-shell ionization of centrosymmetric molecules, including those that only contain hydrogen atoms around the central atoms, e.g., CH. To validate the conclusions of our work, we have carried out synchrotron radiation experiments at the SOLEIL synchrotron and determined photoelectron spectra and -ratios for HO in a wide range of photon energies, from threshold up to 150 eV. The agreement with the theoretical predictions is good.
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http://dx.doi.org/10.1063/1.5106431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739208PMC
September 2019

Role of Valence Band States and Plasmonic Enhancement in Electron-Transfer-Induced Transformation of Nitrothiophenol.

J Phys Chem Lett 2019 Jun 28;10(11):3153-3158. Epub 2019 May 28.

Physical Chemistry, Institute of Chemistry , University of Potsdam , Karl-Liebknecht-Str. 24-25 , 14476 Potsdam-Golm , Germany.

Hot-electron-induced reactions are more and more recognized as a critical and ubiquitous reaction in heterogeneous catalysis. However, the kinetics of these reactions is still poorly understood, which is also due to the complexity of plasmonic nanostructures. We determined the reaction rates of the hot-electron-mediated reaction of 4-nitrothiophenol (NTP) on gold nanoparticles (AuNPs) using fractal kinetics as a function of the laser wavelength and compared them with the plasmonic enhancement of the system. The reaction rates can be only partially explained by the plasmonic response of the NPs. Hence, synchrotron X-ray photoelectron spectroscopy (XPS) measurements of isolated NTP-capped AuNP clusters have been performed for the first time. In this way, it was possible to determine the work function and the accessible valence band states of the NP systems. The results show that besides the plasmonic enhancement, the reaction rates are strongly influenced by the local density of the available electronic states of the system.
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http://dx.doi.org/10.1021/acs.jpclett.9b00848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6569622PMC
June 2019

Diagnostic Judgement and Treatment Decisions in Periodontology by Periodontists and General Dental Practitioners in Sweden - A Questionnaire-based Study.

Oral Health Prev Dent 2019 ;17(4):329-337

Purpose: To evaluate if periodontists are coherent in their judgement and treatment decisions of patients with different periodontal conditions, and to compare them with general dental practitioners' (GDPs) findings.

Materials And Methods: Eighty-six periodontists participated in a questionnaire study based on four patient cases: (a) generalised bone loss but minimal signs of inflammation (well-maintained); (b) generalised bone loss and signs of inflammation (periodontitis); (c) negligible bone loss and minimal signs of inflammation (healthy); and (d) negligible bone loss but with signs of inflammation (gingivitis). Periodontists had the option to judge each patient as healthy or diseased, propose a diagnosis, evaluate treatment needs, propose a treatment plan and assess the prognosis. Comparison between periodontists considered: (a) level of experience and (b) judgement of each patient case as healthy or diseased. Periodontists were additionally compared to a previous sample of GDPs (n = 74).

Results: Periodontists' response rate was 77%. The diagnostic judgement of the four patient cases showed rather large variation both among periodontists and GDPs. Periodontists' intention to treat and prognostic assessment depended on their judgement of each patient, as healthy or diseased (p < 0.05). GDPs intended to treat three out of four patient cases (except periodontitis case) more often and were more pessimistic in their prognostic assessment of patients with negligible bone loss (p < 0.05), comparing to periodontists.

Conclusions: Both periodontists and GDPs are defining periodontal health and disease differently, which affects treatment decisions and prognostic assessment. There is a need to define periodontal health and disease more precisely, in order to improve coherence in judgement.
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http://dx.doi.org/10.3290/j.ohpd.a42505DOI Listing
November 2019

exceRpt: A Comprehensive Analytic Platform for Extracellular RNA Profiling.

Cell Syst 2019 04 4;8(4):352-357.e3. Epub 2019 Apr 4.

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Department of Computer Science, Yale University, New Haven, CT, USA. Electronic address:

Small RNA sequencing has been widely adopted to study the diversity of extracellular RNAs (exRNAs) in biofluids; however, the analysis of exRNA samples can be challenging: they are vulnerable to contamination and artifacts from different isolation techniques, present in lower concentrations than cellular RNA, and occasionally of exogenous origin. To address these challenges, we present exceRpt, the exRNA-processing toolkit of the NIH Extracellular RNA Communication Consortium (ERCC). exceRpt is structured as a cascade of filters and quantifications prioritized based on one's confidence in a given set of annotated RNAs. It generates quality control reports and abundance estimates for RNA biotypes. It is also capable of characterizing mappings to exogenous genomes, which, in turn, can be used to generate phylogenetic trees. exceRpt has been used to uniformly process all ∼3,500 exRNA-seq datasets in the public exRNA Atlas and is available from genboree.org and github.gersteinlab.org/exceRpt.
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http://dx.doi.org/10.1016/j.cels.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079576PMC
April 2019

exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids.

Cell 2019 04;177(2):463-477.e15

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, Stamford, CT 06902, USA.

To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
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http://dx.doi.org/10.1016/j.cell.2019.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616370PMC
April 2019

The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research.

Cell 2019 04;177(2):231-242

Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on exRNA/EV biogenesis and function, discovery of exRNA biomarkers, development of exRNA/EV-based therapeutics, and construction of a robust set of reference exRNA profiles for a variety of biofluids. Here, we present progress by ERCC investigators in these areas, and we discuss collaborative projects directed at development of robust methods for EV/exRNA isolation and analysis and tools for sharing and computational analysis of exRNA profiling data.
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http://dx.doi.org/10.1016/j.cell.2019.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601620PMC
April 2019

Protective effects of anthocyanins from bilberry extract in rats exposed to nephrotoxic effects of carbon tetrachloride.

Chem Biol Interact 2019 May 27;304:61-72. Epub 2019 Feb 27.

Department of Biochemistry, Faculty of Medicine, University of Niš, Bulevar dr Zorana Đinđića 81, 18000, Niš, Serbia.

This study examined the nephroprotective effects of 15 different anthocyanins from the bilberry extract on the acute kidney injury caused by CCl. The acute nephrotoxicity in rats was induced 24 h after the treatment with a single dose of CCl (3 mL/kg, i.p.).The nephroprotective effects of the anthocyanins were examined in the animals that had been given the bilberry extract in a single dose of 200 mg of anthocyanins/kg daily, 7 days orally, while on the seventh day, 3 h after the last dose of anthocyanins, the animals received a single dose of CCl (3 mL/kg, i.p.) and were sacrificed 24 h later. When the nephrotoxicant alone was administered, it resulted in a substantial increase of the pro-oxidative (TBARS, CD, HO, XO, and GSSG) and pro-inflammatory markers (TNF-α, NO, and MPO), as well as a noticeable reduction of the antioxidant enzymes (CAT, SOD, POD, GPx, GST, GR) and GSH when compared to the results of the control group. Moreover, the application of CCl significantly influenced a reduction of the renal function, as well as an increase in the sensitive and specific injury indicators of the kidney epithelial cells (β-microglobulin, NGAL, KIM1/TIM1) in the serum and urine of rats. The pretreatment of the animals poisoned with CCl with the anthocyanins from the bilberry extract led to a noticeable reduction in the pro-oxidative and pro-inflammatory markers with reduced consumption of the antioxidant defence kidney capacity, compared to the animals exposed to CCl alone. Anthocyanins have been protective for the kidney parenchyma, with an apparent absence of the tubular and periglomerular necrosis, severe degenerative changes, inflammatory mononuclear infiltrates and dilatation of proximal and distal tubules, in contrast to the CCl-intoxicated animals. The nephroprotective effects of anthocyanins can be explained by strong antioxidant and anti-inflammatory effects achieved through the stabilization and neutralization of highly reactive and unstable toxic CCl metabolites.
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http://dx.doi.org/10.1016/j.cbi.2019.02.022DOI Listing
May 2019

Vacuum-UV and Low-Energy Electron-Induced DNA Strand Breaks - Influence of the DNA Sequence and Substrate.

Chemphyschem 2019 03 26;20(6):823-830. Epub 2019 Feb 26.

Institute of Chemistry - Physical Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany.

DNA is effectively damaged by radiation, which can on the one hand lead to cancer and is on the other hand directly exploited in the treatment of tumor tissue. DNA strand breaks are already induced by photons having an energy below the ionization energy of DNA. At high photon energies, most of the DNA strand breaks are induced by low-energy secondary electrons. In the present study we quantified photon and electron induced DNA strand breaks in four different 12mer oligonucleotides. They are irradiated directly with 8.44 eV vacuum ultraviolet (VUV) photons and 8.8 eV low energy electrons (LEE). By using Si instead of VUV transparent CaF as a substrate the VUV exposure leads to an additional release of LEEs, which have a maximum energy of 3.6 eV and can significantly enhance strand break cross sections. Atomic force microscopy is used to visualize strand breaks on DNA origami platforms and to determine absolute values for the strand break cross sections. Upon irradiation with 8.44 eV photons all the investigated sequences show very similar strand break cross sections in the range of 1.7-2.3×10  cm . The strand break cross sections for LEE irradiation at 8.8 eV are one to two orders of magnitude larger than the ones for VUV photons, and a slight sequence dependence is observed. The sequence dependence is even more pronounced for LEEs with energies <3.6 eV. The present results help to assess DNA damage by photons and electrons close to the ionization threshold.
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http://dx.doi.org/10.1002/cphc.201801152DOI Listing
March 2019

Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders.

Genet Med 2019 09 23;21(9):1977-1986. Epub 2019 Jan 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Purpose: Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs).

Methods: Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD.

Results: Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management.

Conclusion: In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.
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http://dx.doi.org/10.1038/s41436-019-0442-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650380PMC
September 2019

Histoepigenetic analysis of HPV- and tobacco-associated head and neck cancer identifies both subtype-specific and common therapeutic targets despite divergent microenvironments.

Oncogene 2019 05 17;38(19):3551-3568. Epub 2019 Jan 17.

Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, USA.

Although head and neck squamous cell carcinoma (HNSCC) has in the past been largely associated with tobacco use, human papillomavirus (HPV+) oropharynx cancer has in recent years emerged as the fastest growing type of HNSCC. Patients with HPV+ HNSCC have a better prognosis; however, the 5-year survival for both HPV+ and HPV- subtypes with recurrent or metastatic disease is poor. To gain insights into the tumor microenvironments of both HNSCC subtypes and identify potential therapeutic targets, we performed epigenomic deconvolution on 580 HNSCC samples from the TCGA dataset. Deconvolution revealed distinct molecular and histoepigenetic profiles of the two tumor subtypes, including their cellular composition, epigenomic profiles and gene expression for constituent cell types, and potential cancer cell-specific targets. Our analyses show that high abundance of both CD8 T-cells and B-cells explains better prognosis in HPV+ HNSCC. Deconvolution of gene expression profiles revealed higher expression of the immunotherapy target PD-1 in HPV+ immune cells compared to HPV- cells, suggesting that HPV+ tumors may preferentially benefit from PD-1 targeted therapy. Further analyses identified HPV+ and HPV- cancer cell surface proteins that can also serve as potential targets for therapy. Specifically, Wnt pathway receptor ROR2 is preferentially overexpressed in HPV+ subtypes, suggesting opportunities for development of targeted therapy based on HPV status. In summary, the comprehensive molecular and histoepigenetic analysis of tumor microenvironments by epigenomic deconvolution reveals potential novel biomarkers and targets for precision therapy of HNSCC.
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http://dx.doi.org/10.1038/s41388-018-0659-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756123PMC
May 2019

Vacuum-UV induced DNA strand breaks - influence of the radiosensitizers 5-bromouracil and 8-bromoadenine.

Phys Chem Chem Phys 2019 Jan;21(4):1972-1979

Institute of Chemistry - Physical Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.

Radiation therapy is a basic part of cancer treatment. To increase the DNA damage in carcinogenic cells and preserve healthy tissue at the same time, radiosensitizing molecules such as halogenated nucleobase analogs can be incorporated into the DNA during the cell reproduction cycle. In the present study 8.44 eV photon irradiation induced single strand breaks (SSB) in DNA sequences modified with the radiosensitizer 5-bromouracil (5BrU) and 8-bromoadenine (8BrA) are investigated. 5BrU was incorporated in the 13mer oligonucleotide flanked by different nucleobases. It was demonstrated that the highest SSB cross sections were reached, when cytosine and thymine were adjacent to 5BrU, whereas guanine as a neighboring nucleobase decreases the activity of 5BrU indicating that competing reaction mechanisms are active. This was further investigated with respect to the distance of guanine to 5BrU separated by an increasing number of adenine nucleotides. It was observed that the SSB cross sections were decreasing with an increasing number of adenine spacers between guanine and 5BrU until the SSB cross sections almost reached the level of a non-modified DNA sequence, which demonstrates the high sequence dependence of the sensitizing effect of 5BrU. 8BrA was incorporated in a 13mer oligonucleotide as well and the strand breaks were quantified upon 8.44 eV photon irradiation in direct comparison to a non-modified DNA sequence of the same composition. No clear enhancement of the SSB yield of the modified in comparison to the non-modified DNA sequence could be observed. Additionally, secondary electrons with a maximum energy of 3.6 eV were generated when using Si as a substrate giving rise to further DNA damage. A clear enhancement in the SSB yield can be ascertained, but to the same degree for both the non-modified DNA sequence and the DNA sequence modified with 8BrA.
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http://dx.doi.org/10.1039/c8cp06813eDOI Listing
January 2019

Tricuspid valve avulsion 3 years after blunt chest trauma.

J Card Surg 2018 Dec 11;33(12):787-788. Epub 2018 Dec 11.

Institute for Cardiovascular Diseases of Vojvodina, Clinic of Cardiovascular Surgery, Sremska Kamenica, Serbia.

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http://dx.doi.org/10.1111/jocs.13939DOI Listing
December 2018

Photoionization of the iodine 3d, 4s, and 4p orbitals in methyl iodide.

J Chem Phys 2018 Oct;149(14):144302

Daresbury Laboratory, Daresbury, Warrington, Cheshire WA4 4AD, United Kingdom.

Ionization of the I 3d, 4s, and 4p orbitals in methyl iodide (CHI) has been studied by using synchrotron radiation to measure the total ion yield and by recording photoelectron spectra with linearly polarized radiation in two polarization orientations. The complete photoelectron spectrum of CHI has been recorded at several photon energies, and bands due to the C 1s, I 3d, 4s, 4p, and 4d atomic-like orbitals, as well as the molecular orbitals, have been observed and assigned. In the vicinity of the I 3d and 3d ionization thresholds at 626.8 and 638.3 eV, respectively, the ion yield displays weak structure in the pre-edge region due to transitions into valence or Rydberg states, and, at higher energies, a shoulder and a broad maximum attributed to the I 3d → f and the I 3d → f shape resonances, respectively. The absorption spectrum calculated using time-dependent density functional theory, within the Tamm-Dancoff approximation, has allowed assignments to be proposed for the valence and Rydberg states. The Stieltjes imaging technique has been used to simulate the absorption spectrum above the ionization threshold and indicates that transitions into the f( = 3) continuum channel dominate. This conclusion has been corroborated by a Continuum Multiple Scattering-Xα (CMS-Xα) calculation. The asymmetric broadening of the photoelectron bands associated with the I 3d orbital, due to post collision interaction, is taken into account in our experimental analysis. Experimentally derived photoelectron anisotropy parameters for the I 3d orbital are in good agreement with the theoretical predictions obtained with the CMS-Xα approach. The I 3d shake-up/shake-off photoelectron spectrum has been recorded, and assignments have been proposed for several of the satellites. The MNN and MNN Auger electron yields have been measured, and that for the MNN decay exhibits a maximum due to interchannel coupling between the 3d and 3d continua. The photoelectron band associated with the I 4p orbital has an unusual appearance. Based upon previous theoretical work for the analogous Xe 4p orbital, it appears that the initial I 4p hole state decays rapidly through Coster-Kronig and super-Coster-Kronig transitions. This leads to a redistribution of the spectral intensity associated with the I 4p orbital and results in a photoelectron spectrum containing a single structured band together with an extended continuum. Another continuum is observed on the high binding energy side of the peak due to the 4s orbital, and we assign this to super-Coster-Kronig transitions into the 4p4d continuum.
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http://dx.doi.org/10.1063/1.5035496DOI Listing
October 2018

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group.

Hum Mutat 2018 11;39(11):1677-1685

Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon.

The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Group's (AWG) protocol for evidence synthesis and semi-quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.
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http://dx.doi.org/10.1002/humu.23631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211797PMC
November 2018

ClinGen advancing genomic data-sharing standards as a GA4GH driver project.

Hum Mutat 2018 11;39(11):1686-1689

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

The Clinical Genome Resource (ClinGen)'s work to develop a knowledge base to support the understanding of genes and variants for use in precision medicine and research depends on robust, broadly applicable, and adaptable technical standards for sharing data and information. To forward this goal, ClinGen has joined with the Global Alliance for Genomics and Health (GA4GH) to support the development of open, freely-available technical standards and regulatory frameworks for secure and responsible sharing of genomic and health-related data. In its capacity as one of the 15 inaugural GA4GH "Driver Projects," ClinGen is providing input on the key standards needs of the global genomics community, and has committed to participate on GA4GH Work Streams to support the development of: (1) a standard model for computer-readable variant representation; (2) a data model for linking variant data to annotations; (3) a specification to enable sharing of genomic variant knowledge and associated clinical interpretations; and (4) a set of best practices for use of phenotype and disease ontologies. ClinGen's participation as a GA4GH Driver Project will provide a robust environment to test drive emerging genomic knowledge sharing standards and prove their utility among the community, while accelerating the construction of the ClinGen evidence base.
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http://dx.doi.org/10.1002/humu.23625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188700PMC
November 2018

ClinGen Allele Registry links information about genetic variants.

Hum Mutat 2018 11;39(11):1690-1701

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Effective exchange of information about genetic variants is currently hampered by the lack of readily available globally unique variant identifiers that would enable aggregation of information from different sources. The ClinGen Allele Registry addresses this problem by providing (1) globally unique "canonical" variant identifiers (CAids) on demand, either individually or in large batches; (2) access to variant-identifying information in a searchable Registry; (3) links to allele-related records in many commonly used databases; and (4) services for adding links to information about registered variants in external sources. A core element of the Registry is a canonicalization service, implemented using in-memory sequence alignment-based index, which groups variant identifiers denoting the same nucleotide variant and assigns unique and dereferenceable CAids. More than 650 million distinct variants are currently registered, including those from gnomAD, ExAC, dbSNP, and ClinVar, including a small number of variants registered by Registry users. The Registry is accessible both via a web interface and programmatically via well-documented Hypertext Transfer Protocol (HTTP) Representational State Transfer Application Programming Interface (REST-APIs). For programmatic interoperability, the Registry content is accessible in the JavaScript Object Notation for Linked Data (JSON-LD) format. We present several use cases and demonstrate how the linked information may provide raw material for reasoning about variant's pathogenicity.
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http://dx.doi.org/10.1002/humu.23637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519371PMC
November 2018

Auger electron angular distributions following excitation or ionization of the I 3d level in methyl iodide.

J Chem Phys 2018 Sep;149(9):094304

Daresbury Laboratory, Daresbury, Warrington, Cheshire WA4 4AD, United Kingdom.

Auger electron spectra following excitation or ionization of the I 3d level in CHI have been recorded with horizontally or vertically plane polarized synchrotron radiation. These spectra have enabled the Auger electron angular distributions, as characterized by the parameter, to be determined. The I 3d photoionization partial cross section of CHI has been calculated with the continuum multiple scattering approach, and the results show that in the photon energy range over which Auger spectra were measured, the I 3d cross section exhibits an atomic-like behavior and is dominated by transitions into the f continuum channel. In this limit, the theoretical value of the alignment parameter () characterizing the core ionized state in an atom becomes constant, independent of photon energy. This theoretical value has been used to obtain the Auger electron intrinsic anisotropy parameters () from the parameters extracted from our normal (non-resonant) molecular Auger spectra. The resulting anisotropy parameters for the MNN transitions in CHI have been compared to those calculated for the corresponding transitions in xenon, and the experimental and theoretical results are in good agreement. Anisotropy parameters have also been measured for the MNN, MNN, and MNO transitions. For the MNN and MNN Auger decays in CHI, the experimentally derived angular distributions do not exhibit the strong dependence on the final ionic state that is predicted for these transitions in xenon. Resonantly excited Auger spectra have been recorded at 620.4 and 632.0 eV, coinciding with the I 3d → σ and 3d → σ transitions, respectively. The resulting Auger electron angular distributions for the MNN and MNN decays were found to exhibit a higher anisotropy than those for the normal process. This is due to the larger photo-induced alignment in the neutral core excited state. For a particular Auger transition, the Auger electron kinetic energy measured in the resonantly excited spectrum is higher than that in the normal spectrum. This shift, due to the screening provided by the electron excited into the σ orbital, has been rationalized by calculating orbital ionization energies of I 3d excited and I 3d ionized states in CHI.
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http://dx.doi.org/10.1063/1.5045640DOI Listing
September 2018