bluuebunny/crossref_metadata_2025 huggingface dataset:
Ribonucleotide incorporation in yeast genomic DNA shows preference for cytosine and guanosine preceded by deoxyadenosine
Authors: Balachander Sathya , Gombolay Alli L. , Yang Taehwan , Xu Penghao , Newnam Gary , Keskin Havva , El-Sayed Waleed M. M. , Bryksin Anton V. , Tao Sijia , Bowen Nicole E. , Schinazi Raymond F. , Kim Baek , Koh Kyung Duk , Vannberg Fredrik O. , Storici Francesca
Published: May 2020

Despite the abundance of ribonucleoside monophosphates (rNMPs) in DNA, sites of rNMP incorporation remain poorly characterized. Here, by using ribose-seq and Ribose-Map techniques, we built and analyzed high-throughput sequencing libraries of rNMPs derived from mitochondrial and nuclear DNA of budding and fission yeast. We reveal both common and unique features of rNMP sites among yeast species and strains, and between wild type and different ribonuclease H-mutant genotypes. We demonstrate that the rNMPs are not randomly incorporated in DNA. We highlight signatures and patterns of rNMPs, including sites within trinucleotide-repeat tracts. Our results uncover that the deoxyribonucleotide immediately upstream of the rNMPs has a strong influence on rNMP distribution, suggesting a mechanism of rNMP accommodation by DNA polymerases as a driving force of rNMP incorporation. Consistently, we find deoxyadenosine upstream from the most abundant genomic rCMPs and rGMPs. This study establishes a framework to better understand mechanisms of rNMP incorporation in DNA.
Application of combinatorial optimization strategies in synthetic biology
Authors: Naseri Gita , Koffas Mattheos A. G.
Published: May 2020

In the first wave of synthetic biology, genetic elements, combined into simple circuits, are used to control individual cellular functions. In the second wave of synthetic biology, the simple circuits, combined into complex circuits, form systems-level functions. However, efforts to construct complex circuits are often impeded by our limited knowledge of the optimal combination of individual circuits. For example, a fundamental question in most metabolic engineering projects is the optimal level of enzymes for maximizing the output. To address this point, combinatorial optimization approaches have been established, allowing automatic optimization without prior knowledge of the best combination of expression levels of individual genes. This review focuses on current combinatorial optimization methods and emerging technologies facilitating their applications.
Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
Authors: Saatci Ozge , Kaymak Aysegul , Raza Umar , Ersan Pelin G. , Akbulut Ozge , Banister Carolyn E. , Sikirzhytski Vitali , Tokat Unal Metin , Aykut Gamze , Ansari Suhail A. , Dogan Hayriye Tatli , Dogan Mehmet , Jandaghi Pouria , Isik Aynur , Gundogdu Fatma , Kosemehmetoglu Kemal , Dizdar Omer , Aksoy Sercan , Akyol Aytekin , Uner Aysegul , Buckhaults Phillip J. , Riazalhosseini Yasser , Sahin Ozgur
Published: May 2020

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
Universal mechanical exfoliation of large-area 2D crystals
Authors: Huang Yuan , Pan Yu-Hao , Yang Rong , Bao Li-Hong , Meng Lei , Luo Hai-Lan , Cai Yong-Qing , Liu Guo-Dong , Zhao Wen-Juan , Zhou Zhang , Wu Liang-Mei , Zhu Zhi-Li , Huang Ming , Liu Li-Wei , Liu Lei , Cheng Peng , Wu Ke-Hui , Tian Shi-Bing , Gu Chang-Zhi , Shi You-Guo , Guo Yan-Feng , Cheng Zhi Gang , Hu Jiang-Ping , Zhao Lin , Yang Guan-Hua , Sutter Eli , Sutter Peter , Wang Ye-Liang , Ji Wei , Zhou Xing-Jiang , Gao Hong-Jun
Published: May 2020

Two-dimensional materials provide extraordinary opportunities for exploring phenomena arising in atomically thin crystals. Beginning with the first isolation of graphene, mechanical exfoliation has been a key to provide high-quality two-dimensional materials, but despite improvements it is still limited in yield, lateral size and contamination. Here we introduce a contamination-free, one-step and universal Au-assisted mechanical exfoliation method and demonstrate its effectiveness by isolating 40 types of single-crystalline monolayers, including elemental two-dimensional crystals, metal-dichalcogenides, magnets and superconductors. Most of them are of millimeter-size and high-quality, as shown by transfer-free measurements of electron microscopy, photo spectroscopies and electrical transport. Large suspended two-dimensional crystals and heterojunctions were also prepared with high-yield. Enhanced adhesion between the crystals and the substrates enables such efficient exfoliation, for which we identify a gold-assisted exfoliation method that underpins a universal route for producing large-area monolayers and thus supports studies of fundamental properties and potential application of two-dimensional materials.
Large-scale network analysis captures biological features of bacterial plasmids
Authors: Acman Mislav , van Dorp Lucy , Santini Joanne M. , Balloux Francois
Published: May 2020

Many bacteria can exchange genetic material through horizontal gene transfer (HGT) mediated by plasmids and plasmid-borne transposable elements. Here, we study the population structure and dynamics of over 10,000 bacterial plasmids, by quantifying their genetic similarities and reconstructing a network based on their shared k-mer content. We use a community detection algorithm to assign plasmids into cliques, which correlate with plasmid gene content, bacterial host range, GC content, and existing classifications based on replicon and mobility (MOB) types. Further analysis of plasmid population structure allows us to uncover candidates for yet undescribed replicon genes, and to identify transposable elements as the main drivers of HGT at broad phylogenetic scales. Our work illustrates the potential of network-based analyses of the bacterial ‘mobilome’ and opens up the prospect of a natural, exhaustive classification framework for bacterial plasmids.
Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma
Authors: Hua Xing , Zhao Wei , Pesatori Angela C. , Consonni Dario , Caporaso Neil E. , Zhang Tongwu , Zhu Bin , Wang Mingyi , Jones Kristine , Hicks Belynda , Song Lei , Sampson Joshua , Wedge David C. , Shi Jianxin , Landi Maria Teresa
Published: May 2020

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.
Freeze-frame imaging of synaptic activity using SynTagMA
Authors: Perez-Alvarez Alberto , Fearey Brenna C. , O’Toole Ryan J. , Yang Wei , Arganda-Carreras Ignacio , Lamothe-Molina Paul J. , Moeyaert Benjamien , Mohr Manuel A. , Panzera Lauren C. , Schulze Christian , Schreiter Eric R. , Wiegert J. Simon , Gee Christine E. , Hoppa Michael B. , Oertner Thomas G.
Published: May 2020

Information within the brain travels from neuron to neuron across billions of synapses. At any given moment, only a small subset of neurons and synapses are active, but finding the active synapses in brain tissue has been a technical challenge. Here we introduce SynTagMA to tag active synapses in a user-defined time window. Upon 395–405 nm illumination, this genetically encoded marker of activity converts from green to red fluorescence if, and only if, it is bound to calcium. Targeted to presynaptic terminals, preSynTagMA allows discrimination between active and silent axons. Targeted to excitatory postsynapses, postSynTagMA creates a snapshot of synapses active just before photoconversion. To analyze large datasets, we show how to identify and track the fluorescence of thousands of individual synapses in an automated fashion. Together, these tools provide an efficient method for repeatedly mapping active neurons and synapses in cell culture, slice preparations, and in vivo during behavior.
Cooperative transport mechanism of human monocarboxylate transporter 2
Authors: Zhang Bo , Jin Qiuheng , Xu Lizhen , Li Ningning , Meng Ying , Chang Shenghai , Zheng Xiang , Wang Jiangqin , Chen Yuan , Neculai Dante , Gao Ning , Zhang Xiaokang , Yang Fan , Guo Jiangtao , Ye Sheng
Published: May 2020

Proton-linked monocarboxylate transporters (MCTs) must transport monocarboxylate efficiently to facilitate monocarboxylate efflux in glycolytically active cells, and transport monocarboxylate slowly or even shut down to maintain a physiological monocarboxylate concentration in glycolytically inactive cells. To discover how MCTs solve this fundamental aspect of intracellular monocarboxylate homeostasis in the context of multicellular organisms, we analyzed pyruvate transport activity of human monocarboxylate transporter 2 (MCT2). Here we show that MCT2 transport activity exhibits steep dependence on substrate concentration. This property allows MCTs to turn on almost like a switch, which is physiologically crucial to the operation of MCTs in the cellular context. We further determined the cryo-electron microscopy structure of the human MCT2, demonstrating that the concentration sensitivity of MCT2 arises from the strong inter-subunit cooperativity of the MCT2 dimer during transport. These data establish definitively a clear example of evolutionary optimization of protein function.
Mitigation of Arctic permafrost carbon loss through stratospheric aerosol geoengineering
Authors: Chen Yating , Liu Aobo , Moore John C.
Published: May 2020

The Arctic is warming far faster than the global average, threatening the release of large amounts of carbon presently stored in frozen permafrost soils. Increasing Earth’s albedo by the injection of sulfate aerosols into the stratosphere has been proposed as a way of offsetting some of the adverse effects of climate change. We examine this hypothesis in respect of permafrost carbon-climate feedbacks using the PInc-PanTher process model driven by seven earth system models running the Geoengineering Model Intercomparison Project (GeoMIP) G4 stratospheric aerosol injection scheme to reduce radiative forcing under the Representative Concentration Pathway (RCP) 4.5 scenario. Permafrost carbon released as CO2 is halved and as CH4 by 40% under G4 compared with RCP4.5. Economic losses avoided solely by the roughly 14 Pg carbon kept in permafrost soils amount to about US$ 8.4 trillion by 2070 compared with RCP4.5, and indigenous habits and lifestyles would be better conserved.
HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Authors: Pao Ping-Chieh , Patnaik Debasis , Watson L. Ashley , Gao Fan , Pan Ling , Wang Jun , Adaikkan Chinnakkaruppan , Penney Jay , Cam Hugh P. , Huang Wen-Chin , Pantano Lorena , Lee Audrey , Nott Alexi , Phan Trongha X. , Gjoneska Elizabeta , Elmsaouri Sara , Haggarty Stephen J. , Tsai Li-Huei
Published: May 2020

DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer’s disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.
Suppression of superconductivity and enhanced critical field anisotropy in thin flakes of FeSe
Authors: Farrar Liam S. , Bristow Matthew , Haghighirad Amir A. , McCollam Alix , Bending Simon J. , Coldea Amalia I.
Published: May 2020

FeSe is a unique superconductor that can be manipulated to enhance its superconductivity using different routes, while its monolayer form grown on different substrates reaches a record high temperature for a two-dimensional system. In order to understand the role played by the substrate and the reduced dimensionality on superconductivity, we examine the superconducting properties of exfoliated FeSe thin flakes by reducing the thickness from bulk down towards 9 nm. Magnetotransport measurements performed in magnetic fields up to 16 T and temperatures down to 2 K help to build up complete superconducting phase diagrams of different thickness flakes. While the thick flakes resemble the bulk behaviour, by reducing the thickness the superconductivity of FeSe flakes is suppressed. The observation of the vortex-antivortex unbinding transition in different flakes provide a direct signature of a dominant two-dimensional pairing channel. However, the upper critical field reflects the evolution of the multi-band nature of superconductivity in FeSe becoming highly two-dimensional and strongly anisotropic only in the thin limit. Our study provides detailed insights into the evolution of the superconducting properties of a multi-band superconductor FeSe in the thin limit in the absence of a dopant substrate.
Integrating water-quality analysis in national household surveys: water and sanitation sector learnings of Ecuador
Authors: Moreno Lorena , Pozo Mónica , Vancraeynest Koenraad , Bain Robert , Palacios Juan Carlos , Jácome Fausto
Published: May 2020

To respond to the global Sustainable Development Goals framework, Ecuador through the National Institute of Statistics and Censuses (INEC) has been strengthening its monitoring system since 2016, specifically on SDG 6.1 and 6.2. The World Bank Group, UNICEF Ecuador Country Office and WHO/UNICEF Joint Monitoring Programme provided initial support. Additional parameters were included in household surveys, including a water sample analysis to detect presence or absence of E. coli bacteria, and the SDG indicators were adapted to the national context. Ecuador collected water-quality data in two national household surveys in 2016 and 2019, including water quality at household's point of consumption for the 2019 survey. This opens opportunities to extend the analysis beyond access to safely managed drinking water services, toward comparison of water quality between source and point of consumption, and analyzing correlations with other parameters, such as handwashing with soap, water treatment, and safe storage and open defecation. This article describes the principal findings of the extended analysis carried out by INEC, as well as the opportunities to present the results for sector advocacy and decision-making purposes. This study concludes that alignment of the national monitoring systems to the SDG 6.1 framework provided strong evidence that water quality is the principal bottleneck in the water sector in Ecuador. Water-quality testing at the point of consumption was evidenced, as well as the importance of household water treatment and possible effects of other hygiene practices like handwashing with soap and open defecation on water quality at the point of consumption.
Large database for the analysis and prediction of spliced and non-spliced peptide generation by proteasomes
Authors: Specht Gerd , Roetschke Hanna P. , Mansurkhodzhaev Artem , Henklein Petra , Textoris-Taube Kathrin , Urlaub Henning , Mishto Michele , Liepe Juliane
Published: May 2020

Proteasomes are the main producers of antigenic peptides presented to CD8+ T cells. They can cut proteins and release their fragments or recombine non-contiguous fragments thereby generating novel sequences, i.e. spliced peptides. Understanding which are the driving forces and the sequence preferences of both reactions can streamline target discovery in immunotherapies against cancer, infection and autoimmunity. Here, we present a large database of spliced and non-spliced peptides generated by proteasomes in vitro, which is available as simple CSV file and as a MySQL database. To generate the database, we performed in vitro digestions of 55 unique synthetic polypeptide substrates with different proteasome isoforms and experimental conditions. We measured the samples using three mass spectrometers, filtered and validated putative peptides, identified 22,333 peptide product sequences (15,028 spliced and 7,305 non-spliced product sequences). Our database and datasets have been deposited to the Mendeley (doi:10.17632/nr7cs764rc.1) and PRIDE (PXD016782) repositories. We anticipate that this unique database can be a valuable source for predictors of proteasome-catalyzed peptide hydrolysis and splicing, with various future translational applications.
Detecting qualitative changes in biological systems
Authors: Mitrea Cristina , Bollig-Fischer Aliccia , Voichiţa Călin , Donato Michele , Romero Roberto , Drăghici Sorin
Published: May 2020

Currently, most diseases are diagnosed only after significant disease-associated transformations have taken place. Here, we propose an approach able to identify when systemic qualitative changes in biological systems happen, thus opening the possibility for therapeutic interventions before the occurrence of symptoms. The proposed method exploits knowledge from biological networks and longitudinal data using a system impact analysis. The method is validated on eight biological phenomena, three synthetic datasets and five real datasets, for seven organisms. Most importantly, the method accurately detected the transition from the control stage (benign) to the early stage of hepatocellular carcinoma on an eight-stage disease dataset.
Complete analytic solutions for convection-diffusion-reaction-source equations without using an inverse Laplace transform
Authors: Kim Albert S.
Published: May 2020

Transient mass-transfer phenomena occurring in natural and engineered systems consist of convection, diffusion, and reaction processes. The coupled phenomena can be described by using the unsteady convection-diffusion-reaction (CDR) equation, which is classified in mathematics as a linear, parabolic partial-differential equation. The availability of analytic solutions is limited to simple cases, e.g., unsteady diffusion and steady convective diffusion. The CDR equation has been considered analytically intractable, depending on the initial and boundary conditions. If spatial adsorption and desorption of matter are super-positioned in the CDR equation as sink and source functions, respectively, then the governing equation becomes an unsteady convection-diffusion-reaction-source (CDRS) equation, of which general solutions are unknown. In this study, a general 1D analytic solution of the CDRS equation is obtained by using a one-sided Laplace transform, by assuming constant diffusivity, velocity, and reactivity. This paper also provides a general formalism to derive 1D analytic solutions for Dirichlet/Dirichlet and Dirichlet/Neumann boundary conditions. Derivations of the analytic solutions are found to be straightforward if a combination of the source function and the initial concentration provide a non-zero singularity pole of inverse Laplace transform.
Effects of two probiotic spores of Bacillus species on hematological, biochemical, and inflammatory parameters in Salmonella Typhimurium infected rats
Authors: Mazkour Somaye , Shekarforoush Seyed Shahram , Basiri Sara , Nazifi Saeed , Yektaseresht Azadeh , Honarmand Masoumeh
Published: May 2020

Salmonella infections have become a major health concern in recent decades. This pathogen has evolved to become resistant to antibiotics, which has caused problems in its treatment. As such, finding a novel preventive method is important in the treatment and management of this infection. In recent years, uses of probiotics, especially spore-former genera such as Bacillus spp. has become increasingly popular. In this study spores of two probiotic bacteria, Bacillus subtilis and Bacillus coagulans were fed to rats for three weeks through their daily water intake after which Salmonella Typhimurium was gavaged to the rats. On days 1, 3, 5 and 7 after gavaging, the number of Salmonella was counted in liver, spleen, mesenteric lymph nodes, feces and content of ileum and cecum. Hematological and biochemical parameters, inflammatory mediators, total antioxidant capacity and malondialdehyde were also measured. The results showed that B. subtilis and B. coagulans caused delation in infiltration of Salmonella into the lymph nodes, spleen and liver, reduction of the inflammatory mediators, and decreases in oxidative stress, hematological and biochemical changes. The overall count of Salmonella in the above mentioned parameters has also decreased and a faster return to normal base were also witnessed. The results showed that the use of B. subtilis and B. coagulans can potentially help boost the body’s immune system, to combat the effects of exposure to the Salmonella pathogen.
A single TRPV1 amino acid controls species sensitivity to capsaicin
Authors: Chu Ying , Cohen Bruce E. , Chuang Huai-hu
Published: May 2020

Chili peppers produce capsaicin (a vanilloid) that activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) on sensory neurons to alter their membrane potential and induce pain. To identify residues responsible for differential TRPV1 capsaicin sensitivity among species, we used intracellular Ca2+ imaging to characterize chimeras composed of capsaicin-sensitive rat TRPV1 (rTRPV1) and capsaicin-insensitive chicken TRPV1 (cTRPV1) exposed to a series of capsaicinoids. We found that chimeras containing rat E570-V686 swapped into chicken receptors displayed capsaicin sensitivity, and that simply changing the alanine at position 578 in the S4-S5 helix of the chicken receptor to a glutamic acid was sufficient to endow it with capsaicin sensitivity in the micromolar range. Moreover, introduction of lysine, glutamine or proline at residue A578 also elicited capsaicin sensitivity in cTRPV1. Similarly, replacing corresponding rTRPV1 residue E570 with lysine or glutamine retained capsaicin sensitivity. The hydrophilic capsaicin analog Cap-EA activated a cTRPV1-A578E mutant, suggesting that A578 may participate in vanilloid binding. The hydrophilic vanilloid agonist zingerone did not activate any A578 mutants with capsaicin sensitivity, suggesting that the vanilloid group alone is not sufficient for receptor activation. Our study demonstrates that a subtle modification of TRPV1 in different species globally alters capsaicin responses.
Introduced species and extreme weather as key drivers of reproductive output in three sympatric albatrosses
Authors: Cleeland Jaimie B. , Pardo Deborah , Raymond Ben , Terauds Aleks , Alderman Rachael , McMahon Clive R. , Phillips Richard A. , Lea Mary-Anne , Hindell Mark A.
Published: May 2020

Invasive species present a major conservation threat globally and nowhere are their affects more pronounced than in island ecosystems. Determining how native island populations respond demographically to invasive species can provide information to mitigate the negative effects of invasive species. Using 20 years of mark-recapture data from three sympatric species of albatrosses (black-browedThalassarche melanophris, grey-headedT. chrysostoma, and light-mantled albatrossesPhoebetria palpebrata), we quantified the influence of invasive European rabbitsOryctolagus cuniculusand extreme weather patterns on breeding probability and success. Temporal variability in rabbit density explained 33–76% of the variability in breeding probability for all three species, with severe decreases in breeding probability observed after a lag period following highest rabbit numbers. For black-browed albatrosses, the combination of extreme rainfall and high rabbit density explained 33% of total trait variability and dramatically reduced breeding success. We showed that invasive rabbits and extreme weather events reduce reproductive output in albatrosses and that eliminating rabbits had a positive effect on albatross reproduction. This illustrates how active animal management at a local breeding site can result in positive population outcomes even for wide ranging animals like albatrosses where influencing vital rates during their at-sea migrations is more challenging.
High confidence copy number variants identified in Holstein dairy cattle from whole genome sequence and genotype array data
Authors: Butty Adrien M. , Chud Tatiane C. S. , Miglior Filippo , Schenkel Flavio S. , Kommadath Arun , Krivushin Kirill , Grant Jason R. , Häfliger Irene M. , Drögemüller Cord , Cánovas Angela , Stothard Paul , Baes Christine F.
Published: May 2020

Multiple methods to detect copy number variants (CNV) relying on different types of data have been developed and CNV have been shown to have an impact on phenotypes of numerous traits of economic importance in cattle, such as reproduction and immunity. Further improvements in CNV detection are still needed in regard to the trade-off between high-true and low-false positive variant identification rates. Instead of improving single CNV detection methods, variants can be identified in silico with high confidence when multiple methods and datasets are combined. Here, CNV were identified from whole-genome sequences (WGS) and genotype array (GEN) data on 96 Holstein animals. After CNV detection, two sets of high confidence CNV regions (CNVR) were created that contained variants found in both WGS and GEN data following an animal-based (n = 52) and a population-based (n = 36) pipeline. Furthermore, the change in false positive CNV identification rates using different GEN marker densities was evaluated. The population-based approach characterized CNVR, which were more often shared among animals (average 40% more samples per CNVR) and were more often linked to putative functions (48 vs 56% of CNVR) than CNV identified with the animal-based approach. Moreover, false positive identification rates up to 22% were estimated on GEN information. Further research using larger datasets should use a population-wide approach to identify high confidence CNVR.
Structural variability of dyads relates to calcium release in rat ventricular myocytes
Authors: Novotová Marta , Zahradníková Alexandra , Nichtová Zuzana , Kováč Radoslav , Kráľová Eva , Stankovičová Tatiana , Zahradníková Alexandra , Zahradník Ivan
Published: May 2020

Cardiac excitation-contraction coupling relies on dyads, the intracellular calcium synapses of cardiac myocytes, where the plasma membrane contacts sarcoplasmic reticulum and where electrical excitation triggers calcium release. The morphology of dyads and dynamics of local calcium release vary substantially. To better understand the correspondence between the structure and the functionality of dyads, we estimated incidences of structurally different dyads and of kinetically different calcium release sites and tested their responsiveness to experimental myocardial injury in left ventricular myocytes of rats. According to the structure of dyads estimated in random electron microscopic images of myocardial tissue, the dyads were sorted into ‘compact’ or ‘loose’ types. The calcium release fluxes, triggered at local calcium release sites in patch-clamped ventricular myocytes and recorded by laser scanning confocal fluorescence microscopy, were decomposed into ‘early’ and ‘late’ components. ANOVA tests revealed very high correlation between the relative amplitudes of early and late calcium release flux components and the relative occurrences of compact and loose dyads in the control and in the injured myocardium. This finding ascertained the relationship between the structure of dyads and the functionality of calcium release sites and the responsiveness of calcium release sites to physical load in cardiac myocytes.
Clinical Characteristics of Developmentally Delayed Children based on Interdisciplinary Evaluation
Authors: Kim S. W. , Jeon H. R. , Jung H. J. , Kim J. A. , Song J.-E. , Kim J.
Published: May 2020

The aim of this study is to examine the clinical characteristics of children suspected to have neurodevelopmental disorders and to present features that could be helpful diagnostic clues at the clinical assessment stage. All children who visited the interdisciplinary clinic for developmental problems from May 2001 to December 2014 were eligible for this study. Medical records of the children were reviewed. A total of 1,877 children were enrolled in this study. Most children were classified into four major diagnostic groups: global developmental delay (GDD), autism spectrum disorder (ASD), developmental language disorder (DLD) and motor delay (MD). GDD was the most common (43.9%), and boys were significantly more predominant than girls in all groups. When evaluating the predictive power of numerous risk factors, the probability of GDD was lower than the probability of ASD among boys, while the probability of GDD increased as independent walking age increased. Compared with GDD and DLD, the probability of GDD was increased when there was neonatal history or when the independent walking age was late. Comparison of ASD and DLD showed that the probability of ASD decreased when a maternal history was present, whereas the probability of ASD increased with male gender. To conclude, the present study revealed the clinical features of children with various neurodevelopmental disorders. These results are expected to be helpful for more effectively flagging children with potential neurodevelopmental disorders in the clinical setting.
Transcriptomic evidence that insulin signalling pathway regulates the ageing of subterranean termite castes
Authors: Haroon  , Ma Xiao-Ming , Li Yu-Xin , Zhang Hong-Xin , Liu Qing , Su Xiao-Hong , Xing Lian-Xi
Published: May 2020

Insulin is a protein hormone that controls the metabolism of sugar, fat and protein via signal transduction in cells, influencing growth and developmental processes such as reproduction and ageing. From nematodes to fruit flies, rodents and other animals, glucose signalling mechanisms are highly conserved. Reproductive termites (queens and kings) exhibit an extraordinarily long lifespan relative to non-reproductive individuals such as workers, despite being generated from the same genome, thus providing a unique model for the investigation of longevity. The key reason for this molecular mechanism, however, remains unclear. To clarify the molecular mechanism underlying this phenomenon, we sequenced the transcriptomes of the primary kings (PKs), primary queens (PQs), male (WMs) and female (WFs) workers of the lower subterranean termite Reticulitermes chinensis. We performed RNA sequencing and identified 33 insulin signalling pathway-related genes in R. chinensis. RT-qPCR analyses revealed that EIF4E and RPS6 genes were highly expressed in WMs and WFs workers, while mTOR expression was lower in PKs and PQs than in WMs and WFs. PQs and PKs exhibited lower expression of akt2-a than female workers. As the highly conserved insulin signalling pathway can significantly prolong the healthspan and lifespan, so we infer that the insulin signalling pathway regulates ageing in the subterranean termite R. chinensis. Further studies are recommended to reveal the biological function of insulin signalling pathway-related genes in the survival of termites to provide new insights into biomolecular homeostasis maintenance and its relationship to remarkable longevity.
MEGF11 is related to tumour recurrence in triple negative breast cancer via chemokine upregulation
Authors: Chiu Jen-Hwey , Tseng Ling-Ming , Huang Tzu-Ting , Liu Chun-Yu , Wang Jir-You , Huang Ching-Po , Tsai Yi-Fang , Hsu Chih-Yi
Published: May 2020

Our previous study demonstrated that upregulation of multiple epidermal growth factor-like domains 11 (MEGF11) gene expression is involved in the mechanism by which recurrence of Triple Negative Breast Cancer (TNBC) occurs. Our aim was to elucidate the role of MEGF11 expression in TNBC cells, both in vitro and in vivo, and in human tissue. Following MEGF11 gene knockdown (∆MEGF11) or over-expression in MDA-MB-231 and MB-468 cells, cell growth and chemokine gene expression were evaluated. In vivo, tumour growth of implanted human TNBC cells and the number of circulating 4T1 mouse tumour cells were measured. There was a significant decrease in cell growth via inhibition of AKT, NF-kB, CREB and AP-1 activation in ∆MEGF11 MDA-MB-231 and 468 cells. This also resulted, in vivo, in a suppression of tumour growth and a decrease in the number of mouse circulating 4T1 breast cancer cells. Surprisingly, overexpression of MEGF11 upregulated the expression of various chemokines and proinflammatory cytokines via AKT activation, but there was no increase in cell proliferation. MEGF11 was found to cross-talk positively with IL-17A signalling. Patients with tumours that over-expressed MEGF11 had a poorer prognosis. We conclude that MEGF11 plays an important role in tumour survival and that overexpression of MEGF11 induces both a cytokine and a chemokine cascade, which will favour the tumour microenvironment in terms of distant metastasis. MEGF11 might be a potential therapeutic target for preventing TNBC recurrence.
Facile preparation of air-stable n-type thermoelectric single-wall carbon nanotube films with anionic surfactants
Authors: Seki Yuhei , Nagata Kizashi , Takashiri Masayuki
Published: May 2020

Thermoelectric generators based on single-wall carbon nanotubes (SWCNTs) have great potential for use in wearable and skin electronics because of their lightweight and mechanically soft structure. However, the fabrication of air-stable n-type thermoelectric SWCNTs using conventional processes is challenging. Herein, we propose a facile process for fabricating air-stable n-type SWCNT films with anionic surfactants via drop casting followed by heat treatment. We examined different surfactants (Sodium Dodecyl Sulfate, Sodium Dodecylbenzene Sulfonate, and Sodium Cholate) and heat-treatment temperatures. The optimal SWCNT film maintained the n-type Seebeck coefficient for 35 days. Moreover, to further extend the n-type Seebeck coefficient maintenance, we periodically reheated the SWCNT film with a surfactant that had returned to the p-type Seebeck coefficient. The reheated film recovered the n-type Seebeck coefficient, and the effect of the reheating treatment lasted for several reheating cycles. Finally, we elucidated a simple mechanism for realizing an air-stable n-type Seebeck coefficient based on spectroscopic analyses of the SWCNT films.
High circulating levels of midregional proenkephalin A predict vascular dementia: a population-based prospective study
Authors: Holm H. , Nägga K. , Nilsson E. D. , Ricci F. , Melander O. , Hansson O. , Bachus E. , Fedorowski A. , Magnusson M.
Published: May 2020

Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases.
Genome-wide Analysis of Four Enterobacter cloacae complex type strains: Insights into Virulence and Niche Adaptation
Authors: Mustafa Areeqa , Ibrahim Muhammad , Rasheed Muhammad Asif , Kanwal Sumaira , Hussain Annam , Sami Asma , Ahmed Raza , Bo Zhu
Published: May 2020

Enterobacter cloacaecomplex (Ecc) species are widely distributed opportunistic pathogens mainly associated with humans and plants. In this study, the genomes of clinical isolates includingE. hormaechei, E. kobei, andE. ludwigiiand non-clinical isolate includingE. nimipressuraliswere analysed in combination with the genome ofE. asburiaeby using the reference strainE. cloacaesubsp.cloacaeATCC 13047; the Ecc strains were tested on artificial sputum media (ASM), which mimics the host, to evaluate T6SS genes as a case study. All five Ecc strains were sequenced in our lab. Comparative genome analysis of the Ecc strains revealed that genes associated with the survival of Ecc strains, including genes of metal-requiring proteins, defence-associated genes and genes associated with general physiology, were highly conserved in the genomes. However, the genes involved in virulence and drug resistance, specifically those involved in bacterial secretion, host determination and colonization of different strains, were present in different genomic regions. For example, T6SS accessory and core components, T4SS, and multidrug resistance genes/efflux system genes seemed vital for the survival of Ecc strains in various environmental niches, such as humans and plants. Moreover, the ASM host-mimicking growth medium revealed significantly high expression of T6SS genes, including PrpC, which is a regulatory gene of the T6SS, in all tested Ecc strains compared to the control medium. The variations in T6SS gene expression in ASM vs. control showed that the ASM system represents a simple, reproducible and economical alternative to animal models for studies such as those aimed at understanding the divergence of Ecc populations. In summary, genome sequencing of clinical and environmental Ecc genomes will assist in understanding the epidemiology of Ecc strains, including the isolation, virulence characteristics, prevention and treatment of infectious disease caused by these broad-host-range niche-associated species.
Association of Arachidonic Acid-derived Lipid Mediators with Subsequent Onset of Acute Myocardial Infarction in Patients with Coronary Artery Disease
Authors: Huang Chin-Chou , Chang Meng-Ting , Leu Hsin-Bang , Yin Wei-Hsian , Tseng Wei-Kung , Wu Yen-Wen , Lin Tsung-Hsien , Yeh Hung-I , Chang Kuan-Cheng , Wang Ji-Hung , Wu Chau-Chung , Shyur Lie-Fen , Chen Jaw-Wen
Published: May 2020

Polyunsaturated fatty acids (PUFAs) have been suggested for cardiovascular health. This study was conducted to investigate the prognostic impacts of the PUFA metabolites, oxylipins, on clinical outcomes in coronary artery disease (CAD). A total of 2,239 patients with stable CAD were prospectively enrolled and followed up regularly. Among them, twenty-five consecutive patients with new onset of acute myocardial infarction (AMI) within 2-year follow-up were studied. Another 50 gender- and age-matched patients without clinical cardiovascular events for more than 2 years were studied for control. Baseline levels of specific arachidonic acid metabolites were significantly higher in patients with subsequent AMI than in the controls. In Kaplan-Meier analysis, the incidence of future AMI was more frequently seen in patients with higher baseline levels of 8-hydroxyeicosatetraenoic acid (HETE), 9-HETE, 11-HETE, 12-HETE, 15-HETE, 19-HETE, 20-HETE, 5,6-epoxyeicosatrienoic acid (EET), 8,9-EET, 11,12-EET, or 14-15-EET when compared to their counterparts (all the P < 0.01). Further, serum levels of these specific HETEs, except for 11,12-EET, were positively correlated to the levels of some inflammatory and cardiac biomarker such as tumor necrosis factor-α and N-terminal pro B-type natriuretic peptide. Accordingly, serum specific oxylipins levels are increased and associated with the consequent onset of AMI, suggesting their potential role for secondary prevention in clinically stable CAD.
Posterior scleral deformation and autonomic dysfunction in normal tension glaucoma
Authors: Shin Da Young , Jeon Soo Ji , Park Hae Young Lopilly , Park Chan Kee
Published: May 2020

In meta-analyses, it has been reported that myopia is a risk factor for glaucoma and there is increasing evidence that autonomic dysfunction causing vascular dysregulation or perfusion dysfunction is considered an important factor in the progression of glaucoma. There have been experimental studies to find out the association between autonomic nervous system and ocular growth, but no clinical study yet has evaluated the relationship between them. Therefore, we enrolled 208 open angle glaucoma patients and measured heart-rate-variability(HRV). We used the standard deviation value of the qualified normal to normal intervals (SDNN) parameter of HRV, which is considered an autonomic influence index and characterized the total effect of the regulation of autonomic blood circulation. Patients were classified into the two groups according to SDNN: those with low possibility of autonomic dysfunction (LoAD group) and those with high possibility of autonomic dysfunction (HiAD group). We evaluated myopic features employing a ‘posterior scleral profile’ identified by the disc tilt ratio, disc torsion, fovea-BMO center (FoBMO) angle and peripapapillary area(PPA) to disc ratio. HiAD group showed higher values than LoAD group in posterior scleral deformation profile such like axial length, disc tilt, torsion degree. We suggest the possibility of association between myopic deformation and autonomic dysfunction.
Quantification of Colistin in Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study
Authors: Matar Kamal M. , Al-Refai Batool
Published: May 2020

Colistin is a polymixin antibiotic (polymixin E) that is produced by Bacillus colistinus bacteria. The aim of the present study was to develop and validate a method to quantify colistin levels in plasma using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique and then apply it in experimental animals (rats) to investigate the pharmacokinetic profile of colistin in this species. Polymyxin B was used as an internal standard (IS) and the quantitation was carried out using ESI + interface and employing multiple reaction monitoring (MRM) mode. A mobile phase consisting of acetonitrile:water:formic acid (30:70:0.1%; v/v/v) was employed and Zorbax eclipse plus C18 (1.8 µm, 2.1 mm i.d. x 50 mm) was the optimal column for this method and utilized at a flow rate of 0.2 mL/min. The full scan mass spectra of precursor/product ions of colistin A were at m/z 585.5 > 100.8, for colistin B at m/z 578.8 > 101 and for the IS at m/z 602.8 > 101. The lower limit of quantification (LLOQ) was 0.5 µg/mL. The method demonstrated acceptable intra-run and inter-run precision and accuracy for both colistin A and colistin B. Colistin was stable when assessed for long-term stability, freeze-thaw stability and autosampler stability. However, it was not stable when stored at room temperature. The matrix effect evaluation showed minimal or no effect. Incurred sample reanalysis findings were within acceptable ranges (<20% of the nominal concentration). The pharmacokinetic parameters of colistin were investigated in rats using the present method. The developed method for colistin demonstrates that it is rapid, sensitive, specific, accurate, precise, and reliable.
Popliteal Artery Branching Variations: A Study on Multidetector CT Angiography
Authors: Oner Serkan , Oner Zulal
Published: May 2020

Determining the branching pattern of the popliteal artery (PA) is an important step in planning some radiological and surgical procedures. The aim of this study was to investigate the course and morphology of the terminal branches of the popliteal artery using multidetector computed tomography (MDCT) angiography, and also to determine possible role gender in branching pattern. Three-hundred forty lower extremity MDCT angiography images for 170 patients (118 M, 52 F), who were between 20–80 years old, were examined. Popliteal artery branching types were grouped as percentage incidences. TPT diameters and lengths in Type IA extremities were compared based on gender and right or left side. Anterior tibial artery (ATA), posterior tibial artery (PTA) and peroneal artery dominance rates were calculated. 5000 times measurement data was mixed so that the cascade mean filter values were calculated for the right and left TPT length each time. It was observed that Type IA was the most common branching pattern (89.4%). The variational pattern incidence was 10.6% and the most common category was Type III (4.1%). The most common pattern was Type IB (3.2%). Variational pattern was 2 times more prevalent in females when compared to the males. The mean TPT diameter was 4.5 mm (2.7–7.3 mm) and there was no difference based on gender and the right-left side. The most common dominant artery for the right and left legs was PTA in both genders. The cut-off values calculated for the right and left TPT independent of gender were 31.30 ± 2.40 and 28.36 ± 2.58, respectively. Three new subtypes were identified as short (S ≤ 2 cm), standard (N = 2–4 cm) and long (L ≥ 4 cm) in Type IA, since it is in a wide variational range although it is a typical PA branching pattern.