bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner
Authors: Mei Lin , Shen Cheng , Miao Ran , Wang Jing-Zi , Cao Mend-Da , Zhang Yi-Sheng , Shi Liang-Hui , Zhao Guo-Hai , Wang Ming-Hai , Wu Li-Sheng , Wei Ji-Fu
Published: April 2020

The RNA methyltransferase NSUN2 has been involved in the cell proliferation and senescence, and is upregulated in various types of cancers. However, the role and potential mechanism of NSUN2 in gastric cancer remains to be determined. Our study showed that NSUN2 was significantly upregulated in gastric cancers, compared to adjacent normal gastric tissues. Moreover, NSUN2 could promote gastric cancer cell proliferation both in vitro and in vivo. Further study demonstrated that CDKN1C (p57Kip2) was the potential downstream gene of regulated by NSUN2 in gastric cancer. NSUN2 could promote gastric cancer cell proliferation through repressing p57Kip2 in an m5C-dependent manner. Our findings suggested that NSUN2 acted as an oncogene through promoting gastric cancer development by repressing p57Kip2 in an m5C-dependent manner, which may provide a novel therapeutic target against gastric cancer.
FUT1 deficiency elicits immune dysregulation and corneal opacity in steady state and under stress
Authors: Kim Kyoung Woo , Ryu Jin Suk , Ko Jung Hwa , Kim Jun Yeob , Kim Hyeon Ji , Lee Hyun Ju , Oh Jang-Hee , Chung Jin Ho , Oh Joo Youn
Published: April 2020

Fucosylation is a biological process that plays a critical role in multiple cellular functions from cell adhesion to immune regulation. Fucosyltransferases (FUTs) mediate fucosylation, and dysregulation of genes encoding FUTs is associated with various diseases. FUT1 and its fucosylated products are expressed in the ocular surface and ocular adnexa; however, the role of FUT1 in the ocular surface health and disease is yet unclear. Here, we investigated the effects of FUT1 on the ocular surface in steady-state conditions with age and under desiccating stress using a Fut1 knockout (KO) mouse model. We found that corneal epithelial defects and stromal opacity developed in Fut1 KO mice. Also, inflammatory responses in the ocular surface and Th1 cell activation in ocular draining lymph nodes (DLNs) were upregulated. Desiccating stress further aggravated Th1 cell-mediated immune responses in DLNs, lacrimal gland, and ocular surface in Fut1 KO mice, leading to severe corneal epithelial disruption and opacity. Mixed lymphocyte reaction assays revealed that the activity of splenocytes to stimulate CD4 T-cell proliferation was increased in Fut1 KO mice. Together, these data demonstrate that FUT1 deficiency induces immune dysregulation in the ocular surface and corneal opacity in steady state and under desiccating stress.
Confidence reports in decision-making with multiple alternatives violate the Bayesian confidence hypothesis
Authors: Li Hsin-Hung , Ma Wei Ji
Published: April 2020

Decision confidence reflects our ability to evaluate the quality of decisions and guides subsequent behavior. Experiments on confidence reports have almost exclusively focused on two-alternative decision-making. In this realm, the leading theory is that confidence reflects the probability that a decision is correct (the posterior probability of the chosen option). There is, however, another possibility, namely that people are less confident if the best two options are closer to each other in posterior probability, regardless of how probable they are in absolute terms. This possibility has not previously been considered because in two-alternative decisions, it reduces to the leading theory. Here, we test this alternative theory in a three-alternative visual categorization task. We found that confidence reports are best explained by the difference between the posterior probabilities of the best and the next-best options, rather than by the posterior probability of the chosen (best) option alone, or by the overall uncertainty (entropy) of the posterior distribution. Our results upend the leading notion of decision confidence and instead suggest that confidence reflects the observer’s subjective probability that they made the best possible decision.
Fatal heart disease among cancer patients
Authors: Stoltzfus Kelsey C. , Zhang Ying , Sturgeon Kathleen , Sinoway Lawrence I. , Trifiletti Daniel M. , Chinchilli Vernon M. , Zaorsky Nicholas G.
Published: April 2020

As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing and the surviving population is aging, it is necessary to identify cancer patients who are at an increased risk of death from heart disease. The purpose of this study is to identify cancer patients at highest risk of fatal heart disease compared to the general population and other cancer patients at risk of death during the study time period. Here we report that 394,849 of the 7,529,481 cancer patients studied died of heart disease. The heart disease-specific mortality rate is 10.61/10,000-person years, and the standardized mortality ratio (SMR) of fatal heart disease is 2.24 (95% CI: 2.23–2.25). Compared to other cancer patients, patients who are older, male, African American, and unmarried are at a greatest risk of fatal heart disease. For almost all cancer survivors, the risk of fatal heart disease increases with time.
Self-organizing maps of typhoon tracks allow for flood forecasts up to two days in advance
Authors: Chang Li-Chiu , Chang Fi-John , Yang Shun-Nien , Tsai Fong-He , Chang Ting-Hua , Herricks Edwin E.
Published: April 2020

Typhoons are among the greatest natural hazards along East Asian coasts. Typhoon-related precipitation can produce flooding that is often only predictable a few hours in advance. Here, we present a machine-learning method comparing projected typhoon tracks with past trajectories, then using the information to predict flood hydrographs for a watershed on Taiwan. The hydrographs provide early warning of possible flooding prior to typhoon landfall, and then real-time updates of expected flooding along the typhoon’s path. The method associates different types of typhoon tracks with landscape topography and runoff data to estimate the water inflow into a reservoir, allowing prediction of flood hydrographs up to two days in advance with continual updates. Modelling involves identifying typhoon track vectors, clustering vectors using a self-organizing map, extracting flow characteristic curves, and predicting flood hydrographs. This machine learning approach can significantly improve existing flood warning systems and provide early warnings to reservoir management.
Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice
Authors: Duerr Julia , Leitz Dominik H. W. , Szczygiel Magdalena , Dvornikov Dmytro , Fraumann Simon G. , Kreutz Clemens , Zadora Piotr K. , Seyhan Agircan Ayça , Konietzke Philip , Engelmann Theresa A. , Hegermann Jan , Mulugeta Surafel , Kawabe Hiroshi , Knudsen Lars , Ochs Matthias , Rotin Daniela , Muley Thomas , Kreuter Michael , Herth Felix J. F. , Wielpütz Mark O. , Beers Michael F. , Klingmüller Ursula , Mall Marcus A.
Published: April 2020

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.
FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku
Authors: Jin Hanyong , Lee Boeun , Luo Yongyang , Choi Yuri , Choi Eui-Hwan , Jin Hong , Kim Kee-Beom , Seo Sang Beom , Kim Yong-Hak , Lee Hyung Ho , Kim Keun Pil , Lee Kangseok , Bae Jeehyeon
Published: April 2020

The balance between major DNA double-strand break (DSB) repair pathways is influenced by binding of the Ku complex, a XRCC5/6 heterodimer, to DSB ends, initiating non-homologous end joining (NHEJ) but preventing additional DSB end resection and homologous recombination (HR). However, the key molecular cue for Ku recruitment to DSB sites is unknown. Here, we report that FOXL2, a forkhead family transcriptional factor, directs DSB repair pathway choice by acetylation-dependent binding to Ku. Upon DSB induction, SIRT1 translocates to the nucleus and deacetylates FOXL2 at lysine 124, leading to liberation of XRCC5 and XRCC6 from FOXL2 and formation of the Ku complex. FOXL2 ablation enhances Ku recruitment to DSB sites, imbalances DSB repair kinetics by accelerating NHEJ and inhibiting HR, and thus leads to catastrophic genomic events. Our study unveils the SIRT1-(de)acetylated FOXL2-Ku axis that governs the balance of DSB repair pathways to maintain genome integrity.
A magma ocean origin to divergent redox evolutions of rocky planetary bodies and early atmospheres
Authors: Deng Jie , Du Zhixue , Karki Bijaya B. , Ghosh Dipta B. , Lee Kanani K. M.
Published: April 2020

Magma oceans were once ubiquitous in the early solar system, setting up the initial conditions for different evolutionary paths of planetary bodies. In particular, the redox conditions of magma oceans may have profound influence on the redox state of subsequently formed mantles and the overlying atmospheres. The relevant redox buffering reactions, however, remain poorly constrained. Using first-principles simulations combined with thermodynamic modeling, we show that magma oceans of Earth, Mars, and the Moon are likely characterized with a vertical gradient in oxygen fugacity with deeper magma oceans invoking more oxidizing surface conditions. This redox zonation may be the major cause for the Earth’s upper mantle being more oxidized than Mars’ and the Moon’s. These contrasting redox profiles also suggest that Earth’s early atmosphere was dominated by CO2 and H2O, in contrast to those enriched in H2O and H2 for Mars, and H2 and CO for the Moon.
Accurate estimation of cell composition in bulk expression through robust integration of single-cell information
Authors: Jew Brandon , Alvarez Marcus , Rahmani Elior , Miao Zong , Ko Arthur , Garske Kristina M. , Sul Jae Hoon , Pietiläinen Kirsi H. , Pajukanta Päivi , Halperin Eran
Published: April 2020

We present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data. These transformations significantly improve decomposition performance compared to existing methods when there is significant technical variation in the generation of the reference profile and observed bulk expression. Importantly, compared to existing methods, our approach is extremely efficient, making it suitable for the analysis of large genomic datasets that are becoming ubiquitous. When applied to subcutaneous adipose and dorsolateral prefrontal cortex expression datasets with both bulk RNA-seq and snRNA-seq data, Bisque replicates previously reported associations between cell type proportions and measured phenotypes across abundant and rare cell types. We further propose an additional mode of operation that merely requires a set of known marker genes.
Decoding the stoichiometric composition and organisation of bacterial metabolosomes
Authors: Yang Mengru , Simpson Deborah M. , Wenner Nicolas , Brownridge Philip , Harman Victoria M. , Hinton Jay C. D. , Beynon Robert J. , Liu Lu-Ning
Published: April 2020

Some enteric bacteria including Salmonella have evolved the propanediol-utilising microcompartment (Pdu MCP), a specialised proteinaceous organelle that is essential for 1,2-propanediol degradation and enteric pathogenesis. Pdu MCPs are a family of bacterial microcompartments that are self-assembled from hundreds of proteins within the bacterial cytosol. Here, we seek a comprehensive understanding of the stoichiometric composition and organisation of Pdu MCPs. We obtain accurate stoichiometry of shell proteins and internal enzymes of the natural Pdu MCP by QconCAT-driven quantitative mass spectrometry. Genetic deletion of the major shell protein and absolute quantification reveal the stoichiometric and structural remodelling of metabolically functional Pdu MCPs. Decoding the precise protein stoichiometry allows us to develop an organisational model of the Pdu metabolosome. The structural insights into the Pdu MCP are critical for both delineating the general principles underlying bacterial organelle formation, structural robustness and function, and repurposing natural microcompartments using synthetic biology for biotechnological applications.
Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity
Authors: Pfister Simona P. , Schären Olivier P. , Beldi Luca , Printz Andrea , Notter Matheus D. , Mukherjee Mohana , Li Hai , Limenitakis Julien P. , Werren Joel P. , Tandon Disha , Cuenca Miguelangel , Hagemann Stefanie , Uster Stephanie S. , Terrazos Miguel A. , Gomez de Agüero Mercedes , Schürch Christian M. , Coelho Fernanda M. , Curtiss Roy , Slack Emma , Balmer Maria L. , Hapfelmeier Siegfried
Published: April 2020

There is the notion that infection with a virulent intestinal pathogen induces generally stronger mucosal adaptive immunity than the exposure to an avirulent strain. Whether the associated mucosal inflammation is important or redundant for effective induction of immunity is, however, still unclear. Here we use a model of auxotrophicSalmonellainfection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Although live auxotrophicSalmonellano longer causes inflammation, its mucosal virulence factors remain the main drivers of protective mucosal immunity; virulence factor-deficient, like killed, bacteria show reduced efficacy. Assessing the involvement of innate pathogen sensing mechanisms, we show MYD88/TRIF, Caspase-1/Caspase-11 inflammasome, and NOD1/NOD2 nodosome signaling to be individually redundant. In colonized animals we show that microbiota metabolite cross-feeding may recover intestinal luminal colonization but not pathogenicity. Consequent immunoglobulin A immunity and microbial niche competition synergistically protect againstSalmonellawild-type infection.
Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts
Authors: Georgakopoulos-Soares Ilias , Koh Gene , Momen Sophie E. , Jiricny Josef , Hemberg Martin , Nik-Zainal Serena
Published: April 2020

The mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. Here, we introduce a method to evaluate indels, orientating them relative to gene transcription. In so doing, we reveal a number of surprising findings: First, there is a transcriptional strand asymmetry in the distribution of mononucleotide repeat tracts in the reference human genome. Second, there is a strong transcriptional strand asymmetry of indels across 2,575 whole genome sequenced human cancers. We suggest that this is due to the activity of transcription-coupled nucleotide excision repair (TC-NER). Furthermore, TC-NER interacts with mismatch repair (MMR) under physiological conditions to produce strand bias. Finally, we show how insertions and deletions differ in their dependencies on these repair pathways. Our analytical approach reveals insights into the contribution of DNA repair towards indel mutagenesis in human cells.
Endogenous and exogenous control of visuospatial selective attention in freely behaving mice
Authors: You Wen-Kai , Mysore Shreesh P.
Published: April 2020

Visuospatial selective attention has been investigated primarily in head-fixed animals and almost exclusively in primates. Here, we develop two human-inspired, discrimination-based behavioral paradigms for studying selective visuospatial attention in freely behaving mice. In the ‘spatial probability’ task, we find enhanced accuracy, sensitivity, and rate of evidence accumulation at the location with higher probability of target occurrence, and opposite effects at the lower probability location. Together with video-based 3D head-tracking, these results demonstrate endogenous expectation-driven shifts of spatial attention. In the ‘flanker’ task, we find that a second stimulus presented with the target, but with conflicting information, causes switch-like decrements in accuracy and sensitivity as a function of its contrast, and slower evidence accumulation, demonstrating exogenous capture of spatial attention. The ability to study primate-like selective attention rigorously in unrestrained mice opens a rich avenue for research into neural circuit mechanisms underlying this critical executive function in a naturalistic setting.
Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes
Authors: Liu Deli , Shoag Jonathan E. , Poliak Daniel , Goueli Ramy S. , Ravikumar Vaishali , Redmond David , Vosoughi Aram , Fontugne Jacqueline , Pan Heng , Lee Daniel , Thomas Domonique , Salari Keyan , Wang Zongwei , Romanel Alessandro , Te Alexis , Lee Richard , Chughtai Bilal , Olumi Aria F. , Mosquera Juan Miguel , Demichelis Francesca , Elemento Olivier , Rubin Mark A. , Sboner Andrea , Barbieri Christopher E.
Published: April 2020

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.
Interspecies radiative transition in warm and superdense plasma mixtures
Authors: Hu S. X. , Karasiev V. V. , Recoules V. , Nilson P. M. , Brouwer N. , Torrent M.
Published: April 2020

Superdense plasmas widely exist in planetary interiors and astrophysical objects such as brown-dwarf cores and white dwarfs. How atoms behave under such extreme-density conditions is not yet well understood, even in single-species plasmas. Here, we apply thermal density functional theory to investigate the radiation spectra of superdense iron–zinc plasma mixtures at mass densities of ρ = 250 to 2000 g cm−3 and temperatures of kT = 50 to 100 eV, accessible by double-shell–target implosions. Our ab initio calculations reveal two extreme atomic-physics phenomena—firstly, an interspecies radiative transition; and, secondly, the breaking down of the dipole-selection rule for radiative transitions in isolated atoms. Our first-principles calculations predict that for superdense plasma mixtures, both interatomic radiative transitions and dipole-forbidden transitions can become comparable to the normal intra-atomic Kα-emission signal. These physics phenomena were not previously considered in detail for extreme high-density plasma mixtures at super-high energy densities.
Confining H3PO4 network in covalent organic frameworks enables proton super flow
Authors: Tao Shanshan , Zhai Lipeng , Dinga Wonanke A. D. , Addicoat Matthew A. , Jiang Qiuhong , Jiang Donglin
Published: April 2020

Development of porous materials combining stability and high performance has remained a challenge. This is particularly true for proton-transporting materials essential for applications in sensing, catalysis and energy conversion and storage. Here we report the topology guided synthesis of an imine-bonded (C=N) dually stable covalent organic framework to construct dense yet aligned one-dimensional nanochannels, in which the linkers induce hyperconjugation and inductive effects to stabilize the pore structure and the nitrogen sites on pore walls confine and stabilize the H3PO4 network in the channels via hydrogen-bonding interactions. The resulting materials enable proton super flow to enhance rates by 2–8 orders of magnitude compared to other analogues. Temperature profile and molecular dynamics reveal proton hopping at low activation and reorganization energies with greatly enhanced mobility.
In-situ preservation of nitrogen-bearing organics in Noachian Martian carbonates
Authors: Koike Mizuho , Nakada Ryoichi , Kajitani Iori , Usui Tomohiro , Tamenori Yusuke , Sugahara Haruna , Kobayashi Atsuko
Published: April 2020

Understanding the origin of organic material on Mars is a major issue in modern planetary science. Recent robotic exploration of Martian sedimentary rocks and laboratory analyses of Martian meteorites have both reported plausible indigenous organic components. However, little is known about their origin, evolution, and preservation. Here we report that 4-billion-year-old (Ga) carbonates in Martian meteorite, Allan Hills 84001, preserve indigenous nitrogen(N)-bearing organics by developing a new technique for high-spatial resolution in situ N-chemical speciation. The organic materials were synthesized locally and/or delivered meteoritically on Mars during Noachian age. The carbonates, alteration minerals from the Martian near-surface aqueous fluid, trapped and kept the organic materials intact over long geological times. This presence of N-bearing compounds requires abiotic or possibly biotic N-fixation and ammonia storage, suggesting that early Mars had a less oxidizing environment than today.
Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer
Authors: Corona Rosario I. , Seo Ji-Heui , Lin Xianzhi , Hazelett Dennis J. , Reddy Jessica , Fonseca Marcos A. S. , Abassi Forough , Lin Yvonne G. , Mhawech-Fauceglia Paulette Y. , Shah Sohrab P. , Huntsman David G. , Gusev Alexander , Karlan Beth Y. , Berman Benjamin P. , Freedman Matthew L. , Gayther Simon A. , Lawrenson Kate
Published: April 2020

The functional consequences of somatic non-coding mutations in ovarian cancer (OC) are unknown. To identify regulatory elements (RE) and genes perturbed by acquired non-coding variants, here we establish epigenomic and transcriptomic landscapes of primary OCs using H3K27ac ChIP-seq and RNA-seq, and then integrate these with whole genome sequencing data from 232 OCs. We identify 25 frequently mutated regulatory elements, including an enhancer at 6p22.1 which associates with differential expression of ZSCAN16 (P = 6.6 × 10-4) and ZSCAN12 (P = 0.02). CRISPR/Cas9 knockout of this enhancer induces downregulation of both genes. Globally, there is an enrichment of single nucleotide variants in active binding sites for TEAD4 (P = 6 × 10-11) and its binding partner PAX8 (P = 2×10-10), a known lineage-specific transcription factor in OC. In addition, the collection ofcisREs associated with PAX8 comprise the most frequently mutated set of enhancers in OC (P = 0.003). These data indicate that non-coding somatic mutations disrupt the PAX8 transcriptional network during OC development.
Macroscopic Polarization Change via Electron Transfer in a Valence Tautomeric Cobalt Complex
Authors: Wu Shu-Qi , Liu Meijiao , Gao Kaige , Kanegawa Shinji , Horie Yusuke , Aoyama Genki , Okajima Hajime , Sakamoto Akira , Baker Michael L. , Huzan Myron S. , Bencok Peter , Abe Tsukasa , Shiota Yoshihito , Yoshizawa Kazunari , Xu Wenhuang , Kou Hui-Zhong , Sato Osamu
Published: April 2020

Polarization change induced by directional electron transfer attracts considerable attention owing to its fast switching rate and potential light control. Here, we investigate electronic pyroelectricity in the crystal of a mononuclear complex, [Co(phendiox)(rac-cth)](ClO4)·0.5EtOH (1·0.5EtOH, H2phendiox = 9, 10-dihydroxyphenanthrene,rac-cth = racemic 5, 5, 7, 12, 12, 14-hexamethyl-1, 4, 8, 11-tetraazacyclotetradecane), which undergoes a two-step valence tautomerism (VT). Correspondingly, pyroelectric current exhibits double peaks in the same temperature domain with the polarization change consistent with the change in dipole moments during the VT process. Time-resolved Infrared (IR) spectroscopy shows that the photo-induced metastable state can be generated within 150 ps at 190 K. Such state can be trapped for tens of minutes at 7 K, showing that photo-induced polarization change can be realized in this system. These results directly demonstrate that a change in the molecular dipole moments induced by intramolecular electron transfer can introduce a macroscopic polarization change in VT compounds.
MethCORR modelling of methylomes from formalin-fixed paraffin-embedded tissue enables characterization and prognostication of colorectal cancer
Authors: Mattesen Trine B. , Rasmussen Mads H. , Sandoval Juan , Ongen Halit , Árnadóttir Sigrid S. , Gladov Josephine , Martinez-Cardus Anna , Castro de Moura Manuel , Madsen Anders H. , Laurberg Søren , Dermitzakis Emmanouil T. , Esteller Manel , Andersen Claus L. , Bramsen Jesper B.
Published: April 2020

Abstract

Transcriptional characterization and classification has potential to resolve the inter-tumor heterogeneity of colorectal cancer and improve patient management. Yet, robust transcriptional profiling is difficult using formalin-fixed, paraffin-embedded (FFPE) samples, which complicates testing in clinical and archival material. We present MethCORR, an approach that allows uniform molecular characterization and classification of fresh-frozen and FFPE samples. MethCORR identifies genome-wide correlations between RNA expression and DNA methylation in fresh-frozen samples. This information is used to infer gene expression information in FFPE samples from their methylation profiles. MethCORR is here applied to methylation profiles from 877 fresh-frozen/FFPE samples and comparative analysis identifies the same two subtypes in four independent cohorts. Furthermore, subtype-specific prognostic biomarkers that better predicts relapse-free survival (HR = 2.66, 95%CI [1.67–4.22], P value < 0.001 (log-rank test)) than UICC tumor, node, metastasis (TNM) staging and microsatellite instability status are identified and validated using DNA methylation-specific PCR. The MethCORR approach is general, and may be similarly successful for other cancer types.
A masked initiation region in retinoblastoma protein regulates its proteasomal degradation
Authors: Tomita Takuya , Huibregtse Jon M. , Matouschek Andreas
Published: April 2020

Retinoblastoma protein (Rb) is a tumor suppressor that binds and represses E2F transcription factors. In cervical cancer cells, human papilloma virus (HPV) protein E7 binds to Rb, releasing it from E2F to promote cell cycle progression, and inducing ubiquitination of Rb. E7-mediated proteasomal degradation of Rb requires action by another protease, calpain, which cleaves Rb after Lys 810. However, it is not clear why cleavage is required for Rb degradation. Here, we report that the proteasome cannot initiate degradation efficiently on full-length Rb. Calpain cleavage exposes a region that is recognized by the proteasome, leading to rapid proteolysis of Rb. These findings identify a mechanism for regulating protein stability by controlling initiation and provide a better understanding of the molecular mechanism underlying transformation by HPV.
Vertical two-dimensional layered fused aromatic ladder structure
Authors: Noh Hyuk-Jun , Im Yoon-Kwang , Yu Soo-Young , Seo Jeong-Min , Mahmood Javeed , Yildirim Taner , Baek Jong-Beom
Published: April 2020

Planar two-dimensional (2D) layered materials such as graphene, metal-organic frameworks, and covalent-organic frameworks are attracting enormous interest in the scientific community because of their unique properties and potential applications. One common feature of these materials is that their building blocks (monomers) are flat and lie in planar 2D structures, with interlayer π–π stacking, parallel to the stacking direction. Due to layer-to-layer confinement, their segmental motion is very restricted, which affects their sorption/desorption kinetics when used as sorbent materials. Here, to minimize this confinement, a vertical 2D layered material was designed and synthesized, with a robust fused aromatic ladder (FAL) structure. Because of its unique structural nature, the vertical 2D layered FAL structure has excellent gas uptake performance under both low and high pressures, and also a high iodine (I2) uptake capacity with unusually fast kinetics, the fastest among reported porous organic materials to date.
On the importance of time-resolved electrochemical evaluation in corrosion inhibitor-screening studies
Authors: Taheri Peyman , Milošev Ingrid , Meeusen Mats , Kapun Barbara , White Paul , Kokalj Anton , Mol Arjan
Published: April 2020

Efficiency of corrosion inhibitors in aqueous solutions depends on several interfacial parameters, which may vary over time. Therefore, reliable electrochemical techniques are demanded for screening the efficiency of corrosion inhibitors and monitoring their performance over time. Here, we evaluate corrosion inhibition efficiency of imidazole-based compounds on bare Cu surfaces and highlight the importance of electrochemical evaluation of the inhibitor over time, characterized by linear polarization resistance techniques as a reliable, instantaneous and non-invasive method for assessing intrinsic inhibitor performance in lab screening studies.
Relationship between quality of life and behavioural disorders in children with persistent asthma: a Multiple Indicators Multiple Causes (MIMIC) model
Authors: Montalbano Laura , Ferrante Giuliana , Montella Silvia , Cilluffo Giovanna , Di Marco Antonio , Bozzetto Sara , Di Palmo Emanuela , Licari Amelia , Leonardi Lucia , Caldarelli Valeria , Ghezzi Michele , La Grutta Stefania , Rusconi Franca ,   the Italian Pediatric Severe Asthma Network (IPSAN) Program of Italian Paediatric Respiratory Society (IPRS), Amarri S. , Barni S. , Capizzi A. , Cardinale F. , Carraro S. , Cazzato S. , Cutrera R. , Di Pillo S. , Duse M. , Fenu G. , Kantar A. , Leonardi S. , Lombardi E. , Marseglia G. L. , Nosetti L. , Novembre E. , Patria M. F. , Piacentini G. , Pisi G. , Ricci G. , Sacco O. , Santamaria F. , Tenero L. , Tosca M. A. , Tripodi M. C. , Volpini A.
Published: April 2020

Knowledge on multiple interdependences between quality of life (QoL) and behavioural problems in relation to asthma severity and control is undetermined. The aims of the study were: (i) to assess the relationship of QoL and behavioural problems with asthma severity and control (ii) to predict children’s “abnormal/borderline” status with variation in QoL. For these purposes a multicenter case-control study on 47 Severe Asthma (SA) and 94 Moderate Asthma (MA) children was performed. The MIMIC approach was applied to investigate the effect of SA and non-controlled asthma (NC) on QoL and behavioural disorders. Logistic regression was used to estimate probabilities of having an “abnormal/borderline” status with variation in QoL. The MIMIC model showed that the magnitude of the effect of SA and NC was larger on QoL (β = −0.37 and β = −0.30, respectively) than on behavioural problems (β = 0.27). With regards to the probability of having a borderline status, in MA a QoL of 1 returned a probability of 0.81, whereas in SA a QoL of 1 returned a probability of 0.89. In conclusion, SA children are highly affected by impaired QoL and behavioural problems. The MIMIC model allowed us to obtain a comprehensive assessment of QoL and behavioural problems with asthma severity and control.
A 96-well culture platform enables longitudinal analyses of engineered human skeletal muscle microtissue strength
Authors: Afshar Mohammad E. , Abraha Haben Y. , Bakooshli Mohsen A. , Davoudi Sadegh , Thavandiran Nimalan , Tung Kayee , Ahn Henry , Ginsberg Howard J. , Zandstra Peter W. , Gilbert Penney M.
Published: April 2020

Three-dimensional (3D) in vitro models of human skeletal muscle mimic aspects of native tissue structure and function, thereby providing a promising system for disease modeling, drug discovery or pre-clinical validation, and toxicity testing. Widespread adoption of this research approach is hindered by the lack of easy-to-use platforms that are simple to fabricate and that yield arrays of human skeletal muscle micro-tissues (hMMTs) in culture with reproducible physiological responses that can be assayed non-invasively. Here, we describe a design and methods to generate a reusable mold to fabricate a 96-well platform, referred to as MyoTACTIC, that enables bulk production of 3D hMMTs. All 96-wells and all well features are cast in a single step from the reusable mold. Non-invasive calcium transient and contractile force measurements are performed on hMMTs directly in MyoTACTIC, and unbiased force analysis occurs by a custom automated algorithm, allowing for longitudinal studies of function. Characterizations of MyoTACTIC and resulting hMMTs confirms the capability of the device to support formation of hMMTs that recapitulate biological responses. We show that hMMT contractile force mirrors expected responses to compounds shown by others to decrease (dexamethasone, cerivastatin) or increase (IGF-1) skeletal muscle strength. Since MyoTACTIC supports hMMT long-term culture, we evaluated direct influences of pancreatic cancer chemotherapeutics agents on contraction competent human skeletal muscle myotubes. A single application of a clinically relevant dose of Irinotecan decreased hMMT contractile force generation, while clear effects on myotube atrophy were observed histologically only at a higher dose. This suggests an off-target effect that may contribute to cancer associated muscle wasting, and highlights the value of the MyoTACTIC platform to non-invasively predict modulators of human skeletal muscle function.
Spontaneous spin-up induced by turbulence-driven topological transition of orbits in a collisionless tokamak plasma
Authors: Wang Shaojie
Published: April 2020

Spontaneous spin-up are widely observed in tokamak plasmas, which is crucially important for plasma confinement. A kinetic theory is proposed to show that a toroidal rotation of core plasma is induced by the topological transition of orbits driven by turbulent diffusion in a collisionless tokamak plasma. The theoretical prediction agrees well with the well-known Rice-scaling of intrinsic core plasma flow. This new theory predicts an intrinsic co-current core parallel flow of ~100 km/s in the International Thermonuclear Experimental Reactor.
Late-pregnancy uterine artery ligation increases susceptibility to postnatal Western diet-induced fat accumulation in adult female offspring
Authors: Jahandideh Forough , Bourque Stephane L. , Armstrong Edward A. , Cherak Stephana J. , Panahi Sareh , Macala Kimberly F. , Davidge Sandra T. , Yager Jerome Y.
Published: April 2020

Stressors during the fetal and postnatal period affect the growth and developmental trajectories of offspring, causing lasting effects on physiologic regulatory systems. Here, we tested whether reduced uterine artery blood flow in late pregnancy would alter body composition in the offspring, and whether feeding offspring a western diet (WD) would aggravate these programming effects. Pregnant rats underwent bilateral uterine artery ligation (BUAL) or sham surgery on gestational day (GD)18 (term = GD22). At weaning, offspring from each group received either a normal diet (ND) or a WD. BUAL surgery increased fetal loss and caused offspring growth restriction, albeit body weights were no longer different at weaning, suggesting postnatal catch-up growth. BUAL did not affect body weight gain, fat accumulation, or plasma lipid profile in adult male offspring. In contrast, while ND-fed females from BUAL group were smaller and leaner than their sham-littermates, WD consumption resulted in excess weight gain, fat accumulation, and visceral adiposity. Moreover, WD increased plasma triglycerides and cholesterol in the BUAL-treated female offspring without any effect on sham littermates. These results demonstrate that reduced uterine artery blood flow during late pregnancy in rodents can impact body composition in the offspring in a sex-dependent manner, and these effects may be exacerbated by postnatal chronic WD consumption.
Wideband tunable microwave signal generation in a silicon-micro-ring-based optoelectronic oscillator
Authors: Do Phuong T. , Alonso-Ramos Carlos , Le Roux Xavier , Ledoux Isabelle , Journet Bernard , Cassan Eric
Published: April 2020

Si photonics has an immense potential for the development of compact and low-loss opto-electronic oscillators (OEO), with applications in radar and wireless communications. However, current Si OEO have shown a limited performance. Si OEO relying on direct conversion of intensity modulated signals into the microwave domain yield a limited tunability. Wider tunability has been shown by indirect phase-modulation to intensity-modulation conversion. However, the reported tuning range is lower than 4 GHz. Here, we propose a new approach enabling Si OEOs with wide tunability and direct intensity-modulation to microwave conversion. The microwave signal is created by the beating between an optical source and single sideband modulation signal, selected by an add-drop ring resonator working as an optical bandpass filter. The tunability is achieved by changing the wavelength spacing between the optical source and a resonance peak of the resonator. Based on this concept, we experimentally demonstrate microwave signal generation between 6 GHz and 18 GHz, the widest range for a Si-micro-ring-based OEO. Moreover, preliminary results indicate that the proposed Si OEO provides precise refractive index monitoring, with a sensitivity of 94350 GHz/RIU and a potential limit of detection of only 10−8 RIU, opening a new route for the implementation of high-performance Si photonic sensors.
Kv1 potassium channels control action potential firing of putative GABAergic deep cerebellar nuclear neurons
Authors: Feria Pliego Jessica Abigail , Pedroarena Christine M.
Published: April 2020

Low threshold voltage activated Kv1 potassium channels play key roles in regulating action potential (AP) threshold, neural excitability, and synaptic transmission. Kv1 channels are highly expressed in the cerebellum and mutations of human Kv1 genes are associated to episodic forms of ataxia (EAT-1). Besides the well-established role of Kv1 channels in controlling the cerebellar basket-Purkinje cells synapses, Kv1 channels are expressed by the deep cerebellar nuclear neurons (DCNs) where they regulate the activity of principal DCNs carrying the cerebellar output. DCNs include as well GABAergic neurons serving important functions, such as those forming the inhibitory nucleo-olivary pathway, the nucleo-cortical DCNs providing feed-back inhibition to the cerebellar cortex, and those targeting principal DCNs, but whether their function is regulated by Kv1 channels remains unclear. Here, using cerebellar slices from mature GAD67-GFP mice to identify putative GABAergic-DCNs (GAD + DCN) we show that specific Kv1 channel blockers (dendrotoxin-alpha/I/K, DTXs) hyperpolarized the threshold of somatic action potentials, increased the spontaneous firing rate and hampered evoked high frequency repetitive responses of GAD + DCNs. Moreover, DTXs induced somatic depolarization and tonic firing in previously silent, putative nucleo-cortical DCNs. These results reveal a novel role of Kv1 channels in regulating GABAergic-DCNs activity and thereby, cerebellar function at multiple levels.
Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury
Authors: Zhang Zhao-huan , Wang Yue-rong , Li Fei , Liu Xiu-ling , Zhang Hui , Zhu Zhong-zheng , Huang Hai , Xu Xiao-hui
Published: April 2020

Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up- and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.
Development of a stereo dip-coating system for fabrication of tube-shaped blood vessel models
Authors: Shimizu Yasutomo , Tupin Simon , Kiyomitsu Chihaya , Kitamura Ko , Takashima Kazuto , Ohta Makoto
Published: April 2020

Tube-shaped blood vessel models that mimic their geometries and mechanical properties can deliver reliable and realistic behavioral information such as deformation and rupture during procedures such as insertion of medical devices. Thickness of vessel walls is an important parameter for fabricating the blood vessel models owing to their strong influence on the model behavior, especially during deformation. The dip-coating method is used to fabricate blood vessel models; however, non-uniform wall thicknesses are observed using this method. This study aimed at finding the characteristics of stereo “angular control dip-coating” (ACDC) system to develop a dip-coating system that can produce tubular models with uniformed wall thickness. The system developed here enables an observation of the substrate behavior from two different views. The conditions of dip-coating used in this study produce 1.36–1.82 mm in the maximum and 0.188–0.435 mm in minimum wall thickness and the fabricated walls cover the realistic range of carotid arterial dimensions. The characteristics of the ACDC system indicate that ACDC is effective for fabricating the uniform wall thickness particularly in the strong curved parts.
FIBTEM Improves the Sensitivity of Hyperfibrinolysis Detection in Severe Trauma Patients: A Retrospective Study Using Thromboelastometry
Authors: Wang Il-Jae , Park Sung-Wook , Bae Byung-Kwan , Lee Sung-Hwa , Choi Hyuk Jin , Park Sung Jin , Ahn Tae Young , Goh Tae Sik , Lee Min Jee , Yeom Seok Ran
Published: April 2020

Rotational thromboelastometry (ROTEM) can only detect high-degree hyperfibrinolysis (HF), despite being frequently used in trauma patients. We investigated whether considering FIBTEM HF (the presence of maximal lysis (ML) > 15%) could increase ROTEM-based HF detection’s sensitivity. This observational cohort study was performed at a level 1 trauma centre. Trauma patients with an Injury Severity Score (ISS) > 15 who underwent ROTEM in the emergency department between 2016 and 2017 were included. EXTEM HF was defined as ML > 15% in EXTEM. We compared mortality rates between EXTEM HF, FIBTEM HF, and non-HF patient groups. Overall, 402 patients were included, of whom 45% were men (mean age, 52.5 years; mean ISS, 27). The EXTEM HF (n = 37), FIBTEM HF (n = 132), and non-HF (n = 233) groups had mortality rates of 81.1%, 22.3%, and 10.3%, respectively. The twofold difference in mortality rates between the FIBTEM HF and non-HF groups remained statistically significant after Bonferroni correction (P = 0.01). On multivariable Cox regression analysis, FIBTEM HF was independently associated with in-hospital mortality (adjusted hazard ratio 2.15, 95% confidence interval 1.21–3.84, P = 0.009). Here, trauma patients with FIBTEM HF had significantly higher mortality rates than those without HF. FIBTEM be a valuable diagnostic method to improve HF detection’s sensitivity in trauma patients.
Identification of novel HNF1B mRNA splicing variants and their qualitative and semi-quantitative profile in selected healthy and tumour tissues
Authors: Hojny Jan , Bartu Michaela , Krkavcova Eva , Nemejcova Kristyna , Sevcik Jan , Cibula David , Fryba Vladimir , Plincelnerova Lenka , Dundr Pavel , Struzinska Ivana
Published: April 2020

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor crucial for the development of several tissues, and a promising biomarker of certain solid tumours. Thus far, two HNF1B alternative splicing variants (ASVs) have been described, however, the complete spectrum, prevalence and role of HNF1B ASVs in tumorigenesis are unclear. Considering the equivocal data about HNF1B ASVs and expression presented in literature, our aim was to characterize the spectrum of HNF1B mRNA splicing variants across different tissues. Here, we characterize HNF1B ASVs with high sensitivity in carcinomas of the uterine corpus, large intestine, kidney, pancreas, and prostate, with selected paired healthy tissues, using the previously described multiplex PCR and NGS approach. We identified 45 ASVs, of which 43 were novel. The spectrum and relative quantity of expressed ASVs mRNA differed among the analysed tissue types. Two known (3p, Δ7_8) and two novel (Δ7, Δ8) ASVs with unknown biological functions were detected in all the analysed tissues in a higher proportion. Our study reveals the wide spectrum of HNF1B ASVs in selected tissues. Characterization of the HNF1B ASVs is an important prerequisite for further expression studies to delineate the HNF1B splicing pattern, potential ASVs functional impact, and eventual refinement of HNF1B’s biomarker role.