bluuebunny/crossref_metadata_2025 huggingface dataset:
Conformational heterogeneity in human interphase chromosome organization reconciles the FISH and Hi-C paradox
Authors: Shi Guang , Thirumalai D.
Published: August 2019

Hi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Contact probability should decrease as the spatial distance between two loci increases. However, studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci, with larger Hi-C readout, is paradoxically larger compared to another pair with a smaller value of the contact probability. Here, we show that the FISH-Hi-C paradox can be resolved using a theory based on a Generalized Rouse Model for Chromosomes (GRMC). The FISH-Hi-C paradox arises because the cell population is highly heterogeneous, which means that a given contact is present in only a fraction of cells. Insights from the GRMC is used to construct a theory, without any adjustable parameters, to extract the distribution of subpopulations from the FISH data, which quantitatively reproduces the Hi-C data. Our results show that heterogeneity is pervasive in genome organization at all length scales, reflecting large cell-to-cell variations.
Author Correction: Discrepancy in scientific authority and media visibility of climate change scientists and contrarians
Authors: Petersen Alexander Michael , Vincent Emmanuel M. , Westerling Anthony LeRoy
Published: August 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Quantitative assessments and clinical outcomes in HER2 equivocal 2018 ASCO/CAP ISH group 4 breast cancer
Authors: Gupta Swati , Neumeister Veronique , McGuire John , Song Yan S. , Acs Balazs , Ho Kenneth , Weidler Jodi , Wong Wendy , Rhees Brian , Bates Michael , Rimm David L. , Bossuyt Veerle
Published: August 2019

We quantified human epidermal growth factor receptor 2 (HER2) RNA and protein expression in 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) in situ hybridization (ISH) group 4 (HER2/centromeric probe 17 (CEP17) ratio <2.0, average HER2 copy number ≥4.0 and <6.0, and 2013 ASCO/CAP ISH equivocal) breast cancers. Breast cancers in 2018 ASCO/CAP ISH group 4 between 2014 and 2017 were identified from the Yale archives. Sixty-three patients (34 with HER2 immunohistochemistry (IHC) 0/1+ and 29 with HER2 IHC 2+) were included. We compared patient characteristics, systemic treatments, and outcomes. We assessed HER2 by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and quantitative immunofluorescence (QIF). Among ISH group 4 cancers, higher HER2 mRNA (P < 0.0001) but similar HER2 protein levels were observed in IHC 2+ compared to IHC 0/1+ cancers. The distribution of RT-qPCR and QIF scores were independent of fluorescence in situ hybridization (FISH) ratio/copy number. Concordance between HER2 RT-qPCR and QIF was 69.8% (r = 0.52). Among 29 patients with IHC2+ results, 16 were HER2 positive by RT-qPCR and 12 were HER2 positive by QIF. Systemic treatment, recurrence, and survival outcomes were comparable among ISH group 4 cancers regardless of IHC 0/1+ or 2+ results. ISH group 4 cancers appear to form a distinct group with intermediate levels of RNA/protein expression, close to positive/negative cut points. Therefore, adjudication into positive or negative categories may not be meaningful. Our results support the 2018 ASCO/CAP recommendation to refrain from routine additional testing of these samples. Additional outcome information after trastuzumab treatment for patients in this special group might help to guide treatment decisions in these patients.
Predicting the dissolution kinetics of silicate glasses by topology-informed machine learning
Authors: Liu Han , Zhang Tony , Anoop Krishnan N. M. , Smedskjaer Morten M. , Ryan Joseph V. , Gin Stéṕhane , Bauchy Mathieu
Published: August 2019

Machine learning (ML) regression methods are promising tools to develop models predicting the properties of materials by learning from existing databases. However, although ML models are usually good at interpolating data, they often do not offer reliable extrapolations and can violate the laws of physics. Here, to address the limitations of traditional ML, we introduce a “topology-informed ML” paradigm—wherein some features of the network topology (rather than traditional descriptors) are used as fingerprint for ML models—and apply this method to predict the forward (stage I) dissolution rate of a series of silicate glasses. We demonstrate that relying on a topological description of the atomic network (i) increases the accuracy of the predictions, (ii) enhances the simplicity and interpretability of the predictive models, (iii) reduces the need for large training sets, and (iv) improves the ability of the models to extrapolate predictions far from their training sets. As such, topology-informed ML can overcome the limitations facing traditional ML (e.g., accuracy vs. simplicity tradeoff) and offers a promising route to predict the properties of materials in a robust fashion.
Seasonal and annual changes in PAH concentrations in a remote site in the Pacific Ocean
Authors: Miura Kaori , Shimada Kojiro , Sugiyama Taichi , Sato Kei , Takami Akinori , Chan Chak K. , Kim In Sun , Kim Yong Pyo , Lin Neng-Huei , Hatakeyama Shiro
Published: August 2019

This paper reports the long term observation of particle-associated polycyclic aromatic hydrocarbons (PAHs) at Cape Hedo Atmosphere and Aerosol Monitoring Station, a remote site in the Western Pacific Ocean, from 2008 to 2015. This is the first long-term study that evaluated the contribution of long-range transport of PAHs in East Asia. No obvious trend (P > 0.05) was found in a particular season over the years. However, there are seasonal variations of PAH concentrations with higher in spring and winter. The higher PAH are attributed to air masses from the area including part of China. Source apportionment using three different approaches, i.e., PAH compositional pattern analysis, PAH diagnostic ratio analysis and positive matrix factorization modeling, showed the combined high contribution of biomass burning (18%, 14%) and coal combustion (33%, 24%) in spring and winter. In addition, the contribution of ship emissions (35%) was relatively high in spring, whereas that of vehicle emissions (36%) was relatively high in winter. The contribution of coal combustion to PAH has decreased throughout the years, likely due to changes in energy structure in China. The contribution of biomass burning to PAH has showed no trend, being stable, and that of vehicular emissions has increased.
Association of caspase 8 polymorphisms -652 6N InsDel and Asp302His with progression-free survival and tumor infiltrating lymphocytes in early breast cancer
Authors: Kuhlmann Jan Dominik , Bachmann Hagen Sjard , Link Theresa , Wimberger Pauline , Kröber Eric , Thomssen Christoph , Mallé Brahima , Bethmann Daniel , Vetter Martina , Kantelhardt Eva Johanna
Published: August 2019

The caspase 8 variantsCASP8-652 6N InsDel and Asp302His have previously been identified to promote survival of T-lymphocytes and to indicate reduced breast cancer susceptibility. Besides some preliminary findings, prognostic relevance of these polymorphisms in patients with existing breast cancer has not been investigated. Considering an immunomodulatory role of these polymorphisms, we genotyped 785 early breast cancer patients and correlated caspase 8 variants with disease-free survival (DFS) and the presence of tumor infiltrating lymphocytes (TILs). Early breast cancer specimens were collected as part of the multicenter prospective PiA study. Genotyping was performed by pyrosequencing, TILs status was assessed using hematoxylin & eosin staining. TheCASP8-652Del variant was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652Del variant was an independent predictor for improved DFS (HR = 0.36; 95% CI = 0.174–0.726; p = 0.005). In patients with the 302HisHis genotype, there was no event of recurrence during observation time. Combined analysis of diplotypes revealed an influence of both polymorphisms on DFS (p = 0.029). Interestingly, patients with the 302HisHis variant among the unstratified patient cohort (and among the luminal-like subtype, by trend) had tumors with lower lymphocyte infiltration (p = 0.025). We propose a prognostically favorable role of the -652Del and the 302His variant in primary breast cancer and suggest for the first time an association between polymorphisms in apoptosis-related genes and the immunophenotype in breast cancer. Our findings encourage further investigation of caspase 8 polymorphisms as biomarkers for prognostic and immunotherapeutic considerations.
A Langevin equation that governs the irregular stick-slip nano-scale friction
Authors: Jannesar M. , Sadeghi A. , Meyer E. , Jafari G. R.
Published: August 2019

Friction force at the nanoscale, as measured from the lateral deflection of the tip of an atomic force microscope, usually shows a regular stick-slip behavior superimposed by a stochastic part (fluctuations). Previous studies showed the overall fluctuations to be correlated and multi-fractal, and thus not describable simply by e.g. a white noise. In the present study, we investigate whether one can extract an equation to describe nano-friction fluctuations directly from experimental data. Analysing the raw data acquired by a silicon tip scanning the NaCl(001) surface (of lattice constant 5.6 Å) at room temperature and in ultra-high vacuum, we found that the fluctuations possess a Markovian behavior for length scales greater than 0.7 Å. Above this characteristic length, the Kramers-Moyal approach applies. However, the fourth-order KM coefficient turns out to be negligible compared to the second order coefficients, such that the KM expansion reduces to the Langevin equation. The drift and diffusion terms of the Langevin equation show linear and quadratic trends with respect to the fluctuations, respectively. The slope 0.61 ± 0.02 of the drift term, being identical to the Hurst exponent, expresses a degree of correlation among the fluctuations. Moreover, the quadratic trend in the diffusion term causes the scaling exponents to become nonlinear, which indicates multifractality in the fluctuations. These findings propose the practical way to correct the prior models that consider the fluctuations as a white noise.
Energy dissipation in functionally two-dimensional phase transforming cellular materials
Authors: Zhang Yunlan , Restrepo David , Velay-Lizancos Mirian , Mankame Nilesh D. , Zavattieri Pablo D.
Published: August 2019

Phase Transforming Cellular Materials (PXCMs) are periodic cellular materials whose unit cells exhibit multiple stable or meta-stable configurations. Transitions between the various (meta-) stable configurations at the unit cell level enable these materials to exhibit reusable solid state energy dissipation. This energy dissipation arises from the storage and non-equilibrium release of strain energy accompanying the limit point traversals underlying these transitions. The material deformation is fully recoverable, and thus the material can be reused to absorb and dissipate energy multiple times. In this work, we present two designs for functionally two-dimensional PXCMs: the S-type with four axes of reflectional symmetry based on a square motif and, the T-type with six axes of symmetry based on a triangular motif. We employ experiments and simulations to understand the various mechanisms that are triggered under multiaxial loading conditions. Our numerical and experimental results indicate that these materials exhibit similar solid state energy dissipation for loads applied along the various axes of reflectional symmetry of the material. The specific energy dissipation capacity of the T-type is slightly greater and less sensitive to the loading direction than the S-type under the most of loading directions. However, both types of material are shown to be very effective in dissipating energy.
The horizontal gene transfer of Agrobacterium T-DNAs into the series Batatas (Genus Ipomoea) genome is not confined to hexaploid sweetpotato
Authors: Quispe-Huamanquispe Dora G. , Gheysen Godelieve , Yang Jun , Jarret Robert , Rossel Genoveva , Kreuze Jan F.
Published: August 2019

The discovery of the insertion of IbT-DNA1 and IbT-DNA2 into the cultivated (hexaploid) sweetpotato [Ipomoea batatas (L.) Lam.] genome constitutes a clear example of an ancient event of Horizontal Gene Transfer (HGT). However, it remains unknown whether the acquisition of both IbT-DNAs by the cultivated sweetpotato occurred before or after its speciation. Therefore, this study aims to evaluate the presence of IbT-DNAs in the genomes of sweetpotato’s wild relatives belonging to the taxonomic group series Batatas. Both IbT-DNA1 and IbT-DNA2 were found in tetraploid I. batatas (L.) Lam. and had highly similar sequences and at the same locus to those found in the cultivated sweetpotato. Moreover, IbT-DNA1 was also found in I. cordatotriloba and I. tenuissima while IbT-DNA2 was detected in I. trifida. This demonstrates that genome integrated IbT-DNAs are not restricted to the cultivated sweetpotato but are also present in tetraploid I. batatas and other related species.
Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease
Authors: Hoang Stephen A. , Oseini Abdul , Feaver Ryan E. , Cole Banumathi K. , Asgharpour Amon , Vincent Robert , Siddiqui Mohammad , Lawson Mark J. , Day Nathan C. , Taylor Justin M. , Wamhoff Brian R. , Mirshahi Faridoddin , Contos Melissa J. , Idowu Michael , Sanyal Arun J.
Published: August 2019

The heterogeneity of biological processes driving the severity of nonalcoholic fatty liver disease (NAFLD) as reflected in the transcriptome and the relationship between the pathways involved are not well established. Well-defined associations between gene expression profiles and disease progression would benefit efforts to develop novel therapies and to understand disease heterogeneity. We analyzed hepatic gene expression in controls and a cohort with the full histological spectrum of NAFLD. Protein-protein interaction and gene set variation analysis revealed distinct sets of coordinately regulated genes and pathways whose expression progressively change over the course of the disease. The progressive nature of these changes enabled us to develop a framework for calculating a disease progression score for individual genes. We show that, in aggregate, these scores correlate strongly with histological measures of disease progression and can thus themselves serve as a proxy for severity. Furthermore, we demonstrate that the expression levels of a small number of genes (~20) can be used to infer disease severity. Finally, we show that patient subgroups can be distinguished by the relative distribution of gene-level scores in specific gene sets. While future work is required to identify the specific disease characteristics that correspond to patient clusters identified on this basis, this work provides a general framework for the use of high-content molecular profiling to identify NAFLD patient subgroups.
Near-Field Scanning Microwave Microscopy in the Single Photon Regime
Authors: Geaney S. , Cox D. , Hönigl-Decrinis T. , Shaikhaidarov R. , Kubatkin S. E. , Lindström T. , Danilov A. V. , de Graaf S. E.
Published: August 2019

The microwave properties of nano-scale structures are important in a wide variety of applications in quantum technology. Here we describe a low-power cryogenic near-field scanning microwave microscope (NSMM) which maintains nano-scale dielectric contrast down to the single microwave photon regime, up to 109 times lower power than in typical NSMMs. We discuss the remaining challenges towards developing nano-scale NSMM for quantum coherent interaction with two-level systems as an enabling tool for the development of quantum technologies in the microwave regime.
Deep Machine Learning Techniques for the Detection and Classification of Sperm Whale Bioacoustics
Authors: Bermant Peter C. , Bronstein Michael M. , Wood Robert J. , Gero Shane , Gruber David F.
Published: August 2019

We implemented Machine Learning (ML) techniques to advance the study of sperm whale (Physeter macrocephalus) bioacoustics. This entailed employing Convolutional Neural Networks (CNNs) to construct an echolocation click detector designed to classify spectrograms generated from sperm whale acoustic data according to the presence or absence of a click. The click detector achieved 99.5% accuracy in classifying 650 spectrograms. The successful application of CNNs to clicks reveals the potential of future studies to train CNN-based architectures to extract finer-scale details from cetacean spectrograms. Long short-term memory and gated recurrent unit recurrent neural networks were trained to perform classification tasks, including (1) “coda type classification” where we obtained 97.5% accuracy in categorizing 23 coda types from a Dominica dataset containing 8,719 codas and 93.6% accuracy in categorizing 43 coda types from an Eastern Tropical Pacific (ETP) dataset with 16,995 codas; (2) “vocal clan classification” where we obtained 95.3% accuracy for two clan classes from Dominica and 93.1% for four ETP clan types; and (3) “individual whale identification” where we obtained 99.4% accuracy using two Dominica sperm whales. These results demonstrate the feasibility of applying ML to sperm whale bioacoustics and establish the validity of constructing neural networks to learn meaningful representations of whale vocalizations.
Time of Day and its Association with Risk of Death and Chance of Discharge in Critically Ill Patients: A Retrospective Study
Authors: Zajic Paul , Bauer Peter , Rhodes Andrew , Moreno Rui , Fellinger Tobias , Metnitz Barbara , Posch Martin , Metnitz Philipp G. H.
Published: August 2019

Outcomes following admission to intensive care units (ICU) may vary with time and day. This study investigated associations between time of day and risk of ICU mortality and chance of ICU discharge in acute ICU admissions. Adult patients (age ≥ 18 years) who were admitted to ICUs participating in the Austrian intensive care database due to medical or surgical urgencies and emergencies between January 2012 and December 2016 were included in this retrospective study. Readmissions were excluded. Statistical analysis was conducted using the Fine-and-Gray proportional subdistribution hazards model concerning ICU mortality and ICU discharge within 30 days adjusted for SAPS 3 score. 110,628 admissions were analysed. ICU admission during late night and early morning was associated with increased hazards for ICU mortality; HR: 1.17; 95% CI: 1.08–1.28 for 00:00–03:59, HR: 1.16; 95% CI: 1.05–1.29 for 04:00–07:59. Risk of death in the ICU decreased over the day; lowest HR: 0.475, 95% CI: 0.432–0.522 for 00:00–03:59. Hazards for discharge from the ICU dropped sharply after 16:00; lowest HR: 0.024; 95% CI: 0.019–0.029 for 00:00–03:59. We conclude that there are “time effects” in ICUs. These findings may spark further quality improvement efforts.
Toxoplasma gondii-induced host cellular cell cycle dysregulation is linked to chromosome missegregation and cytokinesis failure in primary endothelial host cells
Authors: Velásquez Zahady D. , Conejeros Iván , Larrazabal Camilo , Kerner Katharina , Hermosilla Carlos , Taubert Anja
Published: August 2019

Toxoplasma gondii is a zoonotic and intracellular parasite with fast proliferating properties leading to rapid host cell lysis. T. gondii modulates its host cell on numerous functional levels. T. gondii was previously reported to influence host cellular cell cycle and to dampen host cell division. By using primary endothelial host cells, we show for the first time that T. gondii tachyzoite infections led to increased host cell proliferation and to an enhanced number of multi-nucleated host cells. As detected on DNA content level, parasite infections induced a G2/M cell cycle arrest without affecting expression of G2-specific cyclin B1. In line, parasite-driven impairment mainly concerned mitotic phase of host cells by propagating several functional alterations, such as chromosome segregation errors, mitotic spindle alteration and blockage of cytokinesis progression, with the latter most likely being mediated by the downregulation of the Aurora B kinase expression.
High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver
Authors: Naito Hisao , Yoshikawa-Bando Yuki , Yuan Yuan , Hashimoto Sayuki , Kitamori Kazuya , Yatsuya Hiroshi , Nakajima Tamie
Published: August 2019

Precise molecular pathways involved in the progression of non-alcoholic steatohepatitis (NASH) remain to be elucidated. As Mallory–Denk bodies were occasionally observed in the enlarged hepatocytes in NASH model rat (SHRSP5/Dmcr) fed high-fat and high-cholesterol (HFC) diet, we aimed to clarify the roles of autophagy and endoplasmic reticulum (ER) stress in NASH progression. Male SHRSP5/Dmcr were randomly divided into 4 groups. Two groups were fed a control diet; the other two groups were fed a HFC diet for 2 and 8 weeks, respectively. The HFC diet increased the autophagy-related proteins levels and microtubule-associated protein 1 light chain 3-II/I ratio after 2 and 8 weeks, respectively. However, regarding ER stress-related proteins, the HFC diet decreased the levels of phosphorylated (p-) inositol-requiring kinase-1 (p-IRE-1) and p-protein kinase RNA-like ER kinase after 2 weeks. Additionally, the HFC diet increased anti-ubiquitin-positive cells and the level of the autophagy substrate p62, suggesting that the HFC diet induced dysfunction in ubiquitin-dependent protein degradation pathways. In conclusion, the HFC diet arrested the autophagy process in the liver; this was particularly associated with decreases in p-IRE-1 expression.
Dynamic of a Delayed Predator-Prey Model with Application to Network’ Users’ Data Forwarding
Authors: Zhang Yaming , Koura Yaya Hamadou , Su Yanyuan
Published: August 2019

In most situations where entities interact by sharing limited resources, controlling populations’ density is crucial to maintain ecosystem sustainability. This is the case in a predator-prey type interaction when predator survival relies on its ability to harvest and consume resources. In this article, we analyzed a modified predator-prey model based on Rosenzweig-MacArthur characterized by a delayed conversion of prey into resources and applied the proposed model to network users’ data forwarding at a bottleneck node. We discuss system fixed points behaviour and prove that delaying the handling time has a significant impact on the dynamic of interaction and system bifurcates, exhibits chaotic behaviour and is highly responsive to small perturbations.
Comparative analysis demonstrates cell type-specific conservation of SOX9 targets between mouse and chicken
Authors: Yamashita Satoshi , Kataoka Kensuke , Yamamoto Hiroto , Kato Tomoko , Hara Satoshi , Yamaguchi Katsushi , Renard-Guillet Claire , Katou Yuki , Shirahige Katsuhiko , Ochi Haruki , Ogino Hajime , Uchida Tokujiro , Inui Masafumi , Takada Shuji , Shigenobu Shuji , Asahara Hiroshi
Published: August 2019

SRY (sex-determining region Y)-box 9 (SOX9) is a transcription factor regulating both chondrogenesis and sex determination. Among vertebrates, SOX9’s functions in chondrogenesis are well conserved, while they vary in sex determination. To investigate the conservation of SOX9’s regulatory functions in chondrogenesis and gonad development among species, we performed chromatin immunoprecipitation sequencing (ChIP-seq) using developing limb buds and male gonads from embryos of two vertebrates, mouse and chicken. In both mouse and chicken, SOX9 bound to intronic and distal regions of genes more frequently in limb buds than in male gonads, while SOX9 bound to the proximal upstream regions of genes more frequently in male gonads than in limb buds. In both species, SOX palindromic repeats were identified more frequently in SOX9 binding regions in limb bud genes compared with those in male gonad genes. The conservation of SOX9 binding regions was significantly higher in limb bud genes. In addition, we combined RNA expression analysis (RNA sequencing) with the ChIP-seq results at the same stage in developing chondrocytes and Sertoli cells and determined SOX9 target genes in these cells of the two species and disclosed that SOX9 targets showed high similarity of targets in chondrocytes, but not in Sertoli cells.
Molecular Mechanisms of Natural Carotenoid-based Pigmentation of Queen Loach, Botia dario (Hamilton, 1822) Under Captive Condition
Authors: Tripathy Partha Sarathi , Devi Ningthoujam Chaoba , Parhi Janmejay , Priyadarshi Himanshu , Patel Arun Bhai , Pandey Pramod Kumar , Mandal Sagar Chandra
Published: August 2019

The genetic basis and expression patterns of key genes are important aspects of study to understand the colouration. This trait differs between wild and domesticated fish which is a matter of research. Botia dario is an indigenous fish, having ornamental and aesthetic value, which shows faded appearance in terms of colour in domesticated condition than wild. In the present study the carotenoid-fed B. dario were examined through incorporation of marigold petal meal in the diets at the rate of 5, 10 and 15% w/w along with wild fish. The carotenoid content of tissues that is skin, muscle and intestine along with intensity of colouration increased in a dose dependant manner of carotenoid in the diet. Important carotenoid-based colouration genes that is csf1r, BCDO2, SR-B1, MLN64, STAR5, GSTA2 and PLIN2 were characterized in the fish, to find out their role in fish pigmentation. The significant difference (p < 0.05) in the expression of these genes in different tissues, when compared among carotenoid-fed domesticated and wild fish, revealed the mechanism responsible for faded colouration and also revealed the means to enhance colour in the fish.
Assessing Susceptibility of Debris Flow in Southwest China Using Gradient Boosting Machine
Authors: Di Baofeng , Zhang Hanyue , Liu Yongyao , Li Jierui , Chen Ningsheng , Stamatopoulos Constantine A. , Luo Yuzhou , Zhan Yu
Published: August 2019

A gradient boosting machine (GBM) was developed to model the susceptibility of debris flow in Sichuan, Southwest China for risk management. A total of 3839 events of debris flow during 1949–2017 were compiled from the Sichuan Geo-Environment Monitoring program, field surveys, and satellite imagery interpretation. In the cross-validation, the GBM showed better performance, with the prediction accuracy of 82.0% and area under curve of 0.88, than the benchmark models, including the Logistic Regression, the K-Nearest Neighbor, the Support Vector Machine, and the Artificial Neural Network. The elevation range, precipitation, and aridity index played the most important role in determining the susceptibility. In addition, the water erosion intensity, road construction, channel gradient, and human settlement sites also largely contributed to the formation of debris flow. The susceptibility map produced by the GBM shows that the spatial distributions of high-susceptibility watersheds were highly coupled with the locations of the topographical extreme belt, fault zone, seismic belt, and dry valleys. This study provides critical information for risk mitigating and prevention of debris flow.
Dissecting phenotypic responses of the druggable targetome in cancers
Authors: Jeong Euna , Park Choa , Moon Sung Ung , Cho Juyeon , Song Mee , Ryoo Seungeun , Gu Hyejeong , Lee Yejin , Kim Wooyoung , Yoon Sukjoon
Published: August 2019

Although a large amount of screening data comprising target genes and/or drugs tested against cancer cell line panels are available, different assay conditions and readouts limit the integrated analysis and batch-to-batch comparison of these data. Here, we systematically produced and analyzed the anticancer effect of the druggable targetome to understand the varied phenotypic outcomes of diverse functional classes of target genes. A library of siRNAs targeting ~4,800 druggable genes was screened against cancer cell lines under 2D and/or 3D assay conditions. The anticancer effect was simultaneously measured by quantifying cell proliferation and/or viability. Hit rates varied significantly depending on assay conditions and/or phenotypic readouts. Functional classes of hit genes were correlated with the microenvironment difference between the 2D monolayer cell proliferation and 3D sphere formation assays. Furthermore, multiplexing of cell proliferation and viability measures enabled us to compare the sensitivity and resistance responses to the gene knockdown. Many target genes that inhibited cell proliferation increased the single-cell-level viability of surviving cells, leading to an increase in self-renewal potential. In this study, combinations of parallel 2D/3D assays and multiplexing of cell proliferation and viability measures provided functional insights into the varied phenotypic outcomes of the cancer targetome.
Blocked O-GlcNAc cycling disrupts mouse hematopoeitic stem cell maintenance and early T cell development
Authors: Abramowitz Lara K. , Harly Christelle , Das Arundhoti , Bhandoola Avinash , Hanover John A.
Published: August 2019

Small numbers of hematopoietic stem cells (HSCs) balance self-renewal and differentiation to produce the diversity and abundance of cell types that make up the blood system. How nutrients are recruited to support this massive differentiation and proliferation process remains largely unknown. The unique metabolism of adult HSCs, which rely on glycolysis and glutaminolysis, suggests a potential role for the post-translational modification O-GlcNAc as a critical nutrient signal in these cells. Glutamine, glucose, and other metabolites drive the hexosamine biosynthetic pathway (HBP) ultimately leading to the O-GlcNAc modification of critical intracellular targets. Here, we used a conditional targeted genetic deletion of the enzyme that removes O-GlcNAc, O-GlcNAcase (OGA), to determine the consequences of blocked O-GlcNAc cycling on HSCs. Oga deletion in mouse HSCs resulted in greatly diminished progenitor pools, impaired stem cell self-renewal and nearly complete loss of competitive repopulation capacity. Further, early T cell specification was particularly sensitive to Oga deletion. Loss of Oga resulted in a doubling of apoptotic cells within the bone marrow and transcriptional deregulation of key genes involved in adult stem cell maintenance and lineage specification. These findings suggest that O-GlcNAc cycling plays a critical role in supporting HSC homeostasis and early thymocyte development.
Deep Learning to Improve Breast Cancer Detection on Screening Mammography
Authors: Shen Li , Margolies Laurie R. , Rothstein Joseph H. , Fluder Eugene , McBride Russell , Sieh Weiva
Published: August 2019

The rapid development of deep learning, a family of machine learning techniques, has spurred much interest in its application to medical imaging problems. Here, we develop a deep learning algorithm that can accurately detect breast cancer on screening mammograms using an “end-to-end” training approach that efficiently leverages training datasets with either complete clinical annotation or only the cancer status (label) of the whole image. In this approach, lesion annotations are required only in the initial training stage, and subsequent stages require only image-level labels, eliminating the reliance on rarely available lesion annotations. Our all convolutional network method for classifying screening mammograms attained excellent performance in comparison with previous methods. On an independent test set of digitized film mammograms from the Digital Database for Screening Mammography (CBIS-DDSM), the best single model achieved a per-image AUC of 0.88, and four-model averaging improved the AUC to 0.91 (sensitivity: 86.1%, specificity: 80.1%). On an independent test set of full-field digital mammography (FFDM) images from the INbreast database, the best single model achieved a per-image AUC of 0.95, and four-model averaging improved the AUC to 0.98 (sensitivity: 86.7%, specificity: 96.1%). We also demonstrate that a whole image classifier trained using our end-to-end approach on the CBIS-DDSM digitized film mammograms can be transferred to INbreast FFDM images using only a subset of the INbreast data for fine-tuning and without further reliance on the availability of lesion annotations. These findings show that automatic deep learning methods can be readily trained to attain high accuracy on heterogeneous mammography platforms, and hold tremendous promise for improving clinical tools to reduce false positive and false negative screening mammography results. Code and model available at: https://github.com/lishen/end2end-all-conv.
Fine-tuning the expression of target genes using a DDI2 promoter gene switch in budding yeast
Authors: Wang Yong , Zhang Kaining , Li Hanfei , Xu Xin , Xue Huijun , Wang Pingping , Fu Yu V.
Published: August 2019

Tuned gene expression is crucial to the proper growth and response to the environmental changes of an organism. To enable tunable gene expression as designed is desirable in both scientific research and industrial application. Here, we introduce a novel promoter switching method based on the DDI2 promoter (PDDI2) that can fine tune the expression of target genes. We constructed a recyclable cassette (PDDI2-URA3-PDDI2) and integrated it upstream of yeast target genes to replace the native promoters by DDI2 promoter without introducing any junk sequence. We found that the presence or absence of cyanamide as an inducer could turn on or off the expression of target genes. In addition, we showed that PDDI2 could act as a gene switch to linearly regulate the expression levels of target genes in vivo. We switched the original promoters of RAD18, TUP1, and CDC6 with PDDI2 as a proof-of-concept.
Laser-induced fluorescence (LIF) as a smart method for fast environmental virological analyses: validation on Picornaviruses
Authors: Gabbarini Valentina , Rossi Riccardo , Ciparisse Jean-François , Malizia Andrea , Divizia Andrea , De Filippis Patrizia , Anselmi Maurizio , Carestia Mariachiara , Palombi Leonardo , Divizia Maurizio , Gaudio Pasqualino
Published: August 2019

Virological analysis is time-consuming and expensive. The aim of this work is to demonstrate the applicability of laser-induced fluorescence (LIF) to the classification of viruses, reducing the time for this analysis and its costs. Experimental tests were performed in which different viruses were irradiated with a UV laser emitting at 266 nm and the emitted spectra were recorded by a spectrometer. The classification techniques show the possibility of discriminating viruses. Although the application of the LIF technique to biological agents has been thoroughly studied by many researchers over the years, this work aims at validating for the first time its applicability to virological analyses. The development of a fast virological analysis may revolutionize this field, allowing fast responses to epidemiologic events, reducing their risks and improving the efficiency of monitoring environments. Moreover, a cost reduction may lead to an increase in the monitoring frequency, with an obvious enhancement of safety and prevention.
Estimating the immunogenicity of measles-rubella vaccination administered during a mass campaign in Lao People’s Democratic Republic using multi-valent seroprevalence data
Authors: Vynnycky Emilia , Miyano Shinsuke , Komase Katsuhiro , Mori Yoshio , Takeda Makoto , Kitamura Tomomi , Xeuatvongsa Anonh , Hachiya Masahiko
Published: August 2019

Measles and rubella are important causes of morbidity and mortality globally. Despite high coverage reported for measles vaccination, outbreaks continue to occur in some countries. The reasons for these outbreaks are poorly understood. We apply Bayesian methods to multi-valent seroprevalence data for measles and rubella, collected 2 years and 3 months after a mass measles-rubella vaccination campaign in Lao PDR to estimate the immunogenicity and vaccination coverage. When the vaccination coverage was constrained to exceed 95% or 90%, consistent with officially-reported values, the immunogenicity of the measles vaccine component was unexpectedly low (75% (95% CR: 63–82%) and 79% (CR: 70–87%) respectively. The estimated immunogenicity increased after relaxing constraints on the vaccination coverage, with best-fitting values of 83% (95% CR: 73–91%) and 97% (95% CR: 90–100%) for the measles and rubella components respectively, with an estimated coverage of 83% (95% CR: 80–88%). The findings suggest that, if the vaccine coverage was as high as that reported, continuing measles outbreaks in Lao PDR, and potentially elsewhere, may be attributable to suboptimal immunogenicity attained in mass campaigns. Vaccine management in countries with high reported levels of coverage and ongoing measles outbreaks needs to be reviewed if measles elimination targets are to be achieved.
Visual short-term memory binding deficit with age-related hearing loss in cognitively normal older adults
Authors: Loughrey David G. , Parra Mario A. , Lawlor Brian A.
Published: August 2019

Age-related hearing loss (ARHL) has been posited as a possible modifiable risk factor for neurocognitive impairment and dementia. Measures sensitive to early neurocognitive changes associated with ARHL would help to elucidate the mechanisms underpinning this relationship. We hypothesized that ARHL might be associated with decline in visual short-term memory binding (VSTMB), a potential biomarker for preclinical dementia due to Alzheimer’s disease (AD). We examined differences in accuracy between older adults with hearing loss and a control group on the VSTMB task from a single feature (shapes) condition to a feature binding (shapes-colors) condition. Hearing loss was associated with a weaker capacity to process bound features which appeared to be accounted for by a weaker sensitivity for change detection (A’). Our findings give insight into the neural mechanisms underpinning neurocognitive decline with ARHL and its temporal sequence.
Ensuring access to high-quality resources reduces the impacts of heat stress on bees
Authors: Vanderplanck Maryse , Martinet Baptiste , Carvalheiro Luísa Gigante , Rasmont Pierre , Barraud Alexandre , Renaudeau Coraline , Michez Denis
Published: August 2019

Pollinators are experiencing declines globally, negatively affecting the reproduction of wild plants and crop production. Well-known drivers of these declines include climatic and nutritional stresses, such as a change of dietary resources due to the degradation of habitat quality. Understanding potential synergies between these two important drivers is needed to improve predictive models of the future effects of climate change on pollinator declines. Here, bumblebee colony bioassays were used to evaluate the interactive effects of heat stress, a reduction of dietary resource quality, and colony size. Using a total of 117 colonies, we applied a fully crossed experiment to test the effect of three dietary quality levels under three levels of heat stress with two colony sizes. Both nutritional and heat stress reduced colony development resulting in a lower investment in offspring production. Small colonies were much more sensitive to heat and nutritional stresses than large ones, possibly because a higher percentage of workers helps maintain social homeostasis. Strikingly, the effects of heat stress were far less pronounced for small colonies fed with suitable diets. Overall, our study suggests that landscape management actions that ensure access to high-quality resources could reduce the impacts of heat stress on bee decline.
de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation
Authors: Schneeberger Pauline E. , Bierhals Tatjana , Neu Axel , Hempel Maja , Kutsche Kerstin
Published: August 2019

In eukaryotes, the elongation phase of transcription by RNA polymerase II (RNAP II) is regulated by the transcription elongation factor b (P-TEFb), composed of Cyclin-T1 and cyclin-dependent kinase 9. The release of RNAP II is mediated by phosphorylation through P-TEFb that in turn is under control by the inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex. The 7SK snRNP consists of the 7SK non-coding RNA and the proteins MEPCE, LARP7, and HEXIM1/2. Biallelic LARP7 loss-of-function variants underlie Alazami syndrome characterized by growth retardation and intellectual disability. We report a boy with global developmental delay and seizures carrying the de novo MEPCE nonsense variant c.1552 C > T/p.(Arg518*). mRNA and protein analyses identified nonsense-mediated mRNA decay to underlie the decreased amount of MEPCE in patient fibroblasts followed by LARP7 and 7SK snRNA downregulation and HEXIM1 upregulation. Reduced binding of HEXIM1 to Cyclin-T1, hyperphosphorylation of the RNAP II C-terminal domain, and upregulated expression of ID2, ID3, MRPL11 and snRNAs U1, U2 and U4 in patient cells are suggestive of enhanced activation of P-TEFb. Flavopiridol treatment and ectopic MEPCE protein expression in patient fibroblasts rescued increased expression of six RNAP II-sensitive genes and suggested a possible repressive effect of MEPCE on P-TEFb-dependent transcription of specific genes.
Hypercalcemia is common during Pneumocystis pneumonia in kidney transplant recipients
Authors: Hamroun Aghilès , Lenain Rémi , Bui Nguyen Linh , Chamley Paul , Loridant Séverine , Neugebauer Yann , Lionet Arnaud , Frimat Marie , Hazzan Marc
Published: August 2019

A few cases of hypercalcemia related to Pneumocystis jirovecii pneumonia (PJP) have previously been described, supposedly associated with an 1α-hydroxylase enzyme-dependent mechanism. The prevalence and significance of hypercalcemia in PJP remain unclear, especially in kidney transplant recipients (KTR) who frequently display hypercalcemia via persisting hyperparathyroidism. We here retrospectively identified all microbiologically-proven PJP in adult KTR from 2005 to 2017 in the Lille University Hospital, and studied the mineral and bone metabolism parameters during the peri-infectious period. Clinical features of PJP-patients were analyzed according to their serum calcium level. Hypercalcemia (12.6 ± 1.6 mg/dl) was observed in 37% (18/49) of PJP-patients and regressed concomitantly to specific anti-infectious treatment in all cases. No other cause of hypercalcemia was identified. In hypercalcemic patients, serum levels of 1,25-dihydroxyvitamin D were high at the time of PJP-diagnosis and decreased after anti-infectious treatment (124 ± 62 versus 28 ± 23 pg/mL, p = 0.006) while PTH serum levels followed an inverse curve (35 ± 34 versus 137 ± 99 pg/mL, p = 0.009), suggesting together a granuloma-mediated mechanism. Febrile dyspnea was less frequent in hypercalcemic PJP-patients compared to non-hypercalcemic (29 versus 67%). In summary, hypercalcemia seems common during PJP in KTR. Unexplained hypercalcemia could thus lead to specific investigations in this particular population, even in the absence of infectious or respiratory symptoms.
Association between long-term orthokeratology responses and corneal biomechanics
Authors: Lam Andrew K. C. , Hon Ying , Leung Stanley Y. Y. , Shu-Ho Lu , Chong Jones , Lam David C. C.
Published: August 2019

Myopia is very prevalent worldwide, especially among Asian populations. Orthokeratology is a proven intervention to reduce myopia progression. The current study investigated association between baseline corneal biomechanics and orthokeratology responses, and changes of corneal biomechanics from long-term orthokeratology. We fitted 59 adult subjects having myopia between −4.00D to −5.00D with overnight orthokeratology. Corneal biomechanics was measured through dynamic bidirectional corneal applanation (in terms of corneal hysteresis, CH and corneal resistance factor, CRF) and corneal indentation (in terms of corneal stiffness, S and tangent modulus, E). Subjects with poor orthokeratology responses had lower E (mean 0.474 MPa) than subjects with good orthokeratology responses (mean 0.536 MPa). Successful orthokeratology for 6 months resulted in reducing CH (reduced by 5.8%) and CRF (reduced by 8.7%). Corneal stiffness was stable, but E showed an increasing trend. Among subjects with successful orthokeratology, a higher baseline S resulted in greater myopia reduction (Pearson correlation coefficient, r = 0.381, p = 0.02).
Genome-wide single nucleotide polymorphism array analysis unveils the origin of heterozygous androgenetic complete moles
Authors: Usui Hirokazu , Nakabayashi Kazuhiko , Maehara Kayoko , Hata Kenichiro , Shozu Makio
Published: August 2019

Hydatidiform moles are abnormal pregnancies, which show trophoblastic hyperplasia. Most often, the nuclear genome in complete hydatidiform moles (CHMs) is composed of only paternal chromosomes. Diploid androgenetic conceptuses can be divided into homozygous and heterozygous CHMs. Heterozygous CHMs originate from two sperms or a diploid sperm, the distinction of which has not been established. Here, we assessed the origin of heterozygous CHMs using single nucleotide polymorphism (SNP) array. Thirteen heterozygous CHMs were analysed using B allele frequency (BAF) plotting to determine the centromeric zygosity status of all chromosomes. One case was from the duplication of a single sperm with an XY chromosome. In the other twelve cases, centromeric zygosity was random, i.e. mixed status. Thus, the twelve heterozygous CHMs were considered to be of dispermic origin but not diploid sperm origin. BAF plotting of SNP array can be a powerful tool to estimate the type of hydatidiform moles.
Retrieval of negative autobiographical memories is associated with hostile attributions in ambiguous situations amongst people with schizophrenia
Authors: Barry Tom J. , Hernández-Viadel José V. , Fernández Dolores , Ros Laura , Ricarte Jorge J. , Berna Fabrice
Published: August 2019

Schizophrenia is characterised by difficulty understanding the thoughts and intentions of other people. Misunderstandings could lead people to attribute hostility to others’ actions. Theories suggest that we use our autobiographical memories to inform our understanding of other people but no study has examined the relation between memory and hostile attributions in schizophrenia. People with (n = 42) and without (n = 34) schizophrenia diagnoses completed The Ambiguous Intentions and Hostility Questionnaire (AIHQ) to assess their tendency to attribute hostility to other people’s actions and the Autobiographical Memory Test (AMT) to assess their ability to recall specific positive and negative autobiographical memories. In linear regressions the interaction between diagnostic group and the proportion of specific negative memories participants retrieved explained significant variance in each AIHQ index. Follow-up correlation analyses showed that participants with schizophrenia who retrieved more negative memories also attributed greater hostility to other people’s actions (r = 0.47) and reported that they would respond with greater aggression (r = 0.59). These correlations were in the opposite direction for controls. People with schizophrenia may use their memories for negative past events to understand the actions and intentions of other people, leading to attributions of hostility for otherwise benign actions.
A graphene-assisted all-pass filter for a tunable terahertz transmissive modulator with near-perfect absorption
Authors: Tran Thang Q. , Lee Sangjun , Kim Sangin
Published: August 2019

We proposed an all-pass filter based perfect absorber scheme which also can function as a highly efficient transmissive modulator. We theoretically analyzed the proposed scheme using the temporal coupled mode theory and showed that near-perfect absorption could be achieved with practically modest deviation from the critical coupling condition. We also demonstrated the feasibility of the proposed scheme in a grating-based all-pass filter device with a variable loss implemented by two separate graphene layers, achieving an absorption of ~99.8% and a transmission modulation depth of ~70 dB in a terahertz frequency range. We also numerically investigated the tunability of the designed device.