bluuebunny/crossref_metadata_2025 huggingface dataset:
Antidepressant suppression of REM and spindle sleep impairs hippocampus-dependent learning and memory but fosters striatal-dependent strategies
Authors: Watts Alain , Gritton Howard , Sweigart Jamie , Poe Gina
Published: July 2019

REM sleep enhances hippocampus-dependent associative memory but has little impact on striatal-dependent procedural learning. Antidepressant medications like desipramine (DMI) inhibit rapid-eye-movement (REM) sleep but it is little understood how antidepressant treatments affect learning. We found that DMI strongly suppressed REM sleep in rats for several hours and impaired reconsolidation of a familiar maze and consolidation of moved baited positions (reversal learning) in a sleep-dependent fashion. Unexpectedly, DMI also reduced the spindle-rich transition-to-REM sleep state (TR) and spatial memory changes were more related to TR than to REM sleep. Working memory was unaffected, but overnight reference memory was significantly impaired and subjects increased reliance on non-hippocampal strategies. Procedural memory performance was positively correlated with increases in non-REM sleep after DMI serving to offset memory declines, partially preserving performance. Our results suggest that familiar memories are re-consolidated during REM sleep, reversal memories consolidated during TR, and procedural memories consolidated during non-REM sleep.
Slug-based epithelial-mesenchymal transition gene signature is associated with prolonged time to recurrence in glioblastoma
Authors: Cheng Wei-Yi , Kandel Jessica , Yamashiro Darrell , Canoll Peter , Anastassiou Dimitris
Published: July 2019

Background

We previously identified a precise stage-associated gene expression signature of coordinately expressed genes, including the transcription factor Slug (SNAI2) and other epithelial mesenchymal transition (EMT) markers, present in samples from publicly available gene expression datasets in multiple cancer types. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT like process of mesenchymal transition to varying degrees.Findings Here we show that this signature in glioblastoma multiforme (GBM) is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3x10^-7^). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas.

Conclusions

Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients.
A similarity criterion for forest growth curves
Authors: Alexandrov Georgii , Golitsyn Georgy
Published: July 2019

Comparison of forest growth curves has led many to the conclusion that there is a similarity between forest stands growing in different conditions. Here we treat the same subject from the viewpoint of similarity theory. Our goal is to form a dimensionless ratio of biophysical entities that could parameterize the diversity of forest growth curves. (Such ratios are called similarity criteria.) Pursuing this goal, we focus on the analogy between tree crown growth and atomic explosion. A blast wave is formed when the rate of energy release is much higher than the rate of energy dissipation. The difference between the rates of energy release and dissipation is the essence of this phenomenon. The essential feature of crown growth is the difference between the rates of non-structural carbohydrate supply and demand. Since the rate of supply is much higher than the rate of demand, the flow of non-structural carbohydrates achieves the tips of branches and enables the radial growth of crown. Proceeding from these ideas, we derived the similarity criterion which supposedly captures the “essence of growth” that emerges from the geometric similarity of tree crowns.
Food Physical Chemistry and Biophysical Chemistry
Authors: Baianu I.C.
Published: July 2019

Food Physical Chemistry is considered to be a branch of Food Chemistry^1,2^ concerned with the study of both physical and chemical interactions in foods in terms of physical and chemical principles applied to food systems, as well as the applications of physical/chemical techniques and instrumentation for the study of foods^3,4,5,6^. This field encompasses the "physiochemical principles of the reactions and conversions that occur during the manufacture, handling, and storage of foods"^7^. Two rapidly growing, related areas are Food Biotechnology and Food Biophysical Chemistry.
Variability of Mauna Loa melt inclusions
Authors: Armienti Pietro , Gasperini Daniela
Published: July 2019

A major element of variability of olivine melt inclusions in Mauna Loa lavas is here proved to be strictly related to olivine crystallization at inclusion walls, at low pressure and decreasing temperature.In so doing it is probably worth it to interpret trace elements and isotope variability in these olivine trapped liquids as the effect of disequilibrium (isotope) fractionation. In this respect, the accurate analytical work performed by Sobolev et al. (2011) does not document the presence of a heterogeneous source, rather representing a tool to explore poorly documented aspects of magmatic crystallization that are controlled by the kinetics of liquid-solid phase transition.
Trans-Disciplinary Protein Binding Of Drug: Docking Approach
Authors: Ajeet Ajeet
Published: July 2019

The purpose of present work is to introduce the binding of existing drugs to the trans-disciplinary protein with the help of docking procedures. Docking procedures allows virtually screening a database of compounds and predict the strongest binder based on various scoring functions. This work has been performed with the help of Molegro Virtual docker, in which two drugs are docked with their corresponding and non-corresponding (trans-disciplinary) protein. Results reveals that the protein-ligand interaction energy, hydrogen bond energy and MolDock scores provided by molegro virtual docker, between legands (Levodopa and Acyclovir) and trans-disciplinary proteins have been equivalent or even better than that of between legands and corresponding proteins.
Determinative atom model and the nature of chemical bond
Authors: Hu Wanchung
Published: July 2019

Quantum mechanics including Schrodinger and Dirac’s equations are used to describe the atom model. However, the basic assumption assuming electron energy can be described by E=h’w is wrong. If E=h’w, then the total energy of the electron will be E=rmv^2 in contrary to E=rmc^2 from special relativity. Here, I propose a new atom model integrating frame-dragging force, centrifugal force, electrostatic force, and magnetic force. In this new model, the proton group and neutron group in atomic nucleus are rotating in different direction. Thus, they provide equal and opposite frame-dragging force for orbiting electrons. The electrons are orbiting in the equator plane of nucleus. There is no net force or net acceleration for electrons to allow electrons for stable orbiting. 1.Electrostatic force from protons balances centrifugal force. 2. Electrostatic force from paired electron itself balances magnetic force from spinning electrons. 3. No net frame-dragging force from proton group and neutron group. In addition, by using De Brodglie’s matter wave and standing wave concept, we can explain the atomic magic number 2,8,8,18,18,32,32. The electron is basically a particle, but it moves like a wave. By using this atom model, we can explain the chemical structure and the nature of chemical bond formation.
Ultrasonically sculpted virtual relay lens for in situ microimaging
Authors: Scopelliti Matteo Giuseppe , Chamanzar Maysamreza
Published: July 2019

We demonstrate in situ non-invasive relay imaging through a medium without inserting physical optical components. We show that a virtual optical graded-index (GRIN) lens can be sculpted in the medium using in situ reconfigurable ultrasonic interference patterns to relay images through the medium. Ultrasonic wave patterns change the local density of the medium to sculpt a graded refractive index pattern normal to the direction of light propagation, which modulates the phase front of light, causing it to focus within the medium and effectively creating a virtual relay lens. We demonstrate the in situ relay imaging and resolving of small features (22 µm) through a turbid medium (optical thickness = 5.7 times the scattering mean free path), which is normally opaque. The focal distance and the numerical aperture of the sculpted optical GRIN lens can be tuned by changing the ultrasonic wave parameters. As an example, we experimentally demonstrate that the axial focal distance can be continuously scanned over a depth of 5.4 mm in the modulated medium and that the numerical aperture can be tuned up to 21.5%. The interaction of ultrasonic waves and light can be mediated through different physical media, including turbid media, such as biological tissue, in which the ultrasonically sculpted GRIN lens can be used for relaying images of the underlying structures through the turbid medium, thus providing a potential alternative to implanting invasive endoscopes.
Autophagosome accumulation-mediated ATP energy deprivation induced by penfluridol triggers nonapoptotic cell death of lung cancer via activating unfolded protein response
Authors: Hung Wen-Yueh , Chang Jer-Hwa , Cheng Yu , Cheng Guo-Zhou , Huang Hsiang-Ching , Hsiao Michael , Chung Chi-Li , Lee Wei-Jiunn , Chien Ming-Hsien
Published: July 2019

Anticancer chemotherapeutic drugs mainly trigger apoptosis induction to eliminate malignant cells. However, many cancer cells are chemoresistant because of defective apoptosis induction. Targeting the autophagic pathway is currently regarded as an alternative strategy for cancer drug discovery. Penfluridol, an antipsychotic drug, has been reported to exert oncostatic effects, but the effect of penfluridol on lung cancer remains unknown. Herein, the antitumor activity of penfluridol was determined in vitro in non-small-cell lung cancer (NSCLC) cell lines using MTS, plate clonogenic, and transwell migration assays and in vivo in an orthotopic xenograft model. Flow cytometry, holotomographic microscopy, immunofluorescence, and immunohistochemistry were employed to determine the cell-death phenotype induced by penfluridol in vitro and in vivo. Western blotting and genetic knockdown by small interfering RNA were performed to explore the underlying mechanisms involved in penfluridol-mediated cell death. We uncovered that penfluridol inhibited the viability and motility of NSCLC cells in vitro and in vivo. Penfluridol induced nonapoptotic cell death by blocking autophagic flux and inducing accumulation of autophagosome-related protein, light chain 3 (LC3) B-II, in HCC827 and A549 NSCLC cells, and in an A549 orthotopic xenograft tumor model. Autophagosome accumulation-induced cell viability inhibition by penfluridol was mainly attributed to ATP energy deprivation. Moreover, we observed that patients with lung tumors expressing high LC3B had longer overall and disease-free survival times. Mechanistically, upregulation of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways and activation of p38 mitogen-activated protein kinase (MAPK) were critical for penfluridol-induced autophagosome accumulation. Our findings identify that penfluridol acts as an inducer of ER stress and p38 MAPK activation, which led to UPR-mediated nonapoptotic cell death via autophagosome accumulation-caused energy loss. Penfluridol is clinically used for schizophrenia, and our study results strongly support penfluridol as a repurposed drug for treating NSCLC.
STK11 is required for the normal program of ciliated cell differentiation in airways
Authors: Chu Qiqi , Yao Changfu , Qi Xiangbing , Stripp Barry Raymond , Tang Nan
Published: July 2019

The functional properties of mucosal surfaces are dependent on establishing the correct proportions of specialized epithelial cell types. Multiciliated cells (also known as ciliated cells) are evolutionarily conserved and functionally indispensable epithelial cells, as suggested by the link between ciliated cell dysfunction and chronic human disease. Ciliated cell differentiation is an ordered process that involves initial cell fate determination and multiciliogenesis. STK11, a serine/threonine kinase, has been reported to be downregulated in human diseases associated with ciliopathies and functions as a tumor suppressor. Here, we show that STK11 is a physiological factor for the normal program of ciliated cell differentiation by phosphorylating MARK3, which directly suppresses ERK1/2 mediated pRB inactivation. Loss of Stk11 in airway progenitors impairs the differentiation of ciliated cells in both embryonic and adult airways. Our study establishes that STK11/MARK3/ERK1/2 signaling cascade is a key regulator to integrate ciliated cell fate commitment and the subsequent process of multiciliogenesis.
Disentangling conical intersection and coherent molecular dynamics in methyl bromide with attosecond transient absorption spectroscopy
Authors: Timmers Henry , Zhu Xiaolei , Li Zheng , Kobayashi Yuki , Sabbar Mazyar , Hollstein Maximilian , Reduzzi Maurizio , Martínez Todd J. , Neumark Daniel M. , Leone Stephen R.
Published: July 2019

Attosecond probing of core-level electronic transitions provides a sensitive tool for studying valence molecular dynamics with atomic, state, and charge specificity. In this report, we employ attosecond transient absorption spectroscopy to follow the valence dynamics of strong-field initiated processes in methyl bromide. By probing the 3d core-to-valence transition, we resolve the strong field excitation and ensuing fragmentation of the neutral σ* excited states of methyl bromide. The results provide a clear signature of the non-adiabatic passage of the excited state wavepacket through a conical intersection. We additionally observe competing, strong field initiated processes arising in both the ground state and ionized molecule corresponding to vibrational and spin-orbit motion, respectively. The demonstrated ability to resolve simultaneous dynamics with few-femtosecond resolution presents a clear path forward in the implementation of attosecond XUV spectroscopy as a general tool for probing competing and complex molecular phenomena with unmatched temporal resolution.
Zebrafish preserve global germline DNA methylation while sex-linked rDNA is amplified and demethylated during feminisation
Authors: Ortega-Recalde Oscar , Day Robert C. , Gemmell Neil J. , Hore Timothy A.
Published: July 2019

The germline is the only cellular lineage capable of transferring genetic information from one generation to the next. Intergenerational transmission of epigenetic memory through the germline, in the form of DNA methylation, has been proposed; however, in mammals this is largely prevented by extensive epigenetic erasure during germline definition. Here we report that, unlike mammals, the continuously-defined ‘preformed’ germline of zebrafish does not undergo genome-wide erasure of DNA methylation during development. Our analysis also uncovers oocyte-specific germline amplification and demethylation of an 11.5-kb repeat region encoding 45S ribosomal RNA (fem-rDNA). The peak of fem-rDNA amplification coincides with the initial expansion of stage IB oocytes, the poly-nucleolar cell type responsible for zebrafish feminisation. Given that fem-rDNA overlaps with the only zebrafish locus identified thus far as sex-linked, we hypothesise fem-rDNA expansion could be intrinsic to sex determination in this species.
Membrane protein-regulated networks across human cancers
Authors: Lin Chun-Yu , Lee Chia-Hwa , Chuang Yi-Hsuan , Lee Jung-Yu , Chiu Yi-Yuan , Wu Lee Yan-Hwa , Jong Yuh-Jyh , Hwang Jenn-Kang , Huang Sing-Han , Chen Li-Ching , Wu Chih-Hsiung , Tu Shih-Hsin , Ho Yuan-Soon , Yang Jinn-Moon
Published: July 2019

Alterations in membrane proteins (MPs) and their regulated pathways have been established as cancer hallmarks and extensively targeted in clinical applications. However, the analysis of MP-interacting proteins and downstream pathways across human malignancies remains challenging. Here, we present a systematically integrated method to generate a resource of cancer membrane protein-regulated networks (CaMPNets), containing 63,746 high-confidence protein–protein interactions (PPIs) for 1962 MPs, using expression profiles from 5922 tumors with overall survival outcomes across 15 human cancers. Comprehensive analysis of CaMPNets links MP partner communities and regulated pathways to provide MP-based gene sets for identifying prognostic biomarkers and druggable targets. For example, we identify CHRNA9 with 12 PPIs (e.g., ERBB2) can be a therapeutic target and find its anti-metastasis agent, bupropion, for treatment in nicotine-induced breast cancer. This resource is a study to systematically integrate MP interactions, genomics, and clinical outcomes for helping illuminate cancer-wide atlas and prognostic landscapes in tumor homo/heterogeneity.
Non-Abelian gauge field optics
Authors: Chen Yuntian , Zhang Ruo-Yang , Xiong Zhongfei , Hang Zhi Hong , Li Jensen , Shen Jian Qi , Chan C. T.
Published: July 2019

The concept of gauge field is a cornerstone of modern physics and the synthetic gauge field has emerged as a new way to manipulate particles in many disciplines. In optics, several schemes of Abelian synthetic gauge fields have been proposed. Here, we introduce a new platform for realizing synthetic SU(2) non-Abelian gauge fields acting on two-dimensional optical waves in a wide class of anisotropic materials and discover novel phenomena. We show that a virtual non-Abelian Lorentz force arising from material anisotropy can induce light beams to travel along Zitterbewegung trajectories even in homogeneous media. We further design an optical non-Abelian Aharonov–Bohm system which results in the exotic spin density interference effect. We can extract the Wilson loop of an arbitrary closed optical path from a series of gauge fixed points in the interference fringes. Our scheme offers a new route to study SU(2) gauge field related physics using optics.
Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Authors: Argemi Josepmaria , Latasa Maria U. , Atkinson Stephen R. , Blokhin Ilya O. , Massey Veronica , Gue Joel P. , Cabezas Joaquin , Lozano Juan J. , Van Booven Derek , Bell Aaron , Cao Sheng , Vernetti Lawrence A. , Arab Juan P. , Ventura-Cots Meritxell , Edmunds Lia R. , Fondevila Constantino , Stärkel Peter , Dubuquoy Laurent , Louvet Alexandre , Odena Gemma , Gomez Juan L. , Aragon Tomas , Altamirano Jose , Caballeria Juan , Jurczak Michael J. , Taylor D. Lansing , Berasain Carmen , Wahlestedt Claes , Monga Satdarshan P. , Morgan Marsha Y. , Sancho-Bru Pau , Mathurin Philippe , Furuya Shinji , Lackner Carolin , Rusyn Ivan , Shah Vijay H. , Thursz Mark R. , Mann Jelena , Avila Matias A. , Bataller Ramon
Published: July 2019

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
Microinvasion by Streptococcus pneumoniae induces epithelial innate immunity during colonisation at the human mucosal surface
Authors: Weight Caroline M. , Venturini Cristina , Pojar Sherin , Jochems Simon P. , Reiné Jesús , Nikolaou Elissavet , Solórzano Carla , Noursadeghi Mahdad , Brown Jeremy S. , Ferreira Daniela M. , Heyderman Robert S.
Published: July 2019

Control ofStreptococcus pneumoniaecolonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Here, we use an experimental human pneumococcal carriage model (EHPC) to show thatS. pneumoniaecolonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium shaped the host transcriptomic response in vitro. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling and regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. Our results indicate that, rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances inflammatory and innate immune responses associated with clearance.
A zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery
Authors: de Valk Kim S. , Handgraaf Henricus J. , Deken Marion M. , Sibinga Mulder Babs G. , Valentijn Adrianus R. , Terwisscha van Scheltinga Anton G. , Kuil Joeri , van Esdonk Michiel J. , Vuijk Jaap , Bevers Rob F. , Peeters Koen C. , Holman Fabian A. , Frangioni John V. , Burggraaf Jacobus , Vahrmeijer Alexander L.
Published: July 2019

Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.
Programmable graphene nanobubbles with three-fold symmetric pseudo-magnetic fields
Authors: Jia Pengfei , Chen Wenjing , Qiao Jiabin , Zhang Miao , Zheng Xiaohu , Xue Zhongying , Liang Rongda , Tian Chuanshan , He Lin , Di Zengfeng , Wang Xi
Published: July 2019

Graphene nanobubbles (GNBs) have attracted much attention due to the ability to generate large pseudo-magnetic fields unattainable by ordinary laboratory magnets. However, GNBs are always randomly produced by the reported protocols, therefore, their size and location are difficult to manipulate, which restricts their potential applications. Here, using the functional atomic force microscopy (AFM), we demonstrate the ability to form programmable GNBs. The precision of AFM facilitates the location definition of GNBs, and their size and shape are tuned by the stimulus bias of AFM tip. With tuning the tip voltage, the bubble contour can gradually transit from parabolic to Gaussian profile. Moreover, the unique three-fold symmetric pseudo-magnetic field pattern with monotonous regularity, which is only theoretically predicted previously, is directly observed in the GNB with an approximately parabolic profile. Our study may provide an opportunity to study high magnetic field regimes with the designed periodicity in two dimensional materials.
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes
Authors: Singh Mandeep , Al-Eryani Ghamdan , Carswell Shaun , Ferguson James M. , Blackburn James , Barton Kirston , Roden Daniel , Luciani Fabio , Giang Phan Tri , Junankar Simon , Jackson Katherine , Goodnow Christopher C. , Smith Martin A. , Swarbrick Alexander
Published: July 2019

High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly diverse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells sampled from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.
Cerebellar disruption impairs working memory during evidence accumulation
Authors: Deverett Ben , Kislin Mikhail , Tank David W. , Wang Samuel S.-H.
Published: July 2019

To select actions based on sensory evidence, animals must create and manipulate representations of stimulus information in memory. Here we report that during accumulation of somatosensory evidence, optogenetic manipulation of cerebellar Purkinje cells reduces the accuracy of subsequent memory-guided decisions and causes mice to downweight prior information. Behavioral deficits are consistent with the addition of noise and leak to the evidence accumulation process. We conclude that the cerebellum can influence the accurate maintenance of working memory.
Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders
Authors: Shik Mun Kyu , Arora Kavisha , Huang Yunjie , Yang Fanmuyi , Yarlagadda Sunitha , Ramananda Yashaswini , Abu-El-Haija Maisam , Palermo Joseph J. , Appakalai Balamurugan N. , Nathan Jaimie D. , Naren Anjaparavanda P.
Published: July 2019

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.
An electrostatic spectral neighbor analysis potential for lithium nitride
Authors: Deng Zhi , Chen Chi , Li Xiang-Guo , Ong Shyue Ping
Published: July 2019

Machine-learned interatomic potentials based on local environment descriptors represent a transformative leap over traditional potentials based on rigid functional forms in terms of prediction accuracy. However, a challenge in their application to ionic systems is the treatment of long-ranged electrostatics. Here, we present a highly accurate electrostatic Spectral Neighbor Analysis Potential (eSNAP) for ionic α-Li3N, a prototypical lithium superionic conductor of interest as a solid electrolyte or coating for rechargeable lithium-ion batteries. We show that the optimized eSNAP model substantially outperforms traditional Coulomb–Buckingham potential in the prediction of energies and forces, as well as various properties, such as lattice constants, elastic constants, and phonon dispersion curves. We also demonstrate the application of eSNAP in long-time, large-scale Li diffusion studies in Li3N, providing atomistic insights into measures of concerted ionic motion (e.g., the Haven ratio) and grain boundary diffusion. This work aims at providing an approach to developing quantum-accurate force fields for multi-component ionic systems under the SNAP formalism, enabling large-scale atomistic simulations for such systems.
Solvent-Assisted Paper Spray Ionization Mass Spectrometry (SAPSI-MS) for the Analysis of Biomolecules and Biofluids
Authors: Riboni Nicoló , Quaranta Alessandro , Motwani Hitesh V. , Österlund Nicklas , Gräslund Astrid , Bianchi Federica , Ilag Leopold L.
Published: July 2019

Paper Spray Ionization (PSI) is commonly applied for the analysis of small molecules, including drugs, metabolites, and pesticides in biological fluids, due to its high versatility, simplicity, and low costs. In this study, a new setup called Solvent Assisted Paper Spray Ionization (SAPSI), able to increase data acquisition time, signal stability, and repeatability, is proposed to overcome common PSI drawbacks. The setup relies on an integrated solution to provide ionization potential and constant solvent flow to the paper tip. Specifically, the ion source was connected to the instrument fluidics along with the voltage supply systems, ensuring a close control over the ionization conditions. SAPSI was successfully applied for the analysis of different classes of biomolecules: amyloidogenic peptides, proteins, and N-glycans. The prolonged analysis time allowed real-time monitoring of processes taking places on the paper tip, such as amyloid peptides aggregation and disaggregation phenomena. The enhanced signal stability allowed to discriminate protein species characterized by different post translational modifications and adducts with electrophilic compounds, both in aqueous solutions and in biofluids, such as serum and cerebrospinal fluid, without any sample pretreatment. In the next future, application to clinical relevant modifications, could lead to the development of quick and cost-effective diagnostic tools.
Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells
Authors: Becatti Matteo , Bencini Andrea , Nistri Silvia , Conti Luca , Fabbrini Maria Giulia , Lucarini Laura , Ghini Veronica , Severi Mirko , Fiorillo Claudia , Giorgi Claudia , Sorace Lorenzo , Valtancoli Barbara , Bani Daniele
Published: July 2019

Oxidative stress due to excess superoxide anion ($${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$

O

2

⋅

−

) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$

O

2

⋅

−

-scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2 quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2−, where L = Q2 and M2) due to the involvement of quinoline in metal binding and to the hydrophobic features of the ligand which improve metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to hypoxia-reoxygenation. MnQ2 and MnM2 (10 μmol L−1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial $${{\bf{O}}}_{{\bf{2}}}^{{\boldsymbol{\cdot }}{\boldsymbol{-}}}$$

O

2

⋅

−

, decreased cell lipid peroxidation, reduced mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new anti-oxidant drugs.
Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment
Authors: Keller Samantha M. , Doherty Tiffany S. , Roth Tania L.
Published: July 2019

The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. We previously found that female rats with a history of maltreatment during infancy mistreat their own offspring. One proposed mechanism through which early-life experiences influence behavior is via epigenetic modifications. Indeed, our lab has identified a number of brain epigenetic alterations in female rats with a history of maltreatment. Here we sought to investigate the role of DNA methylation in aberrant maternal behavior. We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring. First, we replicate that dams with a history of maltreatment mistreat their own offspring. Second, we show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring. Third, we show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care. Lastly, we show altered methylation and gene expression in maltreated dams normalized by zebularine. These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.
Genome and plasmid diversity of Extended-Spectrum β-Lactamase-producing Escherichia coli ST131 – tracking phylogenetic trajectories with Bayesian inference
Authors: Ny Sofia , Sandegren Linus , Salemi Marco , Giske Christian G.
Published: July 2019

Clonal lineages of ESBL (Extended-Spectrum β-Lactamase)-producing E. coli belonging to sequence type 131 (ST131) have disseminated globally during the last 30 years, leading to an increased prevalence of resistance to fluoroquinolones and extended-spectrum cephalosporins in clinical isolates of E. coli. We aimed to study if Swedish ESBL-producing ST131 isolates originated from single or multiple introductions to the population by assessing the amount of genetic variation, on chromosomal and plasmid level, between Swedish and international E. coli ST131. Bayesian inference of Swedish E. coli ST131 isolates (n = 29), sequenced using PacBio RSII, together with an international ST131 dataset showed that the Swedish isolates were part of the international ST131 A, C1 and C2 clades. Highly conserved plasmids were identified in three clusters although they were separated by several years, which indicates a strong co-evolution between some ST131 lineages and specific plasmids. In conclusion, the tight clonal relationship observed within the ST131 clades, together with highly conserved plasmids, challenges investigation of strain transmission events. A combination of few SNPs on a genome-wide scale and an epidemiological temporospatial link, are needed to track the spread of the ST131 subclones.
IFT88 controls NuMA enrichment at k-fibers minus-ends to facilitate their re-anchoring into mitotic spindles
Authors: Taulet Nicolas , Douanier Audrey , Vitre Benjamin , Anguille Christelle , Maurin Justine , Dromard Yann , Georget Virginie , Delaval Benedicte
Published: July 2019

To build and maintain mitotic spindle architecture, molecular motors exert spatially regulated forces on microtubules (MT) minus-ends. This spatial regulation is required to allow proper chromosomes alignment through the organization of kinetochore fibers (k-fibers). NuMA was recently shown to target dynactin to MT minus-ends and thus to spatially regulate dynein activity. However, given that k-fibers are embedded in the spindle, our understanding of the machinery involved in the targeting of proteins to their minus-ends remains limited. Intraflagellar transport (IFT) proteins were primarily studied for their ciliary roles but they also emerged as key regulators of cell division. Taking advantage of MT laser ablation, we show here that IFT88 concentrates at k-fibers minus-ends and is required for their re-anchoring into spindles by controlling NuMA accumulation. Indeed, IFT88 interacts with NuMA and is required for its enrichment at newly generated k-fibers minus-ends. Combining nocodazole washout experiments and IFT88 depletion, we further show that IFT88 is required for the reorganization of k-fibers into spindles and thus for efficient chromosomes alignment in mitosis. Overall, we propose that IFT88 could serve as a mitotic MT minus-end adaptor to concentrate NuMA at minus-ends thus facilitating k-fibers incorporation into the main spindle.
Transparent non-cubic laser ceramics with fine microstructure
Authors: Furuse Hiroaki , Horiuchi Naohiro , Kim Byung-Nam
Published: July 2019

Transparent polycrystalline ceramics with cubic crystal structure have played important roles in a wide variety of solid-state laser applications, whereas for non-cubic structures, single crystal only has been used. For further progress in optical technologies, effective materials beyond the current limitations are necessary. Here we report a new type of non-cubic ceramic laser material that overturns conventional common sense. It is hexagonal Nd-doped fluorapatite (Nd:FAP) ceramics with an optical quality comparable to single crystal while having random crystal orientation. It is composed of ultrafine grains with a loss coefficient of 0.18 cm−1 at a lasing wavelength of 1063 nm, and its laser oscillation was demonstrated. This is the first verification of lasing in randomly oriented non-cubic ceramics. Laser oscillation in the non-cubic ceramics was realized through both advanced liquid-phase nano-powder synthesis technology and highly controlled pulsed-current sintering techniques. Our findings should open new avenues for future solid-state laser and optical applications.
HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells
Authors: Nishikawa Tatsuya , Kuwano Yuki , Takahara Yumiko , Nishida Kensei , Rokutan Kazuhito
Published: July 2019

The human TRA2B gene consists of 10 exons and 9 introns and produces 5 splice isoforms (TRA2β1 to TRA2β5). TRA2B exon 2 encodes multiple premature termination codons. TRA2β1 lacks exon 2 and is translated into a functional transformer 2β (Tra2β) protein, whereas TRA2β4 contains 10 exons and works as a functional RNA. Overexpressed Tra2β and ectopic expression of TRA2β4 may be oncogenic. We found that heterogeneous nuclear ribonucleoprotein (hnRNP)A1 and hnRNPU interacted with TRA2β4 exon 2. Minigene assays revealed that hnRNPA1 facilitated inclusion of exon 2, whereas hnRNPU promoted its skipping. However, knockdown of hnRNPA1 or hnRNPU reduced both TRA2β1 and TRA2β4 levels, and overexpression of these hnRNPs increased levels of both isoforms, suggesting that hnRNPA1 and hnRNPU mainly regulate the transcription of TRA2B. In fact, hnRNPA1 and hnRNPU positively regulated the promoter activity of TRA2B. Circular dichroism analyses, electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated the presence of G-quadruplex (G4) formation in the promoter of TRA2B. Formation of G4 suppressed TRA2B transcription, whereas hnRNPA1, but not hnRNPU, interacted with the G4 to facilitate transcription. Our results suggest that hnRNPA1 may modulate TRA2B transcription through its regulation of G4 formation in its promoter in colon cancer cells.
Leaf Anatomy and 3-D Structure Mimic to Solar Cells with light trapping and 3-D arrayed submodule for Enhanced Electricity Production
Authors: Yun Min Ju , Sim Yeon Hyang , Cha Seung I. , Lee Dong Yoon
Published: July 2019

Plant leaves are efficient light scavengers. We take a ‘botanical approach’ toward the creation of next-generation photovoltaic cells for urban environments. Our cells exhibit high energy conversion efficiency under indirect weak illumination. We used two features of leaves to improve dye-sensitized solar cells (DSSCs). Leaves feature a cuticle, a covering epidermis, and palisade and spongy cells. Leaves are also carefully arrayed within the plant crown. To mimic these features, we first created a light-trapping layer on top of the solar cells and microscale-patterned the photoanodes. Then we angled the three-dimensional DSSCs to create submodules. These simple mimics afforded a 50% enhancement of simulated daily electricity production. Our new design optimizes light distribution, the photoanode structure, and the DSSC array (by creating modules), greatly improving cell performance.
The association between accelerometer-assessed physical activity and respiratory function in older adults differs between smokers and non-smokers
Authors: Benadjaoud Mohamed Amine , Menai Mehdi , van Hees Vincent T. , Zipunnikov Vadim , Regnaux Jean-Philippe , Kivimäki Mika , Singh-Manoux Archana , Sabia Séverine
Published: July 2019

The association between physical activity and lung function is thought to depend on smoking history but most previous research uses self-reported measures of physical activity. This cross-sectional study investigates whether the association between accelerometer-derived physical activity and lung function in older adults differs by smoking history. The sample comprised 3063 participants (age = 60–83 years) who wore an accelerometer during 9 days and undertook respiratory function tests. Forced vital capacity (FVC) was associated with moderate-to-vigorous physical activity (MVPA; acceleration ≥0.1 g (gravity)) in smokers but not in never smokers: FVC differences for 10 min increase in MVPA were 58.6 (95% Confidence interval: 21.1, 96.1), 27.8 (4.9, 50.7), 16.6 (7.9, 25.4), 2.8 (−5.2, 10.7) ml in current, recent ex-, long-term ex-, and never-smokers, respectively. A similar trend was observed for forced expiratory volume in 1 second. Functional data analysis, a threshold-free approach using the entire accelerometry distribution, showed an association between physical activity and lung function in all smoking groups, with stronger association in current and recent ex-smokers than in long-term ex- and never-smokers; the associations were evident in never smokers only at activity levels above the conventional 0.1 g MVPA threshold. These findings suggest that the association between lung function and physical activity in older adults is more pronounced in smokers than non-smokers.
Hypothalamic and pituitary transcriptome profiling using RNA-sequencing in high-yielding and low-yielding laying hens
Authors: Wang Chunqiang , Ma Wei
Published: July 2019

The reproductive physiology and laying performance of laying hens are regulated by the hypothalamus and pituitary. To understand the mechanism of egg laying regulation, we sequenced and analysed the hypothalamus and pituitary expression profiles in high- and low-yielding laying Chinese Dagu Chickens (CDC) using RNA-seq. More than 46 million clean reads and 24,873 tentative genes were obtained using the Gallus gallus genome as a reference. Transcriptome analysis in hypothalamus and pituitary revealed seven and 39 differentially expressed genes (DEGs) between high- and low-yielding CDC hens, respectively. A total of 24 and 22 DEGs were up-regulated and down-regulated, respectively, and 13 novel genes were identified. Functional annotation and pathway enrichment analysis showed that DEGs in the hypothalamus were mainly enriched in glycosaminoglycan biosynthesis. DEGs significantly enriched in the pituitary primarily affected the extracellular matrix, the protein extracellular matrix, and the extracellular space. Pathways involving phenylalanine metabolism, 2-oxocarboxylic acid metabolism, the glycosphingolipid biosynthesis-ganglion series, and local adhesion were significantly enriched in the pituitary. Eight DEGs, PRDX6, TRIB2, OVCH2, CFD, Peptidase M20, SLC7A10, and two other amino acid transporters, are involved in the metabolism and transport of amino acids. To our knowledge, this is the first study comparing the hypothalamus and pituitary transcriptomes of high- and low-yielding laying hens. Our findings suggest that putative differences in gene expression can provide a base for further research in this field. Moreover, we identified increased expression of genes involved in amino acid metabolism, glycosaminoglycan biosynthesis, and oestrogen negative feedback systems in low-yielding laying hens, highlighting their potential as biomarkers of egg production.