bluuebunny/crossref_metadata_2025 huggingface dataset:
Holocene Interactions Between Glacier Retreat, Sea Ice Formation, and Atlantic Water Advection at the Inner Northeast Greenland Continental Shelf
Authors: Syring Nicole , Lloyd Jeremy M. , Stein Ruediger , Fahl Kirsten , Roberts Dave H. , Callard Louise , O'Cofaigh Colm
Published: October 2020

During the past four decades significant decrease in Arctic sea ice and a dramatic ice mass loss of the Greenland Ice Sheet (GIS) has been coincident with global warming and an increase in atmospheric CO2. In Northeast Greenland significant mass loss from the outlet glaciers Nioghalvfjerdsbræ (79NG) and Zachariæ Isstrøm (ZI) and intensive seasonal breakup of the local Norske Øer Ice Barrier (NØIB) have also been observed since 2000. In order to better understand the processes driving these modern changes, studies of paleoclimate records are important and of major societal relevance. A multiproxy study including organic‐biogeochemical and micropaleontological proxies was carried out on a marine sediment core recovered directly in front of 79NG. Data from Core PS100/270 evidenced a strong inflow of warm recirculating Atlantic Water across the Northeast Greenland shelf from the early Holocene between ~10 and 7.5 ka. An overall high in phytoplankton productivity occurred within a stable sea ice margin regime, accompanied by 79NG retreat most probably triggered by peak solar insolation and changes in the local ocean circulation. Enhanced basal melt of the underside of 79NG at ~7.5 ka then led to the total disintegration of the ice shelf. The released freshwater would have driven water column stratification and promoted the formation of the local landfast ice barrier, which is shown by lowered biomarker values and foraminifera abundances toward the end of the early Holocene. Near perennial sea ice conditions with short summers and 79NG retreat to the inner fjord then prevailed from ~7.5 to ~0.8 ka.
Relationships between nitrogen cycling microbial community abundance and composition reveal the indirect effect of soil pH on oak decline
Authors: Scarlett K , Denman S , Clark D R , Forster J , Vanguelova E , Brown N , Whitby C
Published: October 2020

Tree decline is a global concern and the primary cause is often unknown. Complex interactions between fluctuations in nitrogen (N) and acidifying compounds have been proposed as factors causing nutrient imbalances and decreasing stress tolerance of oak trees. Microorganisms are crucial in regulating soil N available to plants, yet little is known about the relationships between soil N-cycling and tree health. Here, we combined high-throughput sequencing and qPCR analysis of key nitrification and denitrification genes with soil chemical analyses to characterise ammonia-oxidising bacteria (AOB), archaea (AOA) and denitrifying communities in soils associated with symptomatic (declining) and asymptomatic (apparently healthy) oak trees (Quercus robur and Q. petraea) in the United Kingdom. Asymptomatic trees were associated with a higher abundance of AOB that is driven positively by soil pH. No relationship was found between AOA abundance and tree health. However, AOA abundance was driven by lower concentrations of NH4+, further supporting the idea of AOA favouring lower soil NH4+ concentrations. Denitrifier abundance was influenced primarily by soil C:N ratio, and correlations with AOB regardless of tree health. These findings indicate that amelioration of soil acidification by balancing C:N may affect AOB abundance driving N transformations, reducing stress on declining oak trees.
BioID-based proteomic analysis of the Bid interactome identifies novel proteins involved in cell-cycle-dependent apoptotic priming
Authors: Pedley Robert , King Louise E. , Mallikarjun Venkatesh , Wang Pengbo , Swift Joe , Brennan Keith , Gilmore Andrew P.
Published: October 2020

Apoptotic priming controls the commitment of cells to apoptosis by determining how close they lie to mitochondrial permeabilisation. Variations in priming are important for how both healthy and cancer cells respond to chemotherapeutic agents, but how it is dynamically coordinated by Bcl-2 proteins remains unclear. The Bcl-2 family protein Bid is phosphorylated when cells enter mitosis, increasing apoptotic priming and sensitivity to antimitotic drugs. Here, we report an unbiased proximity biotinylation (BioID) screen to identify regulators of apoptotic priming in mitosis, using Bid as bait. The screen primarily identified proteins outside of the canonical Bid interactome. Specifically, we found that voltage-dependent anion-selective channel protein 2 (VDAC2) was required for Bid phosphorylation-dependent changes in apoptotic priming during mitosis. These results highlight the importance of the wider Bcl-2 family interactome in regulating the temporal control of apoptotic priming.
Metastable alloying structures in MAPbI3−xClx crystals
Authors: Qiao Wen-Cheng , Yang Jianming , Dong Wei , Yang Guang , Bao Qinye , Huang Rong , Wang Xue Lu , Yao Ye-Feng
Published: October 2020

Chlorine incorporation engineering has been widely used in optoelectronic devices based on methylammonium lead iodide (MAPbI3) perovskites. However, the characteristics of I/Cl alloying structures in MAPbI3−xClx mixed-halide perovskites and their influences on the optoelectronic properties have been issues of a long-standing controversy. Here, we present a detailed study of the I/Cl alloying structures in MAPbI3−xClx (x = 0.0 to 0.3) single crystals. We found that a small amount of Cl can substitute for the iodide of the PbI3 inorganic lattice, leading to a phase transition from the tetragonal to cubic phase and anomalous cation dynamics evolution. Analyses based on time-dependent X-ray diffraction, 207Pb NMR, and 2H NMR indicate that the alloying structures of the MAPbI3−xClx crystals are metastable and decompose over time. In addition, the photocurrent response measurement of MAPbI3−xClx proved a close correlation between the alloying structures and photoelectric properties of the material. This work sheds light on the essential understanding of the I/Cl alloying structure and provides a plausible explanation for the controversy regarding the role of chloride ions in optoelectronic devices.
Orbital climate variability on the northeastern Tibetan Plateau across the Eocene–Oligocene transition
Authors: Ao Hong , Dupont-Nivet Guillaume , Rohling Eelco J. , Zhang Peng , Ladant Jean-Baptiste , Roberts Andrew P. , Licht Alexis , Liu Qingsong , Liu Zhonghui , Dekkers Mark J. , Coxall Helen K. , Jin Zhangdong , Huang Chunju , Xiao Guoqiao , Poulsen Christopher J. , Barbolini Natasha , Meijer Niels , Sun Qiang , Qiang Xiaoke , Yao Jiao , An Zhisheng
Published: October 2020

The first major build-up of Antarctic glaciation occurred in two consecutive stages across the Eocene–Oligocene transition (EOT): the EOT-1 cooling event at ~34.1–33.9 Ma and the Oi-1 glaciation event at ~33.8–33.6 Ma. Detailed orbital-scale terrestrial environmental responses to these events remain poorly known. Here we present magnetic and geochemical climate records from the northeastern Tibetan Plateau margin that are dated precisely from ~35.5 to 31 Ma by combined magneto- and astro-chronology. These records suggest a hydroclimate transition at ~33.7 Ma from eccentricity dominated cycles to oscillations paced by a combination of eccentricity, obliquity, and precession, and confirm that major Asian aridification and cooling occurred at Oi-1. We conclude that this terrestrial orbital response transition coincided with a similar transition in the marine benthic δ18O record for global ice volume and deep-sea temperature variations. The dramatic reorganization of the Asian climate system coincident with Oi-1 was, thus, a response to coeval atmospheric CO2 decline and continental-scale Antarctic glaciation.
DIALib-QC an assessment tool for spectral libraries in data-independent acquisition proteomics
Authors: Midha Mukul K. , Campbell David S. , Kapil Charu , Kusebauch Ulrike , Hoopmann Michael R. , Bader Samuel L. , Moritz Robert L.
Published: October 2020

Data-independent acquisition (DIA) mass spectrometry, also known as Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH), is a popular label-free proteomics strategy to comprehensively quantify peptides/proteins utilizing mass spectral libraries to decipher inherently multiplexed spectra collected linearly across a mass range. Although there are many spectral libraries produced worldwide, the quality control of these libraries is lacking. We present the DIALib-QC (DIA library quality control) software tool for the systematic evaluation of a library’s characteristics, completeness and correctness across 62 parameters of compliance, and further provide the option to improve its quality. We demonstrate its utility in assessing and repairing spectral libraries for correctness, accuracy and sensitivity.
The protein translation machinery is expressed for maximal efficiency in Escherichia coli
Authors: Hu Xiao-Pan , Dourado Hugo , Schubert Peter , Lercher Martin J.
Published: October 2020

Protein synthesis is the most expensive process in fast-growing bacteria. Experimentally observed growth rate dependencies of the translation machinery form the basis of powerful phenomenological growth laws; however, a quantitative theory on the basis of biochemical and biophysical constraints is lacking. Here, we show that the growth rate-dependence of the concentrations of ribosomes, tRNAs, mRNA, and elongation factors observed in Escherichia coli can be predicted accurately from a minimization of cellular costs in a mechanistic model of protein translation. The model is constrained only by the physicochemical properties of the molecules and has no adjustable parameters. The costs of individual components (made of protein and RNA parts) can be approximated through molecular masses, which correlate strongly with alternative cost measures such as the molecules’ carbon content or the requirement of energy or enzymes for their biosynthesis. Analogous cost minimization approaches may facilitate similar quantitative insights also for other cellular subsystems.
Reversible multicolor chromism in layered formamidinium metal halide perovskites
Authors: Rosales Bryan A. , Mundt Laura E. , Allen Taylor G. , Moore David T. , Prince Kevin J. , Wolden Colin A. , Rumbles Garry , Schelhas Laura T. , Wheeler Lance M.
Published: October 2020

Metal halide perovskites feature crystalline-like electronic band structures and liquid-like physical properties. The crystal–liquid duality enables optoelectronic devices with unprecedented performance and a unique opportunity to chemically manipulate the structure with low energy input. In this work, we leverage the low formation energy of metal halide perovskites to demonstrate multicolor reversible chromism. We synthesized layered Ruddlesden-Popper FAn+1PbnX3n+1(FA = formamidinium, X = I, Br;n = number of layers = 1, 2, 3 … ∞) and reversibly tune the dimensionality (n) by modulating the strength and number of H-bonds in the system. H-bonding was controlled by exposure to solvent vapor (solvatochromism) or temperature change (thermochromism), which shuttles FAX salt pairs between the FAn+1PbnX3n+1domains and adjacent FAX “reservoir” domains. Unlike traditional chromic materials that only offer a single-color transition, FAn+1PbnX3n+1films reversibly switch between multiple colors including yellow, orange, red, brown, and white/colorless. Each colored phase exhibits distinct optoelectronic properties characteristic of 2D superlattice materials with tunable quantum well thickness.
Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6
Authors: Liu Wallace H. , Zheng Jie , Feldman Jessica L. , Klein Mark A. , Kuznetsov Vyacheslav I. , Peterson Craig L. , Griffin Patrick R. , Denu John M.
Published: October 2020

The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding at the higher affinity site through recognition of nucleosomal DNA. Together, multivalent interactions couple productive binding to efficient deacetylation of histones on endogenous chromatin. Unique among histone deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with nucleosomes for efficient activity.
Analysis of protein-DNA interactions in chromatin by UV induced cross-linking and mass spectrometry
Authors: Stützer Alexandra , Welp Luisa M. , Raabe Monika , Sachsenberg Timo , Kappert Christin , Wulf Alexander , Lau Andy M. , David Stefan-Sebastian , Chernev Aleksandar , Kramer Katharina , Politis Argyris , Kohlbacher Oliver , Fischle Wolfgang , Urlaub Henning
Published: October 2020

Protein–DNA interactions are key to the functionality and stability of the genome. Identification and mapping of protein–DNA interaction interfaces and sites is crucial for understanding DNA-dependent processes. Here, we present a workflow that allows mass spectrometric (MS) identification of proteins in direct contact with DNA in reconstituted and native chromatin after cross-linking by ultraviolet (UV) light. Our approach enables the determination of contact interfaces at amino-acid level. With the example of chromatin-associated protein SCML2 we show that our technique allows differentiation of nucleosome-binding interfaces in distinct states. By UV cross-linking of isolated nuclei we determined the cross-linking sites of several factors including chromatin-modifying enzymes, demonstrating that our workflow is not restricted to reconstituted materials. As our approach can distinguish between protein–RNA and DNA interactions in one single experiment, we project that it will be possible to obtain insights into chromatin and its regulation in the future.
Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ
Authors: Yu Wei , Lescale Chloé , Babin Loelia , Bedora-Faure Marie , Lenden-Hasse Hélène , Baron Ludivine , Demangel Caroline , Yelamos José , Brunet Erika , Deriano Ludovic
Published: October 2020

The alternative non-homologous end-joining (NHEJ) pathway promotes DNA double-strand break (DSB) repair in cells deficient for NHEJ or homologous recombination, suggesting that it operates at all stages of the cell cycle. Here, we use an approach in which DNA breaks can be induced in G1 cells and their repair tracked, enabling us to show that joining of DSBs is not functional in G1-arrested XRCC4-deficient cells. Cell cycle entry into S-G2/M restores DSB repair by Pol θ-dependent and PARP1-independent alternative NHEJ with repair products bearing kilo-base long DNA end resection, micro-homologies and chromosome translocations. We identify a synthetic lethal interaction between XRCC4 and Pol θ under conditions of G1 DSBs, associated with accumulation of unresolved DNA ends in S-G2/M. Collectively, our results support the conclusion that the repair of G1 DSBs progressing to S-G2/M by alternative NHEJ drives genomic instability and represent an attractive target for future DNA repair-based cancer therapies.
Structural basis for two metal-ion catalysis of DNA cleavage by Cas12i2
Authors: Huang Xue , Sun Wei , Cheng Zhi , Chen Minxuan , Li Xueyan , Wang Jiuyu , Sheng Gang , Gong Weimin , Wang Yanli
Published: October 2020

To understand how the RuvC catalytic domain of Class 2 Cas proteins cleaves DNA, it will be necessary to elucidate the structures of RuvC-containing Cas complexes in their catalytically competent states. Cas12i2 is a Class 2 type V-I CRISPR-Cas endonuclease that cleaves target dsDNA by an unknown mechanism. Here, we report structures of Cas12i2–crRNA–DNA complexes and a Cas12i2–crRNA complex. We reveal the mechanism of DNA recognition and cleavage by Cas12i2, and activation of the RuvC catalytic pocket induced by a conformational change of the Helical-II domain. The seed region (nucleotides 1–8) is dispensable for RuvC activation, but the duplex of the central spacer (nucleotides 9–15) is required. We captured the catalytic state of Cas12i2, with both metal ions and the ssDNA substrate bound in the RuvC catalytic pocket. Together, our studies provide significant insights into the DNA cleavage mechanism by RuvC-containing Cas proteins.
Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19
Authors: Carissimo Guillaume , Xu Weili , Kwok Immanuel , Abdad Mohammad Yazid , Chan Yi-Hao , Fong Siew-Wai , Puan Kia Joo , Lee Cheryl Yi-Pin , Yeo Nicholas Kim-Wah , Amrun Siti Naqiah , Chee Rhonda Sin-Ling , How Wilson , Chan Stephrene , Fan Bingwen Eugene , Andiappan Anand Kumar , Lee Bernett , Rötzschke Olaf , Young Barnaby Edward , Leo Yee-Sin , Lye David Chien , Renia Laurent , Ng Lai Guan , Larbi Anis , Ng Lisa FP
Published: October 2020

SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.
Quantum chemical accuracy from density functional approximations via machine learning
Authors: Bogojeski Mihail , Vogt-Maranto Leslie , Tuckerman Mark E. , Müller Klaus-Robert , Burke Kieron
Published: October 2020

Kohn-Sham density functional theory (DFT) is a standard tool in most branches of chemistry, but accuracies for many molecules are limited to 2-3 kcal ⋅ mol−1 with presently-available functionals. Ab initio methods, such as coupled-cluster, routinely produce much higher accuracy, but computational costs limit their application to small molecules. In this paper, we leverage machine learning to calculate coupled-cluster energies from DFT densities, reaching quantum chemical accuracy (errors below 1 kcal ⋅ mol−1) on test data. Moreover, density-based Δ-learning (learning only the correction to a standard DFT calculation, termed Δ-DFT ) significantly reduces the amount of training data required, particularly when molecular symmetries are included. The robustness of Δ-DFT  is highlighted by correcting “on the fly” DFT-based molecular dynamics (MD) simulations of resorcinol (C6H4(OH)2) to obtain MD trajectories with coupled-cluster accuracy. We conclude, therefore, that Δ-DFT  facilitates running gas-phase MD simulations with quantum chemical accuracy, even for strained geometries and conformer changes where standard DFT fails.
Xenon iron oxides predicted as potential Xe hosts in Earth’s lower mantle
Authors: Peng Feng , Song Xianqi , Liu Chang , Li Quan , Miao Maosheng , Chen Changfeng , Ma Yanming
Published: October 2020

An enduring geological mystery concerns the missing xenon problem, referring to the abnormally low concentration of xenon compared to other noble gases in Earth’s atmosphere. Identifying mantle minerals that can capture and stabilize xenon has been a great challenge in materials physics and xenon chemistry. Here, using an advanced crystal structure search algorithm in conjunction with first-principles calculations we find reactions of xenon with recently discovered iron peroxide FeO2, forming robust xenon-iron oxides Xe2FeO2and XeFe3O6with significant Xe-O bonding in a wide range of pressure-temperature conditions corresponding to vast regions in Earth’s lower mantle. Calculated mass density and sound velocities validate Xe-Fe oxides as viable lower-mantle constituents. Meanwhile, Fe oxides do not react with Kr, Ar and Ne. It means that if Xe exists in the lower mantle at the same pressures as FeO2, xenon-iron oxides are predicted as potential Xe hosts in Earth’s lower mantle and could provide the repository for the atmosphere’s missing Xe. These findings establish robust materials basis, formation mechanism, and geological viability of these Xe-Fe oxides, which advance fundamental knowledge for understanding xenon chemistry and physics mechanisms for the possible deep-Earth Xe reservoir.
Non-invasive decision support for NSCLC treatment using PET/CT radiomics
Authors: Mu Wei , Jiang Lei , Zhang JianYuan , Shi Yu , Gray Jhanelle E. , Tunali Ilke , Gao Chao , Sun Yingying , Tian Jie , Zhao Xinming , Sun Xilin , Gillies Robert J. , Schabath Matthew B.
Published: October 2020

Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments.
Author Correction: The Seminavis robusta genome provides insights into the evolutionary adaptations of benthic diatoms
Authors: Osuna-Cruz Cristina Maria , Bilcke Gust , Vancaester Emmelien , De Decker Sam , Bones Atle M. , Winge Per , Poulsen Nicole , Bulankova Petra , Verhelst Bram , Audoor Sien , Belisova Darja , Pargana Aikaterini , Russo Monia , Stock Frederike , Cirri Emilio , Brembu Tore , Pohnert Georg , Piganeau Gwenael , Ferrante Maria Immacolata , Mock Thomas , Sterck Lieven , Sabbe Koen , De Veylder Lieven , Vyverman Wim , Vandepoele Klaas
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Tactile to visual number priming in the left intraparietal cortex of sighted Braille readers
Authors: Rączy Katarzyna , Czarnecka Maria , Paplińska Małgorzata , Hesselmann Guido , Knops André , Szwed Marcin
Published: October 2020

Numbers can be presented in different notations and sensory modalities. It is currently debated to what extent these formats overlap onto a single representation. We asked whether such an overlap exists between symbolic numbers represented in two sensory modalities: Arabic digits and Braille numbers. A unique group of sighted Braille readers underwent extensive Braille reading training and was tested in an fMRI repetition-suppression paradigm with tactile Braille digit primes and visual Arabic digit targets. Our results reveal cross-modal priming: compared to repetition of two different quantities (e.g., Braille “5” and Arabic “2”), repetition of the same quantity presented in two modalities (e.g., Braille “5” and Arabic “5”) led to a reduction of activation in several sub-regions of the Intraparietal Sulcus (IPS), a key cortical region for magnitude processing. Thus, in sighted Braille readers, the representations of numbers read by sight and by touch overlap to a degree sufficient to cause repetition suppression. This effect was modulated by the numerical prime-probe distance. Altogether this indicates that the left parietal cortex hosts neural assemblies that are sensitive to numerical information from different notations (number words or Arabic digits) and modalities (tactile and visual).
Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival
Authors: Denner Joachim , Längin Matthias , Reichart Bruno , Krüger Luise , Fiebig Uwe , Mokelke Maren , Radan Julia , Mayr Tanja , Milusev Anastasia , Luther Fabian , Sorvillo Nicoletta , Rieben Robert , Brenner Paolo , Walz Christoph , Wolf Eckhard , Roshani Berit , Stahl-Hennig Christiane , Abicht Jan-Michael
Published: October 2020

Xenotransplantation using pig organs has achieved survival times up to 195 days in pig orthotopic heart transplantation into baboons. Here we demonstrate that in addition to an improved immunosuppressive regimen, non-ischaemic preservation with continuous perfusion and control of post-transplantation growth of the transplant, prevention of transmission of the porcine cytomegalovirus (PCMV) plays an important role in achieving long survival times. For the first time we demonstrate that PCMV transmission in orthotopic pig heart xenotransplantation was associated with a reduced survival time of the transplant and increased levels of IL-6 and TNFα were found in the transplanted baboon. Furthermore, high levels of tPA-PAI-1 complexes were found, suggesting a complete loss of the pro-fibrinolytic properties of the endothelial cells. These data show that PCMV has an important impact on transplant survival and call for elimination of PCMV from donor pigs.
Analytical determination of theoretic quantities for multiple potential
Authors: Onate C. A. , Onyeaju M. C. , Abolarinwa A. , Lukman A. F.
Published: October 2020

The approximate analytical solutions of the three-dimensional radial Schrödinger wave equation with a multiple potential function has been studied using a suitable approximation scheme to the centrifugal term in the framework of parametric Nikiforov–Uvarov method. The energy equation and the wave function were obtained. The calculated wave function was used to study Shannon entropy and variance via expectation values. The behaviour of Shannon entropy and variance respectively with the equilibrium bond length were examined in detail. A special case of the multiple potential (pseudoharmonic-like potential) was equally examined under Shannon entropy and variance. For further application of the study, some diatomic molecules were examined under variance and Shannon entropy. Finally, some variance inequalities were derived using Cramer-Rao uncertainty relation and these were justified by numerical results.
Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics
Authors: Rashid Md Mamunur , Lee Hyunbeom , Jung Byung Hwa
Published: October 2020

PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various cancer types. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. After 3 weeks of PP242 treatment, a reduction in tumor size and weight was observed without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, in this study, it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. This study reveals new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further to facilitate the understanding of PP242 effects in the clinical application.
BRCA1 and BRCA2 genes mutations among high risk breast cancer patients in Jordan
Authors: Abu-Helalah Munir , Azab Belal , Mubaidin Rasmi , Ali Dema , Jafar Hanan , Alshraideh Hussam , Drou Nizar , Awidi Abdalla
Published: October 2020

Familial breast cancer is estimated to account for 15–20% of all cases of breast cancer. Surveillance for familial breast cancer is well-established world-wide. However, this service does not exist in Jordan, due to the scarcity of information with regard to the genetic profiling of these patients, and therefore lack of recommendations for policy-makers. As such, patients with very strong family history of breast or ovarian cancers are not screened routinely; leading to preventable delay in diagnosis. Whole coding sequencing forBCRA1/BCRA2using next-generation sequencing (NGS)/Ion PGM System was performed. Sanger sequencing were then used to confirm the pathogenic variants detected by NGS. In this study, 192 breast cancer patients (and 8 ovarian cancer cases) were included. The prevalence of recurrent pathogenic mutations was 14.5%, while the prevalence of newly detected mutations was 3.5%. Two novel pathogenic mutations were identified inBRCA2genes. The common mutations in the Ashkenazi population used for screening may not apply in the Jordanian population, as previously reported mutations were not prevalent, and other new mutations were identified. These data will aid to establish a specific screening test forBRCA 1/BRCA2in the Jordanian population.
Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats
Authors: Subramanian Madhan , Edwards Laura , Melton Avery , Branen Lyndee , Herron Angela , Sivasubramanian Mahesh Kumar , Monteiro Raisa , Stansbury Samantha , Balasubramanian Priya , Morris Lynsie , Elkholey Khaled , Niewiadomska Monika , Stavrakis Stavros
Published: October 2020

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.
Recruitment of parvalbumin and somatostatin interneuron inputs to adult born dentate granule neurons
Authors: Remmers Christine L. , Castillon Charlotte C. M. , Armstrong John N. , Contractor Anis
Published: October 2020

GABA is a key regulator of adult-born dentate granule cell (abDGC) maturation so mapping the functional connectivity between abDGCs and local interneurons is required to understand their development and integration into the hippocampal circuit. We recorded from birthdated abDGCs in mice and photoactivated parvalbumin (PV) and somatostatin (SST) interneurons to map the timing and strength of inputs to abDGCs during the first 4 weeks after differentiation. abDGCs received input from PV interneurons in the first week, but SST inputs were not detected until the second week. Analysis of desynchronized quantal events established that the number of GABAergic synapses onto abDGCs increased with maturation, whereas individual synaptic strength was constant. Voluntary wheel running in mice scaled the GABAergic input to abDGCs by increasing the number of synaptic contacts from both interneuron types. This demonstrates that GABAergic innervation to abDGCs develops during a prolonged post-mitotic period and running scales both SST and PV synaptic afferents.
A computer vision approach to improving cattle digestive health by the monitoring of faecal samples
Authors: Atkinson Gary A. , Smith Lyndon N. , Smith Melvyn L. , Reynolds Christopher K. , Humphries David J. , Moorby Jon M. , Leemans David K. , Kingston-Smith Alison H.
Published: October 2020

The digestive health of cows is one of the primary factors that determine their well-being and productivity. Under- and over-feeding are both commonplace in the beef and dairy industry; leading to welfare issues, negative environmental impacts, and economic losses. Unfortunately, digestive health is difficult for farmers to routinely monitor in large farms due to many factors including the need to transport faecal samples to a laboratory for compositional analysis. This paper describes a novel means for monitoring digestive health via a low-cost and easy to use imaging device based on computer vision. The method involves the rapid capture of multiple visible and near-infrared images of faecal samples. A novel three-dimensional analysis algorithm is then applied to objectively score the condition of the sample based on its geometrical features. While there is no universal ground truth for comparison of results, the order of scores matched a qualitative human prediction very closely. The algorithm is also able to detect the presence of undigested fibres and corn kernels using a deep learning approach. Detection rates for corn and fibre in image regions were of the order 90%. These results indicate the potential to develop this system for on-farm, real time monitoring of the digestive health of individual animals, allowing early intervention to effectively adjust feeding strategy.
Classification of aortic stenosis using conventional machine learning and deep learning methods based on multi-dimensional cardio-mechanical signals
Authors: Yang Chenxi , Ojha Banish D. , Aranoff Nicole D. , Green Philip , Tavassolian Negar
Published: October 2020

This paper introduces a study on the classification of aortic stenosis (AS) based on cardio-mechanical signals collected using non-invasive wearable inertial sensors. Measurements were taken from 21 AS patients and 13 non-AS subjects. A feature analysis framework utilizing Elastic Net was implemented to reduce the features generated by continuous wavelet transform (CWT). Performance comparisons were conducted among several machine learning (ML) algorithms, including decision tree, random forest, multi-layer perceptron neural network, and extreme gradient boosting. In addition, a two-dimensional convolutional neural network (2D-CNN) was developed using the CWT coefficients as images. The 2D-CNN was made with a custom-built architecture and a CNN based on Mobile Net via transfer learning. After the reduction of features by 95.47%, the results obtained report 0.87 on accuracy by decision tree, 0.96 by random forest, 0.91 by simple neural network, and 0.95 by XGBoost. Via the 2D-CNN framework, the transfer learning of Mobile Net shows an accuracy of 0.91, while the custom-constructed classifier reveals an accuracy of 0.89. Our results validate the effectiveness of the feature selection and classification framework. They also show a promising potential for the implementation of deep learning tools on the classification of AS.
Structure-based design and discovery of novel anti-tissue factor antibodies with cooperative double-point mutations, using interaction analysis
Authors: Chiba Shuntaro , Tanabe Aki , Nakakido Makoto , Okuno Yasushi , Tsumoto Kouhei , Ohta Masateru
Published: October 2020

The generation of a wide range of candidate antibodies is important for the successful development of drugs that simultaneously satisfy multiple requirements. To find cooperative mutations and increase the diversity of mutants, an in silico double-point mutation approach, in which 3D models of all possible double-point mutant/antigen complexes are constructed and evaluated using interaction analysis, was developed. Starting from an antibody with very high affinity, four double-point mutants were designed in silico. Two of the double-point mutants exhibited improved affinity or affinity comparable to that of the starting antibody. The successful identification of two active double-point mutants showed that a cooperative mutation could be found by utilizing information regarding the interactions. The individual single-point mutants of the two active double-point mutants showed decreased affinity or no expression. These results suggested that the two active double-point mutants cannot be obtained through the usual approach i.e. a combination of improved single-point mutants. In addition, a triple-point mutant, which combines the distantly located active double-point mutation and an active single-point mutation collaterally obtained in the process of the double-point mutation strategy, was designed. The triple-point mutant showed improved affinity. This finding suggested that the effects of distantly located mutations are independent and additive. The double-point mutation approach using the interaction analysis of 3D structures expands the design repertoire for mutants, and hopefully paves a way for the identification of cooperative multiple-point mutations.
SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β cells
Authors: Hu Li , He Fengli , Huang Meifeng , Zhao Qian , Cheng Lamei , Said Neveen , Zhou Zhiguang , Liu Feng , Dai Yan-Shan
Published: October 2020

SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we showed that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of β-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc −/− mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in the islets from sparc −/− mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M-stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic β cells.
Multiscale fluorescent tracking of immune cells in the liver with a highly biocompatible far-red emitting polymer probe
Authors: Daniel Malo , Dubreil Laurence , Fleurisson Romain , Judor Jean-Paul , Bresson Timothée , Brouard Sophie , Favier Arnaud , Charreyre Marie-Thérèse , Conchon Sophie
Published: October 2020

The development of innovative immune cell therapies relies on efficient cell tracking strategies. For this, multiscale fluorescence-based analyses of transferred cells into the host with complementary techniques, including flow cytometry for high-throughput cell analysis and two-photon microscopy for deep tissue imaging would be highly beneficial. Ideally, cells should be labelled with a single fluorescent probe combining all the properties required for these different techniques. Due to the intrinsic autofluorescence of most tissues and especially the liver, far-red emission is also an important asset. However, the development of far-red emitting probes suitable for two-photon microscopy and compatible with clearing methods to track labelled immune cells in thick samples, remains challenging. A newly-designed water-soluble far-red emitting polymer probe, 19K-6H, with a large Stokes shift, was thus evaluated for the tracking of primary immune CD8 T cells. These cells, prepared from mouse spleen, were efficiently labelled with the 19K-6H probe, which was internalized via endocytosis and was highly biocompatible at concentrations up to 20 μM. Labelled primary CD8 T cells were detectable in culture by both confocal and two-photon microscopy as well as flow cytometry, even after 3 days of active proliferation. Finally, 19K-6H-labelled primary CD8 T cells were injected to mice in a classical model of immune mediated hepatitis. The efficient tracking of the transferred cells in the liver by flow cytometry (on purified non-parenchymal cells) and by two-photon microscopy on 800 μm thick cleared sections, demonstrated the versatility of the 19K-6H probe.
Association between mortality and serum uric acid levels in non-diabetes-related chronic kidney disease: An analysis of the National Health and Nutrition Examination Survey, USA, 1999–2010
Authors: Lee Chia-Lin , Tsai Shang-Feng
Published: October 2020

The relationship between serum uric acid (SUA) and cardiovascular (CV) mortality in patients with chronic kidney disease (CKD) has been described as either a J- or U-shaped function. However, its effect in non-diabetic CKD (and varying severities of CKD) remains unclear. We analyzed the database of the National Health and Nutrition Examination Survey, USA, from the years 1999 to 2010. We then grouped the subjects into 4 categories according to their SUA levels: (a) < 5 mg/dl, (b) 5–7 mg/dl, (c) 7–9 mg/dl and (d) ≥ 9 mg/dl. For mortality comparison purposes (CV related, cancer related and all-cause mortality), we set the SUA group of 5–7 mg/dl as the reference. We also separated this population into moderate (stage 3) and severe (stages 4 and 5) CKD. A total of 1860 participants were included in this study. Results showed that the group with the lowest SUA levels (< 5 mg/dl), were the least male gender (19.25%), had the lowest body mass index (26.41(95% CI = 25.66–27.16) kg/m2), highest systolic blood pressure (139.02 (95% CI 135.72–142.32) mmHg), highest high-density cholesterol (59.55 (95% CI 57.37–61.74) mg/dl), lowest blood glucose (95.46 (95% CI 93.16–97.76) mg/dl), highest total cholesterol (210.31 (95% CI 203.36–217.25) mg/dl), lowest serum albumin (4.09 (95% CI 4.04–4.14) g/dl), highest estimated glomerular filtration rate (eGFR) (47.91 (95% CI 45.45–50.49) ml/min/1.732m2), least history of hypertension (54.4%), and least total energy intake (1643.7 (95% CI 1536.13–1751.27) kcal/day). In the group with SUA ≥ 9 mg/dl, patients had higher all-cause mortality (HR = 2.15) whatever their baseline CVD status. In non-DM CKD patients with a CVD history, the group with SUA ≥ 9 mg/dl had the highest all-cause mortality (HR = 5.39), CVD mortality (HR = 8.18) and CVD or cancer (HR = 8.25) related mortality. In non-DM patients with severe CKD (eGFR < 30 ml/min/1.732m2), the group with SUA < 5 had a significantly increased all-cause mortality. On the contrary, in non-DM patients with moderate CKD (eGFR = 30–60 ml/min/1.832m2), the group with SUA ≥ 9 had a significantly increased all-cause mortality. In moderate non-DM CKD, SUA ≥ 9 mg/dl is associated with higher all-cause mortality. However, once progressing to severe non-DM CKD, SUA < 5 mg/dl is associated with higher all-cause mortality (even though it has the least risk factors for metabolic syndrome).
Study of vitamin D status and vitamin D receptor polymorphisms in a cohort of Italian patients with juvenile idiopathic arthritis
Authors: Marini Francesca , Falcini Fernanda , Stagi Stefano , Fabbri Sergio , Ciuffi Simone , Rigante Donato , Cerinic Marco Matucci , Brandi Maria Luisa
Published: October 2020

Juvenile idiopathic arthritis (JIA) is the most common chronic arthritis of children and adolescents. Autoimmune mechanisms are suspected to have a central role in its development. Vitamin D is an immuno-modulator in a variety of conditions, including autoimmune diseases. Low levels of vitamin D have commonly been found in JIA patients, but the influence of this hormone insufficiency in JIA pathogenesis is still unclear. Vitamin D receptor (VDR) mediates a great majority of vitamin D biological activities; specific polymorphisms of the VDR gene have been associated with different biologic responses to vitamin D. In this study, we analysed clinical characteristics of a cohort of 103 Italian JIA patients. The distribution of VDR polymorphisms in affected patients versus healthy controls was evaluated, as well as if and how these polymorphic variants associate with different disease presentations (active disease vs non-active disease), different JIA subtypes, serum levels of 25-hydroxy-vitamin D and parathyroid hormone (PTH), and lumbar spine Z-score values (osteopenia vs normal bone mineral density). A great majority of our JIA patients (84.5%) showed a suboptimal vitamin D status, in many cases (84.1%) not solved by vitamin D supplementation. Vitamin D status resulted to be independent of VDR genotypes. ApaI genotypes showed a highly significant different distribution between JIA patients and unaffected controls, with both the TT genotype and the T allele significantly more frequent in patient group.
Endogenous hydrogen sulfide maintains eupnea in an in situ arterially perfused preparation of rats
Authors: Okazaki Minako , Uozu Saori , Sato Yuma , Matsumoto Masayuki , Koganezawa Tadachika
Published: October 2020

Hydrogen sulfide (H2S) is constitutively generated in the human body and works as a gasotransmitter in synaptic transmission. In this study, we aimed to evaluate the roles of endogenous H2S in generating eupnea at the respiratory center. We employed an in situ arterially perfused preparation of decerebrated rats and recorded the central respiratory outputs. When the H2S-producing enzyme cystathionine β-synthase (CBS) was inhibited, respiration switched from the 3-phase eupneic pattern, which consists of inspiration, postinspiration, and expiration, to gasping-like respiration, which consists of inspiration only. On the other hand, when H2S synthesis was inhibited via cystathionine γ-lyase (CSE) or when H2S synthesis was activated via CBS, eupnea remained unchanged. These results suggest that H2S produced by CBS has crucial roles in maintaining the neuronal network to generate eupnea. The mechanism of respiratory pattern generation might be switched from a network-based system to a pacemaker cell-based system in low H2S conditions.