bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins
Authors: Dharuman Suresh , Wilt Laura A. , Liu Jiuyu , Reeve Stephanie M. , Thompson Carl W. , Elmore John M. , Shcherbakov Dimitri , Lee Robin B. , Böttger Erik C. , Lee Richard E.
Published: January 2021

Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, the effects of deoxygenation of the 2- and 6-hydroxy group positions on the spectinomycin actinamine ring are probed to evaluate their relationship to ribosomal binding and the antimicrobial activities of spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), and spectinamides. To generate these analogs, an improved synthesis of 6-deoxyspectinomycin was developed using the Barton deoxygenation reaction. 6-Dehydrospectinamide was also synthesized from spectinamide 4 to evaluate the H-bond acceptor character on the C-6 position. All the synthesized analogs were tested for antibacterial activity against a panel of Gram (+) and Gram (−) pathogens, plus Mycobacterium tuberculosis. The molecular contribution of the 2- and 6-hydroxy group and the aryl functionalities of all analogs were examined by measuring inhibition of ribosomal translation and molecular dynamics experiments with MM/GBSA analysis. The results of this work indicate that the 6-hydroxy group, which is the primary target of AMEs, is a required motif for antimicrobial activity in current analogs. Removal of the 6-hydroxy group could be partially rescued by offsetting ribosomal binding contributions made by the aryl side chains found in the spectinamide and amSPCs. This study builds on the knowledge of the structure–activity relationships of spectinomycin analogs and is being used to aid the design of next-generation spectinomycins.
A CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis
Authors: McKinney Eoin F. , Cuthbertson Iona , Harris Kristina M. , Smilek Dawn E. , Connor Christopher , Manferrari Giulia , Carr Edward J. , Zamvil Scott S. , Smith Kenneth G. C.
Published: January 2021

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with the majority of cases characterised by relapsing/remitting (RRMS) attacks of neurologic dysfunction followed by variable resolution. Improving clinical outcomes in RRMS requires both a better understanding of the immunological mechanisms driving recurrent demyelination and better means of predicting future disease course to facilitate early targeted therapy. Here, we apply hypothesis-generating network transcriptomics to CD8+ cells isolated from patients in RRMS, identifying a signature reflecting expansion of a subset of CD8+ natural killer cells (NK8+) associated with favourable outcome. NK8+ are capable of regulating CD4+ T cell activation and proliferation in vitro, with reduced expression of HLA-G binding inhibitory receptors and consequent reduced sensitivity to HLA-G-mediated suppression. We identify surrogate markers of the NK8+ signature in peripheral blood leucocytes and validate their association with clinical outcome in an independent cohort, suggesting their measurement may facilitate early, targeted therapy in RRMS.
Structures of the archaerhodopsin-3 transporter reveal that disordering of internal water networks underpins receptor sensitization
Authors: Bada Juarez Juan F. , Judge Peter J. , Adam Suliman , Axford Danny , Vinals Javier , Birch James , Kwan Tristan O. C. , Hoi Kin Kuan , Yen Hsin-Yung , Vial Anthony , Milhiet Pierre-Emmanuel , Robinson Carol V. , Schapiro Igor , Moraes Isabel , Watts Anthony
Published: January 2021

Many transmembrane receptors have a desensitized state, in which they are unable to respond to external stimuli. The family of microbial rhodopsin proteins includes one such group of receptors, whose inactive or dark-adapted (DA) state is established in the prolonged absence of light. Here, we present high-resolution crystal structures of the ground (light-adapted) and DA states of Archaerhodopsin-3 (AR3), solved to 1.1 Å and 1.3 Å resolution respectively. We observe significant differences between the two states in the dynamics of water molecules that are coupled via H-bonds to the retinal Schiff Base. Supporting QM/MM calculations reveal how the DA state permits a thermodynamic equilibrium between retinal isomers to be established, and how this same change is prevented in the ground state in the absence of light. We suggest that the different arrangement of internal water networks in AR3 is responsible for the faster photocycle kinetics compared to homologs.
Integrating deep learning CT-scan model, biological and clinical variables to predict severity of COVID-19 patients
Authors: Lassau Nathalie , Ammari Samy , Chouzenoux Emilie , Gortais Hugo , Herent Paul , Devilder Matthieu , Soliman Samer , Meyrignac Olivier , Talabard Marie-Pauline , Lamarque Jean-Philippe , Dubois Remy , Loiseau Nicolas , Trichelair Paul , Bendjebbar Etienne , Garcia Gabriel , Balleyguier Corinne , Merad Mansouria , Stoclin Annabelle , Jegou Simon , Griscelli Franck , Tetelboum Nicolas , Li Yingping , Verma Sagar , Terris Matthieu , Dardouri Tasnim , Gupta Kavya , Neacsu Ana , Chemouni Frank , Sefta Meriem , Jehanno Paul , Bousaid Imad , Boursin Yannick , Planchet Emmanuel , Azoulay Mikael , Dachary Jocelyn , Brulport Fabien , Gonzalez Adrian , Dehaene Olivier , Schiratti Jean-Baptiste , Schutte Kathryn , Pesquet Jean-Christophe , Talbot Hugues , Pronier Elodie , Wainrib Gilles , Clozel Thomas , Barlesi Fabrice , Bellin Marie-France , Blum Michael G. B.
Published: January 2021

The SARS-COV-2 pandemic has put pressure on intensive care units, so that identifying predictors of disease severity is a priority. We collect 58 clinical and biological variables, and chest CT scan data, from 1003 coronavirus-infected patients from two French hospitals. We train a deep learning model based on CT scans to predict severity. We then construct the multimodal AI-severity score that includes 5 clinical and biological variables (age, sex, oxygenation, urea, platelet) in addition to the deep learning model. We show that neural network analysis of CT-scans brings unique prognosis information, although it is correlated with other markers of severity (oxygenation, LDH, and CRP) explaining the measurable but limited 0.03 increase of AUC obtained when adding CT-scan information to clinical variables. Here, we show that when comparing AI-severity with 11 existing severity scores, we find significantly improved prognosis performance; AI-severity can therefore rapidly become a reference scoring approach.
Homodyne-based quantum random number generator at 2.9 Gbps secure against quantum side-information
Authors: Gehring Tobias , Lupo Cosmo , Kordts Arne , Solar Nikolic Dino , Jain Nitin , Rydberg Tobias , Pedersen Thomas B. , Pirandola Stefano , Andersen Ulrik L.
Published: January 2021

Quantum random number generators promise perfectly unpredictable random numbers. A popular approach to quantum random number generation is homodyne measurements of the vacuum state, the ground state of the electro-magnetic field. Here we experimentally implement such a quantum random number generator, and derive a security proof that considers quantum side-information instead of classical side-information only. Based on the assumptions of Gaussianity and stationarity of noise processes, our security analysis furthermore includes correlations between consecutive measurement outcomes due to finite detection bandwidth, as well as analog-to-digital converter imperfections. We characterize our experimental realization by bounding measured parameters of the stochastic model determining the min-entropy of the system’s measurement outcomes, and we demonstrate a real-time generation rate of 2.9 Gbit/s. Our generator follows a trusted, device-dependent, approach. By treating side-information quantum mechanically an important restriction on adversaries is removed, which usually was reserved to semi-device-independent and device-independent schemes.
Particle-resolved topological defects of smectic colloidal liquid crystals in extreme confinement
Authors: Wittmann René , Cortes Louis B. G. , Löwen Hartmut , Aarts Dirk G. A. L.
Published: January 2021

Confined samples of liquid crystals are characterized by a variety of topological defects and can be exposed to external constraints such as extreme confinements with nontrivial topology. Here we explore the intrinsic structure of smectic colloidal layers dictated by the interplay between entropy and an imposed external topology. Considering an annular confinement as a basic example, a plethora of competing states is found with nontrivial defect structures ranging from laminar states to multiple smectic domains and arrays of edge dislocations, which we refer to as Shubnikov states in formal analogy to the characteristic of type-II superconductors. Our particle-resolved results, gained by a combination of real-space microscopy of thermal colloidal rods and fundamental-measure-based density functional theory of hard anisotropic bodies, agree on a quantitative level.
Treadmilling FtsZ polymers drive the directional movement of sPG-synthesis enzymes via a Brownian ratchet mechanism
Authors: McCausland Joshua W. , Yang Xinxing , Squyres Georgia R. , Lyu Zhixin , Bruce Kevin E. , Lamanna Melissa M. , Söderström Bill , Garner Ethan C. , Winkler Malcolm E. , Xiao Jie , Liu Jian
Published: January 2021

The FtsZ protein is a central component of the bacterial cell division machinery. It polymerizes at mid-cell and recruits more than 30 proteins to assemble into a macromolecular complex to direct cell wall constriction. FtsZ polymers exhibit treadmilling dynamics, driving the processive movement of enzymes that synthesize septal peptidoglycan (sPG). Here, we combine theoretical modelling with single-molecule imaging of live bacterial cells to show that FtsZ’s treadmilling drives the directional movement of sPG enzymes via a Brownian ratchet mechanism. The processivity of the directional movement depends on the binding potential between FtsZ and the sPG enzyme, and on a balance between the enzyme’s diffusion and FtsZ’s treadmilling speed. We propose that this interplay may provide a mechanism to control the spatiotemporal distribution of active sPG enzymes, explaining the distinct roles of FtsZ treadmilling in modulating cell wall constriction rate observed in different bacteria.
Shedding light on the nature of the catalytically active species in photocatalytic reactions using Bi2O3 semiconductor
Authors: Riente Paola , Fianchini Mauro , Llanes Patricia , Pericàs Miquel A. , Noël Timothy
Published: January 2021

The importance of discovering the true catalytically active species involved in photocatalytic systems allows for a better and more general understanding of photocatalytic processes, which eventually may help to improve their efficiency. Bi2O3 has been used as a heterogeneous photocatalyst and is able to catalyze several synthetically important visible-light-driven organic transformations. However, insight into the operative catalyst involved in the photocatalytic process is hitherto missing. Herein, we show through a combination of theoretical and experimental studies that the perceived heterogeneous photocatalysis with Bi2O3 in the presence of alkyl bromides involves a homogeneous BinBrm species, which is the true photocatalyst operative in the reaction. Hence, Bi2O3 can be regarded as a precatalyst which is slowly converted in an active homogeneous photocatalyst. This work can also be of importance to mechanistic studies involving other semiconductor-based photocatalytic processes.
Lead-free hybrid perovskite N(CH3)4SnI3 with robust ferroelectricity induced by large and non-polar N(CH3)4+ molecular cation
Authors: Wei Hai , Yang Yali , Chen Shiyou , Xiang H. J.
Published: January 2021

The ferroelectricity in the hybrid perovskite CH3NH3PbI3 is under debate because it results from the polar molecular cation CH3NH3+ while the molecular orientation was reported to be random. Here we predict that a Pb-free hybrid perovskite N(CH3)4SnI3 with non-polar molecular cation N(CH3)4+ has strong ferroelectricity with a spontaneous polarization of 16.13 μC cm−2. The large polarization results from the distortion of SnI6 octahedron induced by the large N(CH3)4+ and is independent of the molecular orientation, so the ferroelectricity is robust. The ferroelectric R3m perovskite structure of N(CH3)4SnI3 can be synthesized as the ground state under a hydrostatic pressure over 3 GPa and remains stable under ambient pressure. Given the strong ferroelectricity, good stability and high visible-light absorption, N(CH3)4SnI3 may be an ideal light-absorber semiconductor for high-efficiency solar cells because its ferroelectric polarization can facilitate electron-hole separation and produce large bulk photovoltaic effect, making the design of homogeneous bulk photovoltaic devices possible.
The molecular dynamics of subdistal appendages in multi-ciliated cells
Authors: Ryu Hyunchul , Lee Haeryung , Lee Jiyeon , Noh Hyuna , Shin Miram , Kumar Vijay , Hong Sejeong , Kim Jaebong , Park Soochul
Published: January 2021

The motile cilia of ependymal cells coordinate their beats to facilitate a forceful and directed flow of cerebrospinal fluid (CSF). Each cilium originates from a basal body with a basal foot protruding from one side. A uniform alignment of these basal feet is crucial for the coordination of ciliary beating. The process by which the basal foot originates from subdistal appendages of the basal body, however, is unresolved. Here, we show FGFR1 Oncogene Partner (FOP) is a useful marker for delineating the transformation of a circular, unpolarized subdistal appendage into a polarized structure with a basal foot. Ankyrin repeat and SAM domain-containing protein 1A (ANKS1A) interacts with FOP to assemble region I of the basal foot. Importantly, disruption of ANKS1A reduces the size of region I. This produces an unstable basal foot, which disrupts rotational polarity and the coordinated beating of cilia in young adult mice. ANKS1A deficiency also leads to severe degeneration of the basal foot in aged mice and the detachment of cilia from their basal bodies. This role of ANKS1A in the polarization of the basal foot is evolutionarily conserved in vertebrates. Thus, ANKS1A regulates FOP to build and maintain the polarity of subdistal appendages.
A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice
Authors: Li Ting , Chen Xianjun , Qian Yajie , Shao Jiawei , Li Xie , Liu Shuning , Zhu Linyong , Zhao Yuzheng , Ye Haifeng , Yang Yi
Published: January 2021

Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in stress response, signaling and development. Despite the fascinating discoveries made in the past few years, the mechanisms and functional capabilities of most pulsing systems remain unclear, and one of the critical challenges is the lack of a technology that allows pulsatile regulation of transgene expression both in vitro and in vivo. Here, we describe the development of a synthetic BRET-based transgene expression (LuminON) system based on a luminescent transcription factor, termed luminGAVPO, by fusing NanoLuc luciferase to the light-switchable transcription factor GAVPO. luminGAVPO allows pulsatile and quantitative activation of transgene expression via both chemogenetic and optogenetic approaches in mammalian cells and mice. Both the pulse amplitude and duration of transgene expression are highly tunable via adjustment of the amount of furimazine. We further demonstrated LuminON-mediated blood-glucose homeostasis in type 1 diabetic mice. We believe that the BRET-based LuminON system with the pulsatile dynamics of transgene expression provides a highly sensitive tool for precise manipulation in biological systems that has strong potential for application in diverse basic biological studies and gene- and cell-based precision therapies in the future.
Shadow enhanced self-charging power system for wave and solar energy harvesting from the ocean
Authors: Zhang Qian , Liang Qijie , Nandakumar Dilip Krishna , Qu Hao , Shi Qiongfeng , Alzakia Fuad Indra , Tay Darrell Jun Jie , Yang Lin , Zhang Xueping , Suresh Lakshmi , Lee Chengkuo , Wee Andrew Thye Shen , Tan Swee Ching
Published: January 2021

Hybrid energy-harvesting systems that capture both wave and solar energy from the oceans using triboelectric nanogenerators and photovoltaic cells are promising renewable energy solutions. However, ubiquitous shadows cast from moving objects in these systems are undesirable as they degrade the performance of the photovoltaic cells. Here we report a shadow-tribo-effect nanogenerator that hybrids tribo-effect and shadow-effect together to overcome this issue. Several fiber-supercapacitors are integrated with the shadow-tribo-effect nanogenerator to form a self-charging power system. To capture and store wave/solar energy from oceans, an energy ball based on the self-charging power system is demonstrated. By harnessing the shadow-effect, i.e. the shadow of the moving object in the energy ball, the charging time shortens to 253.3 s to charge the fiber-supercapacitors to the same voltage (0.3 V) as using pure tribo-effect. This cost-effective method to harvest and store the wave/solar energy from the oceans in this work is expected to inspire next-generation large-scale blue energy harvesting.
Subtraction-free and bisulfite-free specific sequencing of 5-methylcytosine and its oxidized derivatives at base resolution
Authors: Liu Yibin , Hu Zhiyuan , Cheng Jingfei , Siejka-Zielińska Paulina , Chen Jinfeng , Inoue Masato , Ahmed Ahmed Ashour , Song Chun-Xiao
Published: January 2021

Although various methods have been developed for sequencing cytosine modifications, it is still challenging for specific and quantitative sequencing of individual modification at base-resolution. For example, to obtain both true 5-methylcytosine (5mC) and true 5-hydroxymethylcytosine (5hmC) information, the two major epigenetic modifications, it usually requires subtraction of two methods, which increases noise and requires high sequencing depth. Recently, we developed TET-assisted pyridine borane sequencing (TAPS) for bisulfite-free direct sequencing of 5mC and 5hmC. Here we demonstrate that two sister methods, TAPSβ and chemical-assisted pyridine borane sequencing (CAPS), can be effectively used for subtraction-free and specific whole-genome sequencing of 5mC and 5hmC, respectively. We also demonstrate pyridine borane sequencing (PS) for whole-genome profiling of 5-formylcytosine and 5-carboxylcytosine, the further oxidized derivatives of 5mC and 5hmC. This work completes the set of versatile borane reduction chemistry-based methods as a comprehensive toolkit for direct and quantitative sequencing of all four cytosine epigenetic modifications.
Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis
Authors: Watson Avia , Li Hao , Ma Bingting , Weiss Ronen , Bendayan Daniele , Abramovitz Lilach , Ben-Shalom Noam , Mor Michael , Pinko Erica , Bar Oz Michal , Wang Zhenqi , Du Fengjiao , Lu Yu , Rybniker Jan , Dahan Rony , Huang Hairong , Barkan Daniel , Xiang Ye , Javid Babak , Freund Natalia T.
Published: January 2021

Mycobacterium tuberculosis(Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduceMycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1 Å and 2.4 Å resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.
Mechano-responsive hydrogen-bonding array of thermoplastic polyurethane elastomer captures both strength and self-healing
Authors: Eom Youngho , Kim Seon-Mi , Lee Minkyung , Jeon Hyeonyeol , Park Jaeduk , Lee Eun Seong , Hwang Sung Yeon , Park Jeyoung , Oh Dongyeop X.
Published: January 2021

Self-repairable materials strive to emulate curable and resilient biological tissue; however, their performance is currently insufficient for commercialization purposes because mending and toughening are mutually exclusive. Herein, we report a carbonate-type thermoplastic polyurethane elastomer that self-heals at 35 °C and exhibits a tensile strength of 43 MPa; this elastomer is as strong as the soles used in footwear. Distinctively, it has abundant carbonyl groups in soft-segments and is fully amorphous with negligible phase separation due to poor hard-segment stacking. It operates in dual mechano-responsive mode through a reversible disorder-to-order transition of its hydrogen-bonding array; it heals when static and toughens when dynamic. In static mode, non-crystalline hard segments promote the dynamic exchange of disordered carbonyl hydrogen-bonds for self-healing. The amorphous phase forms stiff crystals when stretched through a transition that orders inter-chain hydrogen bonding. The phase and strain fully return to the pre-stressed state after release to repeat the healing process.
Thermodynamic resources in continuous-variable quantum systems
Authors: Narasimhachar Varun , Assad Syed , Binder Felix C. , Thompson Jayne , Yadin Benjamin , Gu Mile
Published: January 2021

Thermodynamic resources, beyond their well-known usefulness in work extraction and other thermodynamic tasks, are often important also in tasks that are not evidently thermodynamic. Here we develop a framework for identifying such resources in diverse applications of bosonic continuous-variable systems. Introducing the class of bosonic linear thermal operations to model operationally feasible processes, we apply this model to identify uniquely quantum properties of bosonic states that refine classical notions of thermodynamic resourcefulness. Among these are (1) a suite of temperature-like quantities generalizing the equilibrium temperature to quantum, non-equilibrium scenarios; (2) signal-to-noise ratios quantifying a system’s capacity to carry information in phase-space displacement; and (3) well-established non-classicality measures quantifying the resolution in sensing and parameter estimation tasks.
LimeMap: a comprehensive map of lipid mediator metabolic pathways
Authors: Nishi Akinori , Ohbuchi Katsuya , Kaifuchi Noriko , Shimobori Chika , Kushida Hirotaka , Yamamoto Masahiro , Kita Yoshihiro , Tokuoka Suzumi M. , Yachie Ayako , Matsuoka Yukiko , Kitano Hiroaki
Published: January 2021

Lipid mediators are major factors in multiple biological functions and are strongly associated with disease. Recent lipidomics approaches have made it possible to analyze multiple metabolites and the associations of individual lipid mediators. Such systematic approaches have enabled us to identify key changes of biological relevance. Against this background, a knowledge-based pathway map of lipid mediators would be useful to visualize and understand the overall interactions of these factors. Here, we have built a precise map of lipid mediator metabolic pathways (LimeMap) to visualize the comprehensive profiles of lipid mediators that change dynamically in various disorders. We constructed the map by focusing on ω-3 and ω-6 fatty acid metabolites and their respective metabolic pathways, with manual curation of referenced information from public databases and relevant studies. Ultimately, LimeMap comprises 282 factors (222 mediators, and 60 enzymes, receptors, and ion channels) and 279 reactions derived from 102 related studies. Users will be able to modify the map and visualize measured data specific to their purposes using CellDesigner and VANTED software. We expect that LimeMap will contribute to elucidating the comprehensive functional relationships and pathways of lipid mediators.
High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures
Authors: Franzosa Jill A. , Bonzo Jessica A. , Jack John , Baker Nancy C. , Kothiya Parth , Witek Rafal P. , Hurban Patrick , Siferd Stephen , Hester Susan , Shah Imran , Ferguson Stephen S. , Houck Keith A. , Wambaugh John F.
Published: January 2021

The ToxCast in vitro screening program has provided concentration-response bioactivity data across more than a thousand assay endpoints for thousands of chemicals found in our environment and commerce. However, most ToxCast screening assays have evaluated individual biological targets in cancer cell lines lacking integrated physiological functionality (such as receptor signaling, metabolism). We evaluated differentiated HepaRGTMcells, a human liver-derived cell model understood to effectively model physiologically relevant hepatic signaling. Expression of 93 gene transcripts was measured by quantitative polymerase chain reaction using Fluidigm 96.96 dynamic arrays in response to 1060 chemicals tested in eight-point concentration-response. A Bayesian framework quantitatively modeled chemical-induced changes in gene expression via six transcription factors including: aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, androgen receptor, and peroxisome proliferator-activated receptor alpha. For these chemicals the network model translates transcriptomic data into Bayesian inferences about molecular targets known to activate toxicological adverse outcome pathways. These data also provide new insights into the molecular signaling network of HepaRGTMcell cultures.
Measuring the α-particle charge radius with muonic helium-4 ions
Authors: Krauth Julian J. , Schuhmann Karsten , Ahmed Marwan Abdou , Amaro Fernando D. , Amaro Pedro , Biraben François , Chen Tzu-Ling , Covita Daniel S. , Dax Andreas J. , Diepold Marc , Fernandes Luis M. P. , Franke Beatrice , Galtier Sandrine , Gouvea Andrea L. , Götzfried Johannes , Graf Thomas , Hänsch Theodor W. , Hartmann Jens , Hildebrandt Malte , Indelicato Paul , Julien Lucile , Kirch Klaus , Knecht Andreas , Liu Yi-Wei , Machado Jorge , Monteiro Cristina M. B. , Mulhauser Françoise , Naar Boris , Nebel Tobias , Nez François , dos Santos Joaquim M. F. , Santos José Paulo , Szabo Csilla I. , Taqqu David , Veloso João F. C. A. , Vogelsang Jan , Voss Andreas , Weichelt Birgit , Pohl Randolf , Antognini Aldo , Kottmann Franz
Published: January 2021

The energy levels of hydrogen-like atomic systems can be calculated with great precision. Starting from their quantum mechanical solution, they have been refined over the years to include the electron spin, the relativistic and quantum field effects, and tiny energy shifts related to the complex structure of the nucleus. These energy shifts caused by the nuclear structure are vastly magnified in hydrogen-like systems formed by a negative muon and a nucleus, so spectroscopy of these muonic ions can be used to investigate the nuclear structure with high precision. Here we present the measurement of two 2S–2P transitions in the muonic helium-4 ion that yields a precise determination of the root-mean-square charge radius of the α particle of 1.67824(83) femtometres. This determination from atomic spectroscopy is in excellent agreement with the value from electron scattering1, but a factor of 4.8 more precise, providing a benchmark for few-nucleon theories, lattice quantum chromodynamics and electron scattering. This agreement also constrains several beyond-standard-model theories proposed to explain the proton-radius puzzle2–5, in line with recent determinations of the proton charge radius6–9, and establishes spectroscopy of light muonic atoms and ions as a precise tool for studies of nuclear properties.
HD-EEG for tracking sub-second brain dynamics during cognitive tasks
Authors: Mheich A. , Dufor O. , Yassine S. , Kabbara A. , Biraben A. , Wendling F. , Hassan M.
Published: January 2021

This work provides the community with high-density Electroencephalography (HD-EEG, 256 channels) datasets collected during task-free and task-related paradigms. It includes forty-three healthy participants performing visual naming and spelling tasks, visual and auditory naming tasks and a visual working memory task in addition to resting state. The HD-EEG data are furnished in the Brain Imaging Data Structure (BIDS) format. These datasets can be used to (i) track brain networks dynamics and their rapid reconfigurations at sub-second time scale in different conditions, (naming/spelling/rest) and modalities, (auditory/visual) and compare them to each other, (ii) validate several parameters involved in the methods used to estimate cortical brain networks through scalp EEG, such as the open question of optimal number of channels and number of regions of interest and (iii) allow the reproducibility of results obtained so far using HD-EEG. We hope that delivering these datasets will lead to the development of new methods that can be used to estimate brain cortical networks and to better understand the general functioning of the brain during rest and task. Data are freely available from https://openneuro.org.
Phylogenetic analyses of distantly related clades of bent-toed geckos (genus Cyrtodactylus) reveal an unprecedented amount of cryptic diversity in northern and western Thailand
Authors: Chomdej Siriwadee , Pradit Waranee , Suwannapoom Chatmongkon , Pawangkhanant Parinya , Nganvongpanit Korakot , Poyarkov Nikolay A. , Che Jing , Gao Yangchun , Gong Shiping
Published: January 2021

Cyrtodactylus species are the most diverse of the geckos and are widely distributed in Southeast Asia, including Thailand. However, their patterns of distribution, especially in northern and western parts of Thailand, remain unknown because few Cyrtodactylus species in these regions have been described. Thus, a data set of mitochondrial NADH dehydrogenase 2 (ND2) gene and flanking tRNAs from Cyrtodactylus found in northern and western Thailand, including contiguous areas, was assembled to elucidate phylogenetic relationships and identify the distribution patterns of these geckos. The results showed four well-supported clades, a northwestern clade (A), a northern clade (B), a western clade (C), and a special clade characterized by specific morphological features (D). Clades A–C were grouped with strong support by the geography of their localities from northern Thailand (Mae Hong Son and Chiang Mai Provinces) along the Tenasserim mountain ranges to Phang-Nga Province, Thailand. Clade D is a distinct clade of Cyrtodactylus species characterized by a tuberculate and prehensile tail and distributed widely in mainland Southeast Asia. Overall, the results suggest a pattern of geographic separation and distribution of Cyrtodactylus in northern and western Thailand. Additionally, this study provides evidence of a hidden biodiversity of Cyrtodactylus in these regions.
Cell properties assessment using optimized dielectrophoresis-based cell stretching and lumped mechanical modeling
Authors: Hosseini Imman I. , Moghimi Zand Mahdi , Ebadi Amir Ali , Fathipour Morteza
Published: January 2021

Cells mechanical property assessment has been a promising label-free method for cell differentiation. Several methods have been proposed for single-cell mechanical properties analysis. Dielectrophoresis (DEP) is one method used for single-cell mechanical property assessment, cell separation, and sorting. DEP method has overcome weaknesses of other techniques, including compatibility with microfluidics, high throughput assessment, and high accuracy. However, due to the lack of a general and explicit model for this method, it has not been known as an ideal cell mechanical property evaluation method. Here we present an explicit model using the most general electromagnetic equation (Maxwell Stress Tensor) for single-cell mechanical evaluation based on the DEP method. For proof of concept, we used the proposed model for differentiation between three different types of cells, namely erythrocytes, peripheral blood mononuclear cells (PBMC), and an epithelial breast cancer cells line (T-47D). The results show that, by a lumped parameter that depends on cells' mechanical and electrical properties, the proposed model can successfully distinguish between the mentioned cell types that can be in a single blood sample. The proposed model would open up the chance to use a mechanical assessment method for cell searching in parallel with other methods.
Cytotoxic Escherichia coli strains encoding colibactin, cytotoxic necrotizing factor, and cytolethal distending toxin colonize laboratory common marmosets (Callithrix jacchus)
Authors: McCoy Colleen S. , Mannion Anthony J. , Feng Yan , Madden Carolyn M. , Artim Stephen C. , Au Gina G. , Dolan Mikayla , Haupt Jennifer L. , Burns Monika A. , Sheh Alexander , Fox James G.
Published: January 2021

Cyclomodulins are virulence factors that modulate cellular differentiation, apoptosis, and proliferation. These include colibactin (pks), cytotoxic necrotizing factor (cnf), and cytolethal distending toxin (cdt). Pathogenic pks+, cnf+, and cdt+ E. coli strains are associated with inflammatory bowel disease (IBD) and colorectal cancer in humans and animals. Captive marmosets are frequently afflicted with IBD-like disease, and its association with cyclomodulins is unknown. Cyclomodulin-encoding E. coli rectal isolates were characterized using PCR-based assays in healthy and clinically affected marmosets originating from three different captive sources. 139 E. coli isolates were cultured from 122 of 143 marmosets. The pks gene was detected in 56 isolates (40%), cnf in 47 isolates (34%), and cdt in 1 isolate (0.7%). The prevalences of pks+ and cnf+ E. coli isolates were significantly different between the three marmoset colonies. 98% of cyclomodulin-positive E. coli belonged to phylogenetic group B2. Representative isolates demonstrated cyclomodulin cytotoxicity, and serotyping and whole genome sequencing were consistent with pathogenic E. coli strains. However, the presence of pks+, cnf+, or cdt+ E. coli did not correlate with clinical gastrointestinal disease in marmosets. Cyclomodulin-encoding E. coli colonize laboratory common marmosets in a manner dependent on the source, potentially impacting reproducibility in marmoset models.
Welwitschia: Phylogeography of a living fossil, diversified within a desert refuge
Authors: Jürgens Norbert , Oncken Imke , Oldeland Jens , Gunter Felicitas , Rudolph Barbara
Published: January 2021

Welwitschia mirabilisis one of the most extraordinary plant species on earth. With a fossil record of 112 My and phylogenetically isolated within the order Gnetales, the monotypic genusWelwitschiahas survived only in the northern Namib Desert in Angola and Namibia. Despite its iconic role, the biogeography, ecological niche, and evolutionary history of the species remain poorly understood. Here we present the first comprehensive map of the strongly disjunct species range, and we explore the genetic relationships among all range fragments based on six SSR markers. We also assess the variation of the environmental niche and habitat preference. Our results confirm genetic divergence, which is consistent with the hypothetical existence of two subspecies withinWelwitschia. We identify an efficient geographical barrier separating two gene pools at 18.7°S in northern Namibia. We also identify further diversification within each of the two subspecies, with several different gene pools in ten isolated range fragments. Given the presence of well-isolated populations with unique gene pools and the association with different bioclimatic variables, rock types, and habitats within arid river catchments, we can hypothesize that the present intraspecific diversity may have evolved at least in part within the present refuge of the northern Namib Desert.
Evolving determinants of carotid atherosclerosis vulnerability in asymptomatic patients from the MAGNETIC observational study
Authors: Catalano Oronzo , Bendotti Giulia , Mori Alessia , De Salvo Maria , Falconi Marialuisa , Aloi Teresa L. , Tibollo Valentina , Bellazzi Riccardo , Bardile Alberto Ferrari , Montagna Stefano , Pesarin Clara , Poggi Paolo , Pedretti Roberto F. E. , Priori Silvia G.
Published: January 2021

MRI can assess plaque composition and has demonstrated an association between some atherosclerotic risk factors (RF) and markers of plaque vulnerability in naive patients. We aimed at investigating this association in medically treated asymptomatic patients. This is a cross-sectional interim analysis (August 2013–September 2016) of a single center prospective study on carotid plaque vulnerability (MAGNETIC study). We recruited patients with asymptomatic carotid atherosclerosis (US stenosis > 30%, ECST criteria), receiving medical treatments at a tertiary cardiac rehabilitation. Atherosclerotic burden and plaque composition were quantified with 3.0 T MRI. The association between baseline characteristics and extent of lipid-rich necrotic core (LRNC), fibrous cap (CAP) and intraplaque hemorrhage (IPH) was studied with multiple regression analysis. We enrolled 260 patients (198 male, 76%) with median age of 71-y (interquartile range: 65–76). Patients were on antiplatelet therapy, ACE-inhibitors/angiotensin receptor blockers and statins (196–229, 75–88%). Median LDL-cholesterol was 78 mg/dl (59–106), blood pressure 130/70 mmHg (111–140/65–80), glycosylated hemoglobin 46 mmol/mol (39–51) and BMI 25 kg/m2 (23–28); moreover, 125 out of 187 (67%) patients were ex-smokers. Multivariate analysis of a data-set of 487 (94%) carotid arteries showed that a history of hypercholesterolemia, diabetes, hypertension or smoking did not correlate with LRNC, CAP or IPH. Conversely, maximum stenosis was the strongest independent predictor of LRNC, CAP and IPH (p < 0.001). MRI assessment of plaque composition in patients on treatment for asymptomatic carotid atherosclerosis shows no correlation between plaque vulnerability and the most well-controlled modifiable RF. Conversely, maximum stenosis exhibits a strong correlation with vulnerable features despite treatment.
Salicylic diamines selectively eliminate residual undifferentiated cells from pluripotent stem cell-derived cardiomyocyte preparations
Authors: Burkert Karsten , Taheri Hadiseh , Hamad Sarkawt , Oliverio Matteo , Peinkofer Gabriel , Kornfeld Jan-Wilhelm , Harnying Wacharee , Pfannkuche Kurt , Hescheler Jürgen , Berkessel Albrecht , Šarić Tomo
Published: January 2021

Clinical translation of pluripotent stem cell (PSC) derivatives is hindered by the tumorigenic risk from residual undifferentiated cells. Here, we identified salicylic diamines as potent agents exhibiting toxicity to murine and human PSCs but not to cardiomyocytes (CMs) derived from them. Half maximal inhibitory concentrations (IC50) of small molecules SM2 and SM6 were, respectively, 9- and 18-fold higher for human than murine PSCs, while the IC50 of SM8 was comparable for both PSC groups. Treatment of murine embryoid bodies in suspension differentiation cultures with the most effective small molecule SM6 significantly reduced PSC and non-PSC contamination and enriched CM populations that would otherwise be eliminated in genetic selection approaches. All tested salicylic diamines exerted their toxicity by inhibiting the oxygen consumption rate (OCR) in PSCs. No or only minimal and reversible effects on OCR, sarcomeric integrity, DNA stability, apoptosis rate, ROS levels or beating frequency were observed in PSC-CMs, although effects on human PSC-CMs seemed to be more deleterious at higher SM-concentrations. Teratoma formation from SM6-treated murine PSC-CMs was abolished or delayed compared to untreated cells. We conclude that salicylic diamines represent promising compounds for PSC removal and enrichment of CMs without the need for other selection strategies.
How neurons exploit fractal geometry to optimize their network connectivity
Authors: Smith Julian H. , Rowland Conor , Harland B. , Moslehi S. , Montgomery R. D. , Schobert K. , Watterson W. J. , Dalrymple-Alford J. , Taylor R. P.
Published: January 2021

We investigate the degree to which neurons are fractal, the origin of this fractality, and its impact on functionality. By analyzing three-dimensional images of rat neurons, we show the way their dendrites fork and weave through space is unexpectedly important for generating fractal-like behavior well-described by an ‘effective’ fractal dimension D. This discovery motivated us to create distorted neuron models by modifying the dendritic patterns, so generating neurons across wide ranges of D extending beyond their natural values. By charting the D-dependent variations in inter-neuron connectivity along with the associated costs, we propose that their D values reflect a network cooperation that optimizes these constraints. We discuss the implications for healthy and pathological neurons, and for connecting neurons to medical implants. Our automated approach also facilitates insights relating form and function, applicable to individual neurons and their networks, providing a crucial tool for addressing massive data collection projects (e.g. connectomes).
Large-scale systematic analysis of exposure to multiple cancer risk factors and the associations between exposure patterns and cancer incidence
Authors: Steinberg Julia , Yap Sarsha , Goldsbury David , Nair-Shalliker Visalini , Banks Emily , Canfell Karen , O’Connell Dianne L.
Published: January 2021

Exposures to cancer risk factors such as smoking and alcohol are not mutually independent. We aimed to identify risk factor exposure patterns and their associations with sociodemographic characteristics and cancer incidence. We considered 120,771 female and, separately, 100,891 male participants of the Australian prospective cohort 45 and Up Study. Factor analysis grouped 36 self-reported variables into 8 combined factors each for females (largely representing ‘smoking’, ‘alcohol’, ‘vigorous exercise’, ‘age at childbirth’, ‘Menopausal Hormone Therapy’, ‘parity and breastfeeding’, ‘standing/sitting’, ‘fruit and vegetables’) and males (largely representing ‘smoking’, ‘alcohol’, ‘vigorous exercise’, ‘urology and health’, ‘moderate exercise’, ‘standing/sitting’, ‘fruit and vegetables’, ‘meat and BMI’). Associations with cancer incidence were investigated using multivariable logistic regression (4–8 years follow-up: 6193 females, 8749 males diagnosed with cancer). After multiple-testing correction, we identified 10 associations between combined factors and cancer incidence for females and 6 for males, of which 14 represent well-known relationships (e.g. bowel cancer: females ‘smoking’ factor Odds Ratio (OR) 1.16 (95% Confidence Interval (CI) 1.08–1.25), males ‘smoking’ factor OR 1.15 (95% CI 1.07–1.23)), providing evidence for the validity of this approach. The catalogue of associations between exposure patterns, sociodemographic characteristics, and cancer incidence can help inform design of future studies and targeted prevention programmes.
Growth, lifetime, directional movement and myosin-dependent motility of mutant keratin granules in cultured cells
Authors: Lehmann S. M. , Leube R. E. , Windoffer R.
Published: January 2021

Intermediate filament polypeptides (IFPs) are prominent components of cytoplasmic aggregates, which are pathognomonic for multiple diseases. Recent observations in cultured cells suggest that they are dynamic and subject to regulated turnover. The emerging concept is that multiple factors contribute to motility and turnover of IFP-containing aggregates. To understand their relative contribution, quantitative tools are needed. The current study addresses this need using epithelial cells producing mutant keratin IFPs that have been identified as the cause of the hereditary blister-forming skin disease epidermolysis bullosa simplex. Digital image analysis of individual granules allowed mapping of their complete life cycle, with information on multiple characteristics at any given time-point. The deduced signet features revealed rapid granule fusion and directed transport from the periphery towards the cell centre, and a limited, ~ 30 min lifetime with a slow, continuous growth phase followed by fast disassembly. As paradigmatic proof-of-principle, we demonstrate that inhibition of myosin II selectively reduces granule movement, linking keratin granule motility to retrograde cortical acto-myosin flow. The newly developed methods and established parameters will help in the characterization of known and the identification of novel regulators of IFP-containing aggregates.
Characterizing the impact of pyrite addition on the efficiency of Fe0/H2O systems
Authors: Hu Rui , Cui Xuesong , Xiao Minhui , Gwenzi Willis , Noubactep Chicgoua
Published: January 2021

The role of pyrite (FeS2) in the process of water treatment using metallic iron (Fe0) was investigated. FeS2 was used as a pH-shifting agent while methylene blue (MB) and methyl orange (MO) were used as an indicator of reactivity and model contaminant, respectively. The effect of the final pH value on the extent of MB discoloration was characterized using 5 g L−1 of a Fe0 specimen. pH variation was achieved by adding 0 to 30 g L−1 of FeS2. Quiescent batch experiments with Fe0/FeS2/sand systems (sand loading: 25 g L−1) and 20 mL of MB were performed for 41 days. Final pH values varied from 3.3 to 7.0. Results demonstrated that MB discoloration is only quantitative when the final pH value was larger than 4.5 and that adsorption and co-precipitation are the fundamental mechanisms of decontamination in Fe0/H2O systems. Such mechanisms are consistent with the effects of the pH value on the decontamination process.
Comprehensive somatosensory and neurological phenotyping of NCS1 knockout mice
Authors: Nguyen Lien D. , Nolte Luca G. , Tan Winston J. T. , Giuvelis Denise , Santos-Sacchi Joseph , Bilsky Edward , Ehrlich Barbara E.
Published: January 2021

Neuronal calcium sensor 1 (NCS1) regulates a wide range of cellular functions throughout the mammalian nervous systems. Altered NCS1 expression is associated with neurodevelopmental and neurodegenerative diseases. Previous studies focused on affective and cognitive behaviors in NCS1 knockout (KO) mice, but little is known about the physiological and pathological states associated with the loss of NCS1 in the peripheral nervous system. We previously reported that NCS1 expression was reduced following paclitaxel-induced peripheral neuropathy. Here, we comprehensively investigated the phenotypes of NCS1-KO mice through a battery of behavioral tests examining both central and peripheral nervous systems. Generally, only mild differences were observed in thermal sensation and memory acquisition between NCS1-WT and -KO male mice, but not in female mice. No differences were observed in motor performance, affective behaviors, and hearing in both sexes. These results suggest that NCS1 plays a modulatory role in sensory perceptions and cognition, particularly in male mice. NCS1 has been proposed as a pharmacological target for various diseases. Therefore, the sex-specific effects of NCS1 loss may be of clinical interest. As we examined a constitutive KO model, future studies focusing on various conditional KO models will further elucidate the precise physiological significance of NCS1.