bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanoscopic subcellular imaging enabled by ion beam tomography
Authors: Coskun Ahmet F. , Han Guojun , Ganesh Shambavi , Chen Shih-Yu , Clavé Xavier Rovira , Harmsen Stefan , Jiang Sizun , Schürch Christian M. , Bai Yunhao , Hitzman Chuck , Nolan Garry P. 
Published: February 2021

AbstractMultiplexed ion beam imaging (MIBI) has been previously used to profile multiple parameters in two dimensions in single cells within tissue slices. Here, a mathematical and technical framework for three-dimensional (3D) subcellular MIBI is presented. Ion-beam tomography (IBT) compiles ion beam images that are acquired iteratively across successive, multiple scans, and later assembled into a 3D format without loss of depth resolution. Algorithmic deconvolution, tailored for ion beams, is then applied to the transformed ion image series, yielding 4-fold enhanced ion beam data cubes. To further generate 3D sub-ion-beam-width precision visuals, isolated ion molecules are localized in the raw ion beam images, creating an approach coined as SILM, secondary ion beam localization microscopy, providing sub-25 nm accuracy in original ion images. Using deep learning, a parameter-free reconstruction method for ion beam tomograms with high accuracy is developed for low-density targets. In cultured cancer cells and tissues, IBT enables accessible visualization of 3D volumetric distributions of genomic regions, RNA transcripts, and protein factors with 5 nm axial resolution using isotope-enrichments and label-free elemental analyses. Multiparameter imaging of subcellular features at near macromolecular resolution is implemented by the IBT tools as a general biocomputation pipeline for imaging mass spectrometry.
An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine
Authors: Song Guang , Wang Guohua , Luo Ximei , Cheng Ying , Song Qifeng , Wan Jun , Moore Cedric , Song Hongjun , Jin Peng , Qian Jiang , Zhu Heng 
Published: February 2021

AbstractEpigenetic modifications of DNA play important roles in many biological processes. Identifying readers of these epigenetic marks is a critical step towards understanding the underlying mechanisms. Here, we present an all-to-all approach, dubbed digital affinity profiling via proximity ligation (DAPPL), to simultaneously profile human TF-DNA interactions using mixtures of random DNA libraries carrying different epigenetic modifications (i.e., 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine) on CpG dinucleotides. Many proteins that recognize consensus sequences carrying these modifications in symmetric and/or hemi-modified forms are identified. We further demonstrate that the modifications in different sequence contexts could either enhance or suppress TF binding activity. Moreover, many modifications can affect TF binding specificity. Furthermore, symmetric modifications show a stronger effect in either enhancing or suppressing TF-DNA interactions than hemi-modifications. Finally, in vivo evidence suggests that USF1 and USF2 might regulate transcription via hydroxymethylcytosine-binding activity in weak enhancers in human embryonic stem cells.
Morphology and mechanism of highly selective Cu(II) oxide nanosheet catalysts for carbon dioxide electroreduction
Authors: Wang Xingli , Klingan Katharina , Klingenhof Malte , Möller Tim , Ferreira de Araújo Jorge , Martens Isaac , Bagger Alexander , Jiang Shan , Rossmeisl Jan , Dau Holger , Strasser Peter 
Published: February 2021

AbstractCu oxides catalyze the electrochemical carbon dioxide reduction reaction (CO2RR) to hydrocarbons and oxygenates with favorable selectivity. Among them, the shape-controlled Cu oxide cubes have been most widely studied. In contrast, we report on novel 2-dimensional (2D) Cu(II) oxide nanosheet (CuO NS) catalysts with high C2+ products, selectivities (> 400 mA cm−2) in gas diffusion electrodes (GDE) at industrially relevant currents and neutral pH. Under applied bias, the (001)-orientated CuO NS slowly evolve into highly branched, metallic Cu0 dendrites that appear as a general dominant morphology under electrolyte flow conditions, as attested by operando X-ray absorption spectroscopy and in situ electrochemical transmission electron microscopy (TEM). Millisecond-resolved differential electrochemical mass spectrometry (DEMS) track a previously unavailable set of product onset potentials. While the close mechanistic relation between CO and C2H4 was thereby confirmed, the DEMS data help uncover an unexpected mechanistic link between CH4 and ethanol. We demonstrate evidence that adsorbed methyl species, *CH3, serve as common intermediates of both CH3H and CH3CH2OH and possibly of other CH3-R products via a previously overlooked pathway at (110) steps adjacent to (100) terraces at larger overpotentials. Our mechanistic conclusions challenge and refine our current mechanistic understanding of the CO2 electrolysis on Cu catalysts.
Discovery of an ene-reductase for initiating flavone and flavonol catabolism in gut bacteria
Authors: Yang Gaohua , Hong Sen , Yang Pengjie , Sun Yuwei , Wang Yong , Zhang Peng , Jiang Weihong , Gu Yang 
Published: February 2021

AbstractGut microbial transformations of flavonoids, an enormous class of polyphenolic compounds abundant in plant-based diets, are closely associated with human health. However, the enzymes that initiate the gut microbial metabolism of flavones and flavonols, the two most abundant groups of flavonoids, as well as their underlying molecular mechanisms of action remain unclear. Here, we discovered a flavone reductase (FLR) from the gut bacterium, Flavonifractor plautii ATCC 49531 (originally assigned as Clostridium orbiscindens DSM 6740), which specifically catalyses the hydrogenation of the C2–C3 double bond of flavones/flavonols and initiates their metabolism as a key step. Crystal structure analysis revealed the molecular basis for the distinct catalytic property of FLR. Notably, FLR and its widespread homologues represent a class of ene-reductases that has not been previously identified. Genetic and biochemical analyses further indicated the importance of FLR in gut microbial consumption of dietary and medicinal flavonoids, providing broader insight into gut microbial xenobiotic transformations and possible guidance for personalized nutrition and medicine.
The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases
Authors: Mäkinen Janne J. , Shin Yeonoh , Vieras Eeva , Virta Pasi , Metsä-Ketelä Mikko , Murakami Katsuhiko S. , Belogurov Georgiy A. 
Published: February 2021

AbstractRNA polymerases (RNAPs) synthesize RNA from NTPs, whereas DNA polymerases synthesize DNA from 2′dNTPs. DNA polymerases select against NTPs by using steric gates to exclude the 2′OH, but RNAPs have to employ alternative selection strategies. In single-subunit RNAPs, a conserved Tyr residue discriminates against 2′dNTPs, whereas selectivity mechanisms of multi-subunit RNAPs remain hitherto unknown. Here, we show that a conserved Arg residue uses a two-pronged strategy to select against 2′dNTPs in multi-subunit RNAPs. The conserved Arg interacts with the 2′OH group to promote NTP binding, but selectively inhibits incorporation of 2′dNTPs by interacting with their 3′OH group to favor the catalytically-inert 2′-endo conformation of the deoxyribose moiety. This deformative action is an elegant example of an active selection against a substrate that is a substructure of the correct substrate. Our findings provide important insights into the evolutionary origins of biopolymers and the design of selective inhibitors of viral RNAPs.
Somatic deficiency causes reproductive parasitism in a fungus
Authors: Grum-Grzhimaylo Alexey A. , Bastiaans Eric , van den Heuvel Joost , Berenguer Millanes Cristina , Debets Alfons J. M. , Aanen Duur K. 
Published: February 2021

AbstractSome multicellular organisms can fuse because mergers potentially provide mutual benefits. However, experimental evolution in the fungus Neurospora crassa has demonstrated that free fusion of mycelia favours cheater lineages, but the mechanism and evolutionary dynamics of this exploitation are unknown. Here we show, paradoxically, that all convergently evolved cheater lineages have similar fusion deficiencies. These mutants are unable to initiate fusion but retain access to wild-type mycelia that fuse with them. This asymmetry reduces cheater-mutant contributions to somatic substrate-bound hyphal networks, but increases representation of their nuclei in the aerial reproductive hyphae. Cheaters only benefit when relatively rare and likely impose genetic load reminiscent of germline senescence. We show that the consequences of somatic fusion can be unequally distributed among fusion partners, with the passive non-fusing partner profiting more. We discuss how our findings may relate to the extensive variation in fusion frequency of fungi found in nature.
Engineering advanced logic and distributed computing in human CAR immune cells
Authors: Cho Jang Hwan , Okuma Atsushi , Sofjan Katri , Lee Seunghee , Collins James J. , Wong Wilson W. 
Published: February 2021

AbstractThe immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.
Ratio of the interferon-γ signature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma
Authors: Cui Chuanliang , Xu Canqiang , Yang Wenxian , Chi Zhihong , Sheng Xinan , Si Lu , Xie Yihong , Yu Jinyu , Wang Shun , Yu Rongshan , Guo Jun , Kong Yan 
Published: February 2021

AbstractImmune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumor microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analyzing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-γsignature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 54) and anti-CTLA-4 (n = 42), as well as in patients with gastric cancer treated with anti-PD-1 (n = 45), demonstrating the potential utility of IMS as a predictive biomarker that complements existing GEP signatures for immunotherapy.
A universal molecular prognostic score for gastrointestinal tumors
Authors: Shimizu Hideyuki , Nakayama Keiichi I. 
Published: February 2021

AbstractColorectal and gastric cancers are a leading cause of cancer deaths in developed countries. Precise estimation of prognosis is important with regard to clinical decision making for individuals with such cancers. We here comprehensively compiled a complete atlas of prognostic genes based on an integrated meta-analysis of one of the largest assembled colorectal cancer cohorts. A simple yet robust machine learning approach was then applied to establish a universal molecular prognostic score (mPS_colon) that relies on the expression status of only 16 genes and which was validated with independent data sets. This score was found to be an independent prognostic indicator in multivariate models including cancer stage, to be valid independent of tumor characteristics or patient ethnicity, and to be also applicable to gastric cancer. We conclude that mPS_colon is a universal prognostic classifier for patients with gastrointestinal cancers and that it should prove informative for optimization of personalized therapy for such patients.
Case-finding for COPD clinic acceptability to patients in GPs across Hampshire: a qualitative study
Authors: Rose Danielle , Ray Emma , Summers Rachael H. , Taylor Melinda , Kruk Helen , North Mal , Gillett Kate , Thomas Mike , Wilkinson Tom M. A. 
Published: February 2021

AbstractDespite high mortality and morbidity, COPD remains under-diagnosed. Case-finding strategies are possible, but patients’ perspectives are unexplored. Using qualitative methods, we explored the patient perspective of a case-finding intervention among at-risk patients in primary care. Semi-structured telephone interviews were transcribed and thematic analysis utilised. Seven patients without (mean age 64.5 years (58–74), n = 4) and 8 with obstructed spirometry (mean age 63.5 (53–75), n = 4) were interviewed. Themes identified were motives, challenges and concerns regarding attending the clinic. These included wanting to be well; to help with research; concern over negative impact to life from COPD diagnosis; perceived utility of the clinic; quality of information given; staff manner, approachability and knowledge; and perceived effects of the clinic on lifestyle, self-management and symptoms. The intervention was generally deemed useful and reassuring, although shared information was too detailed or irrelevant for some. Several reported positive lifestyle changes, improved symptoms and improved self-management.
Two-dimensional centrosymmetrical antiferromagnets for spin photogalvanic devices
Authors: Jiang Peng , Tao Xixi , Hao Hua , Liu Yushen , Zheng Xiaohong , Zeng Zhi 
Published: February 2021

AbstractSpin-dependent photogalvanic effect (PGE) in low-dimensional magnetic systems has recently attracted intensive attention. Based on first-principle transport calculations and symmetry analyses, we propose a robust scheme to generate pure spin current by PGE in centrosymmetric materials with spin polarization antisymmetry. As a demonstration, the idea is successfully applied to a photoelectric device constructed with a zigzag graphene nanoribbon (ZGNR), which has intrinsic antiferromagnetic coupling between the two edges and spin degenerate band structure. It suggests that spin splitting is not a prerequisite for pure spin current generation. More interestingly, by further introducing external transverse electric fields to the two leads to lift the spin degeneracy, the device may behave multifunctionally, capable of producing fully spin-polarized current or pure spin current, depending on whether the fields in the two leads are parallel or antiparallel. Very importantly, our scheme of pure spin current generation with PGE is not limited to ZGNR and can be extended to other two-dimensional (2D) centrosymmetric magnetic materials with spin polarization antisymmetry, suggesting a promising category of 2D platforms for PGE-based pure spin current generation.
Waveguide bandgap engineering with an array of superconducting qubits
Authors: Brehm Jan David , Poddubny Alexander N. , Stehli Alexander , Wolz Tim , Rotzinger Hannes , Ustinov Alexey V. 
Published: February 2021

AbstractWaveguide quantum electrodynamics offers a wide range of possibilities to effectively engineer interactions between artificial atoms via a one-dimensional open waveguide. While these interactions have been experimentally studied in the few qubit limit, the collective properties of such systems for larger arrays of qubits in a metamaterial configuration has so far not been addressed. Here, we experimentally study a metamaterial made of eight superconducting transmon qubits with local frequency control coupled to the mode continuum of a waveguide. By consecutively tuning the qubits to a common resonance frequency we observe the formation of super- and subradiant states, as well as the emergence of a polaritonic bandgap. Making use of the qubits quantum nonlinearity, we demonstrate control over the latter by inducing a transparency window in the bandgap region of the ensemble. The circuit of this work extends experiments with one and two qubits toward a full-blown quantum metamaterial, thus paving the way for large-scale applications in superconducting waveguide quantum electrodynamics.
Evidence for metastable photo-induced superconductivity in K3C60
Authors: Budden M. , Gebert T. , Buzzi M. , Jotzu G. , Wang E. , Matsuyama T. , Meier G. , Laplace Y. , Pontiroli D. , Riccò M. , Schlawin F. , Jaksch D. , Cavalleri A. 
Published: February 2021

AbstractExcitation of high-Tc cuprates and certain organic superconductors with intense far-infrared optical pulses has been shown to create non-equilibrium states with optical properties that are consistent with transient high-temperature superconductivity. These non-equilibrium phases have been generated using femtosecond drives, and have been observed to disappear immediately after excitation, which is evidence of states that lack intrinsic rigidity. Here we make use of a new optical device to drive metallic K3C60 with mid-infrared pulses of tunable duration, ranging between one picosecond and one nanosecond. The same superconducting-like optical properties observed over short time windows for femtosecond excitation are shown here to become metastable under sustained optical driving, with lifetimes in excess of ten nanoseconds. Direct electrical probing, which becomes possible at these timescales, yields a vanishingly small resistance with the same relaxation time as that estimated by terahertz conductivity. We provide a theoretical description of the dynamics after excitation, and justify the observed slow relaxation by considering randomization of the order-parameter phase as the rate-limiting process that determines the decay of the light-induced superconductor.
Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization
Authors: Woodard DaNae R. , Nakahara Emi , Hulleman John D. 
Published: February 2021

AbstractDistinct mutations in the secreted extracellular matrix protein, fibulin-3 (F3), have been associated with a number of ocular diseases ranging from primary open angle glaucoma to cuticular age-related macular degeneration to a rare macular dystrophy, Malattia Leventinese (ML). The R345W F3 mutation that causes ML leads to F3 misfolding, inefficient secretion and accumulation at higher intracellular steady state levels in cultured cells. Herein, we determined whether fifteen other clinically-identified F3 mutations also led to similar levels of misfolding and secretion defects, which might provide insight into their potential pathogenicity. Surprisingly, we found that only a single F3 variant, L451F, presented with a significant secretion defect (69.5 ± 2.4% of wild-type (WT) F3 levels) and a corresponding increase in intracellular levels (226.8 ± 25.4% of WT F3 levels). Upon follow-up studies, when this conserved residue (L451) was mutated to a charged (Asp or Arg) or bulky (Pro, Trp, Tyr) residue, F3 secretion was also compromised, indicating the importance of small side chains (Leu, Ala, or Gly) at this residue. To uncover potential inherent F3 instability not easily observed under typical culture conditions, we genetically eliminated the sole stabilizing N-linked glycosylation site (N249) from select clinically-identified F3 mutants. This removal exacerbated R345W and L451F secretion defects (19.8 ± 3.0% and 12.4 ± 1.2% of WT F3 levels, respectively), but also revealed a previously undiscovered secretion defect in another C-terminal variant, Y397H (42.0 ± 10.1% of WT F3 levels). Yet, glycan removal did not change the relative secretion of the N-terminal mutants tested (D49A, R140W, I220F). These results highlight the uniqueness and molecular similarities between the R345W and L451F variants and also suggest that previously identified disease-associated mutations (e.g., R140W) are indistinguishable from WT with respect to secretion, hinting that they may lead to disease by an alternative mechanism.
A novel diagnostic method based on filter bank theory for fast and accurate detection of thermoacoustic instability
Authors: Joo Seongpil , Choi Jongwun , Kim Namkeun , Lee Min Chul 
Published: February 2021

AbstractThis study proposes and analyzes a novel methodology that can effectively detect multi-mode combustion instability (CI) in a gas turbine combustor. The experiment is conducted in a model gas turbine combustor, and dynamic pressure (DP) and flame images are examined during the transition from stable to unstable flame, which is driven by changing fuel compositions. As a powerful technique for early detection of CI in multi-mode as well as in single mode, a new filter bank (FB) method based on spectral analysis of DP is proposed. Sequential processing using a triangular filter with Mel-scaling and a Hamming window is applied to increase the accuracy of the FB method, and the instability criterion is determined by calculating the magnitude of FB components. The performance of the FB method is compared with that of two conventional methods that are based on the root-mean-squared DP and temporal kurtosis. From the results, the FB method shows comparable performance in detection speed, sensitivity, and accuracy with other parameters. In addition, the FB components enable the analysis of various frequencies and multi-mode frequencies. Therefore, the FB method can be considered as an additional prognosis tool to determine the multi-mode CI in a monitoring system for gas turbine combustors.
Cell and tissue system capable of automated culture, stimulation, and monitor with the aim of feedback control of organs-on-a-chip
Authors: Konishi Satoshi , Hashimoto Takeshi , Nakabuchi Tsubasa , Ozeki Takatoshi , Kajita Hiroki 
Published: February 2021

AbstractThis paper presents progress in the automation of cell and tissue systems and attempts toward the in situ feedback control of organs-on-a-chip. Our study aims to achieve feedback control of a cell and tissue system by a personal computer (PC), whereas most studies on organs-on-a-chip focus on the automation of status monitoring. The implemented system is composed of subsystems including automated culture, stimulation, and monitoring. The monitoring function provides imaging as well as sampling and dispensing in combination with an external analyzer. Individual subsystems can be combined accordingly. First, monitoring of skeletal muscle (SM) and adipose tissues using this system was demonstrated. The highlight of this paper is the application of the system to the feedback control of the lipid droplet (LD) size, where biochemical stimulation using insulin and adrenaline is controlled by a PC according to the obtained LD imaging data. In this study, the system demonstrated its function of maintaining the desired size of LDs. Our results expand the possibility of PC-controllable cell and tissue systems by addressing the challenge of feedback control of organs-on-a-chip. The PC-controllable cell and tissue systems will contribute to living systems-on-a-chip based on homeostasis phenomena involving interactions between organs or tissues.