bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
Authors: Hey Joschka , Paulsen Michelle , Toth Reka , Weichenhan Dieter , Butz Simone , Schatterny Jolanthe , Liebers Reinhard , Lutsik Pavlo , Plass Christoph , Mall Marcus A. 
Published: November 2021

AbstractLung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
Structural dynamics in the water and proton channels of photosystem II during the S2 to S3 transition
Authors: Hussein Rana , Ibrahim Mohamed , Bhowmick Asmit , Simon Philipp S. , Chatterjee Ruchira , Lassalle Louise , Doyle Margaret , Bogacz Isabel , Kim In-Sik , Cheah Mun Hon , Gul Sheraz , de Lichtenberg Casper , Chernev Petko , Pham Cindy C. , Young Iris D. , Carbajo Sergio , Fuller Franklin D. , Alonso-Mori Roberto , Batyuk Alex , Sutherlin Kyle D. , Brewster Aaron S. , Bolotovsky Robert , Mendez Derek , Holton James M. , Moriarty Nigel W. , Adams Paul D. , Bergmann Uwe , Sauter Nicholas K. , Dobbek Holger , Messinger Johannes , Zouni Athina , Kern Jan , Yachandra Vittal K. , Yano Junko 
Published: November 2021

AbstractLight-driven oxidation of water to molecular oxygen is catalyzed by the oxygen-evolving complex (OEC) in Photosystem II (PS II). This multi-electron, multi-proton catalysis requires the transport of two water molecules to and four protons from the OEC. A high-resolution 1.89 Å structure obtained by averaging all the S states and refining the data of various time points during the S2 to S3 transition has provided better visualization of the potential pathways for substrate water insertion and proton release. Our results indicate that the O1 channel is the likely water intake pathway, and the Cl1 channel is the likely proton release pathway based on the structural rearrangements of water molecules and amino acid side chains along these channels. In particular in the Cl1 channel, we suggest that residue D1-E65 serves as a gate for proton transport by minimizing the back reaction. The results show that the water oxidation reaction at the OEC is well coordinated with the amino acid side chains and the H-bonding network over the entire length of the channels, which is essential in shuttling substrate waters and protons.
A general theoretical framework to design base editors with reduced bystander effects
Authors: Wang Qian , Yang Jie , Zhong Zhicheng , Vanegas Jeffrey A. , Gao Xue , Kolomeisky Anatoly B. 
Published: November 2021

AbstractBase editors (BEs) hold great potential for medical applications of gene therapy. However, high precision base editing requires BEs that can discriminate between the target base and multiple bystander bases within a narrow active window (4 – 10 nucleotides). Here, to assist in the design of these optimized editors, we propose a discrete-state stochastic approach to build an analytical model that explicitly evaluates the probabilities of editing the target base and bystanders. Combined with all-atom molecular dynamic simulations, our model reproduces the experimental data of A3A-BE3 and its variants for targeting the “TC” motif and bystander editing. Analyzing this approach, we propose several general principles that can guide the design of BEs with a reduced bystander effect. These principles are then applied to design a series of point mutations at T218 position of A3G-BEs to further reduce its bystander editing. We verify experimentally that the new mutations provide different levels of stringency on reducing the bystander editing at different genomic loci, which is consistent with our theoretical model. Thus, our study provides a computational-aided platform to assist in the scientifically-based design of BEs with reduced bystander effects.
Introns control stochastic allele expression bias
Authors: Sands Bryan , Yun Soo , Mendenhall Alexander R. 
Published: November 2021

AbstractMonoallelic expression (MAE) or extreme allele bias can account for incomplete penetrance, missing heritability and non-Mendelian diseases. In cancer, MAE is associated with shorter patient survival times and higher tumor grade. Prior studies showed that stochastic MAE is caused by stochastic epigenetic silencing, in a gene and tissue-specific manner. Here, we used C. elegans to study stochastic MAE in vivo. We found allele bias/MAE to be widespread within C. elegans tissues, presenting as a continuum from fully biallelic to MAE. We discovered that the presence of introns within alleles robustly decreases MAE. We determined that introns control MAE at distinct loci, in distinct cell types, with distinct promoters, and within distinct coding sequences, using a 5’-intron position-dependent mechanism. Bioinformatic analysis showed human intronless genes are significantly enriched for MAE. Our experimental evidence demonstrates a role for introns in regulating MAE, possibly explaining why some mutations within introns result in disease.
SU(2) hadrons on a quantum computer via a variational approach
Authors: Atas Yasar Y. , Zhang Jinglei , Lewis Randy , Jahanpour Amin , Haase Jan F. , Muschik Christine A. 
Published: November 2021

AbstractQuantum computers have the potential to create important new opportunities for ongoing essential research on gauge theories. They can provide simulations that are unattainable on classical computers such as sign-problem afflicted models or time evolutions. In this work, we variationally prepare the low-lying eigenstates of a non-Abelian gauge theory with dynamically coupled matter on a quantum computer. This enables the observation of hadrons and the calculation of their associated masses. The SU(2) gauge group considered here represents an important first step towards ultimately studying quantum chromodynamics, the theory that describes the properties of protons, neutrons and other hadrons. Our calculations on an IBM superconducting platform utilize a variational quantum eigensolver to study both meson and baryon states, hadrons which have never been seen in a non-Abelian simulation on a quantum computer. We develop a hybrid resource-efficient approach by combining classical and quantum computing, that not only allows the study of an SU(2) gauge theory with dynamical matter fields on present-day quantum hardware, but further lays out the premises for future quantum simulations that will address currently unanswered questions in particle and nuclear physics.
CENP-V is required for proper chromosome segregation through interaction with spindle microtubules in mouse oocytes
Authors: Nabi Dalileh , Drechsler Hauke , Pschirer Johannes , Korn Franz , Schuler Nadine , Diez Stefan , Jessberger Rolf , Chacón Mariola 
Published: November 2021

AbstractProper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes. Here we report a role for the scarcely described protein CENP-V in oocyte spindle formation and chromosome segregation. We show that depending on the oocyte maturation state, CENP-V localizes to centromeres, to microtubule organizing centers, and to spindle microtubules. We find that Cenp-V−/− oocytes feature severe deficiencies, including metaphase I arrest, strongly reduced polar body extrusion, increased numbers of mis-aligned chromosomes and aneuploidy, multipolar spindles, unfocused spindle poles and loss of kinetochore spindle fibres. We also show that CENP-V protein binds, diffuses along, and bundles microtubules in vitro. The spindle assembly checkpoint arrests about half of metaphase I Cenp-V−/− oocytes from young adults only. This finding suggests checkpoint weakening in ageing oocytes, which mature despite carrying mis-aligned chromosomes. Thus, CENP-V is a microtubule bundling protein crucial to faithful oocyte meiosis, and Cenp-V−/− oocytes reveal age-dependent weakening of the spindle assembly checkpoint.
Mesenchymal stromal cell apoptosis is required for their therapeutic function
Authors: Pang Swee Heng Milon , D’Rozario Joshua , Mendonca Senora , Bhuvan Tejasvini , Payne Natalie L. , Zheng Di , Hisana Assifa , Wallis Georgia , Barugahare Adele , Powell David , Rautela Jai , Huntington Nicholas D. , Dewson Grant , Huang David C. S. , Gray Daniel H. D. , Heng Tracy S. P. 
Published: November 2021

AbstractMultipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies.
Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D
Authors: Grauel Antonia , Kägi Jan , Rasmussen Tim , Makarchuk Iryna , Oppermann Sabrina , Moumbock Aurélien F. A. , Wohlwend Daniel , Müller Rolf , Melin Frederic , Günther Stefan , Hellwig Petra , Böttcher Bettina , Friedrich Thorsten 
Published: November 2021

AbstractCytochrome bd quinol:O2 oxidoreductases are respiratory terminal oxidases so far only identified in prokaryotes, including several pathogenic bacteria. Escherichia coli contains two bd oxidases of which only the bd-I type is structurally characterized. Here, we report the structure of the Escherichia coli cytochrome bd-II type oxidase with the bound inhibitor aurachin D as obtained by electron cryo-microscopy at 3 Å resolution. The oxidase consists of subunits AppB, C and X that show an architecture similar to that of bd-I. The three heme cofactors are found in AppC, while AppB is stabilized by a structural ubiquinone-8 at the homologous positions. A fourth subunit present in bd-I is lacking in bd-II. Accordingly, heme b595 is exposed to the membrane but heme d embedded within the protein and showing an unexpectedly high redox potential is the catalytically active centre. The structure of the Q-loop is fully resolved, revealing the specific aurachin binding.
Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets
Authors: Fu Ci , Zhang Xiang , Veri Amanda O. , Iyer Kali R. , Lash Emma , Xue Alice , Yan Huijuan , Revie Nicole M. , Wong Cassandra , Lin Zhen-Yuan , Polvi Elizabeth J. , Liston Sean D. , VanderSluis Benjamin , Hou Jing , Yashiroda Yoko , Gingras Anne-Claude , Boone Charles , O’Meara Teresa R. , O’Meara Matthew J. , Noble Suzanne , Robbins Nicole , Myers Chad L. , Cowen Leah E. 
Published: November 2021

AbstractFungal pathogens pose a global threat to human health, with Candida albicans among the leading killers. Systematic analysis of essential genes provides a powerful strategy to discover potential antifungal targets. Here, we build a machine learning model to generate genome-wide gene essentiality predictions for C. albicans and expand the largest functional genomics resource in this pathogen (the GRACE collection) by 866 genes. Using this model and chemogenomic analyses, we define the function of three uncharacterized essential genes with roles in kinetochore function, mitochondrial integrity, and translation, and identify the glutaminyl-tRNA synthetase Gln4 as the target of N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), an antifungal compound.
Coexisting multi-states in catalytic hydrogen oxidation on rhodium
Authors: Winkler P. , Zeininger J. , Raab M. , Suchorski Y. , Steiger-Thirsfeld A. , Stöger-Pollach M. , Amati M. , Gregoratti L. , Grönbeck H. , Rupprechter G. 
Published: November 2021

AbstractCatalytic hydrogen oxidation on a polycrystalline rhodium foil used as a surface structure library is studied by scanning photoelectron microscopy (SPEM) in the 10−6 mbar pressure range, yielding spatially resolved X-ray photoemission spectroscopy (XPS) measurements. Here we report an observation of a previously unknown coexistence of four different states on adjacent differently oriented domains of the same Rh sample at the exactly same conditions. A catalytically active steady state, a catalytically inactive steady state and multifrequential oscillating states are simultaneously observed. Our results thus demonstrate the general possibility of multi-states in a catalytic reaction. This highly unusual behaviour is explained on the basis of peculiarities of the formation and depletion of subsurface oxygen on differently structured Rh surfaces. The experimental findings are supported by mean-field micro-kinetic modelling. The present observations raise the interdisciplinary question of how self-organising dynamic processes in a heterogeneous system are influenced by the permeability of the borders confining the adjacent regions.
Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation
Authors: Wu Zhikun , Jiang Zehang , Li Tong , Xie Chuanbo , Zhao Liansheng , Yang Jiaqi , Ouyang Shuai , Liu Yizhi , Li Tao , Xie Zhi 
Published: November 2021

AbstractA complete characterization of genetic variation is a fundamental goal of human genome research. Long-read sequencing has improved the sensitivity of structural variant discovery. Here, we conduct the long-read sequencing-based structural variant analysis for 405 unrelated Chinese individuals, with 68 phenotypic and clinical measurements. We discover a landscape of 132,312 nonredundant structural variants, of which 45.2% are novel. The identified structural variants are of high-quality, with an estimated false discovery rate of 3.2%. The concatenated length of all the structural variants is approximately 13.2% of the human reference genome. We annotate 1,929 loss-of-function structural variants affecting the coding sequence of 1,681 genes. We discover rare deletions inHBA1/HBA2/HBBassociated with anemia. Furthermore, we identify structural variants related to immunity which differentiate the northern and southern Chinese populations. Our study describes the landscape of structural variants in the Chinese population and their contribution to phenotypes and disease.
Photo-induced catalytic halopyridylation of alkenes
Authors: Guo Shi-Yu , Yang Fan , Song Ting-Ting , Guan Yu-Qing , Min Xiang-Ting , Ji Ding-Wei , Hu Yan-Cheng , Chen Qing-An 
Published: November 2021

AbstractThe Mizoroki-Heck reaction and its reductive analogue are staples of organic synthesis, but the ensuing products often lack a chemical handle for further transformation. Here we report an atom-economical cross-coupling of halopyridines and unactivated alkenes under photoredox catalysis to afford a series of alkene halopyridylation products. This protocol with mild and redox neutral conditions contributes broad substrate scope. As a complement to conventional Heck-type reaction, this radical process avoids the involvement of β-H elimination and thus useful pyridyl and halide groups could be simultaneously and regioselectively incorporated onto alkenes. The success depends on TFA-promoted domino photocatalytic oxidative quenching activation and radical-polar crossover pathway. Plausible mechanism is proposed based on mechanistic investigations. Moreover, the reserved C − X bonds of these products are beneficial for performing further synthetic elaborations.
High dielectric barium titanate porous scaffold for efficient Li metal cycling in anode-free cells
Authors: Wang Chao , Liu Ming , Thijs Michel , Ooms Frans G. B. , Ganapathy Swapna , Wagemaker Marnix 
Published: November 2021

AbstractLi metal batteries are being intensively investigated as a means to achieve higher energy density when compared with standard Li-ion batteries. However, the formation of dendritic and mossy Li metal microstructures at the negative electrode during stripping/plating cycles causes electrolyte decomposition and the formation of electronically disconnected Li metal particles. Here we investigate the use of a Cu current collector coated with a high dielectric BaTiO3 porous scaffold to suppress the electrical field gradients that cause morphological inhomogeneities during Li metal stripping/plating. Applying operando solid-state nuclear magnetic resonance measurements, we demonstrate that the high dielectric BaTiO3 porous scaffold promotes dense Li deposition, improves the average plating/stripping efficiency and extends the cycling life of the cell compared to both bare Cu and to a low dielectric scaffold material (i.e., Al2O3). We report electrochemical tests in full anode-free coin cells using a LiNi0.8Co0.1Mn0.1O2-based positive electrode and a LiPF6-based electrolyte to demonstrate the cycling efficiency of the BaTiO3-coated Cu electrode.
Impactor material records the ancient lunar magnetic field in antipodal anomalies
Authors: Wakita S. , Johnson B. C. , Garrick-Bethell I. , Kelley M. R. , Maxwell R. E. , Davison T. M. 
Published: November 2021

AbstractThe Moon presently has no dynamo, but magnetic fields have been detected over numerous portions of its crust. Most of these regions are located antipodal to large basins, leading to the hypothesis that lunar rock ejected during basin-forming impacts accumulated at the basin antipode and recorded the ambient magnetic field. However, a major problem with this hypothesis is that lunar materials have low iron content and cannot become strongly magnetized. Here we simulate oblique impacts of 100-km-diameter impactors at high resolution and show that an ~700 m thick deposit of potentially iron-rich impactor material accumulates at the basin antipode. The material is shock-heated above the Curie temperature and therefore may efficiently record the ambient magnetic field after deposition. These results explain a substantial fraction of the Moon’s crustal magnetism, and are consistent with a dynamo field strength of at least several tens of microtesla during the basin-forming epoch.
ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization
Authors: Jia Pan , Li Xiang , Wang Xuelei , Yao Liangjiao , Xu Yingying , Hu Yu , Xu Wenwen , He Zhe , Zhao Qifan , Deng Yicong , Zang Yi , Zhang Meiyu , Zhang Yan , Qin Jun , Lu Wei 
Published: November 2021

AbstractSuper-enhancers (SEs) govern macrophage polarization and function. However, the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Here we show that the epigenetic reader ZMYND8 forms liquid compartments with NF-κB/p65 to silence latent SEs and restrict macrophage-mediated inflammation. Mechanistically, the fusion of ZMYND8 and p65 liquid condensates is reinforced by signal-induced acetylation of p65. Then acetylated p65 guides the ZMYND8 redistribution onto latent SEs de novo generated in polarized macrophages, and consequently, recruit LSD1 to decommission latent SEs. The liquidity characteristic of ZMYND8 is critical for its regulatory effect since mutations coagulating ZMYND8 into solid compartments disable the translocation of ZMYND8 and its suppressive function. Thereby, ZMYND8 serves as a molecular rheostat to switch off latent SEs and control the magnitude of the immune response. Meanwhile, we propose a phase separation model by which the latent SEs are fine-tuned in a spatiotemporal manner.
Intrinsic and induced quantum quenches for enhancing qubit-based quantum noise spectroscopy
Authors: Wang Yu-Xin , Clerk Aashish A. 
Published: November 2021

AbstractQuantum sensing protocols that exploit the dephasing of a probe qubit are powerful and ubiquitous methods for interrogating an unknown environment. They have a variety of applications, ranging from noise mitigation in quantum processors, to the study of correlated electron states. Here, we discuss a simple strategy for enhancing these methods, based on the fact that they often give rise to an inadvertent quench of the probed system: there is an effective sudden change in the environmental Hamiltonian at the start of the sensing protocol. These quenches are extremely sensitive to the initial environmental state, and lead to observable changes in the sensor qubit evolution. We show how these new features give access to environmental response properties. This enables methods for direct measurement of bath temperature, and for detecting non-thermal equilibrium states. We also discuss how to deliberately control and modulate this quench physics, which enables reconstruction of the bath spectral function. Extensions to non-Gaussian quantum baths are also discussed, as is the application of our ideas to a range of sensing platforms (e.g., nitrogen-vacancy (NV) centers in diamond, semiconductor quantum dots, and superconducting circuits).
Readout of an antiferromagnetic spintronics system by strong exchange coupling of Mn2Au and Permalloy
Authors: Bommanaboyena S. P. , Backes D. , Veiga L. S. I. , Dhesi S. S. , Niu Y. R. , Sarpi B. , Denneulin T. , Kovács A. , Mashoff T. , Gomonay O. , Sinova J. , Everschor-Sitte K. , Schönke D. , Reeve R. M. , Kläui M. , Elmers H.-J. , Jourdan M. 
Published: November 2021

AbstractIn antiferromagnetic spintronics, the read-out of the staggered magnetization or Néel vector is the key obstacle to harnessing the ultra-fast dynamics and stability of antiferromagnets for novel devices. Here, we demonstrate strong exchange coupling of Mn2Au, a unique metallic antiferromagnet that exhibits Néel spin-orbit torques, with thin ferromagnetic Permalloy layers. This allows us to benefit from the well-established read-out methods of ferromagnets, while the essential advantages of antiferromagnetic spintronics are only slightly diminished. We show one-to-one imprinting of the antiferromagnetic on the ferromagnetic domain pattern. Conversely, alignment of the Permalloy magnetization reorients the Mn2Au Néel vector, an effect, which can be restricted to large magnetic fields by tuning the ferromagnetic layer thickness. To understand the origin of the strong coupling, we carry out high resolution electron microscopy imaging and we find that our growth yields an interface with a well-defined morphology that leads to the strong exchange coupling.