bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in signalling downstream of MLKL
Authors: Jacobsen Annette V. , Pierotti Catia L. , Lowes Kym N. , Au Amanda E. , Zhang Ying , Etemadi Nima , Fitzgibbon Cheree , Kersten Wilhelmus J. A. , Samson André L. , van Delft Mark F. , Huang David C. S. , Sabroux Hélène Jousset , Lessene Guillaume , Silke John , Murphy James M. 
Published: April 2022

AbstractNecroptosis is a form of caspase-independent programmed cell death that arises from disruption of cell membranes by the mixed lineage kinase domain-like (MLKL) pseudokinase after its activation by the upstream kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, within a complex known as the necrosome. Dysregulated necroptosis has been implicated in numerous inflammatory pathologies. As such, new small molecule necroptosis inhibitors are of great interest, particularly ones that operate downstream of MLKL activation, where the pathway is less well defined. To better understand the mechanisms involved in necroptosis downstream of MLKL activation, and potentially uncover new targets for inhibition, we screened known kinase inhibitors against an activated mouse MLKL mutant, leading us to identify the lymphocyte-specific protein tyrosine kinase (Lck) inhibitor AMG-47a as an inhibitor of necroptosis. We show that AMG-47a interacts with both RIPK1 and RIPK3, that its ability to protect from cell death is dependent on the strength of the necroptotic stimulus, and that it blocks necroptosis most effectively in human cells. Moreover, in human cell lines, we demonstrate that AMG-47a can protect against cell death caused by forced dimerisation of MLKL truncation mutants in the absence of any upstream signalling, validating that it targets a process downstream of MLKL activation. Surprisingly, however, we also found that the cell death driven by activated MLKL in this model was completely dependent on the presence of RIPK1, and to a lesser extent RIPK3, although it was not affected by known inhibitors of these kinases. Together, these results suggest an additional role for RIPK1, or the necrosome, in mediating human necroptosis after MLKL is phosphorylated by RIPK3 and provide further insight into reported differences in the progression of necroptosis between mouse and human cells.
Gelation and anomalous viscosity dynamics in aqueous dispersions of synthetic hectorite
Authors: Kimura Yuji , Shimizu Shoichi , Haraguchi Kazutoshi 
Published: April 2022

AbstractExfoliated clay nanosheets (CNSs) of synthetic hectorite (s-hectorite) have been used for synthesizing advanced functional materials and gels that exhibit high transparency, high mechanical toughness, and many unprecedented characteristics like optical anisotropy, cell harvesting, instant strong adhesion, and self-healing. Therefore, it is important to determine the rheological properties of aqueous s-hectorite dispersions in terms of the CNS microstructures formed in the dispersion. Herein, viscosity changes in aqueous dispersions of s-hectorite were determined using a vibration viscometer to measure viscosity under agitated and static conditions. Upon varying the pH and salt concentration, aqueous dispersions of s-hectorite exhibited a maximum viscosity accompanied by gelation. Additionally, the aqueous dispersion with maximum viscosity exhibited large and complex time-dependent viscosity changes in the static state after cessation of stirring. The anomalous viscosity dynamics depended on the types of clay, acid (salt), temperature, repetitions, and agitation conditions used. The mechanisms for viscosity dynamics have been discussed in terms of variations in the CNS microstructures. It is inferred that anomalous viscosity dynamics are a general phenomenon in multicomponent dispersion systems containing CNSs.
100 Hz ROCS microscopy correlated with fluorescence reveals cellular dynamics on different spatiotemporal scales
Authors: Jünger Felix , Ruh Dominic , Strobel Dominik , Michiels Rebecca , Huber Dominik , Brandel Annette , Madl Josef , Gavrilov Alina , Mihlan Michael , Daller Caterina Cora , Rog-Zielinska Eva A. , Römer Winfried , Lämmermann Tim , Rohrbach Alexander 
Published: April 2022

AbstractFluorescence techniques dominate the field of live-cell microscopy, but bleaching and motion blur from too long integration times limit dynamic investigations of small objects. High contrast, label-free life-cell imaging of thousands of acquisitions at 160 nm resolution and 100 Hz is possible by Rotating Coherent Scattering (ROCS) microscopy, where intensity speckle patterns from all azimuthal illumination directions are added up within 10 ms. In combination with fluorescence, we demonstrate the performance of improved Total Internal Reflection (TIR)-ROCS with variable illumination including timescale decomposition and activity mapping at five different examples: millisecond reorganization of macrophage actin cortex structures, fast degranulation and pore opening in mast cells, nanotube dynamics between cardiomyocytes and fibroblasts, thermal noise driven binding behavior of virus-sized particles at cells, and, bacterial lectin dynamics at the cortex of lung cells. Using analysis methods we present here, we decipher how motion blur hides cellular structures and how slow structure motions cover decisive fast motions.
Defining the early stages of intestinal colonisation by whipworms
Authors: Duque-Correa María A. , Goulding David , Rodgers Faye H. , Gillis J. Andrew , Cormie Claire , Rawlinson Kate A. , Bancroft Allison J. , Bennett Hayley M. , Lotkowska Magda E. , Reid Adam J. , Speak Anneliese O. , Scott Paul , Redshaw Nicholas , Tolley Charlotte , McCarthy Catherine , Brandt Cordelia , Sharpe Catherine , Ridley Caroline , Moya Judit Gali , Carneiro Claudia M. , Starborg Tobias , Hayes Kelly S. , Holroyd Nancy , Sanders Mandy , Thornton David J. , Grencis Richard K. , Berriman Matthew 
Published: April 2022

AbstractWhipworms are large metazoan parasites that inhabit multi-intracellular epithelial tunnels in the large intestine of their hosts, causing chronic disease in humans and other mammals. How first-stage larvae invade host epithelia and establish infection remains unclear. Here we investigate early infection events using both Trichuris muris infections of mice and murine caecaloids, the first in-vitro system for whipworm infection and organoid model for live helminths. We show that larvae degrade mucus layers to access epithelial cells. In early syncytial tunnels, larvae are completely intracellular, woven through multiple live dividing cells. Using single-cell RNA sequencing of infected mouse caecum, we reveal that progression of infection results in cell damage and an expansion of enterocytes expressing of Isg15, potentially instigating the host immune response to the whipworm and tissue repair. Our results unravel intestinal epithelium invasion by whipworms and reveal specific host-parasite interactions that allow the whipworm to establish its multi-intracellular niche.
A functional map of HIV-host interactions in primary human T cells
Authors: Hiatt Joseph , Hultquist Judd F. , McGregor Michael J. , Bouhaddou Mehdi , Leenay Ryan T. , Simons Lacy M. , Young Janet M. , Haas Paige , Roth Theodore L. , Tobin Victoria , Wojcechowskyj Jason A. , Woo Jonathan M. , Rathore Ujjwal , Cavero Devin A. , Shifrut Eric , Nguyen Thong T. , Haas Kelsey M. , Malik Harmit S. , Doudna Jennifer A. , May Andrew P. , Marson Alexander , Krogan Nevan J. 
Published: April 2022

AbstractHuman Immunodeficiency Virus (HIV) relies on host molecular machinery for replication. Systematic attempts to genetically or biochemically define these host factors have yielded hundreds of candidates, but few have been functionally validated in primary cells. Here, we target 426 genes previously implicated in the HIV lifecycle through protein interaction studies for CRISPR-Cas9-mediated knock-out in primary human CD4+ T cells in order to systematically assess their functional roles in HIV replication. We achieve efficient knockout (>50% of alleles) in 364 of the targeted genes and identify 86 candidate host factors that alter HIV infection. 47 of these factors validate by multiplex gene editing in independent donors, including 23 factors with restrictive activity. Both gene editing efficiencies and HIV-1 phenotypes are highly concordant among independent donors. Importantly, over half of these factors have not been previously described to play a functional role in HIV replication, providing numerous novel avenues for understanding HIV biology. These data further suggest that host-pathogen protein-protein interaction datasets offer an enriched source of candidates for functional host factor discovery and provide an improved understanding of the mechanics of HIV replication in primary T cells.
Pseudo-adsorption and long-range redox coupling during oxygen reduction reaction on single atom electrocatalyst
Authors: Chen Jie-Wei , Zhang Zisheng , Yan Hui-Min , Xia Guang-Jie , Cao Hao , Wang Yang-Gang 
Published: April 2022

AbstractFundamental understanding of the dynamic behaviors at the electrochemical interface is crucial for electrocatalyst design and optimization. Here, we revisit the oxygen reduction reaction mechanism on a series of transition metal (M = Fe, Co, Ni, Cu) single atom sites embedded in N-doped nanocarbon by ab initio molecular dynamics simulations with explicit solvation. We have identified the dissociative pathways and the thereby emerged solvated hydroxide species for all the proton-coupled electron transfer (PCET) steps at the electrochemical interface. Such hydroxide species can be dynamically confined in a “pseudo-adsorption” state at a few water layers away from the active site and respond to the redox event at the catalytic center in a coupled manner within timescale less than 1 ps. In the PCET steps, the proton species (in form of hydronium in neutral/acidic media or water in alkaline medium) can protonate the pseudo-adsorbed hydroxide without needing to travel to the direct catalyst surface. This, therefore, expands the reactive region beyond the direct catalyst surface, boosting the reaction kinetics via alleviating mass transfer limits. Our work implies that in catalysis the reaction species may not necessarily bind to the catalyst surface but be confined in an active region.
Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin
Authors: Zhu Ya , Lin Xiaowen , Zong Xin , Han Shuo , Wang Mu , Su Yuxuan , Ma Limin , Chu Xiaojing , Yi Cuiying , Zhao Qiang , Wu Beili 
Published: April 2022

AbstractFormyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ42 and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ42, implying its involvement in the pathogenesis of Alzheimer’s disease (AD). However, the interaction pattern between FPR2 and Aβ42 or humanin remains unknown. Here we report the structures of FPR2 bound to Gi and Aβ42 or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ42 and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.
Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer
Authors: Qi Jingjing , Sun Hongxiang , Zhang Yao , Wang Zhengting , Xun Zhenzhen , Li Ziyi , Ding Xinyu , Bao Rujuan , Hong Liwen , Jia Wenqing , Fang Fei , Liu Hongzhi , Chen Lei , Zhong Jie , Zou Duowu , Liu Lianxin , Han Leng , Ginhoux Florent , Liu Yingbin , Ye Youqiong , Su Bing 
Published: April 2022

AbstractColorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP+ fibroblasts and SPP1+ macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP+ fibroblasts and SPP1+ macrophages interaction to improve immunotherapy.
USP1-trapping lesions as a source of DNA replication stress and genomic instability
Authors: Coleman Kate E. , Yin Yandong , Lui Sarah Kit Leng , Keegan Sarah , Fenyo David , Smith Duncan J. , Rothenberg Eli , Huang Tony T. 
Published: April 2022

AbstractThe deubiquitinase USP1 is a critical regulator of genome integrity through the deubiquitylation of Fanconi Anemia proteins and the DNA replication processivity factor, proliferating cell nuclear antigen (PCNA). Uniquely, following UV irradiation, USP1 self-inactivates through autocleavage, which enables its own degradation and in turn, upregulates PCNA monoubiquitylation. However, the functional role for this autocleavage event during physiological conditions remains elusive. Herein, we discover that cells harboring an autocleavage-defective USP1 mutant, while still able to robustly deubiquitylate PCNA, experience more replication fork-stalling and premature fork termination events. Using super-resolution microscopy and live-cell single-molecule tracking, we show that these defects are related to the inability of this USP1 mutant to be properly recycled from sites of active DNA synthesis, resulting in replication-associated lesions. Furthermore, we find that the removal of USP1 molecules from DNA is facilitated by the DNA-dependent metalloprotease Spartan to counteract the cytotoxicity caused by “USP1-trapping”. We propose a utility of USP1 inhibitors in cancer therapy based on their ability to induce USP1-trapping lesions and consequent replication stress and genomic instability in cancer cells, similar to how non-covalent DNA-protein crosslinks cause cytotoxicity by imposing steric hindrances upon proteins involved in DNA transactions.
Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Authors: Saleiro Diana , Wen Jeremy Q. , Kosciuczuk Ewa M. , Eckerdt Frank , Beauchamp Elspeth M. , Oku Chidera V. , Blyth Gavin T. , Fischietti Mariafausta , Ilut Liliana , Colamonici Marco , Palivos William , Atsaves Paula A. , Tan Dean , Kocherginsky Masha , Weinberg Rona Singer , Fish Eleanor N. , Crispino John D. , Hoffman Ronald , Platanias Leonidas C. 
Published: April 2022

AbstractInterferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.
Shape and stiffness memory ionogels with programmable pressure-resistance response
Authors: Zhuo Shuyun , Song Cheng , Rong Qinfeng , Zhao Tianyi , Liu Mingjie 
Published: April 2022

AbstractFlexible pressure sensors usually require functional materials with both mechanical compliance and appropriate electrical performance. Most sensors based on materials with limited compressibility can hardly balance between high sensitivity and broad pressure range. Here, we prepare a heterophasic ionogel with shape and stiffness memory for adaptive pressure sensors. By combining the microstructure alignment for stiffness changing and shape memory micro-inclusions for stiffness fixing, the heterophasic ionogels reveal tunable compressibility. This controllable pressure-deformation property of the ionogels results in the pressure sensors’ programmable pressure-resistance behavior with tunable pressure ranges, varied detection limits, and good resolution at high pressure. Broad pressure ranges to 220 and 380 kPa, and tunable detection limit from 120 to 330 and 950 Pa are realized by the stiffness memory ionogel sensors. Adaptive detection is also brought out to monitor tiny pressure changes at low stiffness and distinguish different human motions at high stiffness. Using shape and stiffness memory materials in pressure sensors is a general design to achieve programmable performance for more complex application scenarios.
Activity-induced interactions and cooperation of artificial microswimmers in one-dimensional environments
Authors: Ketzetzi Stefania , Rinaldin Melissa , Dröge Pim , Graaf Joost de , Kraft Daniela J. 
Published: April 2022

AbstractCooperative motion in biological microswimmers is crucial for their survival as it facilitates adhesion to surfaces, formation of hierarchical colonies, efficient motion, and enhanced access to nutrients. Here, we confine synthetic, catalytic microswimmers along one-dimensional paths and demonstrate that they too show a variety of cooperative behaviours. We find that their speed increases with the number of swimmers, and that the activity induces a preferred distance between swimmers. Using a minimal model, we ascribe this behavior to an effective activity-induced potential that stems from a competition between chemical and hydrodynamic coupling. These interactions further induce active self-assembly into trains where swimmers move at a well-separated, stable distance with respect to each other, as well as compact chains that can elongate, break-up, become immobilized and remobilized. We identify the crucial role that environment morphology and swimmer directionality play on these highly dynamic chain behaviors. These activity-induced interactions open the door toward exploiting cooperation for increasing the efficiency of microswimmer motion, with temporal and spatial control, thereby enabling them to perform intricate tasks inside complex environments.
High-performance hysteresis-free perovskite transistors through anion engineering
Authors: Zhu Huihui , Liu Ao , Shim Kyu In , Jung Haksoon , Zou Taoyu , Reo Youjin , Kim Hyunjun , Han Jeong Woo , Chen Yimu , Chu Hye Yong , Lim Jun Hyung , Kim Hyung-Jun , Bai Sai , Noh Yong-Young 
Published: April 2022

Abstract
Despite the impressive development of metal halide perovskites in diverse optoelectronics, progress on high-performance transistors employing state-of-the-art perovskite channels has been limited due to ion migration and large organic spacer isolation. Herein, we report high-performance hysteresis-free p-channel perovskite thin-film transistors (TFTs) based on methylammonium tin iodide (MASnI3) and rationalise the effects of halide (I/Br/Cl) anion engineering on film quality improvement and tin/iodine vacancy suppression, realising high hole mobilities of 20 cm2 V−1 s−1, current on/off ratios exceeding 107, and threshold voltages of 0 V along with high operational stabilities and reproducibilities. We reveal ion migration has a negligible contribution to the hysteresis of Sn-based perovskite TFTs; instead, minority carrier trapping is the primary cause. Finally, we integrate the perovskite TFTs with commercialised n-channel indium gallium zinc oxide TFTs on a single chip to construct high-gain complementary inverters, facilitating the development of halide perovskite semiconductors for printable electronics and circuits.
Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder
Authors: Dong Kangning , Zhang Shihua 
Published: April 2022

AbstractRecent advances in spatially resolved transcriptomics have enabled comprehensive measurements of gene expression patterns while retaining the spatial context of the tissue microenvironment. Deciphering the spatial context of spots in a tissue needs to use their spatial information carefully. To this end, we develop a graph attention auto-encoder framework STAGATE to accurately identify spatial domains by learning low-dimensional latent embeddings via integrating spatial information and gene expression profiles. To better characterize the spatial similarity at the boundary of spatial domains, STAGATE adopts an attention mechanism to adaptively learn the similarity of neighboring spots, and an optional cell type-aware module through integrating the pre-clustering of gene expressions. We validate STAGATE on diverse spatial transcriptomics datasets generated by different platforms with different spatial resolutions. STAGATE could substantially improve the identification accuracy of spatial domains, and denoise the data while preserving spatial expression patterns. Importantly, STAGATE could be extended to multiple consecutive sections to reduce batch effects between sections and extracting three-dimensional (3D) expression domains from the reconstructed 3D tissue effectively.
Single-crystal two-dimensional material epitaxy on tailored non-single-crystal substrates
Authors: Li Xin , Wu Guilin , Zhang Leining , Huang Deping , Li Yunqing , Zhang Ruiqi , Li Meng , Zhu Lin , Guo Jing , Huang Tianlin , Shen Jun , Wei Xingzhan , Yu Ka Man , Dong Jichen , Altman Michael S. , Ruoff Rodney S. , Duan Yinwu , Yu Jie , Wang Zhujun , Huang Xiaoxu , Ding Feng , Shi Haofei , Tang Wenxin 
Published: April 2022

AbstractThe use of single-crystal substrates as templates for the epitaxial growth of single-crystal overlayers has been a primary principle of materials epitaxy for more than 70 years. Here we report our finding that, though counterintuitive, single-crystal 2D materials can be epitaxially grown on twinned crystals. By establishing a geometric principle to describe 2D materials alignment on high-index surfaces, we show that 2D material islands grown on the two sides of a twin boundary can be well aligned. To validate this prediction, wafer-scale Cu foils with abundant twin boundaries were synthesized, and on the surfaces of these polycrystalline Cu foils, we have successfully grown wafer-scale single-crystal graphene and hexagonal boron nitride films. In addition, to greatly increasing the availability of large area high-quality 2D single crystals, our discovery also extends the fundamental understanding of materials epitaxy.