bluuebunny/crossref_metadata_2025_split huggingface dataset:
The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation
Authors: Fang Fang , Xu Lei , Liang Liqing , Qu Mingyi , Yao Hailei , Yue Wen , Chen Lin , Chen Dongli , Fan Zeng , He Lijuan , Nan Xue , Zhang Huanhuan , Xie Xiaoyan , Pei Xuetao 
Published: October 2022

AbstractErythroblast enucleation is a precisely regulated but not clearly understood process. Polycythemia shows pathological erythroblast enucleation, and we discovered a low miR-125b-5p level in terminal erythroblasts of patients with polycythemia vera (PV) compared to those of healthy controls. Exogenous upregulation of miR-125b-5p levels restored the enucleation rate to normal levels. Direct downregulation of miR-125b-5p in mouse erythroblasts simulated the enucleation issue found in patients with PV, and miR-125b-5p accumulation was found in enucleating erythroblasts, collectively suggesting the importance of miR-125b-5p accumulation for erythroblast enucleation. To elucidate the role of miR-125b-5p in enucleation, gain- and loss-of-function studies were performed. Overexpression of miR-125b-5p improved the enucleation of erythroleukemia cells and primary erythroblasts. Infused erythroblasts with higher levels of miR-125b-5p also exhibited accelerated enucleation. In contrast, miR-125b-5p inhibitors significantly suppressed erythrocyte enucleation. Intracellular imaging revealed that in addition to cytoskeletal assembly and nuclear condensation, miR-125b-5p overexpression resulted in mitochondrial reduction and depolarization. Real-time PCR, western blot analysis, luciferase reporter assays, small molecule inhibitor supplementation and gene rescue assays revealed that Bcl-2, as a direct target of miR-125b-5p, was one of the key mediators of miR-125b-5p during enucleation. Following suppression of Bcl-2, the activation of caspase-3 and subsequent activation of ROCK-1 resulted in cytoskeletal rearrangement and enucleation. In conclusion, this study is the first to reveal the pivotal role of miR-125b-5p in erythroblast enucleation.
HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer
Authors: Xu Guangying , Niu Liling , Wang Youhui , Yang Guang , Zhu Xingwu , Yao Yuan , Zhao Gang , Wang Shaowei , Li Hui 
Published: October 2022

AbstractHistone deacetylase 6 (HDAC6), a member of the HDAC family, has been identified as a potential therapeutic target for tumor therapy, but the function and underlying mechanisms of HDAC6 in colon cancer are incompletely characterized. Our study showed that the infiltration ratio of M2 macrophages was increased in colon cancer tissues with high HDAC6 expression. Similarly, the knockdown of HDAC6 in colon cancer cells inhibited cocultured macrophage M2 polarization in vitro. Analysis of the antibody chip revealed that HDAC6 promoted sIL-6R release to enhance macrophage M2 polarization. Mass spectrometry and immunoprecipitation demonstrated that, mechanistically, HDAC6 interacted with transforming growth factor β–activated kinase 1 (TAK1), deacetylated TAK1 at T178 and promoted TAK1 phosphorylation. TAK1-p38 MAPK signaling could further increase the phosphorylation and activity of ADAM17, which is responsible for shedding of IL-6R. Notably, the expression of phosphorylated TAK1 was positively correlated with HDAC6 expression and macrophage M2 polarization in human colon cancer tissues. Our study revealed a new HDAC6-TAK1-ADAM17 regulatory axis that mediates sIL-6R release and macrophage polarization in colon cancer.
Diverse maturity-dependent and complementary anti-apoptotic brakes safeguard human iPSC-derived neurons from cell death
Authors: Wilkens Ruven , Hoffrichter Anne , Kleinsimlinghaus Karolina , Bohl Bettina , Haag Carolin , Lehmann Nadja , Schmidt Malin , Muñoz Perez-Vico Elena , Wangemann Julia , Rehder Klara Franziska , Horschitz Sandra , Köhr Georg , Ladewig Julia , Koch Philipp 
Published: October 2022

AbstractIn humans, most neurons are born during embryonic development and have to persist throughout the entire lifespan of an individual. Thus, human neurons have to develop elaborate survival strategies to protect against accidental cell death. We set out to decipher the developmental adaptations resulting in neuronal resilience. We demonstrate that, during the time course of maturation, human neurons install a complex and complementary anti-apoptotic signaling network. This includes i.) a downregulation of central proteins of the intrinsic apoptosis pathway including several caspases, ii.) a shift in the ratio of pro- and anti-apoptotic BCL-2 family proteins, and iii.) an elaborate regulatory network resulting in upregulation of the inhibitor of apoptosis protein (IAP) XIAP. Together, these adaptations strongly increase the threshold for apoptosis initiation when confronted with a wide range of cellular stressors. Our results highlight how human neurons are endowed with complex and redundant preemptive strategies to protect against stress and cell death.
Thermodynamic approach for enhancing superconducting critical current performance
Authors: Miura Masashi , Tsuchiya Go , Harada Takumu , Sakuma Keita , Kurokawa Hodaka , Sekiya Naoto , Kato Yasuyuki , Yoshida Ryuji , Kato Takeharu , Nakaoka Koichi , Izumi Teruo , Nabeshima Fuyuki , Maeda Atsutaka , Okada Tatsumori , Awaji Satoshi , Civale Leonardo , Maiorov Boris 
Published: October 2022

AbstractThe addition of artificial pinning centers has led to an impressive increase in the critical current density (Jc) of superconductors, enabling record-breaking all-superconducting magnets and other applications. The Jc of superconductors has reached ~0.2–0.3 Jd, where Jd is the depairing current density, and the numerical factor depends on the pinning optimization. By modifying λ and/or ξ, the penetration depth and coherence length, respectively, we can increase Jd. For (Y0.77Gd0.23)Ba2Cu3Oy ((Y,Gd)123), we can achieve this by controlling the carrier density, which is related to λ and ξ. We can also tune λ and ξ by controlling the chemical pressure in Fe-based superconductors, i.e., BaFe2(As1−xPx)2 films. The variation in λ and ξ leads to an intrinsic improvement in Jc via Jd, allowing extremely high values of Jc of 130 MA/cm2 and 8.0 MA/cm2 at 4.2 K, consistent with an enhancement in Jd of a factor of 2 for both incoherent nanoparticle-doped (Y,Gd)123 coated conductors (CCs) and BaFe2(As1−xPx)2 films, showing that this new material design is useful for achieving high critical current densities in a wide array of superconductors. The remarkably high vortex-pinning force in combination with this thermodynamic and pinning optimization route for the (Y,Gd)123 CCs reached ~3.17 TN/m3 at 4.2 K and 18 T (H||c), the highest values ever reported for any superconductor.
CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro
Authors: Meijboom Katharina E. , Abdallah Abbas , Fordham Nicholas P. , Nagase Hiroko , Rodriguez Tomás , Kraus Carolyn , Gendron Tania F. , Krishnan Gopinath , Esanov Rustam , Andrade Nadja S. , Rybin Matthew J. , Ramic Melina , Stephens Zachary D. , Edraki Alireza , Blackwood Meghan T. , Kahriman Aydan , Henninger Nils , Kocher Jean-Pierre A. , Benatar Michael , Brodsky Michael H. , Petrucelli Leonard , Gao Fen-Biao , Sontheimer Erik J. , Brown Robert H. , Zeier Zane , Mueller Christian 
Published: October 2022

AbstractA GGGGCC24+ hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we used an adeno-associated viral vector system to deliver CRISPR/Cas9 gene-editing machineries to effectuate the removal of the HRE from the C9ORF72 genomic locus. We demonstrate successful excision of the HRE in primary cortical neurons and brains of three mouse models containing the expansion (500–600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, major hallmarks of C9-ALS/FTD, making this a promising therapeutic approach to these diseases.
Experimentally validated memristive memory augmented neural network with efficient hashing and similarity search
Authors: Mao Ruibin , Wen Bo , Kazemi Arman , Zhao Yahui , Laguna Ann Franchesca , Lin Rui , Wong Ngai , Niemier Michael , Hu X. Sharon , Sheng Xia , Graves Catherine E. , Strachan John Paul , Li Can 
Published: October 2022

AbstractLifelong on-device learning is a key challenge for machine intelligence, and this requires learning from few, often single, samples. Memory-augmented neural networks have been proposed to achieve the goal, but the memory module must be stored in off-chip memory, heavily limiting the practical use. In this work, we experimentally validated that all different structures in the memory-augmented neural network can be implemented in a fully integrated memristive crossbar platform with an accuracy that closely matches digital hardware. The successful demonstration is supported by implementing new functions in crossbars, including the crossbar-based content-addressable memory and locality sensitive hashing exploiting the intrinsic stochasticity of memristor devices. Simulations show that such an implementation can be efficiently scaled up for one-shot learning on more complex tasks. The successful demonstration paves the way for practical on-device lifelong learning and opens possibilities for novel attention-based algorithms that were not possible in conventional hardware.
Baby skyrmions in Chern ferromagnets and topological mechanism for spin-polaron formation in twisted bilayer graphene
Authors: Khalaf Eslam , Vishwanath Ashvin 
Published: October 2022

AbstractThe advent of moiré materials has galvanized interest in the nature of charge carriers in topological bands. In contrast to conventional materials with electron-like charge carriers, topological bands allow for more exotic possibilities where charge is carried by nontrivial topological textures, such as skyrmions. However, the real-space description of skyrmions is ill-suited to address the limit of small skyrmions and to account for momentum-space band features. Here, we develop a momentum-space approach to study the formation of the smallest skyrmions – spin polarons, formed as bound states of an electron and a spin flip – in topological ferromagnets. We show that, quite generally, there is an attraction between an electron and a spin flip that is purely topological in origin, promoting the formation of spin polarons. Applying our results to twisted bilayer graphene, we identify a range of parameters where spin polarons are formed and discuss their possible experimental signatures.
Global mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line
Authors: Nielsen Mathias I. , de Haan Noortje , Kightlinger Weston , Ye Zilu , Dabelsteen Sally , Li Minyan , Jewett Michael C. , Bagdonaite Ieva , Vakhrushev Sergey Y. , Wandall Hans H. 
Published: October 2022

AbstractMucin-type-O-glycosylation on proteins is integrally involved in human health and disease and is coordinated by an enzyme family of 20N-acetylgalactosaminyltransferases (GalNAc-Ts). Detailed knowledge on the biological effects of site-specific O-glycosylation is limited due to lack of information on specific glycosylation enzyme activities and O-glycosylation site-occupancies. Here we present a systematic analysis of the isoform-specific targets of all GalNAc-Ts expressed within a tissue-forming human skin cell line, and demonstrate biologically significant effects of O-glycan initiation on epithelial formation. We find over 300 unique glycosylation sites across a diverse set of proteins specifically regulated by one of the GalNAc-T isoforms, consistent with their impact on the tissue phenotypes. Notably, we discover a high variability in the O-glycosylation site-occupancy of 70 glycosylated regions of secreted proteins. These findings revisit the relevance of individual O-glycosylation sites in the proteome, and provide an approach to establish which sites drive biological functions.
Temporally programmed polymer – solvent interactions using a chemical reaction network
Authors: Klemm Benjamin , Lewis Reece W. , Piergentili Irene , Eelkema Rienk 
Published: October 2022

AbstractOut of equilibrium operation of chemical reaction networks (CRNs) enables artificial materials to autonomously respond to their environment by activation and deactivation of intermolecular interactions. Generally, their activation can be driven by various chemical conversions, yet their deactivation to non-interacting building blocks remains largely limited to hydrolysis and internal pH change. To achieve control over deactivation, we present a new, modular CRN that enables reversible formation of positive charges on a tertiary amine substrate, which are removed using nucleophilic signals that control the deactivation kinetics. The modular nature of the CRN enables incorporation in diverse polymer materials, leading to a temporally programmed transition from collapsed and hydrophobic to solvated, hydrophilic polymer chains by controlling polymer-solvent interactions. Depending on the layout of the CRN, we can create stimuli-responsive or autonomously responding materials. This concept will not only offer new opportunities in molecular cargo delivery but also pave the way for next-generation interactive materials.
Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane
Authors: Manioglu Selen , Modaresi Seyed Majed , Ritzmann Noah , Thoma Johannes , Overall Sarah A. , Harms Alexander , Upert Gregory , Luther Anatol , Barnes Alexander B. , Obrecht Daniel , Müller Daniel J. , Hiller Sebastian 
Published: October 2022

AbstractPolymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact with lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize the interaction of polymyxins with native, LPS-containing outer membrane patches of Escherichia coli by high-resolution atomic force microscopy imaging, along with structural and biochemical assays. We find that polymyxins arrange LPS into hexagonal assemblies to form crystalline structures. Formation of the crystalline structures is correlated with the antibiotic activity, and absent in polymyxin-resistant strains. Crystal lattice parameters alter with variations of the LPS and polymyxin molecules. Quantitative measurements show that the crystalline structures decrease membrane thickness and increase membrane area as well as stiffness. Together, these findings suggest the formation of rigid LPS–polymyxin crystals and subsequent membrane disruption as the mechanism of polymyxin action and provide a benchmark for optimization and de novo design of LPS-targeting antimicrobials.
DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
Authors: Fazio Antonella , Bordoni Dora , Kuiper Jan W. P. , Weber-Stiehl Saskia , Stengel Stephanie T. , Arnold Philipp , Ellinghaus David , Ito Go , Tran Florian , Messner Berith , Henning Anna , Bernardes Joana P. , Häsler Robert , Luzius Anne , Imm Simon , Hinrichsen Finn , Franke Andre , Huber Samuel , Nikolaus Susanna , Aden Konrad , Schreiber Stefan , Sommer Felix , Natoli Gioacchino , Mishra Neha , Rosenstiel Philip 
Published: October 2022

AbstractGenetic variants in the DNA methyltransferase 3 A (DNMT3A) locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells from IBD patients and upon tumor necrosis factor treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in intestinal epithelial cells (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.
The influenza virus PB2 protein evades antiviral innate immunity by inhibiting JAK1/STAT signalling
Authors: Yang Hui , Dong Yurui , Bian Ying , Xu Nuo , Wu Yuwei , Yang Fan , Du Yinping , Qin Tao , Chen Sujuan , Peng Daxin , Liu Xiufan 
Published: October 2022

AbstractInfluenza A virus (IAV) polymerase protein PB2 has been shown to partially inhibit the host immune response by blocking the induction of interferons (IFNs). However, the IAV PB2 protein that regulates the downstream signaling pathway of IFNs is not well characterized. Here, we report that IAV PB2 protein reduces cellular sensitivity to IFNs, suppressing the activation of STAT1/STAT2 and ISGs. Furthermore, IAV PB2 protein targets mammalian JAK1 at lysine 859 and 860 for ubiquitination and degradation. Notably, the H5 subtype of highly pathogenic avian influenza virus with I283M/K526R mutations on PB2 increases the ability to degrade mammalian JAK1 and exhibits higher replicate efficiency in mammalian (but not avian) cells and mouse lung tissues, and causes greater mortality in infected mice. Altogether, these data describe a negative regulatory mechanism involving PB2-JAK1 and provide insights into an evasion strategy from host antiviral immunity employed by IAV.
Functional architecture of executive control and associated event-related potentials in macaques
Authors: Sajad Amirsaman , Errington Steven P. , Schall Jeffrey D. 
Published: October 2022

AbstractThe medial frontal cortex (MFC) enables executive control by monitoring relevant information and using it to adapt behavior. In macaques performing a saccade countermanding (stop-signal) task, we simultaneously recorded electrical potentials over MFC and neural spiking across all layers of the supplementary eye field (SEF). We report the laminar organization of neurons enabling executive control by monitoring the conflict between incompatible responses, the timing of events, and sustaining goal maintenance. These neurons were a mix of narrow-spiking and broad-spiking found in all layers, but those predicting the duration of control and sustaining the task goal until the release of operant control were more commonly narrow-spiking neurons confined to layers 2 and 3 (L2/3). We complement these results with evidence for a monkey homolog of the N2/P3 event-related potential (ERP) complex associated with response inhibition. N2 polarization varied with error-likelihood and P3 polarization varied with the duration of expected control. The amplitude of the N2 and P3 were predicted by the spike rate of different classes of neurons located in L2/3 but not L5/6. These findings reveal features of the cortical microcircuitry supporting executive control and producing associated ERPs.
Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment
Authors: Zethoven Magnus , Martelotto Luciano , Pattison Andrew , Bowen Blake , Balachander Shiva , Flynn Aidan , Rossello Fernando J. , Hogg Annette , Miller Julie A. , Frysak Zdenek , Grimmond Sean , Fishbein Lauren , Tischler Arthur S. , Gill Anthony J. , Hicks Rodney J. , Dahia Patricia L. M. , Clifton-Bligh Roderick , Pacak Karel , Tothill Richard W. 
Published: October 2022

AbstractPheochromocytomas (PC) and paragangliomas (PG) are rare neuroendocrine tumors associated with autonomic nerves. Here we use single-nuclei RNA-seq and bulk-tissue gene-expression data to characterize the cellular composition of PCPG and normal adrenal tissues, refine tumor gene-expression subtypes and make clinical and genotypic associations. We confirm seven PCPG gene-expression subtypes with significant genotype and clinical associations. Tumors with mutations in VHL, SDH-encoding genes (SDHx) or MAML3-fusions are characterized by hypoxia-inducible factor signaling and neoangiogenesis. PCPG have few infiltrating lymphocytes but abundant macrophages. While neoplastic cells transcriptionally resemble mature chromaffin cells, early chromaffin and neuroblast markers are also features of some PCPG subtypes. The gene-expression profile of metastatic SDHx-related PCPG indicates these tumors have elevated cellular proliferation and a lower number of non-neoplastic Schwann-cell-like cells, while GPR139 is a potential theranostic target. Our findings therefore clarify the diverse transcriptional programs and cellular composition of PCPG and identify biomarkers of potential clinical significance.
Reduced rotational flows enable the translation of surface-rolling microrobots in confined spaces
Authors: Bozuyuk Ugur , Aghakhani Amirreza , Alapan Yunus , Yunusa Muhammad , Wrede Paul , Sitti Metin 
Published: October 2022

AbstractBiological microorganisms overcome the Brownian motion at low Reynolds numbers by utilizing symmetry-breaking mechanisms. Inspired by them, various microrobot locomotion methods have been developed at the microscale by breaking the hydrodynamic symmetry. Although the boundary effects have been extensively studied for microswimmers and employed for surface-rolling microrobots, the behavior of microrobots in the proximity of multiple wall-based “confinement” is yet to be elucidated. Here, we study the confinement effect on the motion of surface-rolling microrobots. Our experiments demonstrate that the locomotion efficiency of spherical microrollers drastically decreases in confined spaces due to out-of-plane rotational flows generated during locomotion. Hence, a slender microroller design, generating smaller rotational flows, is shown to outperform spherical microrollers in confined spaces. Our results elucidate the underlying physics of surface rolling-based locomotion in confined spaces and present a design strategy with optimal flow generation for efficient propulsion in such areas, including blood vessels and microchannels.