bluuebunny/crossref_metadata_2025_split huggingface dataset:
E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis
Authors: Shi Yuhua , Yang Yang , Xu Weilv , Shi Dongyun , Xu Wei , Fu Xinyu , Lv Qian , Xia Jie , Shi Fushan 
Published: February 2022

AbstractGasdermin D (GSDMD) participates in the activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.
The anthelmintic drug niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression
Authors: Guo Yangyang , Zhu Hengyue , Xiao Yanyi , Guo Hangcheng , Lin Miaomiao , Yuan Ziwei , Yang Xuejia , Huang Youze , Zhang Qiyu , Bai Yongheng 
Published: February 2022

AbstractNiclosamide, a cell-permeable salicylanilide, was approved by the Food and Drug Administration for its anthelmintic efficiency. A growing body of evidence in recent years suggests that niclosamide exhibits potential tumor-suppressive activity. However, the role and molecular mechanism of niclosamide in pancreatic cancer remain unclear. In this study, niclosamide inhibited proliferation of pancreatic cancer cells (PCCs), induced apoptosis via the mitochondrial-mediated pathway, and suppressed cell migration and invasion by antagonizing epithelial-to-mesenchymal transition. Also, niclosamide inhibited tumor growth and metastasis in pancreatic cancer xenograft mouse models. Mechanistically, niclosamide exerted these therapeutic effects via targeting β-catenin. Niclosamide did not reduce β-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced β-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3β phosphorylation, which is involved in the ubiquitination degradation of β-catenin. Pharmacological activation of β-catenin by methyl vanillate and β-catenin overexpression abolished the inhibitory effects of niclosamide. Furthermore, niclosamide potentiated the antitumor effect of the chemotherapy drug gemcitabine and reduced the ability of cancer immune evasion by downregulating the expression levels of PD-L1, which is involved in T cell immunity. Thus, our study indicated that niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability, and suppress pancreatic cancer progression. Niclosamide may be a potential therapeutic candidate for pancreatic cancer.
Distinct molecular phenotypes involving several human diseases are induced by IFN-λ3 and IFN-λ4 in monocyte-derived macrophages
Authors: De Manjarika , Bhushan Anand , Grubbe William S. , Roy Subhajit , Mendoza Juan L. , Chinnaswamy Sreedhar 
Published: February 2022

AbstractHuman Interferon (IFN) lambda 3 (IFN-λ3) and IFN-λ4 are closely linked at the IFNL locus and show association with several diseases in genetic studies. Since they are only ~30% identical to each other, to better understand their roles in disease phenotypes, comparative studies are needed. Monocytes are precursors to macrophages (monocyte-derived macrophages; MDMs) that get differentiated under the influence of various immune factors, including IFNs. In a recent study, we characterized lipopolysaccharide-activated M1 and M2-MDMs that were differentiated in presence of IFN-λ3 or IFN-λ4. In this study, we performed transcriptomics on these M1 and M2-MDMs to further understand their molecular phenotypes. We identified over 760 genes that were reciprocally regulated by IFN-λ3 and IFN-λ4, additionally we identified over 240 genes that are significantly affected by IFN-λ4 but not IFN-λ3. We observed that IFN-λ3 was more active in M2-MDMs while IFN-λ4 showed superior response in M1-MDMs. Providing a structural explanation for these functional differences, molecular modeling showed differences in expected interactions of IFN-λ3 and IFN-λ4 with the extracellular domain of IFN-λR1. Further, pathway analysis showed several human infectious diseases and even cancer-related pathways being significantly affected by IFN-λ3 and/or IFN-λ4 in both M1 and M2-MDMs.
Sculpting tissues by phase transitions
Authors: Lenne Pierre-François , Trivedi Vikas 
Published: February 2022

AbstractBiological systems display a rich phenomenology of states that resemble the physical states of matter - solid, liquid and gas. These phases result from the interactions between the microscopic constituent components - the cells - that manifest in macroscopic properties such as fluidity, rigidity and resistance to changes in shape and volume. Looked at from such a perspective, phase transitions from a rigid to a flowing state or vice versa define much of what happens in many biological processes especially during early development and diseases such as cancer. Additionally, collectively moving confluent cells can also lead to kinematic phase transitions in biological systems similar to multi-particle systems where the particles can interact and show sub-populations characterised by specific velocities. In this Perspective we discuss the similarities and limitations of the analogy between biological and inert physical systems both from theoretical perspective as well as experimental evidence in biological systems. In understanding such transitions, it is crucial to acknowledge that the macroscopic properties of biological materials and their modifications result from the complex interplay between the microscopic properties of cells including growth or death, neighbour interactions and secretion of matrix, phenomena unique to biological systems. Detecting phase transitions in vivo is technically difficult. We present emerging approaches that address this challenge and may guide our understanding of the organization and macroscopic behaviour of biological tissues.
Contrasting impacts of forests on cloud cover based on satellite observations
Authors: Xu Ru , Li Yan , Teuling Adriaan J. , Zhao Lei , Spracklen Dominick V. , Garcia-Carreras Luis , Meier Ronny , Chen Liang , Zheng Youtong , Lin Huiqing , Fu Bojie 
Published: February 2022

AbstractForests play a pivotal role in regulating climate and sustaining the hydrological cycle. The biophysical impacts of forests on clouds, however, remain unclear. Here, we use satellite data to show that forests in different regions have opposite effects on summer cloud cover. We find enhanced clouds over most temperate and boreal forests but inhibited clouds over Amazon, Central Africa, and Southeast US. The spatial variation in the sign of cloud effects is driven by sensible heating, where cloud enhancement is more likely to occur over forests with larger sensible heat, and cloud inhibition over forests with smaller sensible heat. Ongoing forest cover loss has led to cloud increase over forest loss hotspots in the Amazon (+0.78%), Indonesia (+1.19%), and Southeast US (+ 0.09%), but cloud reduction in East Siberia (-0.20%) from 2002-2018. Our data-driven assessment improves mechanistic understanding of forest-cloud interactions, which remain uncertain in Earth system models.
Carbon-coated MoS1.5Te0.5 nanocables for efficient sodium-ion storage in non-aqueous dual-ion batteries
Authors: Liu Yangjie , Hu Xiang , Li Junwei , Zhong Guobao , Yuan Jun , Zhan Hongbing , Tang Yongbing , Wen Zhenhai 
Published: February 2022

AbstractSodium-based dual-ion batteries have received increased attention owing to their appealing cell voltage (i.e., >3 V) and cost-effective features. However, the development of high-performance anode materials is one of the key elements for exploiting this electrochemical energy storage system at practical levels. Here, we report a source-template synthetic strategy for fabricating a variety of nanowire-in-nanotube MSxTey@C (M = Mo, W, Re) structures with an in situ-grown carbon film coating, termed as nanocables. Among the various materials prepared, the MoS1.5Te0.5@C nanocables are investigated as negative electrode active material in combination with expanded graphite at the positive electrode and NaPF6-based non-aqueous electrolyte solutions for dual-ion storage in coin cell configuration. As a result, the dual-ion lab-scale cells demonstrate a prolonged cycling lifespan with 97% capacity retention over 1500 cycles and a reversible capacity of about 101 mAh g−1 at specific capacities (based on the mass of the anode) of 1.0 A g−1 and 5.0 A g−1, respectively.
Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
Authors: De Logu Francesco , Nassini Romina , Hegron Alan , Landini Lorenzo , Jensen Dane D. , Latorre Rocco , Ding Julia , Marini Matilde , Souza Monteiro de Araujo Daniel , Ramírez-Garcia Paulina , Whittaker Michael , Retamal Jeffri , Titiz Mustafa , Innocenti Alessandro , Davis Thomas P. , Veldhuis Nicholas , Schmidt Brian L. , Bunnett Nigel W. , Geppetti Pierangelo 
Published: February 2022

AbstractEfficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
Direct-laser writing for subnanometer focusing and single-molecule imaging
Authors: Coelho Simao , Baek Jongho , Walsh James , Justin Gooding J. , Gaus Katharina 
Published: February 2022

AbstractTwo-photon direct laser writing is an additive fabrication process that utilizes two-photon absorption of tightly focused femtosecond laser pulses to implement spatially controlled polymerization of a liquid-phase photoresist. Two-photon direct laser writing is capable of nanofabricating arbitrary three-dimensional structures with nanometer accuracy. Here, we explore direct laser writing for high-resolution optical microscopy by fabricating unique 3D optical fiducials for single-molecule tracking and 3D single-molecule localization microscopy. By having control over the position and three-dimensional architecture of the fiducials, we improve axial discrimination and demonstrate isotropic subnanometer 3D focusing (<0.8 nm) over tens of micrometers using a standard inverted microscope. We perform 3D single-molecule acquisitions over cellular volumes, unsupervised data acquisition and live-cell single-particle tracking with nanometer accuracy.
The selection force weakens with age because ageing evolves and not vice versa
Authors: Giaimo Stefano , Traulsen Arne 
Published: February 2022

AbstractAccording to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow. The model shows: (i) ageing can stably evolve, but negative ageing cannot; (ii) when ageing is a stable equilibrium, the associated selection force decreases with reproductive age; (iii) non-decreasing selection is either a transient or an unstable phenomenon. Thus, we generalize the classic theory of the evolution of ageing while overturning its logic: the decline of selection with age evolves dynamically, and is not an implicit consequence of certain assumptions.
Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis
Authors: Lionaki Eirini , Gkikas Ilias , Daskalaki Ioanna , Ioannidi Maria-Konstantina , Klapa Maria I. , Tavernarakis Nektarios 
Published: February 2022

AbstractSustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
Inferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks
Authors: Tasaki Shinya , Xu Jishu , Avey Denis R. , Johnson Lynnaun , Petyuk Vladislav A. , Dawe Robert J. , Bennett David A. , Wang Yanling , Gaiteri Chris 
Published: February 2022

AbstractIdentifying the molecular systems and proteins that modify the progression of Alzheimer’s disease and related dementias (ADRD) is central to drug target selection. However, discordance between mRNA and protein abundance, and the scarcity of proteomic data, has limited our ability to advance candidate targets that are mainly based on gene expression. Therefore, by using a deep neural network that predicts protein abundance from mRNA expression, here we attempt to track the early protein drivers of ADRD. Specifically, by applying the clei2block deep learning model to 1192 brain RNA-seq samples, we identify protein modules and disease-associated expression changes that were not directly observed at the mRNA level. Moreover, pseudo-temporal trajectory inference based on the predicted proteome became more closely correlated with cognitive decline and hippocampal atrophy compared to RNA-based trajectories. This suggests that the predicted changes in protein expression could provide a better molecular representation of ADRD progression. Furthermore, overlaying clinical traits on protein pseudotime trajectory identifies protein modules altered before cognitive impairment. These results demonstrate how our method can be used to identify potential early protein drivers and possible drug targets for treating and/or preventing ADRD.
Ligand relay catalysis for cobalt-catalyzed sequential hydrosilylation and hydrohydrazidation of terminal alkynes
Authors: Sun Yufeng , Guo Jun , Shen Xuzhong , Lu Zhan 
Published: February 2022

AbstractSequential double hydrofunctionalizationalization of alkynes is a powerful method to construct useful vicinal compounds. Herein, we report a cobalt-catalyzed sequential hydrosilylation/hydrohydrazidation of alkynes to afford 1,2-N,Si compounds via ligand relay catalysis. A phenomenon of ligand relay is found that the tridentate anionic N-ligand (OPAQ) could capture the cobalt ion from bidentate neutral P-ligand (Xantphos) cobalt complex. This protocol uses three abundant chemical feedstocks, alkynes, silanes, and diazo compounds, and also features operationally simple, mild conditions, low catalyst loading (1 mol%), and excellent functional group tolerance. The 1,2-N,Si compounds can be easily further derivatized to afford various substituted silane derivatives via Si-H functionalization, alcohols via Fleming-Tamao oxidation, free amines and amides via N-N bond cleavage and protection. The asymmetric reaction could also be carried out to afford chiral products with up to 86% ee. The ligand relay has been supported by control experiments and absorption spectra.
Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth
Authors: Miete Cezanne , Solis Gonzalo P. , Koval Alexey , Brückner Martina , Katanaev Vladimir L. , Behrens Jürgen , Bernkopf Dominic B. 
Published: February 2022

AbstractConductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation. Consistently, transient Gαi2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade Gαi2-induced Wnt pathway suppression by decreased Gαi2 expression and inactivating mutations, associated with shorter patient survival. Notably, the Gαi2-activating drug guanabenz inhibited Wnt signaling via conductin, consequently reducing colorectal cancer growth in vitro and in mouse models. In summary, we demonstrate Wnt pathway inhibition via Gαi2-triggered conductin condensation, suggesting a tumor suppressor function for Gαi2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy.
Characterising within-hospital SARS-CoV-2 transmission events using epidemiological and viral genomic data across two pandemic waves
Authors: Lindsey Benjamin B. , Villabona-Arenas Ch. Julián , Campbell Finlay , Keeley Alexander J. , Parker Matthew D. , Shah Dhruv R. , Parsons Helena , Zhang Peijun , Kakkar Nishchay , Gallis Marta , Foulkes Benjamin H. , Wolverson Paige , Louka Stavroula F. , Christou Stella , State Amy , Johnson Katie , Raza Mohammad , Hsu Sharon , Jombart Thibaut , Cori Anne ,   Sheffield COVID-19 Genomics Group, Shah Dhruv R. , Johnson Katie , Hsu Sharon , de Silva Thushan I. , Cope Alison , Ali Nasar , Raghei Rasha , Heffer Joe , Smith Nikki , Whiteley Max , Pohare Manoj , Hansford Samantha E. , Green Luke R. , Wang Dennis , Anckorn Michael , Angyal Adrienn , Brown Rebecca , Hornsby Hailey , Yavuz Mehmet , Groves Danielle C. , Parsons Paul J. , Tucker Rachel M. , Dabrowska Magdalena B. , Saville Thomas , Schutter Jose , Wyles Matthew D. ,   The COVID-19 Genomics UK (COG-UK) consortium, Evans Cariad ,   CMMID COVID-19 working group, Davies Nicholas G. , Pearson Carl A. B. , Quaife Matthew , Tully Damien C. , Abbott Sam , Evans Cariad M. , Partridge David G. , Atkins Katherine E. , Hué Stéphane , de Silva Thushan I. 
Published: February 2022

AbstractHospital outbreaks of COVID19 result in considerable mortality and disruption to healthcare services and yet little is known about transmission within this setting. We characterise within hospital transmission by combining viral genomic and epidemiological data using Bayesian modelling amongst 2181 patients and healthcare workers from a large UK NHS Trust. Transmission events were compared between Wave 1 (1st March to 25th July 2020) and Wave 2 (30th November 2020 to 24th January 2021). We show that staff-to-staff transmissions reduced from 31.6% to 12.9% of all infections. Patient-to-patient transmissions increased from 27.1% to 52.1%. 40%-50% of hospital-onset patient cases resulted in onward transmission compared to 4% of community-acquired cases. Control measures introduced during the pandemic likely reduced transmissions between healthcare workers but were insufficient to prevent increasing numbers of patient-to-patient transmissions. As hospital-acquired cases drive most onward transmission, earlier identification of nosocomial cases will be required to break hospital transmission chains.
Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation
Authors: Zhao Qiang , Han Young-Min , Song Ping , Liu Zhixue , Yuan Zuyi , Zou Ming-Hui 
Published: February 2022

AbstractIn the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 (Stk11) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor (Scf) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11-soluble-Scf axis as a potential cause of DC deficiency syndromes.
Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
Authors: Yan Yiwu , Zhou Bo , Qian Chen , Vasquez Alex , Kamra Mohini , Chatterjee Avradip , Lee Yeon-Joo , Yuan Xiaopu , Ellis Leigh , Di Vizio Dolores , Posadas Edwin M. , Kyprianou Natasha , Knudsen Beatrice S. , Shah Kavita , Murali Ramachandran , Gertych Arkadiusz , You Sungyong , Freeman Michael R. , Yang Wei 
Published: February 2022

AbstractDespite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.