bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
Authors: Jiang Xiangrui , Su Haixia , Shang Weijuan , Zhou Feng , Zhang Yan , Zhao Wenfeng , Zhang Qiumeng , Xie Hang , Jiang Lei , Nie Tianqing , Yang Feipu , Xiong Muya , Huang Xiaoxing , Li Minjun , Chen Ping , Peng Shaoping , Xiao Gengfu , Jiang Hualiang , Tang Renhong , Zhang Leike , Shen Jingshan , Xu Yechun 
Published: October 2023

AbstractThe persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CLpro) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CLpro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CLpro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Extracellular vesicles could be a putative posttranscriptional regulatory mechanism that shapes intracellular RNA levels in Plasmodium falciparum
Authors: Kioko Mwikali , Pance Alena , Mwangi Shaban , Goulding David , Kemp Alison , Rono Martin , Ochola-Oyier Lynette Isabella , Bull Pete C. , Bejon Philip , Rayner Julian C. , Abdi Abdirahman I. 
Published: October 2023

AbstractPlasmodium falciparum secretes extracellular vesicles (PfEVs) that contain parasite-derived RNA. However, the significance of the secreted RNA remains unexplored. Here, we compare secreted and intracellular RNA from asexual cultures of six P. falciparum lines. We find that secretion of RNA via extracellular vesicles is not only periodic throughout the asexual intraerythrocytic developmental cycle but is also highly conserved across P. falciparum isolates. We further demonstrate that the phases of RNA secreted via extracellular vesicles are discernibly shifted compared to those of the intracellular RNA within the secreting whole parasite. Finally, transcripts of genes with no known function during the asexual intraerythrocytic developmental cycle are enriched in PfEVs compared to the whole parasite. We conclude that the secretion of extracellular vesicles could be a putative posttranscriptional RNA regulation mechanism that is part of or synergise the classic RNA decay processes to maintain intracellular RNA levels in P. falciparum.
Challenging an old paradigm by demonstrating transition metal-like chemistry at a neutral nonmetal center
Authors: Biskup David , Schnakenburg Gregor , Boeré René T. , Espinosa Ferao Arturo , Streubel Rainer K. 
Published: October 2023

AbstractWe describe nonmetal adducts of the phosphorus center of terminal phosphinidene complexes using classical C- and N-ligands from metal coordination chemistry. The nature of the L-P bond has been analyzed by various theoretical methods including a refined method on the variation of the Laplacian of electron density ∇2ρ along the L-P bond path. Studies on thermal stability reveal stark differences between N-ligands such as N-methyl imidazole and C-ligands such as tert-butyl isocyanide, including ligand exchange reactions and a surprising formation of white phosphorus. A milestone is the transformation of a nonmetal-bound isocyanide into phosphaguanidine or an acyclic bisaminocarbene bound to phosphorus; the latter is analogous to the chemistry of transition metal-bound isocyanides, and the former reveals the differences. This example has been studied via cutting-edge DFT calculations leading to two pathways differently favored depending on variations in steric demand. This study reveals the emergence of organometallic from coordination chemistry of a neutral nonmetal center.
Partner choice and cooperation in social dilemmas can increase resource inequality
Authors: Stallen Mirre , Snijder Luuk L. , Gross Jörg , Hilbert Leon P. , De Dreu Carsten K. W. 
Published: October 2023

AbstractCooperation is more likely when individuals can choose their interaction partner. However, partner choice may be detrimental in unequal societies, in which individuals differ in available resources and productivity, and thus in their attractiveness as interaction partners. Here we experimentally examine this conjecture in a repeated public goods game. Individuals (n = 336), participating in groups of eight participants, are assigned a high or low endowment and a high or low productivity factor (the value that their cooperation generates), creating four unique participant types. On each round, individuals are either assigned a partner (assigned partner condition) or paired based on their self-indicated preference for a partner type (partner choice condition). Results show that under partner choice, individuals who were assigned a high endowment and high productivity almost exclusively interact with each other, forcing other individuals into less valuable pairs. Consequently, pre-existing resource differences between individuals increase. These findings show how partner choice in social dilemmas can amplify resource inequality.
Chromatin organization drives the search mechanism of nuclear factors
Authors: Mazzocca Matteo , Loffreda Alessia , Colombo Emanuele , Fillot Tom , Gnani Daniela , Falletta Paola , Monteleone Emanuele , Capozi Serena , Bertrand Edouard , Legube Gaelle , Lavagnino Zeno , Tacchetti Carlo , Mazza Davide 
Published: October 2023

AbstractNuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.
Structural insights into the allosteric inhibition of P2X4 receptors
Authors: Shen Cheng , Zhang Yuqing , Cui Wenwen , Zhao Yimeng , Sheng Danqi , Teng Xinyu , Shao Miaoqing , Ichikawa Muneyoshi , Wang Jin , Hattori Motoyuki 
Published: October 2023

AbstractP2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.
Bile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling
Authors: Xiao Jian , Dong Le-Wei , Liu Shuai , Meng Fan-Hua , Xie Chang , Lu Xiao-Yi , Zhang Weiping J. , Luo Jie , Song Bao-Liang 
Published: October 2023

AbstractNiemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the A1272LAL residues dissociates from membrane, exposing the Q1277KR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
Authors: Gautam Milan , Jozic Antony , Su Grace Li-Na , Herrera-Barrera Marco , Curtis Allison , Arrizabalaga Sebastian , Tschetter Wayne , Ryals Renee C. , Sahay Gaurav 
Published: October 2023

AbstractOcular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modified PEG-lipids, and neutral unmodified PEG-lipids (LNP). Subretinal injections of LNPa containing Cre mRNA in the mouse show tdTomato signal in the retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx and LNPz show 27% and 16% photoreceptor transfection, respectively, with striking localization extending from the photoreceptor synaptic pedicle to the outer segments, displaying pan-retinal distribution in the photoreceptors and RPE. LNPx containing Cas9 mRNA and sgAi9 leads to the formation of an oval elongated structure with a neutral charge resulting in 16.4% editing restricted to RPE. Surface modifications of LNPs with PEG variants can alter cellular tropism of mRNA. LNPs enable genome editing in the retina and in the future can be used to correct genetic mutations that lead to blindness.
Unraveling and leveraging in situ surface amorphization for enhanced hydrogen evolution reaction in alkaline media
Authors: Fu Qiang , Wong Lok Wing , Zheng Fangyuan , Zheng Xiaodong , Tsang Chi Shing , Lai Ka Hei , Shen Wenqian , Ly Thuc Hue , Deng Qingming , Zhao Jiong 
Published: October 2023

AbstractSurface amorphization provides electrocatalysts with more active sites and flexibility. However, there is still a lack of experimental observations and mechanistic explanations for the in situ amorphization process and its crucial role. Herein, we propose the concept that by in situ reconstructed amorphous surface, metal phosphorus trichalcogenides could intrinsically offer better catalytic performance for the alkaline hydrogen production. Trace Ru (0.81 wt.%) is doped into NiPS3 nanosheets for alkaline hydrogen production. Using in situ electrochemical transmission electron microscopy technique, we confirmed the amorphization process occurred on the edges of NiPS3 is critical for achieving superior activity. Comprehensive characterizations and theoretical calculations reveal Ru primarily stabilized at edges of NiPS3 through in situ formed amorphous layer containing bridging S22− species, which can effectively reduce the reaction energy barrier. This work emphasizes the critical role of in situ formed active layer and suggests its potential for optimizing catalytic activities of electrocatalysts.
Gut Bacteroides act in a microbial consortium to cause susceptibility to severe malaria
Authors: Mandal Rabindra K. , Mandal Anita , Denny Joshua E. , Namazii Ruth , John Chandy C. , Schmidt Nathan W. 
Published: October 2023

AbstractMalaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.
The parasitic nematode Strongyloides ratti exists predominantly as populations of long-lived asexual lineages
Authors: Cole Rebecca , Holroyd Nancy , Tracey Alan , Berriman Matt , Viney Mark 
Published: October 2023

AbstractNematodes are important parasites of people and animals, and in natural ecosystems they are a major ecological force. Strongyloides ratti is a common parasitic nematode of wild rats and we have investigated its population genetics using single-worm, whole-genome sequencing. We find that S. ratti populations in the UK consist of mixtures of mainly asexual lineages that are widely dispersed across a host population. These parasite lineages are likely very old and may have originated in Asia from where rats originated. Genes that underly the parasitic phase of the parasite’s life cycle are hyperdiverse compared with the rest of the genome, and this may allow the parasites to maximise their fitness in a diverse host population. These patterns of parasitic nematode population genetics have not been found before and may also apply to Strongyloides spp. that infect people, which will affect how we should approach their control.
Characterization of the horse chestnut genome reveals the evolution of aescin and aesculin biosynthesis
Authors: Sun Wei , Yin Qinggang , Wan Huihua , Gao Ranran , Xiong Chao , Xie Chong , Meng Xiangxiao , Mi Yaolei , Wang Xiaotong , Wang Caixia , Chen Weiqiang , Xie Ziyan , Xue Zheyong , Yao Hui , Sun Peng , Xie Xuehua , Hu Zhigang , Nelson David R. , Xu Zhichao , Sun Xinxiao , Chen Shilin 
Published: October 2023

AbstractHorse chestnut (Aesculus chinensis) is an important medicinal tree that contains various bioactive compounds, such as aescin, barrigenol-type triterpenoid saponins (BAT), and aesculin, a glycosylated coumarin. Herein, we report a 470.02 Mb genome assembly and characterize an Aesculus-specific whole-genome duplication event, which leads to the formation and duplication of two triterpenoid biosynthesis-related gene clusters (BGCs). We also show that AcOCS6, AcCYP716A278, AcCYP716A275, and AcCSL1 genes within these two BGCs along with a seed-specific expressed AcBAHD6 are responsible for the formation of aescin. Furthermore, we identify seven Aesculus-originated coumarin glycoside biosynthetic genes and achieve the de novo synthesis of aesculin in E. coli. Collinearity analysis shows that the collinear BGC segments can be traced back to early-diverging angiosperms, and the essential gene-encoding enzymes necessary for BAT biosynthesis are recruited before the splitting of Aesculus, Acer, and Xanthoceras. These findings provide insight on the evolution of gene clusters associated with medicinal tree metabolites.
Cryo-EM structure of cyanophage P-SCSP1u offers insights into DNA gating and evolution of T7-like viruses
Authors: Cai Lanlan , Liu Hang , Zhang Wen , Xiao Shiwei , Zeng Qinglu , Dang Shangyu 
Published: October 2023

AbstractCyanophages, together with their host cyanobacteria, play important roles in marine biogeochemical cycles and control of marine food webs. The recently identified MPP-C (Marine Picocyanobacteria Podovirus clade C) cyanophages, belonging to the T7-like podoviruses, contain the smallest genomes among cyanopodoviruses and exhibit distinct infection kinetics. However, understanding of the MPP-C cyanophage infection process is hindered by the lack of high-resolution structural information. Here, we report the cryo-EM structure of the cyanophage P-SCSP1u, a representative member of the MPP-C phages, in its native form at near-atomic resolution, which reveals the assembly mechanism of the capsid and molecular interaction of the portal-tail complex. Structural comparison of the capsid proteins of P-SCSP1u and other podoviruses with known structures provides insights into the evolution of T7-like viruses. Furthermore, our study provides the near-atomic resolution structure of portal-tail complex for T7-like viruses. On the basis of previously reported structures of phage T7, we identify an additional valve and gate to explain the DNA gating mechanism for the T7-like viruses.
Endothelial discoidin domain receptor 1 senses flow to modulate YAP activation
Authors: Liu Jiayu , Zhao Chuanrong , Xiao Xue , Li Aohan , Liu Yueqi , Zhao Jianan , Fan Linwei , Liang Zhenhui , Pang Wei , Yao Weijuan , Li Wei , Zhou Jing 
Published: October 2023

AbstractMechanotransduction in endothelial cells is critical to maintain vascular homeostasis and can contribute to disease development, yet the molecules responsible for sensing flow remain largely unknown. Here, we demonstrate that the discoidin domain receptor 1 (DDR1) tyrosine kinase is a direct mechanosensor and is essential for connecting the force imposed by shear to the endothelial responses. We identify the flow-induced activation of endothelial DDR1 to be atherogenic. Shear force likely causes conformational changes of DDR1 ectodomain by unfolding its DS-like domain to expose the buried cysteine-287, whose exposure facilitates force-induced receptor oligomerization and phase separation. Upon shearing, DDR1 forms liquid-like biomolecular condensates and co-condenses with YWHAE, leading to nuclear translocation of YAP. Our findings establish a previously uncharacterized role of DDR1 in directly sensing flow, propose a conceptual framework for understanding upstream regulation of the YAP signaling, and offer a mechanism by which endothelial activation of DDR1 promotes atherosclerosis.
Enhanced tribological properties of diesel-based engine oil through synergistic MoS2-graphene nanohybrid additive
Authors: Nagarajan Thachnatharen , Sridewi Nanthini , Wong Weng Pin , Walvekar Rashmi , Khalid Mohammad 
Published: October 2023

AbstractThis research explores the potential of microwave-synthesized MoS2-graphene nanohybrid as additives to enhance the tribological properties of diesel-based engine oil. The synthesis method offers significant advantages, reducing both synthesis time and energy consumption by 90–98% compared to conventional approaches. The synthesized nanohybrids are characterized through FESEM, EDX, XRD, and Raman spectroscopy to understand their morphology and functional group interactions. These nanohybrids are incorporated into 20W40 engine oil following synthesis, and a comprehensive assessment of their properties is conducted. This evaluation covers critical parameters like viscosity index, stability, volatility, as well as tribological properties, oxidation resistance, and thermal conductivity of the oil-nanohybrid system. Results demonstrate that adding just 0.05 wt% of MoS2-graphene nanohybrid leads to a remarkable 58.82% reduction in friction coefficient and a significant 36.26% decrease in the average wear scar diameter. Additionally, oxidation resistance improves by 19.21%, while thermal conductivity increases notably by 19.83% (at 100 °C). The study demonstrates the synergistic effects of these nanohybrids in reducing friction and wear, enhancing oxidation resistance, and improving thermal conductivity. In conclusion, this research highlights the potential of microwave-synthesized MoS2-graphene nanohybrid as promising tribological additives for diesel engine oils. Their successful integration could significantly enhance the performance and durability of critical mechanical components in diesel engines, representing a significant advancement in lubrication technology.
Bacterial networks in Atlantic salmon with Piscirickettsiosis
Authors: Coca Yoandy , Godoy Marcos , Pontigo Juan Pablo , Caro Diego , Maracaja-Coutinho Vinicius , Arias-Carrasco Raúl , Rodríguez-Córdova Leonardo , de Oca Marco Montes , Sáez-Navarrete César , Burbulis Ian 
Published: October 2023

AbstractAn unbalanced composition of gut microbiota in fish is hypothesized to play a role in promoting bacterial infections, but the synergistic or antagonistic interactions between bacterial groups in relation to fish health are not well understood. We report that pathogenic species in the Piscirickettsia, Aeromonas, Renibacterium and Tenacibaculum genera were all detected in the digesta and gut mucosa of healthy Atlantic salmon without clinical signs of disease. Although Piscirickettsia salmonis (and other pathogens) occurred in greater frequencies of fish with clinical Salmonid Rickettsial Septicemia (SRS), the relative abundance was about the same as that observed in healthy fish. Remarkably, the SRS-positive fish presented with a generalized mid-gut dysbiosis and positive growth associations between Piscirickettsiaceae and members of other taxonomic families containing known pathogens. The reconstruction of metabolic phenotypes based on the bacterial networks detected in the gut and mucosa indicated the synthesis of Gram-negative virulence factors such as colanic acid and O-antigen were over-represented in SRS positive fish. This evidence indicates that cooperative interactions between organisms of different taxonomic families within localized bacterial networks might promote an opportunity for P. salmonis to cause clinical SRS in the farm environment.