bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE4drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
Authors: Lee Sangderk , Williams Holden C. , Gorman Amy A. , Devanney Nicholas A. , Harrison Douglas A. , Walsh Adeline E. , Goulding Danielle S. , Tuck Tony , Schwartz James L. , Zajac Diana J. , Macauley Shannon L. , Estus Steven , Julia TCW , Johnson Lance A. , Morganti Josh M.
Published: February 2023

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor ofAPOEwhile also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.
Arachidonic acid does not grease the exocytotic SNARE machinery
Authors: Fasshauer Dirk
Published: February 2023

It has been proposed that arachidonic acid stimulates neurite outgrowth by specifically activating syntaxin 3, a SNARE proteins that mediates the fusion of transport vesicles with the plasma membrane and is thus instrumental for the insertion of new membrane needed for cell growth and proliferation. Considering the important role of arachidonic acid and other polyunsaturated fatty acids for human health, these findings would have wide implications for everyday life. Here, I have report that the effect of arachidonic acid is caused by a nonspecific, detergent-like action on SNARE proteinsin vitro. The action requires unphysiologically high concentrations, is mimicked by several detergents or detergent-like substances forming micelles regardless of whether arachidonic acid is present or not, and is thus highly unlikely to be of any physiological significance for SNARE function.
SUMOylation of PTEN promotes DNA end resection through directly dephosphorylating 53BP1 in homologous recombination repair
Authors: He Jianfeng , Guo Yanmin , Deng Rong , Li Lian , Huang Caihu , Chen Ran , Wang Yanli , Huang Jian , Cheng Jinke , Chen Guo-Qiang , Zheng Junke , Zhao Xian , Yu Jianxiu
Published: February 2023

Homologous recombination (HR) repair for DNA double-strand breaks (DSBs) is critical for maintaining genome stability and cell survival. Nuclear PTEN plays a key role in HR repair, but the underlying mechanism remains largely elusive. We find that SUMOylated PTEN promotes HR repair but represses non-homologous end joining (NHEJ) repair by directly dephosphorylating 53BP1. During DNA damage responses (DDR), p14ARF was phosphorylated and then interacted efficiently with PTEN, thus promoting PTEN SUMOylation as an atypical SUMO E3 ligase. Interestingly, SUMOylated PTEN was subsequently recruited to the chromatin at DNA-break sites. This was because that SUMO1 conjugated to PTEN was recognized and bound by the SUMO-interacting motif (SIM) of BRCA1, which has been located to the core of 53BP1 foci on the chromatin during S/G2 stage. Further, these chromatin-loaded PTEN directly and specifically dephosphorylated pT543 of 53BP1, resulting in the dissociation of 53BP1-complex, which facilitated DNA end resection and ongoing HR repair. The SUMOylation-deficient PTENK254Rmice also showed decreased DNA damage repairin vivo.Blocking PTEN SUMOylation pathway with either an SUMOylation inhibitor or a p14ARF(2-13) peptide sensitized tumor cells to chemotherapy. Our study therefore provides the new mechanistic understanding of PTEN in HR repair and clinical intervention of chemo-resistant tumors.
Excess PrPCinhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
Authors: Tao Jing , Zeng Yanping , Dai Bin , Liu Yin , Pan Xiaohan , Wang Li-Qiang , Chen Jie , Zhou Yu , Lu Zuneng , Xie Liwei , Liang Yi
Published: February 2023

The cellular prion protein (PrPC), a glycoprotein existing in membrane-bound and cytoplasmic forms, has functional importance in skeletal muscle, but the mechanism behind the phenomenon remains poorly understood. Here we report that PrPCis overexpressed and located in the cytoplasm of the skeletal muscle of six myopathy patients; cytoplasmic PrPCstrongly inhibits skeletal muscle cell autophagy and blocks myoblast differentiation. PrPCselectively binds to a subset of miRNAs during myoblast differentiation, and the co-localization of PrPCwith miR-214-3p was clearly observed in the skeletal muscle of six myopathy patients but not in that of four age-matched controls. We demonstrate that PrPCis overexpressed in skeletal muscle cells under pathological conditions and inhibits muscle cell differentiation via physically interacting with a subset of miRNAs to significantly inhibit autophagy-related protein 5-dependent autophagy, and selectively recruits these miRNAs into phase-separated condensates in living myoblasts, which in turn greatly enhances liquid–liquid phase separation (LLPS) of PrPCand results in the subsequent PrP aggregation and muscle bundle formation in myopathy patients characterized by incomplete muscle regeneration. Our findings show how excess PrPCcan inhibit muscle cell differentiation via miRNA-enhanced LLPS implicated in myopathy.
Towards a more robust non-invasive assessment of functional connectivity
Authors: Westner Britta U. , Kujala Jan , Gross Joachim , Schoffelen Jan-Mathijs
Published: February 2023

Non-invasive evaluation of functional connectivity, based on source-reconstructed estimates of phase-difference-based metrics, is notoriously non-robust. This is due to a combination of factors, ranging from a misspecification of seed regions to suboptimal baseline assumptions, and residual signal leakage. In this work, we propose a new analysis scheme of source level phase-difference-based connectivity, which is aimed at optimizing the detection of interacting brain regions. Our approach is based on the combined use of sensor subsampling and dual-source beamformer estimation of all-to-all connectivity on a prespecified dipolar grid. First, a pairwise two-dipole model, to account for reciprocal leakage in the estimation of the localized signals, allows for a usable approximation of the pairwise bias in connectivity due to residual leakage of ‘third party’ noise. Secondly, using sensor array subsampling, the recreation of multiple connectivity maps using different subsets of sensors allows for the identification of consistent spatially localized peaks in the 6-dimensional connectivity maps, indicative of true brain region interactions. These steps are combined with the subtraction of null coherence estimates to obtain the final coherence maps. With extensive simulations, we compared different analysis schemes for their detection rate of connected dipoles, as a function of signal-to-noise ratio, phase difference and connection strength. We demonstrate superiority of the proposed analysis scheme in comparison to single-dipole models, or an approach that discards the zero phase difference component of the connectivity. We conclude that the proposed pipeline allows for a more robust identification of functional connectivity in experimental data, opening up new possibilities to study brain networks with mechanistically inspired connectivity measures in cognition and in the clinic.
Helixer–de novoPrediction of Primary Eukaryotic Gene Models Combining Deep Learning and a Hidden Markov Model
Authors: Holst Felix , Bolger Anthony , Günther Christopher , Maß Janina , Triesch Sebastian , Kindel Felicitas , Kiel Niklas , Saadat Nima , Ebenhöh Oliver , Usadel Björn , Schwacke Rainer , Bolger Marie , Weber Andreas P.M. , Denton Alisandra K.
Published: February 2023

Abstract

Gene structural annotation is a critical step in obtaining biological knowledge from genome sequences yet remains a major challenge in genomics projects. Currentde novoHidden Markov Models are limited in their capacity to model biological complexity; while current pipelines are resource-intensive and their results vary in quality with the available extrinsic data. Here, we build on our previous work in applying Deep Learning to gene calling to make a fully applicable, fast and user friendly tool for predicting primary gene models from DNA sequence alone. The quality is state-of-the-art, with predictions scoring closer by most measures to the references than to predictions from otherde novotools. Helixer’s predictions can be used as is or could be integrated in pipelines to boost quality further. Moreover, there is substantial potential for further improvements and advancements in gene calling with Deep Learning.

Helixer is open source and available athttps://github.com/weberlab-hhu/Helixer

A web interface is available athttps://www.plabipd.de/helixer_main.html
A comprehensivein vivoscreen of yeast farnesyltransferase activity reveals broad reactivity across a majority of CXXX sequences
Authors: Kim June H. , Hildebrandt Emily R. , Sarkar Anushka , Yeung Wayland , Waldon La Ryel A. , Kannan Natarajan , Schmidt Walter K.
Published: February 2023

The current understanding of farnesyltransferase (FTase) specificity was pioneered through investigations of reporters like Ras and Ras-related proteins that possess a C-terminal CaaX motif that consists of 4 amino acid residues: Cysteine – aliphatic1– aliphatic2– variable (X). These studies led to the finding that proteins with the CaaX motif are subject to a 3-step post-translational modification pathway involving farnesylation, proteolysis, and carboxylmethylation. Emerging evidence indicates, however, that FTase can farnesylate sequences outside the CaaX motif and that these sequences do not undergo the canonical 3-step pathway. In this work, we report a comprehensive evaluation of all possible CXXX sequences as FTase targets using the reporter Ydj1, an Hsp40 chaperone that only requires farnesylation for its activity. Our genetic and high throughput sequencing approach reveals an unprecedented profile of sequences that yeast FTase can recognizein vivo, which effectively expands the potential target space of FTase within the yeast proteome. We also document that yeast FTase specificity is majorly influenced by restrictive amino acids at a2and X positions as opposed to the resemblance of CaaX motif as previously regarded. This first complete evaluation of CXXX space expands the complexity of protein isoprenylation and marks a key step forward in understanding the potential scope of targets for this isoprenylation pathway.
Metagenomics of culture isolates and insect tissue illuminate the evolution ofWolbachia,RickettsiaandBartonellasymbionts inCtenocephalidesspp. fleas
Authors: Beliavskaia Alexandra , Tan Kim-Kee , Sinha Amit , Husin Nurul Aini , Lim Fang Shiang , Loong Shih Keng , Bell-Sakyi Lesley , Carlow Clotilde K. S. , Abubakar Sazaly , Darby Alistair C. , Makepeace Benjamin L. , Khoo Jing Jing
Published: February 2023

While fleas are often perceived simply as a biting nuisance and cause of allergic dermatitis, they represent important disease vectors worldwide, especially for bacterial zoonoses such as plague (transmitted by rodent fleas) and some of the rickettsioses and bartonelloses. The cosmopolitan cat (Ctenocephalidesfelis) and dog (C. canis) fleas, as well asC. orientis(restricted to tropical and subtropical Asia), breed in human dwellings and are vectors of cat-scratch fever (caused byBartonellaspp.) andRickettsiaspp. of the so-called "transitional group". The latter includesR. felis(agent of flea-borne spotted fever) andR. asembonensis, an emerging pathogen. The relatively depauperate flea microbiome can also contain arthropod-specific endosymbionts, including a diverse range ofWolbachiastrains. Here, we present circularized genome assemblies for twoC. orientis-associated pathogens (Bartonella clarridgeiaeandR. asembonensis) from Malaysia, a novelWolbachiastrain (wCori), and theC. orientismitochondrion; all obtained by direct metagenomic sequencing of flea tissues. Moreover, we isolated twoWolbachiastrains from MalaysianC. felisinto tick cell culture and recovered circularized genome assemblies for both, one of which (wCfeF) is newly sequenced. We demonstrate that the threeWolbachiastrains are representatives of different major clades ("supergroups"), two of which appear to be flea-specific. TheseWolbachiagenomes exhibit unique combinations of features associated with reproductive parasitism or mutualism, including prophage WO, cytoplasmic incompatibility factors, and the biotin operon of obligate intracellular microbes. The first circularized assembly forR. asembonensisincludes a plasmid with a markedly different structure and gene content compared to the published plasmid; moreover, this novel plasmid was also detected in cat flea metagenomes from the US. Analysis of loci under positive selection in the transitional group revealed genes involved in host-pathogen interactions that may facilitate host switching. Finally, the firstB. clarridgeiaegenome from Asia exhibited largescale genome stability compared to isolates from other continents, except for SNPs in regions predicted to mediate interactions with the vertebrate host. These findings highlight the paucity of data on the genomic diversity ofCtenocephalides-associated bacteria and raise questions regarding how interactions between members of the flea microbiome might influence vector competence.
Structural basis for inactivation of PRC2 by G-quadruplex RNA
Authors: Song Jiarui , Gooding Anne R. , Hemphill Wayne O. , Kasinath Vignesh , Cech Thomas R.
Published: February 2023

The histone methyltransferase PRC2 (Polycomb Repressive Complex 2) silences genes via successively attaching three methyl groups to lysine 27 of histone H3. PRC2 associates with numerous pre-mRNA and lncRNA transcripts with a binding preference for G-quadruplex RNA. Here, we present a 3.3Å-resolution cryo-EM structure of PRC2 bound to a G-quadruplex RNA. Notably, RNA mediates the dimerization of PRC2 by binding both protomers and inducing a protein interface comprised of two copies of the catalytic subunit EZH2, which limits nucleosome DNA interaction and occludes H3 tail accessibility to the active site. Our results reveal an unexpected mechanism for RNA-mediated inactivation of a chromatin-modifying enzyme. Furthermore, the flexible loop of EZH2 that helps stabilize RNA binding also facilitates the handoff between RNA and DNA, an activity implicated in PRC2 regulation by RNA.

One-Sentence Summary

Cryo-EM structure of RNA-bound PRC2 dimer elucidates an unexpected mechanism of PRC2 inhibition by RNA.
Mitochondrial Membranes: Model Lipid Compositions, Material Properties and the Changing Curvature of Cardiolipin
Authors: Konar Sukanya , Arif Hina , Allolio Christoph
Published: February 2023

Mammalian andDrosophila Melanogastermodel mitochondrial membrane compositions are constructed from experimental lipidomics data. Simplified compositions for inner and outer mitochondrial membranes are provided, including an asymmetric inner mitochondrial membrane. We performed atomistic molecular dynamics simulations of these membranes and computed their material properties. When comparing these properties to those obtained by extrapolation from their constituting lipids, we find good overall agreement. Finally, we analyzed the curvature effect of cardiolipin, considering ion concentration effects, oxidation and pH. We draw the conclusion that cardiolipin negative curvature is most likely due to counterion effects, such as cation adsorption, in particular of H3O+. This oft-neglected effect might account for the puzzling behavior of this lipid.

SIGNIFICANCE

Mitochondrial membranes are of fundamental interest to the pathogenesis of neurodegenerative diseases. The biophysics of mitochondrial membranes can be expected to profoundly influence both the electron transport chain and larger-scale mitochondrial morphology. We provide model mitochondrial membrane compositions and examine their mechanic properties. Reconstructing these properties from their constituent lipids, we facilitate the creation of mesoscopic models. Cardiolipin, as the key mitochondrial lipid is given special attention. We find that its mechanical properties, in particular its curvature, are not constant, but highly dependent on specific ion effects, concentration and oxidation state.
Phytoplankton adaptive resilience to climate change collapses in case of extreme events – A modeling study
Authors: Sauterey Boris , Le Gland Guillaume , Cermeño Pedro , Aumont Olivier , Lévy Marina , Vallina Sergio M.
Published: February 2023

As climate change unravels, ecosystems are facing a warming of the climate and an increase in extreme heat events that are unprecedented in recent geological history. We know very little of the ability of oceanic phytoplankton communities, key players in the regulation of Earth’s climate by the oceans, to adapt to these changes. Quantifying the resilience of phytoplankton communities to environmental stressors by means of adaptive evolution is however crucial to accurately predict the response of marine ecosystems to climate change. In this work, we use an eco-evolutionary model to simulate the adaptive response of marine phytoplankton to temperature changes in an initially temperate oligotrophic water-column. By exploring a wide range of scenarios of phytoplankton adaptive capacity, we find that phytoplankton can adapt to temperature increases –even very large ones– as long as they occur over the time scale of a century. However, when rapid and extreme events of temperature change are considered, the phytoplankton adaptive capacity breaks down in a number of our scenarios in which primary productivity plummets as a result. This suggests that current Earth System Models implicitly assuming perfect and instantaneous phytoplankton adaptation to temperature might be overestimating the phytoplankton’s resilience to climate change.
Two novel flavi-like viruses shed light on the plant infecting koshoviruses
Authors: Debat Humberto , Bejerman Nicolás
Published: February 2023

The familyFlaviviridaeis composed of viruses with a positive sense single-stranded RNA genome and includes viruses that are important veterinary and human pathogens. Most members of the family are arthropod and vertebrate-infecting viruses but more recently flavi-like divergent viruses have been identified in marine invertebrate and vertebrate hosts. The striking discovery of gentian Kobu-sho-associated virus (GKaV) expanded the host range of flaviviruses to plants, which was complemented by a recently reported flavi-like virus in carrot, suggesting they could be grouped in a proposed Koshovirus genus. Here, we report the identification in transcriptomic datasets and characterization of two novel RNA viruses from the flowering plantsCoptis teetaandSonchus asper, which have genetic and evolutionary affinity to koshoviruses. These two new viruses are members of novel species which were dubbed Coptis flavi-like virus 1 (CopV1) and Sonchus flavi-like virus 1 (SonV1) and with a viral monopartite RNA of ca. 24 kb, likely have the longest genomes among plant-associated RNA viruses yet. Structural and functional annotations of the polyproteins of all koshoviruses resulted in the detection not only of the expected helicase and RNA-dependent RNA polymerase, but also several additional divergent domains such as AlkB oxigenase, Trypsin-like serine protease, methyltransferase, and envelope E1 flavi-like domains. Phylogenetic analysis groups in a monophyletic clade CopV1, SonV1, GKaV and the carrot flavi-like virus robustly supporting the recently proposed genus Koshovirus of plant infecting flavi-like viruses.
Bilateral asymmetric hip stiffness applied by a robotic hip exoskeleton elicits kinematic and kinetic adaptation
Authors: Abdikadirova Banu , Price Mark , Jaramillo Jonaz Moreno , Hoogkamer Wouter , Huber Meghan E.
Published: February 2023

Wearable robotic exoskeletons hold great promise for gait rehabilitation as portable, accessible tools. However, a better understanding of the potential for exoskeletons to elicit neural adaptation—a critical component of neurological gait rehabilitation—is needed. In this study, we investigated whether humans adapt to bilateral asymmetric stiffness perturbations applied by a hip exoskeleton, taking inspiration from asymmetry augmentation strategies used in split-belt treadmill training. During walking, we applied torques about the hip joints to repel the thigh away from a neutral position on the left side and attract the thigh toward a neutral position on the right side. Six participants performed an adaptation walking trial on a treadmill while wearing the exoskeleton. The exoskeleton elicited time-varying changes and aftereffects in step length and propulsive/braking ground reaction forces, indicating behavioral signatures of neural adaptation. These responses resemble typical responses to split-belt treadmill training, suggesting that the proposed intervention with a robotic hip exoskeleton may be an effective approach to (re)training symmetric gait.
AnAnaplasma phagocytophilumT4SS effector, AteA, is essential for tick infection
Authors: Park Jason M. , Genera Brittany M. , Fahy Deirdre , Swallow Kyle T. , Nelson Curtis M. , Oliver Jonathan D. , Shaw Dana K. , Munderloh Ulrike G. , Brayton Kelly A.
Published: February 2023

Pathogens must adapt to disparate environments in permissive host species, a feat that is especially pronounced for vector-borne microbes, which transition between vertebrate hosts and arthropod vectors to complete their lifecycles. Most knowledge about arthropod-vectored bacterial pathogens centers on their life in the mammalian host, where disease occurs. However, disease outbreaks are driven by the arthropod vectors. Adapting to the arthropod is critical for obligate intracellular rickettsial pathogens, as they depend on eukaryotic cells for survival. To manipulate the intracellular environment, these bacteria use Type IV Secretion Systems (T4SS) to deliver effectors into the host cell. To date, few rickettsial T4SS translocated effectors have been identified and have only been examined in the context of mammalian infection. We identified an effector from the tick-borne rickettsial pathogenAnaplasma phagocytophilum, HGE1_02492, as critical for survival in tick cells and acquisition by ticksin vivo. Conversely, HGE1_02492 was dispensable during mammalian cell culture and murine infection. We show HGE1_02492 is translocatable in a T4SS-dependent manner to the host cell cytosol. In eukaryotic cells, the HGE1_02492 localized with cortical actin filaments, which is dependent on multiple sub-domains of the protein. HGE1_02492 is the first arthropod-vector specific T4SS translocated effector identified from a rickettsial pathogen. Moreover, the subcellular target of HGE1_02492 suggests thatA. phagocytophilumis manipulating actin to enable arthropod colonization. Based on these findings, we propose the name AteA forAnaplasma(phagocytophilum) tick effector A. Altogether, we show thatA. phagocytophilumuses distinct strategies to cycle between mammals and arthropods.

Importance

Ticks are the number one vector of pathogens for livestock worldwide and for humans in the US. The biology of tick transmission is an understudied area. Understanding this critical interaction could provide opportunities to affect the course of disease spread. In this study we examined the zoonotic tick-borne agentAnaplasma phagocytophilumand identified a secreted protein, AteA, that is expressed in a tick-specific manner. These secreted proteins, termed effectors, are the first proteins to interact with the host environment. AteA is essential for survival in ticks and appears to interact with cortical actin. Most effector proteins are studied in the context of the mammalian host; however, understanding how this unique set of proteins affect tick transmission is critical to developing interventions.
Quantitative analyses of interactions between SpoVG and RNA/DNA
Authors: Saylor Timothy C. , Savage Christina R. , Krusenstjerna Andrew C. , Jusufovic Nerina , Zückert Wolfram R. , Brissette Catherine A. , Motaleb Md. , Schlax Paula J. , Stevenson Brian
Published: February 2023

1.

TheBorrelia burgdorferiSpoVG protein has previously been found to be a DNA- and RNA-binding protein. To aid in the elucidation of ligand motifs, affinities for numerous RNAs, ssDNAs, and dsDNAs were measured and compared. The loci used in the study werespoVG, glpFKD, erpAB, bb0242, flaB, andospAB, with particular focus on the untranslated 5’ portion of the mRNAs. Performing binding and competition assays yielded that the 5’ end ofspoVGmRNA had the highest affinity while the lowest observed affinity was to the 5’ end offlaBmRNA. Mutagenesis studies ofspoVGRNA and ssDNA sequences suggested that the formation of SpoVG-nucleic acid complexes are not entirely dependent on either sequence or structure. Additionally, exchanging uracil for thymine in ssDNAs did not affect protein-nucleic acid complex formation.
Library preparation method and DNA source influence endogenous DNA recovery from 100-year-old avian museum specimens
Authors: Settlecowski Amie E. , Marks Ben D. , Manthey Joseph D.
Published: February 2023

Museum specimens collected prior to cryogenic tissue storage are increasingly being used as genetic resources, and though high throughput sequencing is becoming more cost-efficient, whole genome sequencing (WGS) of historical DNA (hDNA) remains inefficient and costly due to its short fragment sizes and high loads of exogenous DNA, among other factors. It is also unclear how sequencing efficiency is influenced by DNA source. We aimed to identify the most efficient method and DNA source for collecting WGS data from avian museum specimens. We analyzed low-coverage WGS from 60 DNA libraries prepared from four American Robin (Turdus migratorius) and four Abyssinian Thrush (Turdus abyssinicus) specimens collected in the 1920s. We compared DNA source (toepad versus incision-line skin clip) and three library preparation methods: 1) double-stranded, single tube (KAPA); 2) single-stranded, multi-tube (IDT); and 3) single-stranded, single-tube (Claret Bioscience). We found that the multi-tube ssDNA method resulted in significantly greater endogenous DNA content, average read length, and sequencing efficiency than the other tested methods. We also tested whether a predigestion step reduced exogenous DNA in libraries from one specimen per species and found promising results that warrant further study. The ~10% increase in average sequencing efficiency of the best performing method over a commonly implemented dsDNA library preparation method has the potential to significantly increase WGS coverage of hDNA from bird specimens. Future work should evaluate the threshold for specimen age at which these results hold and how the combination of library preparation method and DNA source influence WGS in other taxa.
Mono-ADP-ribosyltransferase 1 (Artc1)-deficiency decreases tumorigenesis, increases inflammation, decreases cardiac contractility, and reduces survival
Authors: Ishiwata-Endo Hiroko , Kato Jiro , Oda Hirotake , Sun Junhui , Yu Zu-Xi , Liu Chengyu , Springer Danielle A. , Dagur Pradeep , Lizak Martin J. , Murphy Elizabeth , Moss Joel
Published: February 2023

Arginine-specific mono-ADP-ribosylation is a reversible post-translational modification; arginine-specific, cholera toxin-like mono-ADP-ribosyltransferases (ARTCs) transfer ADP-ribose from NAD+to arginine, followed by cleavage of ADP-ribose-(arginine)protein bond by ADP-ribosylarginine hydrolase 1 (ARH1), generating unmodified (arginine)protein. ARTC1 has been shown to enhance tumorigenicity as doesArh1deficiency. In this study,Artc1-KO andArtc1/Arh1-double-KO mice showed decreased spontaneous tumorigenesis and increased age-dependent, multi-organ inflammation with upregulation of pro-inflammatory cytokine TNF-α. In a xenograft model using tumorigenicArh1-KO mouse embryonic fibroblasts (MEFs), tumorigenicity was decreased inArtc1-KO and heterozygous recipient mice, with tumor infiltration by CD8+T cells and macrophages, leading to necroptosis, suggesting that ARTC1 promotes the tumor microenvironment. Furthermore,Artc1/Arh1-double-KO MEFs showed decreased tumorigenesis in nude mice, showing that tumor cells as well as tumor microenvironment require ARTC1. By echocardiography and MRI,Artc1-KO and heterozygous mice showed male-specific, reduced myocardial contractility. Furthermore,Artc1-KO male hearts exhibited enhanced susceptibility to myocardial ischemia-reperfusion-induced injury with increased receptor-interacting protein kinase 3 (RIP3) protein levels compared to WT mice, suggesting that ARTC1 suppresses necroptosis. Overall survival rate ofArtc1-KO was less than theirArtc1-WT counterparts, primarily due to enhanced immune response and inflammation. Thus, anti-ARTC1 agents may reduce tumorigenesis but may increase multi-organ inflammation and decrease cardiac contractility.

Graphical Abstract
A SARS-CoV-2 vaccine designed for manufacturability results in unexpected potency and non-waning humoral response
Authors: Campbell Elliot , Dobkin Julie , Osorio Louis , Kolloli Afsal , Ramasamy Santhamani , Kumar Ranjeet , Sant’Angelo Derek B. , Subbian Selvakumar , Denzin Lisa K. , Anderson Stephen
Published: February 2023

The rapid development of several highly efficacious SARS-CoV-2 vaccines was an unprecedented scientific achievement that saved millions of lives. However, now that SARS-CoV-2 is transitioning to the endemic stage, there exists an unmet need for new vaccines that provide durable immunity, protection against variants, and can be more easily manufactured and distributed. Here we describe a novel protein component vaccine candidate, MT-001, based on a fragment of the SARS-CoV-2 spike protein that encompasses the receptor binding domain (RBD). Mice and hamsters immunized with a prime-boost regimen of MT-001 demonstrated extremely high anti-spike IgG titers, and remarkably this humoral response did not appreciably wane for up to 12 months following vaccination. Further, virus neutralization titers, including titers against variants such as Delta and Omicron BA.1, remained high without the requirement for subsequent boosting. MT-001 was designed for manufacturability and ease of distribution, and we demonstrate that these attributes are not inconsistent with a highly immunogenic vaccine that confers durable and broad immunity to SARS-CoV-2 and its emerging variants. These properties suggest MT-001 could be a valuable new addition to the toolbox of SARS-CoV-2 vaccines and other interventions to prevent infection and curtail additional morbidity and mortality from the ongoing worldwide pandemic.
Single-cell transcriptomic analyses reveal the cellular and genetic basis of aquatic locomotion in scyphozoan jellyfish
Authors: Li Yongxue , Peng Saijun , Liu Yali , He Kai , Sun Ke , Yu Zhangyi , Ma Yuanqing , Wang Fanghan , Xu Pengzhen , Sun Tingting , Zheng Huiwen , Ye Lijing , Wang Lei , Hao Wenjin , Zhao Jianmin , Lin Qiang , Chen Kai , Dong Zhijun
Published: February 2023

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing. More experimental evidence from whole-mount ISH assay and RNAi assays will be added to support the viewpoints. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Boundary stacking interactions enable cross-TAD enhancer-promoter communication during limb development
Authors: Hung Tzu-Chiao , Kingsley David M. , Boettiger Alistair
Published: February 2023

While long-range enhancers and their target promoters are frequently contained within a TAD, many developmentally important genes have their promoter and enhancers within different TADs. Hypotheses about molecular mechanisms enabling such cross-TAD interactions remain to be assessed. To test these hypotheses, we use Optical Reconstruction of Chromatin Architecture (ORCA) to characterize the conformations of thePitx1locus on thousands of single chromosomes in developing mouse limbs. Our data supports a model in which neighboring boundaries are stacked with each other as a result of loop-extrusion, bringing boundary-proximalcis-elements into contact. This stacking interaction also explains the appearance of architectural stripes in the population average maps (e.g. Hi-C data). Through molecular dynamics simulations, we further propose that increasing boundary strengths facilitates the formation of the stacked boundary conformation, counter-intuitively facilitating border bypass. This work provides a revised view of the TAD borders’ function, both facilitating as well as preventingcis-regulatory interactions, and introduces a framework to distinguish border-crossing from border-respecting enhancer-promoter pairs.
A fast, robust method for quantitative assessment of collagen fibril architecture from transmission electron micrographs
Authors: Rego Bruno V. , Weiss Dar , Humphrey Jay D.
Published: February 2023

Collagen is the most abundant protein in mammals; it exhibits a hierarchical organization and provides structural support to a wide range of soft tissues, including blood vessels. The architecture of collagen fibrils dictates vascular stiffness and strength, and changes therein can contribute to disease progression. While transmission electron microscopy (TEM) is routinely used to examine collagen fibrils under normal and pathological conditions, computational tools that enable fast and minimally subjective quantitative assessment remain lacking. In the present study, we describe a novel semi-automated image processing and statistical modeling pipeline for segmenting individual collagen fibrils from TEM images and quantifying key metrics of interest, including fibril crosssectional area and aspect ratio. For validation, we show illustrative results for adventitial collagen in the thoracic aorta from three different mouse models.
Inferring context-dependent computations through linear approximations of prefrontal cortex dynamics
Authors: Soldado-Magraner Joana , Mante Valerio , Sahani Maneesh
Published: February 2023

The complex neural population activity of prefrontal cortex (PFC) is a hallmark of cognitive processes. How these rich dynamics emerge and support neural computations is largely unknown. Here, we infer mechanisms underlying the context-dependent selection and integration of sensory inputs by fitting dynamical models to PFC population responses of behaving monkeys. A class of models implementing linear dynamics driven by external inputs accurately captured the PFC responses within each context, achieving performance comparable to models without linear constraints. Two distinct mechanisms of input selection and integration were equally consistent with the data. One implemented context-dependent recurrent dynamics, as previously proposed, and relied on transient input amplification. The other relied on the subtle contextual modulation of the inputs, providing quantitative constraints on the attentional effects in sensory areas required to explain flexible PFC responses and behavior. Both mechanisms consistently revealed properties of inputs and recurrent dynamics missing in more simplified, incomplete descriptions of PFC responses. By revealing mechanisms consistent with rich cortical dynamics, our modeling approach provides a principled and general framework to link neural population activity and computation.
C3 in the 10-20 system may not be the best target for the motor hand area
Authors: Kim Hakjoo , Wright David L. , Rhee Joohyun , Kim Taewon
Published: February 2023

The C3 region in the international 10-20 system for electroencephalography (EEG) recording is assumed to represent the right motor hand area. Therefore, in the absence of transcranial magnetic stimulation (TMS) or a neuronavigational system, neuromodulation methods, such as transcranial direct current stimulation, target C3 or C4, based on the international 10-20 system, to influence the cortical excitability of the right and left hand, respectively. The purpose of this study is to compare the peak-to-peak motor evoked potential (MEP) amplitudes of the right first dorsal interosseus (FDI) muscle after single-pulse TMS at C3, C3h, and C1. Using an intensity of 110% of the resting motor threshold, 15 individual MEPs from each of C3, C3h, C1, and hotspots were randomly recorded from FDI for sixteen right-handed undergraduate students. Average MEPs were greatest at C3h and C1, with both being larger than those recorded at C3. These data are congruent with recent findings using topographic analysis of individual MRIs that revealed poor correspondence between C3/C4 and the respective hand knob. Implications for the use of scalp locations determined using the 10-20 system for localizing the hand area are highlighted.

Highlights

MEPs recorded at C3h and C1 were larger than those recorded at C3.

Scalp locations other than C3 offer a more accurate estimation of human hand area.
Phenotype switching of the mutation rate facilitates adaptive evolution
Authors: Lobinska Gabriela , Pilpel Yitzhak , Ram Yoav
Published: February 2023

The mutation rate plays an important role in adaptive evolution. It can be modified by mutator and anti-mutator alleles. Recent empirical evidence hints that the mutation rate may vary among genetically identical individuals: empirical evidence from bacteria suggests that the mutation rate can be affected by translation errors and expression noise in various proteins. Importantly, this non-genetic variation may be heritable via a transgenerational epigenetic mode of inheritance, giving rise to a mutator phenotype that is independent from mutator alleles. Here we investigate mathematically how the rate of adaptive evolution is affected by the rate of mutation rate phenotype switching. We model an asexual population with two mutation rate phenotypes, non-mutator and mutator. An offspring may switch from its parental phenotype to the other phenotype. We find that switching rates that correspond to so-far empirically described non-genetic systems of inheritance of the mutation rate lead to higher rates of adaptation on various fitness landscapes. These switching rates can maintain within the same individuals both a mutator phenotype and pre-existing mutations, a combination that facilitates adaptation. Moreover, non-genetic inheritance increases the proportion of mutators in the population, which in turn increases the probability of hitchhiking of the mutator phenotype with adaptive mutations. This in turns facilitates the acquisition of additional adaptive mutations. Our results rationalize recently observed noise in the expression of proteins that affect the mutation rate and suggest that non-genetic inheritance of this phenotype may facilitate evolutionary adaptive processes.
Transferrin-induced signaling through transferrin receptor and AKT kinase mediates formation of Rab8- and MICAL-L1-positive tubules involved in receptor recycling
Authors: Rangaraj Nandini , Vaibhava Vipul , Sudhakar Cherukuri , Moharir Shivranjani C , Swarup Ghanshyam
Published: February 2023

Transferrin and its receptor play an important role in iron homeostasis. Binding of transferrin to its receptor (TFRC, transferrin receptor protein 1) initiates endocytic trafficking and subsequent recycling of TFRC to the plasma membrane. RAB8-positive tubules emanating from the endocytic recycling compartment play an important role in receptor recycling. However, the signaling pathways or mechanisms that mediate formation of RAB8-positive tubules are not clear. Here, we have investigated the role of transferrin-induced signaling in the regulation of RAB8- and MICAL-L1-positive tubules. Addition of transferrin to the serum starved HeLa cells resulted in enhanced recruitment of RAB8 as well as MICAL-L1 to the tubules, which was mediated by TFRC. Dynasore, an inhibitor of dynamin and endocytosis, completely blocked transferrin-induced formation of RAB8/MICAL-L1-positive tubules. RAB8 showed strong colocalization with MICAL-L1 on the tubules. Blocking of SRC or AKT kinase activity by specific inhibitors abolished transferrin-induced recruitment of RAB8 and MICAL-L1 to the tubules. Recycling of transferrin receptor was inhibited by blocking of AKT activity. TBC1D17, a GTPase activating protein for RAB8, inhibited RAB8/MICAL-L1-positive tubule formation. A phospho-mimicking mutant S366D of TBC1D17 did not inhibit formation of RAB8-positive tubules. Overall, these results show that transferrin induces TFRC mediated signaling dependent on endocytosis that is essential for the formation of RAB8- and MICAL-L1-positive tubules involved in recycling of transferrin receptor. Our results also show that AKT regulates transferrin-induced formation of RAB8- and MICAL-L1-positive tubules, which might be mediated by phosphorylation of TBC1D17.
The representational dynamics of the animal appearance bias in human visual cortex are indicative of fast feedforward processing
Authors: Chen Chiu-Yueh , Leys Gaëlle , Bracci Stefania , de Beeck Hans Op
Published: February 2023

The human visual system has a seemingly unique tendency to interpret zoomorphic objects as animals, not as objects. This animal appearance bias is very strong in the ventral visual pathway as measured through functional magnetic resonance imaging (fMRI), but it is absent in feedforward deep convolutional neural networks. Here we investigate how this bias emerges over time by probing its representational dynamics through multivariate electroencephalography (EEG). The initially activated representations to lookalike zoomorphic objects are very similar to the representations activated by animal pictures and very different from the neural responses to regular objects. Neural responses that reflect the true identity of the zoomorphic objects as inanimate objects are weaker and appear later, as do effects of task context. The strong early emergence of an animal appearance bias strongly supports a feedforward explanation, indicating that lack of recurrence in deep neural networks is not an explanation for their failure to show this bias.
Unraveling codon usage ofEscherichia coliusing machine learning
Authors: Huang Bifang , Hu Yunzhuo , Chen Xuanyang , Lin Shiqiang
Published: February 2023

Machine learning is used to investigate the codon usage of protein-encoding genes, which is one of the fundamental questions of molecular biology. The presentation, parameter learning, and decoding of the conditional random field (CRF) model are implemented and then utilized to analyze the codon usage of the genes ofEscherichia coliand its phages. Most genes ofE. coliuse codons conforming to the weights of the model determined by allE. coligenes. Phages use the codons like their hostE. coli. Finally, the study evaluates the codon usage of several example genes in the context of the model. These results help to understand the codon usage inE. coli.
Bio-Heat Transfer and Monte Carlo Measurement of Near-Infrared Transcranial Stimulation of Human Brain
Authors: Ibrahimi Faezeh , Delrobaei Mehdi
Published: February 2023

Transcranial photobiomodulation is an optical method for non-invasive brain stimulation. The method projects red and near-infrared light through the scalp within 600-1100 nm and low energy within the 1-20J/cm2range. Recent studies have been optimistic about replacing this method with pharmacotherapy and invasive brain stimulation. However, concerns and ambiguities exist regarding the light penetration depth and possible thermal side effects. While the literature survey indicates that the skin temperature rises after experimental optical brain stimulation, inadequate evidence supports a safe increase in temperature or the amount of light penetration in the cortex. Therefore, we aimed to conduct a comprehensive study on the heat transfer of near-infrared stimulation for the human brain. Our research considers the transcranial photobiomodulation over the human brain model by projecting 810 nm light with 100mW/cm2power density to evaluate its thermal and optical effects using bioheat transfer and radiative transfer equation. Our results confirm that the near-infrared light spectrum has a small incremental impact on temperature and approximately penetrates 1 cm, reaching the cortex. A time-variant study of the heat transfer was also carried out to measure the temperature changes during optical stimulation.
Assessing vector competence of mosquitoes from northeastern France to West Nile virus and Usutu virus
Authors: Martinet Jean-Philippe , Bohers Chloé , Vazeille Marie , Ferté Hubert , Mousson Laurence , Mathieu Bruno , Depaquit Jérôme , Failloux Anna-Bella
Published: February 2023

West Nile virus (WNV) and Usutu virus (USUV) are two arthropod-borne viruses that circulate in mainland France. Assessing vector competence has only been conducted so far with mosquitoes from southern France while an increasingly active circulation of WNV and USUV has been reported in the last years. The main vectors are mosquitoes of theCulexgenus and the common mosquitoCulex pipiens. Here, we measure the vector competence of five mosquito species (Aedes rusticus, Aedes albopictus, Anopheles plumbeus, Culex pipiensandCuliseta longiareolata) present in northeastern France. Field-collected populations were exposed to artificial infectious blood meal containing WNV or USUV and examined at different days post-infection. We show that (i)Cx. pipienstransmitted WNV and USUV, (ii)Ae. rusticusonly WNV, and (iii) unexpectedly,Ae. albopictustransmitted both WNV and USUV. Less surprising,An. plumbeuswas not competent for both viruses. Combined with data on distribution and population dynamics, these assessments of vector competence will help in developing a risk map and implementing appropriate prevention and control measures.

Author summary

West Nile virus (WNV) and Usutu virus (USUV) are on the rise in Europe and in France. WNV is reported in France as early as the 1960s in the Camargue and USUV more recently, in 2015 in eastern France. The re-emergence of WNV infections in the Camargue is associated with an expansion towards the North which is also favorable to maintain a viral transmission cycle. USUV frequently co-circulates with WNV sharing the same mosquito vectors.Culex pipiens, able to feed on birds and humans, is considered to be the main vector in France. Our study is the first to investigate the vector competence to WNV and USUV of five different mosquito species collected in northeastern France. We ascertain that FrenchCx. pipiensmosquitoes are competent to both WNV and USUV. More surprisingly, the mosquitoAedes albopictusfrom northeastern France was able to transmit WNV and USUV. Based on our result, we propose that surveillance of mosquitoes combined with viral detections must be implemented in northeastern France to allow early viral detection and timely intervention to prevent outbreaks of these two neurological diseases.