bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in Japanese patients after allogeneic stem cell transplantation
Authors: Watanabe Marika , Yakushijin Kimikazu , Funakoshi Yohei , Ohji Goh , Sakai Hironori , Hojo Wataru , Saeki Miki , Hirakawa Yuri , Matsumoto Sakuya , Sakai Rina , Nagao Shigeki , Kitao Akihito , Miyata Yoshiharu , Koyama Taiji , Saito Yasuyuki , Kawamoto Shinichiro , Ito Mitsuhiro , Murayama Tohru , Matsuoka Hiroshi , Minami Hironobu 
Published: December 2021

AbstractPatients who have undergone hematopoietic stem cell transplantation (HSCT) for hematological disease experience high mortality when infected by coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccine in HSCT patients remains to be investigated. We prospectively evaluated the safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine (Pfizer BioNTech) in 25 Japanese allogeneic HSCT patients in comparison with 19 healthy volunteers. While anti-S1 antibody titers in almost all healthy volunteers after the second dose were higher than the cut-off value reported previously, levels in HSCT patients after the second dose were diverse. Nineteen patients (76%) got seroconversion of anti-S1 IgG. Median optical density of antibody levels in HSCT patients with low IgG levels (< 600 mg/dL), steroid treatment, or low lymphocytes (< 1000 /μL) was significantly lower than that in the other HSCT patients. There were no serious adverse events (> Grade 3), no new development or exacerbation of graft-versus-host disease after vaccination. We concluded BNT162b2 mRNA vaccine is safe and effective in Japanese allogeneic HSCT patients.
Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer’s Disease
Authors: İş Özkan , Wang Xue , Patel Tulsi A. , Quicksall Zachary S. , Heckman Michael G. , White Launia J. , Lewis-Tuffin Laura J. , Deniz Kaancan , Tutor-New Frederick Q. , Carnwath Troy P. , Min Yuhao , Oatman Stephanie R. , Reddy Joseph S. , Carrasquillo Minerva M. , Nguyen Thuy T. , Ho Charlotte C. G. , Malphrus Kimberly G. , Nho Kwangsik , Saykin Andrew J. , Murray Melissa E. , Dickson Dennis W. , Allen Mariet , Ertekin-Taner Nilüfer 
Published: December 2021

AbstractBlood-brain barrier (BBB) dysfunction is well-known in Alzheimer’s disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting in 79,751 nuclei, 4,604 of which formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge-based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the gliovascular unit (GVU) of the BBB. Vascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such asAPOE,APPandECE1. Our findings provide information on transcriptional changes in predicted vascular-astrocytic partners at the GVU, bringing insights to the molecular mechanisms of BBB breakdown in AD.Graphical AbstractPericytes (yellow), endothelia (salmon) and astrocytes (purple) that form the gliovascular unit (GVU) at the blood brain barrier (BBB) were interrogated for their differentially expressed genes (DEG) and vascular cell (pericyte or endothelia) to astrocyte interactions using single nucleus RNA sequencing (RNAseq) transcriptome obtained from brains of Alzheimer’s disease (AD) patients and controls. We identified many upregulated (red) or downregulated (blue) DEGs in AD brains in these cell types. These genes have known biological functions in amyloid ß (Aß) clearance, immune modulation, astrogliosis and neuronal death. Novel predicted interactions were identified between vascular cells and astrocytic DEGs. Collectively, our findings highlight the vast transcriptome changes that occur at the GVU and provide mechanistic insights into BBB dysfunction in AD. This figure was created with Biorender.com.
Inside-out Signalling From Aminopeptidase N (CD13) To Complement Receptor 3 (CR3, CD11b/CD18)
Authors: Díaz-Alvarez Laura , Martínez-Sánchez Mariana Esther , Gray Eleanor , Ortega Enrique 
Published: December 2021

AbstractUpon ligand engagement, certain receptors can activate an integrin through a mechanism called inside-out signalling. This phenomenon prepares the cell for the next steps of the process it will perform. CR3 (Complement receptor 3), the most abundant β2 integrin in monocytes and macrophages, and CD13 (aminopeptidase N) are two immune receptors with overlapping activities: adhesion, phagocytosis of opsonized particles, and respiratory burst induction. They can be found together in functional signalling microdomains, or lipid rafts, on the surface of human leukocytes. Thus, given their common functions, shared physical location and the fact that some phagocytic and adhesion receptors activate a selection of integrins, we hypothesized that CD13 could activate CR3 through an inside-out signalling mechanism. To test this hypothesis, we first ascertained the activation of CR3 after CD13 crosslinking in human monocyte-derived macrophages. We used an integrated analysis of bioinformatics and experimental data to suggest two possible signalling cascades that could explain the phenomenon. Finally, we show that the non-receptor tyrosine kinase Syk is a key attenuator of this pathway. Our results demonstrated that, even in the absence of canonical signalling motifs, and despite having a noticeably short cytoplasmic tail (7-10 amino acids), CD13 was capable of triggering an inside-out signalling cascade, adding a new function to those already known for this moonlighting protein.One Sentence SummaryStimulation of CD13 activated the integrin CR3 via an inside-out signalling pathway, a mechanistic model is proposed.
Reconstitution of the S. aureus agr quorum sensing pathway reveals a direct role for the integral membrane protease MroQ in pheromone biosynthesis
Authors: Zhao Aishan , Bodine Steven P. , Xie Qian , Wang Boyuan , Ram Geeta , Novick Richard P. , Muir Tom W. 
Published: December 2021

AbstractIn Staphylococcus aureus, virulence is under the control of a quorum sensing (QS) circuit encoded in the accessory gene regulator (agr) genomic locus. Key to this pathogenic behavior is the production and signaling activity of a secreted pheromone, the autoinducing peptide (AIP), generated following the ribosomal synthesis and post-translational modification of a precursor polypeptide, AgrD, through two discrete cleavage steps. The integral membrane protease AgrB is known to catalyze the first processing event, generating the AIP biosynthetic intermediate, AgrD (1-32) thiolactone. However, the identity of the second protease in this biosynthetic pathway, which removes an N-terminal leader sequence, has remained ambiguous. Here, we show that MroQ, an integral membrane protease recently implicated in the agr response, is directly involved in AIP production. Genetic complementation and biochemical experiments reveal that MroQ proteolytic activity is required for AIP biosynthesis in agr specifiy groups -I and -II, but not group-III. Notably, as part of this effort, the biosynthesis and AIP-sensing arms of the QS circuit were reconstituted together in vitro. Our experiments also reveal the molecular features guiding MroQ cleavage activity, a critical factor in defining agr specificity group identity. Collectively, our study adds to the molecular understanding of the agr response and Staphylococcus aureus virulence.
Differences in running performance of single- and group-housed mice
Authors: Plenz Uma T. , Kanold Patrick O. 
Published: December 2021

AbstractMice are one of several common animal models in neuroscience and mouse behavior is becoming increasingly relevant. Mice are housed either in groups or alone in standard cages during which they show a variety of different behaviors. Moreover, housing conditions might alter the behavior of the mice as do social interactions. When given access to running wheels as an environmental enrichment, mice tend to run long distances preferentially during their dark cycle. However, it is currently not well understood whether and how mice utilize running wheels when single-housed or group-housed. Here we developed a low-cost running wheel data acquisition system to study running in adult C57BL/6 mice at high temporal resolution under different social conditions. As expected, adult C57BL/6 mice prefer to run in stretches during the dark cycle and mostly rest during the light cycle. When single-housed, running bouts occur independent from each other as indicated by an exponential decaying autocorrelation. In contrast, mice run ∼50% less when housed in groups of n = 3 and their temporal pattern of running exhibits a power law decay in the autocorrelation indicative of potential social interactions. Our results demonstrate that running wheels are a limited resource for which mice compete for when they are group-housed, thereby reducing their overall running activity.Significance StatementVoluntary cage wheel running is an important environmental enrichment for mice housed either alone or in groups. We show that this resource is considerably restricted for group-housed mice.
A spatially resolved stochastic model reveals the role of supercoiling in transcription regulation
Authors: Geng Yuncong , Bohrer Christopher H. , Yehya Nicolás , Hendrix Hunter , Shachaf Lior , Liu Jian , Xiao Jie , Roberts Elijah 
Published: December 2021

AbstractInEscherichia coli, translocation of RNA polymerase (RNAP) during transcription introduces supercoiling to DNA, which influences the initiation and elongation behaviors of RNAP. To quantify the role of supercoiling in transcription regulation, we develop a spatially resolved supercoiling model of transcription, describing RNAP-supercoiling interactions, topoisomerase activities, stochastic topological domain formation, and supercoiling diffusion in all transcription stages. This model establishes that transcription-induced supercoiling mediates the cooperation of co-transcribing RNAP molecules in highly expressed genes. It reveals that supercoiling transmits RNAP-accessible information through DNA and enables different RNAP molecules to communicate within and between genes. It thus predicts that a topological domain could serve as a transcription regulator, generating substantial transcription bursting and coordinating communications between adjacent genes in the domain. The model provides a quantitative platform for further theoretical and experimental investigations of how genome organization impacts transcription.Author SummaryDNA mechanics and transcription dynamics are intimately coupled. During transcription, the translocation of RNA polymerase overwinds the DNA ahead and underwinds the DNA behind, rendering the DNA supercoiled. The supercoiled DNA could, in return, influences the behavior of the RNA polymerase, and consequently the amount of mRNA product it makes. Furthermore, supercoils could propagate on the DNA over thousands of base pairs, impacting RNA polymerase molecules at faraway sites. These complicated interplays between supercoiling and RNA polymerase makes supercoiling an important transcription regulator. To quantitatively investigate the role of supercoiling in transcription, we build a spatially resolved model that links transcription with the generation, propagation, and dissipation of supercoiling. Our model reveals that supercoiling mediates transcription at multiple length scales. At a single-gene scale, we show that supercoiling gives rise to the collective motion of co-transcribing RNA polymerase molecules, supporting recent experimental observations. Additionally, large variations in mRNA production of a gene can arise from the constraints of supercoiling diffusion in a topological domain. At a multi-gene scale, we show that supercoiling dynamics allow two adjacent genes influence each other’s transcription kinetics, thus serving as a transcription regulator.
mRNA-1273 and Ad26.COV2.S vaccines protect against the B.1.621 variant of SARS-CoV-2
Authors: Darling Tamarand L. , Ying Baoling , Whitener Bradley , VanBlargan Laura A. , Bricker Traci L. , Liang Chieh-Yu , Joshi Astha , Bamunuarachchi Gayan , Seehra Kuljeet , Schmitz Aaron J. , Halfmann Peter J. , Kawoaka Yoshihiro , Elbashir Sayda M. , Edwards Darin K. , Thackray Larissa B. , Diamond Michael S. , Boon Adrianus C. M. 
Published: December 2021

ABSTRACTSince the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, viral variants with greater transmissibility or immune evasion properties have arisen, which could jeopardize recently deployed vaccine and antibody-based countermeasures. Here, we evaluated in mice and hamsters the efficacy of preclinical non-GMP Moderna mRNA vaccine (mRNA-1273) and the Johnson & Johnson recombinant adenoviral-vectored vaccine (Ad26.COV2.S) against the B.1.621 (Mu) South American variant of SARS-CoV-2, which contains spike mutations T95I, Y144S, Y145N, R346K, E484K, N501Y, D614G, P681H, and D950N. Immunization of 129S2 and K18-human ACE2 transgenic mice with mRNA-1273 vaccine protected against weight loss, lung infection, and lung pathology after challenge with B.1.621 or WA1/2020 N501Y/D614G SARS-CoV-2 strain. Similarly, immunization of 129S2 mice and Syrian hamsters with a high dose of Ad26.COV2.S reduced lung infection after B.1.621 virus challenge. Thus, immunity induced by mRNA-1273 or Ad26.COV2.S vaccines can protect against the B.1.621 variant of SARS-CoV-2 in multiple animal models.
Geminiviral βC1 orchestrates organellar genomic instability to augment viral infection by hijacking host RecA
Authors: Nair Ashwin , Harshith C.Y. , Anushree N. , Shivaprasad P. V. 
Published: December 2021

AbstractChloroplast is the site for transforming light energy to chemical energy. It also acts as a production unit for a variety of defense-related molecules. These defense moieties are necessary to mount a successful counter defence against pathogens including viruses. Geminiviruses disrupt chloroplast homeostasis as a basic strategy for their successful infection inducing vein-clearing, mosaics and chlorosis in infected plants. Here we show that a geminiviral pathogenicity determinant protein βC1 directly interferes with plastid homeostasis. βC1 was capable of inducing organelle-specific nuclease to degrade plastid genome as well as diverted functions of RecA1 protein, a major player in plastid genome maintenance. βC1 interacted with RecA1 in plants and its homolog in bacteria to reduce the ability of host cells to maintain genomic integrity under stresses. Further, reduction in the coding capacity of plastids severely affected retrograde signalling necessary for viral perception and activation of defense. Induction of chloroplast-specific nuclease by βC1 is similar to phosphate starvation-response in which nucleotides are recycled to augment synthesis of new, potentially viral, DNA. These results indicate the presence of a novel strategy in which a viral protein alters host defence by targeting regulators of chloroplast DNA. We predict that the mechanism identified here might have similarities in other plant-pathogen interactions.One line summaryβC1 alters plastid genome metabolism.
Natural history of nonhuman primates after conjunctival exposure to Ebola virus
Authors: Cross Robert W. , Prasad Abhishek N. , Woolsey Courtney B. , Agans Krystle N. , Borisevich Viktoriya , Dobias Natalie S. , Comer Jason E. , Deer Daniel J. , Geisbert Joan B. , Rasmussen Angela L. , Lipkin W. Ian , Fenton Karla A. , Geisbert Thomas W. 
Published: December 2021

SummaryTransmission of Ebola virus (EBOV) primarily occurs via contact exposure of mucosal surfaces with infected body fluids. Historically, nonhuman primate (NHP) challenge studies have employed intramuscular or small particle aerosol exposure, which are uniformly lethal routes of infection, but mimic worst-case scenarios such as a needlestick. When exposed by more likely routes of natural infection, limited NHP studies have shown delayed onset of disease and reduced mortality. Here we performed a series of systematic natural history studies in cynomolgus macaques with a range of conjunctival exposure doses. Challenge with 10,000 plaque forming units (PFU) of EBOV was uniformly lethal, whereas 5/6 subjects survived low and moderate dose challenges (100 or 500 PFU). Conjunctival challenge resulted in a protracted time-to death. Asymptomatic disease was observed in survivors with limited detection of EBOV replication. Inconsistent seropositivity in survivors may suggest physical or natural immunological barriers are sufficient to prevent widespread viral dissemination.
Rheology of crossbridge ensembles
Authors: Nguyen Khoi D. , Venkadesan Madhusudhan 
Published: December 2021

AbstractHow skeletal muscle responds to mechanical perturbations, its rheology, is important for animal movement control. The molecular machinery of myosin II-actin crossbridge cycling is a crucial part of muscle’s rheological properties, and multiple models have been proposed for this mechanochemical process. But current understanding of the scale-connection from individual molecular motors to ensemble rheology is limited. Here we present computational and mathematical analyses of several different hypotheses of crossbridge dynamics, from 2-state to 5-state myosin II motor models, and show that an ensemble of actomyosin crossbridges exhibits surprisingly simple rheological behavior in all cases. The ensemble rheology is captured by a sum of at most three linear viscoelastic sub-processes, and as few as one for some crossbridge models. This simplification lends itself to computationally efficient phenomenological muscle models with experimentally measurable parameters, while still remaining grounded in crossbridge theory. However, the collapse of the ensemble behavior to few linear sub-processes identifies major limitations of crossbridge models that cannot be resolved by adding complexity to the crossbridge cycle and point to the roles of inter-crossbridge interactions and non-crossbridge elements.
Retrovirus-derived acquired genes, RTL5 and RTL6, are novel constituents of the innate immune system in the eutherian brain
Authors: Irie Masahito , Itoh Johbu , Matuszawa Ayumi , Ikawa Masahito , Suzuki Toru , Hiraoka Yuichi , Ishino Fumitoshi , Kaneko-Ishino Tomoko 
Published: December 2021

AbstractRetrotransposon Gag-like 5 (RTL5, also known as sushi-ichi-related retrotransposon homolog 8 (SIRH8)) and RTL6 (aka SIRH3) are eutherian-specific genes presumably derived from a retrovirus and phylogenetically related to each other. RTL5 encodes a strongly acidic protein while RTL6 encodes an extremely basic protein, and the former is well conserved and the latter extremely well conserved among the eutherians, indicating their unique and critically important roles as acquired genes. Here we report that RTL5 and RTL6 are microglial genes playing roles in the front line of brain innate immune responses against distinct pathogens. Venus and mCherry knock-in mice exhibited expression of RTL5-mCherry and RTL6-Venus fusion proteins in microglia and as extracellular granules in the central nervus system (CNS), and displayed a rapid response to pathogens such as lipopolysaccharide (LPS), double-stranded (ds) RNA analog and non-methylated CpG DNA. These proteins trapped pathogens in microglia in a variety of RTL-pathogen complexes depending on the pathogens. These results demonstrate that RTL5 and RTL6 exert functional effects against different hazardous substances cooperatively and/or independently to protect the developing and/or mature brain. This provides the first evidence that retrovirus-derived genes play a role in the innate immune system of the eutherian brain.
Structural insights into the ion selectivity of the MgtE channel for Mg2+ over Ca2+
Authors: Teng Xinyu , Sheng Danqi , Wang Jin , Yu Ye , Hattori Motoyuki 
Published: December 2021

AbstractMgtE is a Mg2+-selective ion channel whose orthologs are widely distributed from prokaryotes to eukaryotes, including humans, and play an important role in the maintenance of cellular Mg2+ homeostasis. Previous functional analyses showed that MgtE transports divalent cations with high selectivity for Mg2+ over Ca2+. Whereas the high-resolution structure determination of the MgtE transmembrane (TM) domain in complex with Mg2+ ions revealed a Mg2+ recognition mechanism of MgtE, the previous Ca2+-bound structure of the MgtE TM domain was determined only at moderate resolution (3.2 Å resolution), which was insufficient to visualize the water molecules coordinated to Ca2+ ions. Thus, the structural basis of the ion selectivity of MgtE for Mg2+ over Ca2+ has remained unclear. Here, we showed that the metal-binding site of the MgtE TM domain binds to Mg2+ ∼500-fold more strongly than Ca2+. We then determined the crystal structure of the MgtE TM domain in complex with Ca2+ ions at a higher resolution (2.5 Å resolution), allowing us to reveal hexahydrated Ca2+, which is similarly observed in the previously determined Mg2+-bound structure but with extended metal-oxygen bond lengths. Our structural, biochemical, and computational analyses provide mechanistic insights into the ion selectivity of MgtE for Mg2+ over Ca2+.
DENA: training an authentic neural network model using Nanopore sequencing data of Arabidopsis transcripts for detection and quantification ofN6-methyladenosine on RNA
Authors: Qin Hang , Ou Liang , Gao Jian , Chen Longxian , Wang Jiawei , Hao Pei , Li Xuan 
Published: December 2021

AbstractModels developed using Nanopore direct RNA sequencing data fromin vitrosynthetic RNA with all adenosine replaced byN6-methyladenosine (m6A), are likely distorted due to superimposed signals from saturated m6A residues. Here, we develop a neural network,DENA, for m6A quantification using the sequencing data ofin vivotranscripts from Arabidopsis. DENA identifies 90% of miCLIP-detected m6A sites in Arabidopsis, and obtains modification rates in human consistent to those found bySCARLET, demonstrating its robustness across species. We sequence the transcriptome of two additional m6A-deficient Arabidopsis,mtbandfip37-4, using Nanopore and evaluate their single-nucleotide m6A profiles usingDENA.
Macrophages break interneuromast cell quiescence by intervening the inhibition of Schwann cells in zebrafish lateral line
Authors: Lin Meng-Ju , Lee Chia-Ming , Hsu Wei-Lin , Chen Bi-Chang , Lee Shyh-Jye 
Published: December 2021

ABSTRACTIn the zebrafish lateral line system, interneuromast cells (INCs) between neuromasts are normally kept quiescent by underlying Schwann cells (SWCs). Upon severe injuries that cause the complete loss of an entire neuromast, INCs can occasionally differentiate into neuromasts but how they escape from the inhibition by SWCs is still unclear. Using a genetic/chemical method to specifically ablate a neuromast, we found a small portion of larvae can regenerate a new neuromast, but the regeneration was hindered by inhibiting macrophages. By in toto imaging, we further discovered heterogeneities in macrophage behavior and distribution along lateral line. We witnessed the crawling of macrophages in between injured lateral line and SWCs during regeneration and also in between the second primordium and the first mature lateral line during development. It implies that macrophages may physically separate and alleviate the inhibition from pLLn and SWCs to break the quiescence of INCs during regeneration and development in the zebrafish lateral line.