bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enteric bacterial infection inDrosophilainduces whole-body alterations in metabolic gene expression independently of the Immune Deficiency (Imd) signalling pathway
Authors: Deshpande Rujuta , Lee Byoungchun , Grewal Savraj S 
Published: May 2022

SummaryWhen infected by intestinal pathogenic bacteria, animals initiate both local and systemic defence responses. These responses are required to reduce pathogen burden and also to alter host physiology and behaviour to promote infection tolerance, and they are often mediated through alterations in host gene expression. Here, we have used transcriptome profiling to examine gene expression changes induced by enteric infection with the gram-negative bacteriaPseudomonas entomophila (P.e)in adult femaleDrosophila. We find that infection induces a strong upregulation of metabolic gene expression, including gut and fat body-enriched genes involved in lipid transport, lipolysis, and beta-oxidation, as well as glucose and amino acid metabolism genes. Furthermore, we find that the classic innate immune deficiency (Imd)/Relish/NF-KappaB pathway is not required for, and in some cases limits, these infection-mediated increases in metabolic gene expression. We also see that enteric infection withP.e. down regulates the expression of many transcription factors and cell-cell signaling molecules, particularly those previously shown to be involved in gut-to-brain and neuronal signaling. Moreover, as with the metabolic genes, these changes occurred largely independent of the Imd pathway. Together, our study identifies many metabolic, signaling and transcription factor gene expression changes that may contribute to organismal physiological and behavioural responses to enteric pathogen infection.
Response of the plant core microbiome toFusarium oxysporuminfection and identification of the pathobiome
Authors: Qiu Zhiguang , Verma Jay Prakash , Liu Hongwei , Wang Juntao , Batista Bruna D , Kaur Simranjit , de Araujo Pereira Arthur Prudêncio , Macdonald Catriona A. , Trivedi Pankaj , Weaver Tim , Conaty Warren C. , Tissue David T. , Singh Brajesh K. 
Published: May 2022

SummaryPlant core microbiomes consist of persistent key members that provide critical host functions, but their assemblages can be interrupted by biotic and abiotic stresses. The pathobiome is comprised of dynamic microbial interactions in response to disease status of the host. Hence, identifying variation in the core microbiome and pathobiome can significantly advance our understanding of microbial-microbial interactions and consequences for disease progression and host functions. In this study, we combined glasshouse and field studies to analyse the soil and plant rhizosphere microbiome of cotton plants (Gossypium hirsutum) in the presence of a cotton-specific fungal pathogen,Fusarium oxysporumf. sp.vasinfectum(FOV). We found that FOV directly and consistently altered the rhizosphere microbiome, but the biocontrol agents enabled microbial assemblages to resist pathogenic stress. Using co-occurrence network analysis of the core microbiome, we identified the pathobiome comprised of the pathogen and key associate phylotypes in the cotton microbiome. Isolation and application of some negatively correlated pathobiome members provided protection against plant infection. Importantly, our field survey from multiple cotton fields validated the pattern and responses of core microbiomes under FOV infection. This study advances key understanding of core microbiome responses and existence of plant pathobiomes, which provides a novel framework to better manage plant diseases in agriculture and natural settings.
Delivery of Circular mRNA via Degradable Lipid Nanoparticles against SARS-CoV-2 Delta Variant
Authors: Huang Ke , Li Na , Li Yingwen , Zhu Jiafeng , Fan Qianyi , Yang Jiali , Gao Yinjia , Liu Yupin , Hou Qiangbo , Gao Shufeng , Wei Ke , Deng Chao , Zuo Chijian , Sun Zhenhua 
Published: May 2022

ABSTRACTmRNA vaccines have emerged as a most promising and potent platform in the fight against various diseases including the COVID-19 pandemic. However, the intrinsic instability, varying side effects associated with the delivery systems, and continuous emergence of virus variants highlight the urgent need for the development of stable, safe and efficacious mRNA vaccines. In this study, by screening a panel of proprietary biodegradable ionizable lipidoids, we reported on a novel mRNA vaccine (cmRNA-1130) formed from a biodegradable lipidoid with eight ester bonds in the branched tail (AX4) and synthetic circular mRNA (cmRNA) encoding the trimeric Delta receptor binding domain (RBD) of SARS-CoV-2 spike protein for the induction of robust immune activation. The AX4-based lipid nanoparticles (AX4-LNP) revealed much faster elimination rate from liver and spleen in comparison with commercialized MC3-based LNP (MC3-LNP) and afforded normal level of alanine transferase (ALT), aspartate aminotransferase (AST), and creatinine (CRE) in BALB/c mice. Following intramuscular (IM) administration in BALB/c mice, cmRNA-1130 elicited potent and sustained neutralizing antibodies, RBD-specific CD4+ and CD8+ T effector memory cells (Tem), and Th1-biased T cell activations. cmRNA-1130 vaccine showed excellent stability against 6-month storage at 4 □ and freezing-thawing cycles. In brief, our study highlights mRNA vaccines based on cmRNA and biodegradable AX4 lipids hold great potential as superb therapeutic platforms for the treatment of varying diseases.
VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
Authors: Yang Lei , Dong Xichen , Liu Zheng , Tan Jinjing , Huang Xiaoxi , Wen Tao , Qu Hao , Wang Zhenjun 
Published: May 2022

AbstractEfficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-β pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-β signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) and a competing endogenous RNA (ceRNA) to sponge miR-22-5p/514a-3p to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-β/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.
Delineating the transcriptional landscape and clonal diversity of virus-specific CD4+T cells during chronic viral infection
Authors: Zander Ryan , Khatun Achia , Kasmani Moujtaba Y. , Chen Yao , Cui Weiguo 
Published: May 2022

AbstractCD4+T cells responding to chronic viral infection often acquire a dysfunctional phenotype that is characterized by a progressive loss in Th1 differentiation and function, as well as an upregulation of multiple co-inhibitory receptors. Conversely, CD4+T cells, and particularly Tfh cells, gradually increase their production of IL-21 during chronic viral infection, which is critical to sustain humoral immunity and also effector CD8+T cell responses. Recent evidence further indicates that a memory-like CD4+T cell population also develops in the face of persistent infection, although how the transcriptional landscape of this subset, along with the Th1 and Tfh cell subsets from chronic infection, differ from their acute infection counterparts remains unclear. Additionally, whether cell-intrinsic factors such as TCR usage influence CD4+T cell fate commitment during chronic infection has not previously been studied. Herein, we perform single-cell RNA sequencing (scRNA-seq) combined with single-cell T cell receptor sequencing (scTCR-seq) on virus-specific CD4+T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. We identify several transcriptionally distinct states among the Th1, Tfh, and memory-like T cell subsets that form at the peak of chronic infection, including the presence of a previously unrecognized Slamf7+subset with cytolytic features, and show that the relative distribution of these populations differs substantially between acute and persistent LCMV infection. Moreover, while the progeny of most T cell clones displays membership within each of these transcriptionally unique populations, overall supporting a one cell-multiple fate model, a small fraction of clones display a biased cell fate decision, suggesting that TCR usage may impact CD4+T cell development during chronic viral infection. Importantly, a comparative analysis further reveals both subset-specific and core gene expression programs that are differentially regulated between CD4+T cells responding to acute and chronic viral infection. Together, these data may serve as a useful framework and allow for a detailed interrogation into the clonal distribution and transcriptional circuits underlying CD4+T cell differentiation during chronic viral infection.
Stromal Hippo-YAP signaling in stem cell niche controls intestinal homeostasis
Authors: Dang Kyvan , Singh Alka , Cotton Jennifer L. , Tao Zhipeng , Liu Haibo , Zhu Lihua J. , Wu Xu , Mao Junhao 
Published: May 2022

AbstractIntestinal homeostasis is tightly regulated by the reciprocal interaction between gut epithelium and adjacent mesenchyme. The mammalian Hippo-YAP pathway is intimately associated with intestinal epithelial homeostasis and re-generation; however, its role in postnatal gut mesenchyme remains poorly defined. We find that, although removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle has largely no effect; Hippo-YAP signaling in Gli1/PDGFR-expressing intestinal stromal cells is critical to maintain the stem cell niche. We show that YAP/TAZ activation drives over-proliferation and suppresses smooth muscle actin expression in the niche-forming Gli1+ mesenchymal progenitors. In addition, mesenchymal YAP/TAZ activation disrupts the epithelial-mesenchymal crosstalk by promoting Wnt ligand production, leading to epithelial Wnt pathway activation. Our data also reveal that YAP/TAZ are upregulated in the stroma during DSS-induced injury and stromal YAP activation promotes intestinal epithelial regeneration. Altogether, our data identify an essential requirement for stromal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis.HIGHTLIGHTSLats1/2 control proliferation and differentiation of adult gut mesenchymal progenitors.Mesenchymal YAP/TAZ promotes Wnt ligand production in intestinal stem cell niche.YAP/TAZ is up-regulated in the mesenchyme during intestinal injury.Stromal YAP activation promotes intestinal epithelial regeneration.
Cerebellar motor memory expression requires learned alterations to the activity of inhibitory molecular layer interneurons
Authors: Bonnan Audrey , Zhang Ke , Christie Jason M. 
Published: May 2022

AbstractProcedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. Yet, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning requiring climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific causal role of MLI activity changes in motor memory expression. This effect was transitory; after a multi-day consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression.Significance StatementIn the cerebellum, motor learning induces an associative memory of the sensorimotor context of an erroneous movement that, when recalled, results in a new pattern of output that improves subsequent trials of performance. Our study shows that error-driven motor learning induces changes to the activity pattern of cerebellar molecular layer interneurons and that this new pattern of activity is required to express the corrective motor memory.
Evaluating Stored Platelet Shape Change Using Imaging Flow Cytometry
Authors: Yakovenko Olga , Özpolat Tahsin , Stratiievska Anastasiia , Bailey S. Lawrence , Miles Jeffrey , Usaneerungrueng Chomkan , Wu Xiaoping , Stolla Moritz 
Published: May 2022

AbstractPlatelets are routinely stored at room temperature for 5-7 days before transfusion. Stored platelet quality is traditionally assessed by Kunicki’s morphology score. This method requires extensive training, experience, and is highly subjective. Moreover, the number of laboratories familiar with this technique is decreasing. Cold storage of platelets has recently regained interest because of potential advantages such as reduced bacterial growth and preserved function. However, platelets exposed to cold temperatures change uniformly from a discoid to a spherical shape, reducing the morphology score outcomes to a binary “spheres versus discs” during cooling. We developed a simpler, unbiased screening tool to measure temperature-induced platelet shape change using imaging flow cytometry. When reduced to two dimensions, spheres appear circular, while discs are detected on a spectrum from fusiform to circular. We defined circular events as having a transverse axis of > 0.8 of the longitudinal axis and fusiform events ≤ 0.8 of the longitudinal axis. We show that most EGTA-treated platelets and spherical beads are detected in the gate for circular events, while fresh platelets are found mainly in the gate for fusiform events. Using this assay, mouse and human platelets show a temperature and time-dependent, two-dimensional shape change from fusiform to circular, consistent with their three-dimensional change from discs to spheres. The method we describe here is a valuable tool for detecting shape change differences in response to agonists or temperature and will help screen for therapeutic measures to mitigate the cold-induced storage lesion.Plain language summaryWhat is the context?Platelets for transfusion are currently stored for 5-7 days at room temperature, increasing the risk for bacterial growthCold storage reduces the risk for bacterial growth but reduces circulation timeStored platelet quality can be assessed by the light microscopy-based Morphology Score, first described in the 1970sDownsides of the Morphology Score include subjectivity, extensive training, and reduced availability in platelet laboratories.What is new?In this study, we provide data showing that the Morphology score is reduced to a binary spheres versus discs response in cold-exposed plateletsWe developed an imaging flow cytometry-based approach to quantify platelets’ response to cold based on the two-dimensional projection of the three-dimensional shapes, i.e., fusiform (discoid) versus circular (discoid and spherical)We provide validation of this approach in mouse and human plateletsWe provide evidence for increased temperature sensitivity in mouse plateletsWhat is the impact?This study provides an easy and unbiased tool for laboratories working on circumventing the cold-induced storage lesion or documenting spherical shape change in general
Differential modification of the C-terminal tails of different α-tubulins and their importance for microtubule functionin vivo
Authors: Bao Mengjing , Dörig Ruth , Vazquez-Pianzola Paula , Beuchle Dirk , Suter Beat 
Published: May 2022

AbstractMicrotubules (MTs) are built from α-/β-tubulin dimers and used as tracks by kinesin and dynein motors to transport a variety of cargos, such as mRNAs, proteins, and organelles, within the cell. Tubulins are subjected to several post-translational modifications (PTMs). Glutamylation is one of them, and it is responsible for adding one or more glutamic acid residues as branched peptide chains to the C-terminal tails of both α- and β-tubulin. However, very little is known about the specific modifications found on the different tubulin isotypesin vivoand the role of these PTMs in MT transport and other cellular processesin vivo. In this study, we found that inDrosophilaovaries, glutamylation of α-tubulin isotypes occurred clearly on the C-terminal ends of αTub84B and αTub84D (αTub84B/D). In contrast, the ovarian α-tubulin, αTub67C, is not glutamylated. The C-terminal ends of αTub84B/D are glutamylated at several glutamyl side chains in various combinations.Drosophila TTLL5is required for the mono- and poly-glutamylation of ovarian αTub84B/D and with this for the proper localization of glutamylated microtubules. Similarly, proper Kinesin-1 distribution in the germline also depends onTTLL5as well as the refining of Staufen localization and the normal fast ooplasmic streaming with its directional movement, two processes known to depend on Kinesin-1 activities. In the nervous system, the pausing of anterograde axonal transport of mitochondria is affected by an enzymatically dead mutant ofTTLL5. Our results demonstratein vivoroles ofTTLL5in differential glutamylation of α-tubulins and point to thein vivoimportance of α-tubulin glutamylation for Kinesin-1-dependent processes.Summaryα-tubulin glutamylation was established in the C-terminal domain ofDrosophilaαTub84B and αTub84D (αTub84B/D). Multiple glutamyl residues were pinpointed in this domain. The female germline α-tubulin, αTub67C, is, however, not glutamylated.TTLL5is required for mono- and poly-glutamylation of αTub84B/D.TTLL5is required for the proper Kinesin heavy chain (Khc) distribution in the germline, and the kinesin-based refinement of Staufen localization and ooplasmic streaming during late oogenesis.TTLL5is needed for the pausing of anterograde trafficking of mitochondria in axons.
Structural insights for neutralization of BA.1 and BA.2 Omicron variants by a broadly neutralizing SARS-CoV-2 antibody
Authors: Kumar Sanjeev , Patel Anamika , Lai Lilin , Chakravarthy Chennareddy , Valanparambil Rajesh , Davis-Gardner Meredith E. , Edara Venkata Viswanadh , Linderman Susanne , Reddy Elluri Seetharami , Gottimukkala Kamalvishnu , Nayak Kaustuv , Bajpai Prashant , Singh Vanshika , Frank Filipp , Cheedarla Narayanaiah , Verkerke Hans P. , Neish Andrew S. , Roback John D. , Mantus Grace , Goel Pawan Kumar , Rahi Manju , Davis Carl W. , Wrammert Jens , Suthar Mehul S. , Ahmed Rafi , Ortlund Eric , Sharma Amit , Murali-Krishna Kaja , Chandele Anmol 
Published: May 2022

AbstractThe SARS-CoV-2 BA.1 and BA.2 (Omicron) variants contain more than 30 mutations within the spike protein and evade therapeutic monoclonal antibodies (mAbs). Here, we report a receptor-binding domain (RBD) targeting human antibody (002-S21F2) that effectively neutralizes live viral isolates of SARS-CoV-2 variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron (BA.1 and BA.2) with IC50 ranging from 0.02 – 0.05 μg/ml. This near germline antibody 002-S21F2 has unique genetic features that are distinct from any reported SARS-CoV-2 mAbs. Structural studies of the full-length IgG in complex with spike trimers (Omicron and WA.1) reveal that 002-S21F2 recognizes an epitope on the outer face of RBD (class-3 surface), outside the ACE2 binding motif and its unique molecular features enable it to overcome mutations found in the Omicron variants. The discovery and comprehensive structural analysis of 002-S21F2 provide valuable insight for broad and potent neutralization of SARS-CoV-2 Omicron variants BA.1 and BA.2.
Medial temporal lobe structure, mnemonic and perceptual discrimination in healthy older adults and those at risk for mild cognitive impairment
Authors: Gellersen Helena M. , Trelle Alexandra N. , Farrar Benjamin G. , Coughlan Gillian , Korkki Saana M. , Henson Richard N. , Simons Jon S. 
Published: May 2022

AbstractCognitive tests sensitive to the integrity of the medial temporal lobe (MTL), such as mnemonic discrimination of perceptually similar stimuli, may be useful early markers of risk for cognitive decline in older populations. Perceptual discrimination of stimuli with overlapping features also relies on MTL, but remains relatively unexplored in this context. We assessed mnemonic discrimination in two test formats (Forced Choice, Yes/No) and perceptual discrimination of objects and scenes in 111 community-dwelling older adults at different risk status for cognitive impairment based on neuropsychological screening. We also investigated associations between performance and MTL subregion volume and thickness. The at-risk group exhibited reduced entorhinal thickness and impaired perceptual and mnemonic discrimination. Perceptual discrimination impairment partially explained group differences in mnemonic discrimination and correlated with entorhinal thickness. Executive dysfunction accounted for Yes/No deficits in at-risk adults, demonstrating the importance of test format for the interpretation of memory decline. These results suggest that perceptual discrimination tasks may be useful tools for detecting incipient cognitive impairment related to reduced MTL integrity in non-clinical populations.
More accurate estimation of cell composition in bulk expression through robust integration of single-cell information
Authors: Karimnezhad Ali 
Published: May 2022

AbstractThe rapid single-cell transcriptomic technology developments has led to an increasing interest in cellular heterogeneity within cell populations. Although cell-type proportions can be obtained directly from single-cell RNA sequencing (scRNA-seq), it is costly and not feasible in every study. Alternatively, with fewer experimental complications, cell-type compositions are characterized from bulk RNA-seq data. Many computational tools have been developed and reported in the literature. However, they fail to appropriately incorporate the covariance structures in both scRNA-seq and bulk RNA-seq datasets in use.We present a covariance-based single-cell decomposition (CSCD) method that estimates cell-type proportions in bulk data through building a reference expression profile based on a single-cell data, and learning gene-specific bulk expression transformations using a constrained linear inverse model. The approach is similar to Bisque, a cell-type decomposition method that was recently developed. Bisque is limited to a univariate model, thus unable to incorporate gene-gene correlations into the analysis. We introduce a more advanced model that successfully incorporates the covariance structures in both scRNA-seq and bulk RNA-seq datasets into the analysis, and fixes the collinearity issue by utilizing a linear shrinkage estimation of the corresponding covariance matrices. We applied CSCD to several publicly available datasets and measured the performance of CSCD, Bisque and six other common methods in the literature. Our results indicate that CSCD is more accurate and comprehensive than most of the existing methods.