bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gas diffusion kinetics drive embolism spread in angiosperm xylem: evidence from flow-centrifuge experiments and modelling
Authors: Silva Luciano M. , Pereira Luciano , Kaack Lucian , Guan Xinyi , Trabi Christophe L. , Jansen Steven 
Published: April 2023

AbstractUnderstanding xylem embolism formation is challenging due to dynamic changes and multiphase interactions in conduits. If embolism spread involves gas movement in xylem, we hypothesise that it is affected by time. We measured hydraulic conductivity (Kh) in flow-centrifuge experiments over one hour at a given pressure and temperature for stem samples of three angiosperm species. Temporal changes in Khat 5, 22, and 35°C, and at various pressures were compared to modelled gas pressure changes in a recently embolised vessel in the centre of a centrifuge sample. Temporal changes in Khat 22°C showed maximum relative increases between 6% and 40%, and maximum decreases between 41% and 61% at low and high centrifugal speed, respectively. Logarithmic changes in Khwere species-specific, and most pronounced during the first 15 minutes. Embolism formation started near the edges of centrifuge samples and gradually increased at the centre. Moreover, measured decreases in Khstrongly correlated with modelled increases in gas concentration in a recently embolised vessel. Although embolism is mostly pressure-driven, our experimental and modelled data indicate that time, conduit characteristics, and temperature are involved due to their role in gas diffusion. Gas diffusion, however, does not cover the entire process of embolism spread.
A conserved extracellular ribonuclease with broad-spectrum cytotoxic activity enables smut fungi to compete with host-associated bacteria
Authors: Ökmen Bilal , Katzy Philipp , Wemhöner Raphael , Doehlemann Gunther 
Published: April 2023

SummaryRibotoxins are secreted ribonucleases that specifically target and cleave the universally conserved sarcin-ricin loop sequence of rRNA, which leads to inhibition of protein biosynthesis and subsequently to cell death. We have identified and characterized a secreted Ribo1 protein of plant pathogenic smut fungi. Heterologous expression in different model systems showed that smut Ribo1 has cytotoxic activity against bacteria, yeast, host and non-host plants. Recombinant expression of Ribo1 inNicotiana benthamianainduced plant cell death; however, an active site mutant induced cell death only when expressed as a secreted protein. In the maize smutUstilago maydis, transcription ofRibo1is specifically induced in early infection stages. While a knock-out mutant revealed that Ribo1 is dispensable forU. maydisvirulence, the overexpression of Ribo1in-plantahad a strong dominant negative effect on virulence and induced host defense responses including cell death. This suggests a function of Ribo1 during the epiphytic development rather than for invasive colonization of the host. Accordingly, in presence of the biocontrol bacteriaPantoeasp., which were isolated from maize leaves, theribo1knock-out mutant was significantly impaired in virulence. Together, we conclude that Ribo1 enables smut fungi to compete with host-associated bacteria during epiphytic development.
Root barrier surveillance mechanisms convey soil nitrogen status to shoots
Authors: Shen Defeng , Wippel Kathrin , Remmel Simone , Zhang Pengfan , Kuertoes Noah , Neumann Ulla , Kopriva Stanislav , Andersen Tonni Grube 
Published: April 2023

AbstractIn roots, formation of the Casparian strip in the endodermal cell walls provides a mechanism for selective uptake of nutrients and water. Establishment of this filter is under spatial surveillance by a receptor-ligand mechanism termed the Schengen pathway. This system provides a mechanism to initiate downstream signaling responses in case of dysfunctional barrier establishment. Due to this interconnected nature, the endogenous physiological role of this survaillance mechanism remain difficult to untangle from the direct barrier function. This is in particularly evident in complex growth setups where multiple inputs are integrated into general whole-plant responses. In this work, we address this by rewiring the genetic network that underlies root barrier formation. We create plants with enhanced, Schengen-independent Casparian strip formation that are not only suitable to probe the role of stronger barrier establishment, but also to evaluate the associated signaling output independently. With focus on the latter, we subjected the rewired plants, as well as a number of established barrier mutants, to multifaceted growth conditions including nitrogen fertilized agricultural soil conditions. By profiling their above- and belowground (a)biotic responses our work reveals that, while increased Casparian strip formation mainly provides the plant with an improved stress resistance, the Schengen pathway is necessary for establishment of a growth-promoting root microbiome and serves to convey information of soil nitrogen status to the shoot. This identifies the Schengen pathway as an essential receptor-based signaling hub for adaptive integration of barrier status, nutritional responses and (a)biotic signaling between above- and belowground tissues.
CellHeap: A scRNA-seq workflow for large-scale bioinformatics data analysis
Authors: Castro Maria Clicia S. , Silva Vanessa S. , Costa Maiana O. C. , Silva Helena S. I. L. , Walter Maria Emilia M. T. , Melo Alba C. M. A. , Ocaña Kary , dos Santos Marcelo T. , Nicolas Marisa F. , Carvalho Anna Cristina C. , Henriques-Pons Andrea , Silva Fabrício A. B. 
Published: April 2023

AbstractBackgroundSeveral hundred terabytes of single-cell RNA-seq (scRNA-seq) data are available in public repositories. These data refer to various research projects, from microbial population cells to multiple tissues, involving patients with a myriad of diseases and comorbidities. An increase to several Petabytes of scRNA-seq data available in public repositories is a realistic prediction for coming years. Therefore, thoughtful analysis of these data requires large-scale computing infrastructures and software systems optimized for such platforms to generate correct and reliable biological knowledge.ResultsThis paper presents CellHeap, a flexible, portable, and robust platform for analyzing large scRNA-seq datasets, with quality control throughout the execution steps, and deployable on platforms that support large-scale data, such as supercomputers or clouds. As a case study, we designed a workflow to study particular modulations of Fc receptors, considering mild and severe cases of COVID-19. This workflow, deployed in the Brazilian Santos Dumont supercomputer, processed dozens of Terabytes of COVID-19 scRNA-seq raw data. Our results show that most of the workflow total execution time is spent in its initial phases and that there is great potential for a parallel solution to speed up scRNA-seq data analysis significantly. Thus, this workflow includes an efficient solution to use parallel computational resources, improving total execution time. Our case study showed increased Fc receptors transcription in macrophages of patients with severe COVID-19 symptoms, especially FCGR1A, FCGR2A, and FCGR3A. Furthermore, diverse molecules associated with their signaling pathways were upregulated in severe cases, possibly associated with the prominent inflammatory response observed.ConclusionFrom the CellHeap platform, different workflows capable of analyzing large scRNA-seq datasets can be generated. Our case study, a workflow designed to study particular modulations of Fc receptors, considering mild and severe cases of COVID-19, deployed on the Brazilian supercomputer Santos Dumont, had a substantial reduction in total execution time when jobs are triggered simultaneously using the parallelization strategy described in this manuscript. Regarding biological results, our case study identified specific modulations comparing healthy individuals with COVID-19 patients with mild or severe symptoms, revealing an upregulation of several inflammatory pathways and an increase in the transcription of Fc receptors in severe cases.
Global alignment and local curvature of microtubules in mouse fibroblasts are robust against perturbations of vimentin and actin
Authors: Blob Anna , Ventzke David , Rölleke Ulrike , Nies Giacomo , Munk Axel , Schaedel Laura , Köster Sarah 
Published: April 2023

AbstractThe eukaryotic cytoskeleton is an intricate network of three types of mechanically distinct biopolymers – actin filaments, microtubules and intermediate filaments (IFs). These filamentous networks determine essential cellular functions and properties. Among them, microtubules are important for intracellular transport and establishing cell polarity during migration. Despite their intrinsic stiffness, they exhibit characteristic bending and buckling in cells due to non thermal forces acting on them. Interactions between cytoskeletal filaments have been found but are complex and diverse with respect to their effect on the mechanical behavior of the filaments and the architecture of networks. We systematically study how actin and vimentin IFs influence the network structure and local bending of microtubules by analyzing fluorescence microscopy images of mouse fibroblasts on protein micropatterns. Our automated analysis averages over large amounts of data to mitigate the effect of the considerable natural variance in biological cell data. We find that the radial orientation of microtubules in circular cells is robust and is established independently of vimentin and actin networks. Observing the local curvature of microtubules, we find highly similar average bending of microtubules in the entire cell regardless of the cytoskeletal surrounding. Small systematic differences cannot be attributed directly to vimentin and actin densities. Our results suggest that, on average, microtubules in unpolarized mouse fibroblasts are unexpectedly independent of the rest of the cytoskeleton in their global network structure and their local response to forces.
Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation
Authors: Perike Srikanth , Gonzalez-Gonzalez Francisco J. , Abu-Taha Issam , Damen Frederick W. , Lizama Ken S. , Aboonabi Anahita , Capote Andrielle E. , Aguilar-Sanchez Yuriana , Levin Benjamin , Han Zhenbo , Sridhar Arvind , Grand Jacob , Martin Jody , Akar Joseph G. , Warren Chad M. , Solaro R. John , Ong Sang-Ging , Darbar Dawood , Goergen Craig J. , Wolska Beata M. , Dobrev Dobromir , Wehrens Xander H.T. , McCauley Mark D. 
Published: April 2023

ABSTRACTBackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility.MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation.In vitrostudies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies.ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0×10−2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4×10−6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10−2and 6.7×10−3respectively, n=8,8 in each group).In vitrostudies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0×10−6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8×10−2and 4.1×10−2respectively, n= 6,6,5).ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.
Apolipoprotein B and Interleukin 1 Receptor Antagonist: Reversing the Risk of Coronary Heart Disease
Authors: Yang Fangkun , Huangfu Ning , Shen Jiaxi , Su Pengpeng , Zhu Lujie , Cui Hanbin , Yuan Shuai 
Published: April 2023

AbstractBackgroundEpidemiological evidence for the link of interleukin 1 (IL-1) and its inhibition with coronary heart disease (CHD) remains controversial. We aim to investigate the cardiovascular effects of IL-1 receptor antagonist (IL-1Ra) and underlying mechanisms, as well as the potential interaction with lifestyle factors.MethodsA comprehensive multivariable Mendelian randomization study was performed. Genetic variants identified from a genome-wide association study involving 30,931 individuals were used as instrumental variables for the serum IL-1Ra concentrations. Genetic associations with CHD (60,801 cases and 123,504 controls) were extracted from the CARDIoGRAMplusC4D consortium. Inverse-variance weighted method was utilized to derive effect estimates, while supplementary analyses employing various statistical approaches.ResultsGenetically determined IL-1Ra level was associated with increased risk of CHD (odds ratio (OR), 1.07; 95% CI: 1.03-1.17) and myocardial infarction (OR, 1.13; 95% CI: 1.04-1.21). The main results remained consistent in supplementary analyses. Besides, IL-1Ra was associated with circulating levels of various lipoprotein lipids, apolipoproteins and fasting glucose. Interestingly, observed association pattern with CHD was reversed when adjusting for apolipoprotein B (OR, 0.84; 95%CI: 0.71-0.99) and slightly attenuated on accounting for other cardiometabolic risk factors. Appropriate lifestyle intervention was found to lower IL-1Ra concentration and mitigate the heightened CHD risk it posed.ConclusionsApolipoprotein B represents the key driver, and a potential target for reversal of the causal link between serum IL-1Ra and increased risk of CHD/MI. The combined therapy involving IL-1 inhibition and lipid-modifying treatment aimed at apolipoprotein B merit further exploration.
Structural remodeling of the endoplasmic reticulum in response to extracellular signals requires αTAT1-induced microtubule acetylation
Authors: Ortiz Hannah R. , Flores Paola Cruz , Ramonett Aaron , Ahmed Tasmia , Ellis Nathan A. , Langlais Paul R. , Mythreye Karthikeyan , Lee Nam Y. 
Published: April 2023

ABSTRACTDynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to numerous growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT pathway may be a key target in ER stress and dysfunction.
Changes to Astrocyte-associated Protein Expression at Different Timepoints of Cuprizone Treatment
Authors: Frankle Lana , Riley Amanda , Tomor Riely , Lee Hannah , Jarzembak Kole , Benedict Olesia , Sternbach Sarah , Shelestak John , McDonough Jennifer , Clements Robert 
Published: April 2023

AbstractGlial cells, including astrocytes, microglia, and oligodendrocytes, are brain cells that support and dynamically interact with neurons and each other. These intercellular dynamics undergo changes during stress and disease states. In response to most forms of stress, astrocytes will undergo some variation of activation, meaning upregulation in certain proteins expressed and secreted and either upregulations or downregulations to various constitutive and normal functions. While types of activation are many and contingent on the particular disturbance that triggers these changes, there are two main overarching categories that have been delineated thus far: A1 and A2. Named in the convention of microglial activation subtypes, and with the acknowledgement that the types are not completely distinct or completely comprehensive, the A1 subtype is generically associated with toxic and pro-inflammatory factors, and the A2 phenotype is broadly associated with anti-inflammatory and neurogenic factors. The present study served to measure and document dynamic changes in these subtypes at multiple timepoints using an established experimental model of cuprizone toxic demyelination. The authors found increases in proteins associated with both cell types at different timepoints, with protein increases in the A1 marker C3d and the A2 marker Emp1 in the cortex at one week and protein increases in Emp1 in the corpus callosum at three days and four weeks. There were also increases in Emp1 staining specifically colocalized with astrocyte staining in the corpus callosum at the same timepoints as the protein increases, and in the cortex weeks later at four weeks. C3d colocalization with astrocytes also increased most at four weeks. This indicates simultaneous increases of both types of activation as well as the likely existence of astrocytes expressing both markers. The authors also found the increase in two A1 associated proteins (TNF alpha and C3d) did not show a linear relationship in line with findings from other research and indicating a more complex relationship between cuprizone toxicity and astrocyte activation. The increases in TNF alpha and IFN gamma did not occur at timepoints preceding increases in C3d and Emp1, showing that other factors also precipitate the subtypes associated (A1 for C3d and A2 for Emp1). These findings add to the body of research showing the specific early timepoints at which A1 and A2 markers are most increased during the course of cuprizone treatment, including the fact that these increases can be non-linear in the case of Emp1. This provides additional information on optimal times for targeted interventions during the cuprizone model.
Decoding humanin vitroterminal erythropoiesis originating from umbilical cord blood mononuclear cells and pluripotent stem cells
Authors: Wang Xiaoling , Zhang Wei , Zhao Siqi , Yan Hao , Xin Zijuan , Cui Tiantian , Zang Ruge , Zhao Lingping , Wang Haiyang , Zhou Junnian , Li Xuan , Yue Wen , Xi Jiafei , Zhang Zhaojun , Fang Xiangdong , Pei Xuetao 
Published: April 2023

SUMMARYEx vivo RBC production generates unsatisfactory expansion, β-globin expression, and maturation of erythroid cells. The underlying mechanisms behind these limitations and ex vivo terminal erythropoiesis from different origins are largely unexplained. In this study, we mapped an atlas of ex vivo terminally differentiated cells from umbilical cord blood mononuclear cells (UCBMNs) and pluripotent stem cells (PSCs), and observed the differential regulatory dynamics of erythropoiesis from these two origins at a single-cell resolution. We detected the presence of hematopoietic stem progenitor cells (HSPCs), erythroid progenitor (e.g., CFU-E), and non-erythroid cells (e.g., macrophages) in the terminal populations. We observed that UCBMN-derived erythropoiesis is more active than PSC-derived erythropoiesis in terms of the cell cycle, stress erythropoiesis, and autophagy at single cell resolution, which may provide new insights into the limitations in cell expansion, globin expression, and maturation in ex vivo RBC production, respectively. We verified that a stress-erythropoiesis-related gene,TRIB3, increases the expression of globin genes in ex vivo erythropoiesis. As the major unexpected component detected in terminally differentiated cells, CFU-E were further characterized as having high- or low- expansion capacity based on CD99 expression, which generally decreased over erythropoiesis. By inhibiting CD99 gene expression using antagonists, we increased reticulocyte production in the population. Heterogeneous CFU-Es also exist in bone marrow. Moreover, decreased CD99 expression mediates the interactions between macrophages and CFU-E during ex vivo erythropoiesis. Overall, our results provide a reference for facilitating the development of strategies to improve ex vivo RBC regeneration.HighlightsWe performed scRNA-seq and cell typing of late stage UCBMN- and PSC-derived cellsStress erythropoiesis, autophagy and cell cycle related gene expression different in two originsCD99highprogenitor cells are a proliferating colony forming unit erythroid subpopulation
Immediate effect of quadri-pulse stimulation on human brain microstructures
Authors: Kimura Ikko , Hayashi Masamichi J , Amano Kaoru 
Published: April 2023

AbstractSeveral studies have implied that human brain microstructures can change immediately after a behavioral training. However, since widespread regions are involved in behavioral training, it remains unclear whether the microstructure in the living human brain changes immediately after the change in activity of a specific brain area. Hence, we aimed to examine whether the microstructures in the human brain change after the increase and decrease in the specific brain activity by repetitive transcranial magnetic stimulation, namely quadri-pulse stimulation (QPS). Right-handed healthy adults underwent both the excitatory (QPS5) and inhibitory (QPS50) QPS protocols over the left M1. Before and after QPS, diffusion MRI and resting-state fMRI scans were collected to detect any microstructural (fractional anisotropy [FA] and mean diffusivity [MD] values) and functional (functional connectivity between the bilateral M1) changes after QPS5 and QPS50. As a result, we observed no statistically significant change in FA or MD values after either QPS5 or QPS50 in cerebral cortex. This suggests that the brain activity change in widespread area is required to induce microstructural change immediately.