bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNFR2 costimulation differentially impacts regulatory and conventional CD4+ T-cell metabolism
Authors: Mensink Mark , Zaal Esther A. , Tran Ngoc Minh Thi , Schrama Ellen , Berkers Celia R. , Borst Jannie , de Kivit Sander 
Published: March 2022

AbstractCD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types.
circRAB3IP modulates cell proliferation by reorganizing gene expression and mRNA processing in a paracrine manner
Authors: Josipovic Natasa , Ebbesen Karoline K. , Zirkel Anne , Mackay-Danieli Adi , Dieterich Christoph , Kurian Leo , Hansen Thomas B. , Papantonis Argyris 
Published: March 2022

ABSTRACTCircular RNAs are endogenous long-lived and abundant non-coding species. Despite their prevalence, only few circRNAs have been dissected mechanistically to date. Here, we catalogued nascent RNA-enriched circRNAs from primary human cells and functionally assign a role to circRAB3IP in sustaining cellular homeostasis. We combined “omics” and functional experiments to show how circRAB3IP depletion deregulates hundreds of genes, suppresses cell cycle progression, and induces senescence-associated gene expression changes. Conversely, excess circRAB3IP delivered to endothelial cells via extracellular vesicles suffices for accelerating their division. We attribute these effects to the interplay between circRAB3IP and the general splicing factor SF3B1, which impacts transcript usage of cell cycle-related genes. Together, our findings link the maintenance of cell homeostasis to the tightly regulated titers of a single circRNA.
Digital twins and hybrid modelling for simulation of physiological variables and stroke risk
Authors: Herrgårdh Tilda , Hunter Elizabeth , Tunedal Kajsa , Örman Håkan , Amann Julia , Navarro Francisco Abad , Martinez-Costa Catalina , Kelleher John D. , Cedersund Gunnar 
Published: March 2022

ABSTRACTOne of the more interesting ideas for achieving personalized, preventive, and participatory medicine is the concept of a digital twin. A digital twin is a personalized computer model of a patient. So far, digital twins have been constructed using either mechanistic models, which can simulate the trajectory of physiological and biochemical processes in a person, or using machine learning models, which for example can be used to estimate the risk of having a stroke given a cross-section profile at a given timepoint. These two modelling approaches have complementary strengths which can be combined into a hybrid model. However, even though hybrid modelling combining mechanistic modelling and machine learning have been proposed, there are few, if any, real examples of hybrid digital twins available. We now present such a hybrid model for the simulation of ischemic stroke. On the mechanistic side, we develop a new model for blood pressure and integrate this with an existing multi-level and multi-timescale model for the development of type 2 diabetes. This mechanistic model can simulate the evolution of known physiological risk factors (such as weight, diabetes development, and blood pressure) through time, under different intervention scenarios, involving a change in diet, exercise, and certain medications. These forecast trajectories of the physiological risk factors are then used by a machine learning model to calculate the 5-year risk of stroke, which thus also can be calculated for each timepoint in the simulated scenarios. We discuss and illustrate practical issues with clinical implementation, such as data gathering and harmonization. By improving patients’ understanding of their body and health, the digital twin can serve as a valuable tool for patient education and as a conversation aid during the clinical encounter. As such, it can facilitate shared decision-making, promote behavior change towards a healthy lifestyle, and improve adherence to prescribed medications.
Establishing a reproducible approach for the controllable deposition and maintenance of plants cells with 3D bioprinting
Authors: Van den Broeck Lisa , Schwartz Michael F , Krishnamoorthy Srikumar , Spurney Ryan J , Tahir Maimouna Abderamane , Melvin Charles , Gobble Mariah , Peters Rachel , Muhammad Atiyya , Li Baochun , Stuiver Maarten , Horn Timothy , Sozzani Rosangela 
Published: March 2022

AbstractCapturing cell-to-cell and cell-to-environment signals in a defined 3 dimensional (3D) microenvironment is key to study cellular functions, including cellular reprogramming towards tissue regeneration. A major challenge in current culturing methods is that these methods cannot accurately capture this multicellular 3D microenvironment. In this study, we established the framework of 3D bioprinting with plant cells to study cell viability, cell division, and cell identity. We established long-term cell viability for bioprinted Arabidopsis root cells and soybean meristematic cells. To analyze the large image datasets generated during these long-term viability studies, we developed an open source high-throughput image analysis pipeline. Furthermore, we showed the cell cycle re-entry of the isolated Arabidopsis and soybean cells leading to the formation of microcalli. Finally, we showed that the identity of isolated cells of Arabidopsis roots expressing endodermal markers maintained longer periods of time. The framework established in this study paves the way for a general use of 3D bioprinting for studying cellular reprogramming and cell cycle re-entry towards tissue regeneration.
Genetic glyco-profiling and rewiring of insulated flagellin glycosylation pathways
Authors: Kint Nicolas , Dubois Thomas , Viollier Patrick H. 
Published: March 2022

SummaryGlycosylation of surface structures diversifies cells chemically and physically. Sialic acids commonly serve as glycosyl donors, particularly pseudaminic (Pse) or legionaminic acid (Leg) that prominently decorate eubacterial and archaeal surface layers or appendages. We investigated a new class of FlmG protein glycosyltransferases that modify flagellin, the structural subunit of the flagellar filament. Functional insulation of orthologous Pse and Leg biosynthesis pathways accounted for the flagellin glycosylation specificity and motility conferred by the cognate FlmG in the α-proteobacteria Caulobacter crescentus and Brevundimonas subvibrioides, respectively. Exploiting these functions, we conducted genetic glyco-profiling to classify Pse or Leg biosynthesis pathways and we used heterologous reconstitution experiments to unearth a signature determinant of Leg biosynthesis in eubacteria and archaea. These findings and our chimeric FlmG analyses reveal two modular determinants that govern flagellin glycosyltransferase specificity: a glycosyltransferase domain that accepts either Leg or Pse and that uses specialized flagellin-binding domain to identify the substrate.
Effects of variability in manually contoured spinal cord masks on fMRI co-registration and interpretation
Authors: Hoggarth Mark A. , Wang Max C. , Hemmerling Kimberly J. , Vigotsky Andrew D. , Smith Zachary A. , Parrish Todd B. , Weber Kenneth A. , Bright Molly G. 
Published: March 2022

AbstractFunctional magnetic resonance imaging (fMRI) of the human spinal cord (SC) is a unique non-invasive method for characterizing neurovascular responses to stimuli. Group-analysis of SC fMRI data involves co-registration of subject-level data to standard space, which requires manual masking of the cord and may result in bias of group-level SC fMRI results. To test this, we examined variability in SC masks drawn in fMRI data from 21 healthy participants from a completed study mapping responses to sensory stimuli of the C7 dermatome. Masks were drawn on temporal mean functional image by eight raters with varying levels of neuroimaging experience, and the rater from the original study acted as a reference. Spatial agreement between rater and reference masks was measured using the Dice Similarity Coefficient, and the influence of rater and dataset was examined using ANOVA. Each rater’s masks were used to register functional data to the PAM50 template. Gray matter-white matter signal contrast of registered functional data was used to evaluate the spatial normalization accuracy across raters. Subject- and group-level analyses of activation during left- and right-sided sensory stimuli were performed for each rater’s co-registered data. Agreement with the reference SC mask was associated with both rater (F(7,140) = 32.12, P < 2×10−16, η2 = 0.29) and dataset (F(20,140) = 20.58, P < 2×10−16, η2 = 0.53). Dataset variations may reflect image quality metrics: the ratio between the signal intensity of spinal cord voxels and surrounding cerebrospinal fluid was correlated with DSC results (p<0.001). As predicted, variability in the manually-drawn masks influenced spatial normalization, and GM:WM contrast in the registered data showed significant effects of rater and dataset (rater: F(8,160) = 23.57, P < 2×10−16, η2 = 0.24; dataset: F(20,160) = 22.00, P < 2×10−16, η2 = 0.56). Registration differences propagated into subject-level activation maps which showed rater-dependent agreement with the reference. Although group-level activation maps differed between raters, no systematic bias was identified. Increasing consistency in manual contouring of spinal cord fMRI data improved co-registration and inter-rater agreement in activation mapping, however our results suggest that improvements in image acquisition and post-processing are also critical to address.
Spatiotemporal patterns of sleep spindle activity in human anterior thalamus and cortex
Authors: Bernhard Hannah , Schaper Frederic L. W. V. J. , Janssen Marcus L. F. , Gommer Erik D. , Jansma Bernadette M. , Van Kranen-Mastenbroek Vivianne , Rouhl Rob P. W. , Weerd Peter de , Reithler Joel , Roberts Mark J. ,   DBS study group
Published: March 2022

AbstractSleep spindles (8 - 16 Hz) are transient electrophysiological events during non-rapid eye movement sleep. While sleep spindles are routinely observed in the cortex using scalp electroencephalography (EEG), recordings of their thalamic counterparts have not been widely studied in humans. Based on a few existing studies, it has been hypothesized that spindles occur as largely local phenomena. We investigated intra-thalamic and thalamocortical spindle co-occurrence, which may underlie thalamocortical communication. We obtained scalp EEG and thalamic recordings from 7 patients that received bilateral deep brain stimulation (DBS) electrodes to the anterior thalamus for the treatment of drug resistant focal epilepsy. Spindles were categorized into subtypes based on their main frequency (i.e., slow (10±2 Hz) or fast (14±2 Hz)) and their level of thalamic involvement (spanning one channel, or spreading uni- or bilaterally within the thalamus). For the first time, we contrasted observed spindle patterns with permuted data to estimate random spindle co-occurrence. We found that multichannel spindle patterns were systematically coordinated at the thalamic and thalamocortical level. Importantly, distinct topographical patterns of thalamocortical spindle overlap were associated with slow and fast subtypes of spindles. These observations provide further evidence for coordinated spindle activity in thalamocortical networks.HighlightsSleep spindles were measured in human anterior thalamus and on the scalpBoth fast and slow spindles occurred in the anterior thalamus> 25% of spindles spanned multiple channels in thalamus and cortexA novel statistical approach confirmed that spindle co-occurrences were not randomCortical spindle patterns depended on thalamic involvement and spindle frequency
PIP4K2B is a mechanosensor and induces heterochromatin-driven nuclear softening through UHRF1
Authors: Poli Alessandro , Pennacchio Fabrizio A. , Nastaly Paulina , Ghisleni Andrea , Crestani Michele , Pramotton Francesca M. , Iannelli Fabio , Beznusenko Galina , Mironov Alexander A. , Panzetta Valeria , Fusco Sabato , Sheth Bhavwanti , Netti Paolo A. , Poulikakos Dimos , Ferrari Aldo , Gauthier Nils , Divecha Nullin , Maiuri Paolo 
Published: March 2022

AbstractPhosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4, 5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localization. Here, we unveil the role for PIP4K2B as mechanosensor. PIP4K2B protein level, indeed, strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to soft, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.
Degeneracy in the neurological model of auditory speech repetition
Authors: Sajid Noor , Gajardo-Vidal Andrea , Ekert Justyna O. , Lorca-Puls Diego L. ,   PLORAS team, Hope Thomas M. H. , Green David W. , Friston Karl J. , Price Cathy J. 
Published: March 2022

AbstractIn the neurological model of language, repeating heard speech involves four left hemisphere regions: primary auditory cortex for processing sounds; Wernicke’s area for processing auditory images of speech; Broca’s area for processing motor images of speech; and primary motor cortex for overt speech articulation. Previous functional-MRI (fMRI) studies confirm that auditory repetition activates these regions. Here, we used dynamic causal modelling (DCM) to test how the four regions interact with each other during single word and pseudoword auditory repetition. Contrary to expectation, we found that, for both word and pseudoword repetition, the effective connectivity between Wernicke’s and Broca’s areas was predominantly bidirectional and inhibitory; activity in the motor cortex could be driven by either Wernicke’s area or Broca’s area; and the latter effect varied both within and between individuals. Such variability speaks to degenerate functional architectures that support auditory repetition and may explain resilience to functional loss after brain damage.
Myosin waves and a mechanical asymmetry guide the oscillatory migration of Drosophila cardiac progenitors
Authors: Balaghi Negar , Erdemci-Tandogan Gonca , McFaul Christopher , Fernandez-Gonzalez Rodrigo 
Published: March 2022

AbstractHeart development begins with the formation of a tube, as cardiac progenitors migrate from opposite sides of the embryo and meet medially. Defective cardiac progenitor movements cause congenital heart defects. However, the mechanisms of cell migration during early heart development remain poorly understood. We investigated the mechanisms of movement of the Drosophila cardiac progenitors, the cardioblasts. Using quantitative time-lapse microscopy, we found that cardioblasts did not advance monotonically. Instead, cardioblasts took periodic forward and backward steps as they migrated. The forward steps were greater in both amplitude and duration, resulting in net forward movement of the cells. The molecular motor non-muscle myosin II displayed an alternating pattern of localization between the leading and trailing ends of migrating cardioblasts, forming oscillatory waves that traversed the cells. The alternating pattern of myosin polarity was associated with the alternative contraction and relaxation of the leading and trailing edges of the cell. Mathematical modelling predicted that forward migration requires the presence of a stiff boundary at the trailing edge of the cardioblasts. Consistent with this, we found a supracellular actin cable at the trailing edge of the cardioblasts. When we reduced the tension sustained by the actin cable, the amplitude of the backward steps of cardioblasts increased, thus reducing the net forward speed of migration. Together, our results indicate that periodic cell shape changes coupled with a polarized actin cable produce asymmetrical forces that guide cardioblast migration.
PeerPub: A device for concurrent operant oral self-administration by multiple rats
Authors: Lemen Paige M. , Ni Jie , Huang Jun , Chen Hao 
Published: March 2022

AbstractThe social environment has long been recognized to play an important role in substance abuse disorders (SUD). Operant conditioning is the most widely used rodent model of SUD. However, most operant chambers do not accommodate more than one rat at a time. Here, we introduce PeerPub – a novel social operant chamber. PeerPub uses a touch sensor to record the number of licks on drinking spouts. It then delivers a drop of solution with a fixed volume as the reward to the tip of the spout when the number of licks meets the requirement of a reinforcement schedule. A radio-frequency identification (RFID) chip implanted on top of each rat’s skull tracks the identity of the rat. The system is controlled by a Raspberry Pi computer. We tested PeerPub using male Wistar Kyoto rats in daily one-hour sessions where supersac, a solution containing glucose and saccharin, was delivered under a fixed ratio 5 schedule. We found that male rats consumed more supersac in group housing rather than in isolated conditions. These data demonstrated the utility of PeerPub in modeling the interaction between motivated behavior and social context. We anticipate devices like PeerPub will help demonstrate the role of the social environment in SUD phenotypes. The design of PeerPub is available at http://github.com/nijie321/PeerPub
UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS
Authors: Black Holly H. , Roberts Julia E. , Leslie Shannon N. , Campodonico Will , Ebmeier Christopher C. , Lau Cristina I. , Whiteley Alexandra M. 
Published: March 2022

SummaryAmyotrophic Lateral Sclerosis (ALS) is a fatal, neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate a function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon ‘paternally expressed gene 10’ (PEG10) in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus and changes expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.
Unleashing the Potential of Noncanonical Amino Acid Biosynthesis for Creation of Cells with Site-Specific Tyrosine Sulfation
Authors: Chen Yuda , Jin Shikai , Zhang Mengxi , Wu Kuan-lin , Chang Anna , Wang Shichao , Tian Zeru , Wolynes Peter G. , Xiao Han 
Published: March 2022

AbstractIncorporation of noncanonical amino acids (ncAAs) into proteins holds great promise for modulating the structure and function of those proteins and for influencing evolutionary dynamics in organisms. Despite significant progress in improving the efficiency of translational machinery needed for incorporating ncAAs, exogenous feeding of high concentrations of chemically-synthesized ncAAs, especially in the case of polar ncAAs, is required to ensure adequate intracellular ncAA levels. Here, we report the creation of autonomous cells, both prokaryotic and eukaryotic, with the ability to biosynthesize and genetically encode sulfotyrosine (sTyr), an important protein post-translational modification with low membrane permeability. We discovered the first enzyme catalyzing tyrosine sulfation, sulfotransferase 1C1 from Nipponia nippon (NnSULT1C1), using a sequence similarity network (SSN). The unique specificity of NnSULT1C1 for tyrosine has been systematically explored using both bioinformatics and computational methods. This NnSULT1C1 was introduced into both bacterial and mammalian cells so as to yield organisms capable of biosynthesizing high levels of intracellular sTyr. These engineered cells produced site-specifically sulfated proteins at a higher yield than cells fed exogenously even with the highest level of sTyr reported in literature. We have used these autonomous cells to prepare highly potent thrombin inhibitors with site-specific sulfation. By enhancing ncAA incorporation efficiency, this added ability of cells to biosynthesize ncAAs and genetically incorporate them into proteins greatly extends the utility of genetic code expansion methods.TOC