bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptome Regulation by PARP13 in Basal and Antiviral States in Human Cells
Authors: Busa Veronica F. , Ando Yoshinari , Aigner Stefan , Yee Brian A. , Yeo Gene W , Leung Anthony K. L. 
Published: December 2022

SummaryThe RNA-binding protein PARP13 is a primary factor in the innate antiviral response. PARP13 suppresses translation and drives decay of bound viral and host RNA. PARP13 interacts with many proteins encoded by interferon-stimulated genes (ISG) to activate antiviral pathways including post-translational addition of ISG15, or ISGylation. We performed enhanced crosslinking immunoprecipitation (eCLIP) and RNA-seq in human cells to investigate PARP13’s role in transcriptome regulation for both basal and antiviral states. We find that the antiviral response shifts PARP13 target localization but not its binding preferences and that PARP13 supports the expression of ISGylation-related genes, including PARP13’s cofactor, TRIM25. We elucidate a transcriptome-wide periodicity of PARP13 binding around TRIM25 and show they associate in part via RNA-protein interactions. Taken together, our study implicates PARP13 in creating and maintaining a cellular environment poised for an antiviral response through limiting PARP13 translation, regulating access to distinct mRNA pools, and elevating ISGylation machinery expression.
Causal evidence for the involvement of Broca’s area in second language acquisition: A longitudinal HD-tDCS study
Authors: Gallagher Daniel , Matsumoto Kyosuke , Ohta Shinri 
Published: December 2022

ABSTRACTA wealth of correlational evidence suggests that Broca’s area (the left inferior frontal gyrus) plays a role in second language acquisition. With the use of highly focal non-invasive brain stimulation, evidence for a targeted brain region’s causal role in some cognitive behavior can be assessed. Over three sessions, each one week apart, we used online anodal high-definition transcranial direct current stimulation (HD-tDCS) over Broca’s area during a novel foreign grammar training session. During training, participants who were naïve to Spanish were tasked with acquiring present tense conjugation rules for the three Spanish verb endings. In Session 1, we observed significant improvement in performance in two linguistic (reception and production) tasks but not in a non-linguistic (working memory) task. Sessions 2 and 3 were subject to a ceiling effect, which obscured any potentially long-lasting effects of the stimulation. We interpret these results as support for the idea that Broca’s area has languagelike specificity that is not limited to receptive or productive processes and as evidence that Broca’s area plays a causal role in foreign grammar acquisition.
Mathematical Model of Mechanosensing and Mechanically Induced Collective Motility of Cells on Planar Elastic Substrates
Authors: Ahmed Riham K. , Abdalrahman Tamer , Davies Neil H. , Vermolen Fred , Franz Thomas 
Published: December 2022

AbstractCells mechanically interact with their environment to sense, for example, topography, elasticity and mechanical cues from other cells. Mechano-sensing has profound effects on cellular behaviour, including motility. The current study aims to develop a mathematical model of cellular mechano-sensing on planar elastic substrates and demonstrate the model’s predictive capabilities for the motility of individual cells in a colony.In the model, a cell is assumed to transmit an adhesion force, derived from a dynamic focal adhesion integrin density, that locally deforms a substrate, and to sense substrate deformation originating from neighbouring cells. The substrate deformation from multiple cells is expressed as total strain energy density with a spatially varying gradient. The magnitude and direction of the gradient at the cell location define the cell motion. Cell-substrate friction, partial motion randomness, and cell death and division are included.The substrate deformation by a single cell and the motility of two cells are presented for several substrate elasticities and thicknesses. The collective motility of 25 cells on a uniform substrate mimicking the closure of a circular wound of 200 μm is predicted for deterministic and random motion. Cell motility on substrates with varying elasticity and thickness is explored for four cells and 15 cells, the latter again mimicking wound closure. Wound closure by 45 cells is used to demonstrate the simulation of cell death and division during migration.The mathematical model can adequately simulate the mechanically-induced collective cell motility on planar elastic substrates. The model is suitable for extension to other cell and substrates shapes and the inclusion of chemotactic cues, offering the potential to complementin vitroandin vivostudies.
Full-length αIIbβ3 CryoEM structure reveals intact integrin initiate-activation intrinsic architecture
Authors: Huo Tong , Wu Hongjiang , Moussa Zeinab , Sen Mehmet , Dalton Valerie , Wang Zhao 
Published: December 2022

AbstractIntegrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation, thus pivotal for hemostasis, and arterial thrombosis as well as a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the intact full-length αIIbβ3, which covers three distinct states along the activation pathway. Here, we resolve intact αIIbβ3 structure at 3Å resolution, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the head region ligand-binding domain tucked in a specific angle proximity to the TM region. In response to the addition of a Mn2+agonist, we resolved two coexisting states, “intermediate” and “pre-active”. Our structures show conformational changes of the intact αIIbβ3 activating trajectory, as well as a unique twisting of the lower integrin legs representing an intermediate state (TM region at a twisting conformation) and a coexisting pre-active state (bent and opening in leg), which is required for inducing the transitioning platelets to accumulate. Our structure provides for the first time direct structural evidence for the lower legs’ involvement in full-length integrin activation mechanisms. Additionally, our structure offers a new strategy to target the αIIbβ3 lower leg allosterically instead of modulating the affinity of the αIIbβ3 head region.
Longitudinal flux balance analyses of a patient with Crohn’s disease highlight microbiome metabolic alterations
Authors: Basile Arianna , Heinken Almut , Hertel Johannes , Smarr Larry , Li Weizhong , Treu Laura , Valle Giorgio , Campanaro Stefano , Thiele Ines 
Published: December 2022

AbstractInflammatory bowel diseases (IBD) are characterised by episodic inflammation of the gastrointestinal tract. Gut microbial dysbiosis characterises the pathoetiology, but its role remains understudied. We report the first use of constraint-based microbial community modelling on a single individual with IBD, covering seven dates over 16 months, enabling us to identify a number of time-correlated microbial species and metabolites. We find that the individual’s dynamical microbial ecology in the disease state drives time-varyingin silicooverproduction, compared to healthy controls, of more than 24 biologically important metabolites, including oxygen, methane, thiamine, formaldehyde, trimethylamine N-oxide, folic acid, serotonin, histamine, and tryptamine. A number of these metabolites may yield new biomarkers of disease progression. The microbe-metabolite contribution analysis revealed that some genusDialisterspecies changed metabolic pathways according to the disease phases. At the first time point, characterised by the highest levels of blood and faecal inflammation biomarkers, they produced L-serine or formate. The production of the compounds, through a cascade effect, was mediated by the interaction with pathogenicEscherichia colistrains andDesulfovibrio piger. We integrated the microbial community metabolic models of each time point with a male whole-body, organ-resolved model of human metabolism to track the metabolic consequences of dysbiosis at different body sites. The presence ofD. pigerin the gut microbiome influenced the sulphur metabolism with a domino effect affecting the liver. These results underline the importance of tracking an individual’s gut microbiome along a time course, creating a new analysis framework for self-quantified medicine.Graphical abstract
Automated model discovery for skin: Discovering the best model, data, and experiment
Authors: Linka Kevin , Tepole Adrian Buganza , Holzapfel Gerhard A. , Kuhl Ellen 
Published: December 2022

AbstractChoosing the best constitutive model and the right set of model parameters is at the heart of continuum mechanics. For decades, the gold standard in constitutive modeling has been to first select a model and then fit its parameters to data. However, the success of this approach is highly dependent on user experience and personal preference. Here we propose a new method that simultaneously and fully autonomously discovers the best model and parameters to explain experimental data. Mathematically, the model finding is translated into a complex non-convex optimization problem. We solve this problem by formulating it as a neural network, and leveraging the success, robustness, and stability of the optimization tools developed in classical neural network modeling. Instead of using a classical off-the-shelf neural network, we design a new family of Constitutive Artificial Neural Networks with activation functions that feature popular constitutive models and parameters that have a clear physical interpretation. Our new network inherently satisfies general kinematic, thermodynamic, and physical constraints and trains robustly, even with sparse data. We illustrate its potential for biaxial extension experiments on skin and demonstrate that the majority of network weights train to zero, while the small subset of non-zero weights defines the discovered model. Unlike classical network weights, these weights are physically interpretable and translate naturally into engineering parameters and microstructural features such as stiffness and fiber orientation. Our results suggest that Constitutive Artificial Neural Networks enable automated model, parameter, and experiment discovery and could initiate a paradigm shift in constitutive modeling, from user-defined to automated model selection and parameterization. Our source code, data, and examples are available athttps://github.com/LivingMatterLab/CANN.
Analysing the role of SERPINE1 network in the pathogenesis of human glioblastoma
Authors: Khosravi Zahra , Kaliaperumal Chandrasekaran , Kumar Arun HS 
Published: December 2022

AbstractBackgroundGlioblastoma multiforme (GBM) is one of the most aggressive and difficult to treat brain tumour in humans with a 5 year survival rate of less than 6%. SERPINE1 is a novel tumour receptor found on GBM that modulates the progression of this cancer through growth signals and remodelling of the extracellular matrix. Hence, we investigated the role of SERPINE1 and its network proteins in pathogenesis of GBM and assessed its targetability.Material and methodsNetwork proteins of SERPINE1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The expression profile of SERPINE1 in the different brain regions was evaluated to correlate its relevance to GBM pathology. Selected small molecules fromCalotropis giganteawere screened using AutoDock vina to assess targetability of human SERPINE1.ResultsVTN, PLG, TGFB1, VWF, FGF2 and CXCR1 were identified as the major network proteins of SERPINE1. The strongest interaction was observed between SERPINE1 and FGF2 (42884 H-bonds) followed by CXCR1 (20279 H-bonds). Our results suggest that SERPINE1 and its network proteins identified here play a vital role in GBM development and progression through brain parenchyma by creating the prime microenvironment for carcinogenesis, tumour invasion and migration. The highest expression of SERPINE1 was observed in the pons, medulla, midbrain, corpus callosum and spinal cord. Expression of SERPINE1 was consistent with high grade lesions of GBM, suggesting association of SERPINE1 with advanced stages of GBM. The selected small molecules fromCalotropis giganteawere observed to have therapeutically feasible binding affinity (140 - 550 μM) and predicted efficacy (290 - 1115 μM) against human SERPINE1.ConclusionSERPINE1 plays a vital role in the progression of GBM through its critical network proteins identified in this study. The expression of SERPINE1 aligns with the advanced stages of GBM. Small molecules fromCalotropis giganteatested in this study can serve as lead compounds for developing novel anti-SERPINE1 therapeutics for advanced stages of GBM.
Human mutations inSLITRK3implicated in GABAergic synapse development in mice
Authors: Efthymiou Stephanie , Han Wenyan , Ilyas Muhammad , Li Jun , Yu Yichao , Scala Marcello , Malintan Nancy T. , Ilyas Muhammad , Vavouraki Nikoleta , Mankad Kshitij , Maroofian Reza , Rocca Clarissa , Salpietro Vincenzo , Lakhani Shenela , Mallack Eric J. , Palculict Timothy Blake , Li Hong , Zhang Guojun , Zafar Faisal , Rana Nuzhat , Takashima Noriko , Matsunaga Hayato ,   Queen Square Genomics,   SYNAPS Study Group, Striano Pasquale , Lythgoe Mark F. , Aruga Jun , Lu Wei , Houlden Henry 
Published: December 2022

AbstractWe report on biallelic homozygous and monoallelicde-novovariants inSLITRK3in 3 unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay.SLITRK3encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients’ SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, we bring additional evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG, as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, our results exhibit impaired development of peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. Our study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.
Habitat quality, not patch isolation, drives distribution and abundance of two light-demanding butterflies in fragmented coppice landscapes
Authors: Graser Anne , Kelling Marit , Pabst Rebecca , Schulz Meike , Kamp Johannes 
Published: December 2022

AbstractCoppice forests are socio-ecological systems especially rich in biodiversity. They have been transformed into high forest and abandoned across large areas of Europe over the past 200 years. Coppice loss is likely an important driver of insect declines. It is currently unclear whether habitat quality or decreasing connectivity of the remaining fragments is more important for the survival of insect populations. We related the abundance of two coppice-attached butterflies of conservation concern,Satyrium ilicisandMelitaea athalia, to indicators of habitat quality and habitat connectivity. We estimated butterfly densities using Distance Sampling along a successional gradient (time since last cut: 1–9 years; N = 130 plots) across one of the largest remaining simple oak-birch coppice landscapes in Central Europe. Both species reached abundance peaks within four to six years after the last cut, declining rapidly in abundance with subsequent succession. We found no evidence that coupe size, coppice availability and patch (= coupe) connectivity were related to the density of the species. Besides stand age, the cover of larval foodplants explained predicted butterfly densities well. OnlySatyrium ilicisbenefitted from high Red Deer densities.Implications for insect conservation: Our results suggest that habitat quality and sufficient availability of coppice of suitable age matters more than coupe size and fragmentation within a traditional managed coppice landscape. Coppice restoration aiming at the study species should ensure a shifting mosaic of successional habitat to provide a large availability of resprouting oak stools and blueberry vegetation that holds denseMelampyrum pratensestands.
Hybrid-DIA: Intelligent Data Acquisition for Simultaneous Targeted and Discovery Phosphoproteomics in Single Spheroids
Authors: Martínez-Val Ana , Fort Kyle , Koenig Claire , Van der Hoeven Leander , Franciosa Giulia , Moehring Thomas , Ishihama Yasushi , Chen Yu-ju , Makarov Alexander , Xuan Yue , Olsen Jesper V. 
Published: December 2022

AbstractAchieving sufficient coverage of regulatory phosphorylation sites by mass spectrometry (MS)-based phosphoproteomics for signaling pathway reconstitution is challenging when analyzing tiny sample amounts. We present a novel hybrid data-independent acquisition (DIA) strategy (hybrid-DIA) that combines targeted and discovery proteomics through an Application Programming Interface (API) to dynamically intercalate DIA scans with accurate triggering of multiplexed tandem MS scans of predefined (phospho)peptide targets. By spiking-in heavy stable isotope labeled phosphopeptide standards covering seven major signaling pathways, we benchmarked hybrid-DIA against state-of-the-art targeted MS methods (i.e. SureQuant) using EGF-stimulated HeLa cells and found the quantitative accuracy and sensitivity to be comparable while hybrid-DIA also profiled the global phosphoproteome. To demonstrate the robustness, sensitivity and potential of hybrid-DIA, we profiled chemotherapeutic agents in single colon carcinoma multicellular spheroids and evaluated the difference of cancer cells in 2D vs 3D culture. Altogether, we showed that hybrid-DIA is the way-to-go method in highly sensitive phospho-proteomics experiments.
Spatial, temporal and taxonomic patterns of insect extinction in Germany
Authors: Hallmann Caspar A. , Hörren Thomas , Ssymank Axel , Sumser Hubert , Schwan Heinz , Stenmans Werner , Vischer-Leopold Mareike , Schäffler Livia , Sorg Martin 
Published: December 2022

Red lists represent an important instrument for evaluating the decline of species in space and time, for improving decisionmaking and for guiding conservation planning. However, globally, only a fraction of species has been categorized according to a red list, even in countries where insects are relatively well-studied. Such large knowledge gaps hinder conservation planning and ultimately jeopardize the maintenance of ecosystem functions. Given the recent reports on severe insect decline, it is now more than ever of great importance to obtain a reliable complete picture of the state of insects. We here derive an estimate of extinction rates and of the proportion of threatened species for the total insect community in Germany, and asses spatial and temporal of extinction patterns.We found a regional extinction rate of 4.5% (1773-1937 species) for the area of Germany. Among extant insect species, 6% are classified as critically endangered (1856-2024 species), while among remaining species, a staggering 36.1% (10758-11086 species) is classified as threatened.Higher trophic levels of zoophagous insects are often more sensitive to negative environmental changes due to their position in the food web, and at the same time are underrepresented in Red Lists. They are therefore disproportionately affected by these knowledge gaps.This concerns particularly parasitoids which are taxa of regulatory importance and often higher extinction risk levels due to their trophic position.Exemplary examination of the spatial scaling of red list categories indicate a far higher rate and risk and exemplary over ten times higher regional extinction rate when the reference area is gradually scaled down.This illustrates the actual situation regarding the magnitude of regional species extinction events and extirpation risks that we have to assume for certain parts of the reference areas.For a given region, the loss of the gene pool of populations specially adapted to a given region usually represents an irreversible biodiversity loss. In order to avoid further irreparable damage, the species threatened with extinction must be preserved with top priority. There is thus a considerable need for research in order to assess the conservation status of more than 56% of the insect species diversity in Germany and to immediately achieve a more balanced trait group representation in red lists.
Distinct spatial maps and multiple object codes in the lateral entorhinal cortex
Authors: Huang Xu , Schlesiger Magdalene Isabell , Barriuso-Ortega Isabel , Leibold Christian , MacLaren Duncan Archibald Allan , Bieber Nina , Monyer Hannah 
Published: December 2022

SummaryThe lateral entorhinal cortex (LEC) is a major cortical input area to the hippocampus and it is crucial for associative object-place-context memories. An unresolved question is whether these associations are performed exclusively in the hippocampus or also upstream thereof. Anatomical evidence suggests that the LEC processes both object and spatial information. We here describe a gradient of spatial selectivity along the antero-posterior axis of the LEC. We demonstrate that the LEC generates distinct spatial maps for different contexts that are independent of object coding and vice versa, thus providing evidence for pure spatial and pure object codes upstream of the hippocampus. Whilst space and object coding occur by and large separately in the LEC, we identified neurons that encode for space and objects conjunctively. Together, these findings point to a scenario in which the LEC sustains both distinct space and object coding as well as associative space-object coding.