bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous Thrombolysis before Thrombectomy Improves Functional Outcome after Stroke Independent of Reperfusion Grade
Authors: Sedghi Annahita , Kaiser Daniel P. O. , Cuberi Ani , Schreckenbauer Sonja , Wojciechowski Claudia , Friehs Ingeborg , Reichmann Heinz , Barlinn Jessica , Barlinn Kristian , Puetz Volker , Siepmann Timo 
Published: July 2023

AbstractBackgroundWe studied the effect of bridging intravenous thrombolysis (IVT) before thrombectomy for anterior circulation large vessel occlusion (acLVO) on functional outcome and scrutinized its dependence on grade of reperfusion and distal thrombus migration.MethodsWe included consecutive acLVO patients from our prospective registry of thrombectomy-eligible patients treated from 01/01/2017 to 01/01/2023 at a tertiary stroke center in Germany into a retrospective cohort study. We evaluated the effects of bridging IVT on functional outcome quantified via modified Rankin scale (mRS) at 90 days applying multivariable logistic and lasso regression including interaction terms with grade of reperfusion quantified via modified Thrombolysis in Cerebral Infarction (mTICI) scale and distal thrombus migration adjusted for demographic and cardiovascular risk profiles, clinical and imaging stroke characteristics, onset-to-recanalization time and distal thrombus migration. We performed sensitivity analysis using propensity score matching.ResultsIn our study population of 1000 thrombectomy-eligible patients (513 females, median age 77 [67-84, interquartile range]) IVT emerged as predictor of favorable functional outcome (mRS 0-2) independent of mTICI (adjusted OR 0.49; 95% CI [0.32;0.75]; p=0.001). In those who underwent thrombectomy (n=812) the association of IVT and favorable functional outcome was reproduced (adjusted OR 0.49; 95% CI [0.31;0.74]; p=0.001) and was further confirmed on propensity score analysis where IVT led to a 0.35-point decrease in 90-day mRS score [ß=-0.35; 95CI% [-0.68;-0.01]; p=0.04]. The additive benefit of IVT remained independent of mTICI (ß=-1.79; 95% CI [-3.43;-0.15]; p=0.03) and distal thrombus migration (ß=-0.41; 95% CI [-0.69;-0.13]; p=0.004) on interaction analysis. Consequently, IVT showed an additive effect on functional outcome in the subpopulation of thrombectomy patients who achieved successful reperfusion (TICI≥2b; ß=-0.46; 95% CI [-0.74;-0.17]; p=0.002) and remained beneficial in those with unsuccessful reperfusion (TICI≤2a; ß=-0.47; 95% CI [-0.96;-0.01]; p=0.05).ConclusionsIn thrombectomy-eligible acLVO patients IVT improves functional outcome independent of grade of reperfusion and distal thrombus migration.
Epitope Engineered Human Haematopoietic Stem Cells are Shielded from CD123-targeted Immunotherapy
Authors: Marone Romina , Landmann Emmanuelle , Devaux Anna , Lepore Rosalba , Seyres Denis , Zuin Jessica , Burgold Thomas , Engdahl Corinne , Capoferri Giuseppina , Dell’Aglio Alessandro , Larrue Clément , Simonetta Federico , Rositzka Julia , Rhiel Manuel , Andrieux Geoffroy , Gallagher Danielle , Schröder Markus , Wiederkehr Amélie , Sinopoli Alessandro , Do Sacramento Valentin , Haydn Anna , Garcia-Prat Laura , Divsalar Christopher , Camus Anna , Xu Liwen , Bordoli Lorenza , Schwede Torsten , Porteus Matthew , Bonnefoy Jérôme Tamburini , Corn Jacob E. , Cathomen Toni , Cornu Tatjana I. , Urlinger Stefanie , Jeker Lukas T. 
Published: July 2023

SummaryTargeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE) or chimeric antigen receptor (CAR) cells is very effective for haematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for immunotherapy of myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various haematological malignancies, including acute myeloid leukaemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). However, shared expression of CD123 on healthy haematopoietic stem and progenitor cells (HSPCs) bears the risk for extensive myelotoxicity upon targeted depletion. Here, we demonstrate that rationally designed, epitope-engineered HSPCs were completely shielded from CD123-targeted immunotherapy but remained fully functional while CD123-deficient HSPCs displayed a competitive disadvantage. Thus, molecularly shielded HSPCs could allow tumor-selective targeted immunotherapy and in parallel enable rebuilding a fully functional haematopoietic system. We envision that this approach is broadly applicable to many targets and cells, could render hitherto undruggable targets accessible to immunotherapy and will allow continued posttransplant immunotherapy, for instance to treat minimal residual disease (MRD) or be used as a salvage therapy. Since the function of the engineered targets is preserved, multiplexed molecular shielding could also enable targeted combination immunotherapies to address tumor heterogeneity. More generally, epitope shielding will be applicable for replacement of other cell types including the many immune cells which are currently being considered for engineered cellular therapies.
RNAGEN: A generative adversarial network-based model to generate synthetic RNA sequences to target proteins
Authors: Ozden Furkan , Barazandeh Sina , Akboga Dogus , Tabrizi Sobhan Shokoueian , Seker Urartu Ozgur Safak , Cicek A. Ercument 
Published: July 2023

AbstractRNA - protein binding plays an important role in regulating protein activity by affecting localization and stability. While proteins are usually targeted via small molecules or other proteins, easy-to-design and synthesize small RNAs are a rather unexplored and promising venue. The problem is the lack of methods to generate RNA molecules that have the potential to bind to certain proteins. Here, we propose a method based on generative adversarial networks (GAN) that learn to generate short RNA sequences with natural RNA-like properties such as secondary structure and free energy. Using an optimization technique, we fine-tune these sequences to have them bind to a target protein. We use RNA-protein binding prediction models from the literature to guide the model. We show that even if there is no available guide model trained specifically for the target protein, we can use models trained for similar proteins, such as proteins from the same family, to successfully generate a binding RNA molecule to the target protein. Using this approach, we generated piRNAs that are tailored to bind to SOX2 protein using models trained for its relative (SOX10, SOX14, and SOX8) and experimentally validatedin vitrothat the top-2 molecules we generated specifically bind to SOX2.
Studies on the selectivity of the SARS-CoV-2 papain-like protease reveal the importance of the P2′ proline of the viral polyprotein
Authors: Chan H. T. Henry , Brewitz Lennart , Lukacik Petra , Strain-Damerell Claire , Walsh Martin A. , Schofield Christopher J. , Duarte Fernanda 
Published: July 2023

AbstractThe SARS-CoV-2 papain-like protease (PLpro) is an antiviral drug target that catalyzes the hydrolysis of the viral polyproteins pp1a/1ab, releasing the non-structural proteins (nsps) 1-3 that are essential for the coronavirus lifecycle. The LXGG↓X motif found in pp1a/1ab is crucial for recognition and cleavage by PLpro. We describe molecular dynamics, docking, and quantum mechanics/molecular mechanics (QM/MM) calculations to investigate how oligopeptide substrates derived from the viral polyprotein bind to PLpro. The results reveal how the substrate sequence affects the efficiency of PLpro-catalyzed hydrolysis. In particular, a proline at the P2′ position promotes catalysis, as validated by residue substitutions and mass spectrometry-based analyses. Analysis of PLprocatalyzed hydrolysis of LXGG motif-containing oligopeptides derived from human proteins suggests that factors beyond the LXGG motif and the presence of a proline residue at P2′ contribute to catalytic efficiency, possibly reflecting the promiscuity of PLpro. The results will help in identifying PLprosubstrates and guiding inhibitor design.
Blood pressure lowering enhances cerebrospinal fluid efflux primarily via the lymphatic vasculature
Authors: Jukkola Jari , Kaakinen Mika , Singh Abhishek , Moradi Sadegh , Ferdinando Hany , Myllylä Teemu , Kiviniemi Vesa , Eklund Lauri 
Published: July 2023

AbstractBackgroundInside the incompressible cranium, the volume of cerebrospinal fluid (CSF) is directly linked to blood volume: a change in either will induce a compensatory change in the other. Vasodilatory lowering of blood pressure has been shown to result in an increase of intracranial pressure, which, in normal circumstances should return to equilibrium by increased fluid efflux. In this study, we investigated the effect of blood pressure lowering (BPL) on fluorescent CSF tracer absorption into the systemic blood circulation.MethodsBPL was performed by an i.v. administration of nitric oxide donor sodium nitroprusside (5 µg kg-1min-1) or the Ca2+-channel blocker nicardipine hydrochloride (0.5 µg kg-1min-1) for 10 and 15 to 40 mins, respectively. The effect of BPL on CSF clearance was investigated by measuring the efflux of fluorescent tracers (40 kDa FITC-dextran, 45 kDa Texas Red-conjugated ovalbumin) into blood and deep cervical lymph nodes.ResultsNicardipine and sodium nitroprusside reduced blood pressure by 32.0 ± 19.6% and 22.0 ± 2.5%, while temporarily elevating in intracranial pressure by 14.0 ± 6.0% and 11.6 ± 2.0%, respectively. BPL significantly increased tracer accumulation into deep cervical lymph nodes and systemic circulation, but reduced perivascular inflow along penetrating arteries in the brain. The enhanced tracer efflux by BPL into the systemic circulation was markedly reduced (-66.7%) by ligation of lymphatic vessels draining into deep cervical lymph nodes.ConclusionsThis is the first study showing that CSF clearance can be improved with acute hypotensive treatment and that the effect of the treatment is reduced by ligation of a lymphatic drainage pathway. Enhanced CSF clearance by BPL may have therapeutic potential in diseases with dysregulated CSF flow.
Ankyrin B Promotes Developmental Spine Regulation in the Mouse Prefrontal Cortex
Authors: Murphy Kelsey E. , Duncan Bryce W. , Sperringer Justin E. , Zhang Erin Y. , Haberman Victoria A. , Wyatt Elliott V. , Maness Patricia F. 
Published: July 2023

AbstractPostnatal regulation of dendritic spine formation and refinement in cortical pyramidal neurons is critical for excitatory/inhibitory balance in neocortical networks. Recent studies have identified a selective spine pruning mechanism in the mouse prefrontal cortex (PFC) mediated by class 3 Semaphorins and the L1-CAM cell adhesion molecules Neuron-glia related CAM (NrCAM), Close Homolog of L1 (CHL1), and L1. L1-CAMs bind Ankyrin B (AnkB), an actin-spectrin adaptor encoded byAnkyrin2(ANK2), a high confidence gene for autism spectrum disorder (ASD). In a new inducible mouse model (Nex1Cre-ERT2:Ank2flox: RCE),Ank2deletion in early postnatal pyramidal neurons increased spine density on apical dendrites in PFC layer 2/3 of homozygous and heterozygousAnk2-deficient mice. In contrast,Ank2deletion in adulthood had no effect on spine density. Sema3F-induced spine pruning was impaired in cortical neuron cultures from AnkB-null mice and was rescued by re-expression of the 220 kDa AnkB isoform but not 440 kDa AnkB. AnkB bound to NrCAM at a cytoplasmic domain motif (FIGQY1231), and mutation to FIGQH inhibited binding, impairing Sema3F-induced spine pruning in neuronal cultures. Identification of a novel function for AnkB in dendritic spine regulation provides insight into cortical circuit development, as well as potential molecular deficiencies in ASD.
Enhanced long-term memory and increased mushroom body plasticity inHeliconiusbutterflies
Authors: Young Fletcher J. , Alcalde Amaia , Melo-Flórez Lina , Couto Antoine , Foley Jessica , Monllor Monica , McMillan W. Owen , Montgomery Stephen H. 
Published: July 2023

AbstractAs highly labile structures on both individual and evolutionary time-scales, the mushroom bodies, a key site of learning and memory in insects, are an excellent model for investigating the evolution of cognitive variation. We explored the behavioural consequences of mushroom body expansion inHeliconiusbutterflies, which possess greatly expanded mushroom bodies relative to their closest outgroups. We conducted long-term visual memory assays across threeHeliconiusand three other Heliconiini species using trained food-colour associations. We confirm robust differences between clades, withHeliconiusexhibiting greater fidelity to the trained colour after 8 days without reinforcement compared to other Heliconiini, with further evidence of stable preferences at 13 days. We extended this analysis to consider the plastic response of the mushroom body calyces over this time period, measuring the volume of the mushroom body calyx, and the number of neurons and synapses it contains. We find substantial post-eclosion expansion and synaptic pruning in calyx ofHeliconius erato, but not inDryas iulia. InHeliconius erato, visual associative learning experience specifically is associated with a greater retention of calyceal synapses. At an individual level, fidelity to the trained colour inHeliconius eratowas also positively correlated with synapse number. These results point to an enhanced visual long-term memory acrossHeliconius, facilitated not only by phylogenetic expansion of the mushroom body, but also changes in its developmental response to learning experience. The co-evolution of mushroom body expansion, plasticity and specific behaviours provides an important case study in the evolution of cognition.Significance StatementHow are cognitive differences between species supported by evolutionary changes in the brain? We investigated this question usingHeliconiusbutterflies which have expanded mushroom bodies, a region of the insect brain involved in learning and memory. We show thatHeliconiushave more stable visual long-term memories and exhibit more substantial age- and experience-related plasticity than a closely related genus with smaller mushroom bodies. Recall accuracy was also predicted by synapse number inHeliconius erato, but notDryas iulia, suggesting functional importance. These results suggest that increases in the size of specific brain regions and changes in their plastic response to experience may co-evolve to shape the evolution of cognition.
Spatial reorganization ofEscherichia colichromosome contextualizes triclosan stress-related genetic, epigenetic and transcriptome changes
Authors: Ghosh Dipannita , Evans Benjamin A. , Vivekanandan Perumal 
Published: July 2023

ABSTRACTChanges in the spatial organization of bacterial chromosomes under stress conditions and its biological implications remain poorly understood. We mapped the structural landscape of wild-type and Δdcm E. colichromosomes under triclosan stress using Hi-C to identify triclosan-induced chromosomal interaction domains (CIDs). Two CIDs were common to the wild-type and Δdcm E. coli, including a CID with a common boundary atfabIgene, which encodes the triclosan target. All mutations and structural variants under triclosan stress were observed within or in close proximity to triclosan-induced CIDs. Absence of Dcm methylation impacts both short- and long-range interactions in triclosan stress. Single-base resolution methylome maps reveal hypermethylation of adenines (in wild-type and Δdcm) and cytosines (in wild-type) in the two common triclosan-induced CIDs. Furthermore, global gene expression profiling identified enrichment of highly expressed genes within the two common CIDs. Our findings suggest that stress-induced CIDs inE. coliare hotspots for genetic variations and are associated with enhanced transcriptional activity and hypermethylation of Dam/Dcm motifs.
Urbanization spreads antimicrobial resistant enteric pathogens in wild bird microbiomes
Authors: Mourkas Evangelos , Valdebenito José O. , Marsh Hannah , Hitchings Matthew D. , Cooper Kerry K. , Parker Craig T. , Székely Tamás , Johansson Håkan , Ellström Patrik , Pascoe Ben , Waldenström Jonas , Sheppard Samuel K. 
Published: July 2023

AbstractHuman behaviour is dramatically changing global ecology. Nowhere is this more apparent than in urbanization, where novel high human density habitats are disrupting long established ecotones. Resultant changes to the transitional areas between organisms, especially enhanced contact between humans and wild animals, provides new opportunities for the spread of zoonotic pathogens, posing a serious threat to global public health. Here, by studying the multi-host enteric pathogenCampylobacter jejuniisolated from the gut of 30 bird species in 8 countries, we investigated how proximity to urbanization influenced the spread of antimicrobial resistant (AMR) strains. Generalized linear models compared multiple behavioural and ecological traits and confirmed a positive correlation between proximity to urbanization and the number ofC. jejunigenotypes and AMR genes in wild bird hosts. Wild birds from highly urban areas harboured up to four times moreC. jejunigenotypes and six times more AMR genes. This is consistent with increased frequency of transition events. Quantifying zoonotic transmission and gene pool spread is essential for quantitative one health surveillance and control measures against future zoonosis emergences.
The Landscape of Maize-Associated Bacteria and Fungi Across the United States
Authors: Schultz Corey R , Desai Hanish , Wallace Jason G 
Published: July 2023

AbstractThe maize microbiome consists of microbes that are associated with plants, and can be shaped by the host plant, the environment, and microbial partners, some of which can impact plant performance. We used a public dataset to analyze bacteria and fungi in the soil, rhizosphere, roots, and leaves of commercial maize at 30 locations across the US. We found that both tissue type and location had significant effects on community structure and makeup, although the patterns differed in bacteria and fungi based on tissue type. We also found many differences in predicted microbial gene pathways between tissues, with location also shaping predicted functional gene profiles. We found a pattern of potential interaction between fungi and bacteria, and potential intra-kingdom mutualism, in microbiome networks. The robustness of these networks was dependent upon tissue, with endophytes in leaves and roots showing significantly higher natural connectivity. Within a tissue, this connectivity was relatively stable across locations. We identified environment and soil characteristics that may impact tissue specific microbial abundance. Sulfate level in the soil was positively correlated with Proteobacteria abundance, but negatively correlated with Firmicutes abundance in the roots and leafs. Ascomycota appears to be affected by different environmental variables in each tissue. We also identified gene functions and enzymes which may be necessary to allow microbes to transition across compartments and become endophytes.
Spontaneous biases enhance generalisation in the neonate brain
Authors: Wang Shuge , Vasas Vera , Freeland Laura , Osorio Daniel , Versace Elisabetta 
Published: July 2023

AbstractThe ability to use sparse evidence to produce adaptive responses in new contexts and to new stimuli (inductive generalisation) is central to biological and artificial intelligence. Young and inexperienced animals require very little evidence to generalise, raising the question of whether the neonate brain is evolutionarily prepared (predisposed) for generalisation. To understand the principles of spontaneous generalisation, we exposed neonate chicks to an artificial social partner of a specific colour, and measured generalisation by comparing responses to novel and familiar stimuli along either the red-yellow or the blue-green colour continuum. Generalisation responses were inconsistent with an unbiased model, showing biases such as asymmetrical generalisation gradients, faster learning for particular colours (red and blue over yellow and green), preferences for unfamiliar stimuli and different time courses in learning. Moreover, the chicks’ generalisation behaviour was consistent with a Bayesian theoretical model that explicitly incorporates predispositions as initial preferences and treats the learning process as an update of spontaneous preferences. These results show that neonate animals are evolutionarily prepared for generalisation, via biases that do not depend on experience, reinforcement or supervision. Biases that facilitate generalisation are tuned to distinctive features that are unusual in the natural environment, such as the red and blue colours. Predispositions facilitate or hinder learning in the inexperienced brain, determining how experience is used to update the likelihood of predictive models. Neonate animals use spontaneous biases to solve the problem of induction.
The bigger picture: global analysis of solubilization performance of classical detergents versus new synthetic polymers utilizing shotgun proteomics
Authors: Mueller Stefan , Kubicek Jan , Merino Felipe , Hanisch Philipp , Maertens Barbara , Lackmann Jan-Wilm 
Published: July 2023

AbstractIntegral membrane proteins are critical for many cellular functions. Roughly 25% of all human genes code for membrane proteins, and about 70% of all approved drugs target them. Despite their importance, laborious and harsh purification conditions often hinder their characterization. Traditionally, they are removed from the membrane using detergents, thereby taking the proteins out of their native environment, affecting their function. Recently, a variety of synthetic polymers have been introduced, which can extract membrane proteins together with their native lipids into a so-called native nanodisc. However, they usually show lesser solubilization capacity than detergents, and their general applicability for membrane protein biochemistry is poorly understood. Here, we used Hek293 cell membrane extracts and LC-MS-based proteomics to compare the ability of nanodisc-forming polymers against state-of-the- art detergents to solubilize the membrane proteome. Our data demonstrates the general ability of synthetic co-polymers to extract membrane proteins, rivaling the efficacy of commonly used detergents. Interestingly, each class of solubilization agent presents specific solubilization profiles. We found no correlation between efficiency and number of transmembrane domains, isoelectric point, or GRAVY score for any compound. Our data shows that these polymers are a versatile alternative to detergents for the biochemical and structural study of membrane proteins, functional proteomics, or as components of native lysis/solubilization buffers. Our work here represents the first attempt at a proteome-scale comparison of the efficacy of nanodisc-forming polymers. These data should serve as starting reference for researchers looking to purify membrane proteins in near native conditions.