bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peptidoglycan fromBacillus anthracis InhibitsHuman Macrophage Efferocytosis in Part by Reducing Cell Surface Expression of MERTK and TIM-3
Authors: Mytych Joshua S , Pan Zijian , Lopez-Davis Charmaine , Redinger Nancy , Lawrence Christina , Ziegler Jadith , Popescu Narcis I. , James Judith A. , Farris A. Darise 
Published: April 2023

ABSTRACTBacillus anthracispeptidoglycan (PGN) is a major component of the bacterial cell wall and a key pathogen-associated molecular pattern (PAMP) contributing to anthrax pathology, including organ dysfunction and coagulopathy. Increases in apoptotic lymphocytes are a late-stage feature of anthrax and sepsis, suggesting there is a defect in apoptotic clearance. Here, we tested the hypothesis thatB. anthracisPGN inhibits the capacity of human monocyte-derived macrophages (MΦ) to efferocytose apoptotic cells. Exposure of CD163+CD206+MΦ to PGN for 24h impaired efferocytosis in a manner dependent on human serum opsonins but independent of complement component C3. PGN treatment reduced cell surface expression of the pro-efferocytic signaling receptors MERTK, TYRO3, AXL, integrin αVβ5, CD36 and TIM-3, whereas TIM-1, αVβ3, CD300b, CD300f, STABILIN-1 and STABILIN-2 were unaffected. ADAM17 is a major membrane-bound protease implicated in mediating efferocytotic receptor cleavage. We found multiple ADAM17-mediated substrates increased in PGN-treated supernatant suggesting involvement of membrane-bound proteases. ADAM17 inhibitors TAPI-0 and Marimastat prevented TNF release, indicating effective protease inhibition, and modestly increased cell-surface levels of MerTK and TIM-3 but only partially restored efferocytic capacity by PGN-treated MΦ. We conclude that human serum factors are required for optimal recognition of PGN by human MΦ and thatB. anthracisPGN inhibits efferocytosis in part by reducing cell surface expression of MERTK and TIM-3.
Versatile Computer Aided Design of Freeform DNA Nanostructures and Assemblies
Authors: Pfeifer Wolfgang G. , Huang Chao-Min , Poirier Michael G. , Arya Gaurav , Castro Carlos E. 
Published: April 2023

AbstractRecent advances in structural DNA nanotechnology have been facilitated by design tools that continue to push the limits of structural complexity while simplifying an often-tedious design process. We recently introduced the software MagicDNA, which enables design of complex 3D DNA assemblies with many components; however, the design of structures with freeform features like vertices or curvature still required iterative design guided by simulation feedback and user intuition. Here, we present an updated design tool, MagicDNA 2.0, that automates the design of freeform 3D geometries, leveraging design models informed by coarse-grained molecular dynamics simulations. Our GUI-based, stepwise design approach integrates a high level of automation with versatile control over assembly and sub-component design parameters. We experimentally validated this approach by fabricating a range of DNA origami assemblies with complex freeform geometries, including a 3D Nozzle, G-clef, and Hilbert and Trifolium curves, confirming excellent agreement between design input, simulation, and structure formation.
Adaptive behavior deficits in individuals with 3q29 deletion syndrome
Authors: Pollak Rebecca M , Lindsey Burrell T , Cubells Joseph F , Klaiman Cheryl , Murphy Melissa M , Saulnier Celine A , Walker Elaine F , White Stormi Pulver , Mulle Jennifer G 
Published: April 2023

AbstractBackground3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behavior. However, the full profile of adaptive function in 3q29del has not been described, nor has it been compared to other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes.MethodsIndividuals with 3q29del (n=32, 62.5% male) were evaluated using the Vineland Adaptive Behavior Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behavior and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del to published data on Fragile X syndrome, 22q11.2 deletion syndrome, and 16p11.2 deletion and duplication syndromes.ResultsIndividuals with 3q29del had global deficits in adaptive behavior that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behavior, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behavior, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behavior deficits in 3q29del was distinct from previously published data on comparable genomic disorders.ConclusionsIndividuals with 3q29del have significant deficits in adaptive behavior, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behavior than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.
Next-Generation Nanopore Sensors for Enhanced Detection of Nanoparticles
Authors: Confederat Samuel , Lee Seungheon , Vang Der , Soulias Dimitrios , Marcuccio Fabio , Peace Timotheus I. , Edwards Martin Andrew , Strobbia Pietro , Samanta Devleena , Wälti Christoph , Actis Paolo 
Published: April 2023

ABSTRACTNanopore sensing is a technique based on the Coulter principle to analyze and characterize nanoscale materials with single entity resolution. However, its use in nanoparticle characterization has been constrained by the need to tailor the nanopore aperture size to the size of the analyte, precluding the analysis of heterogenous samples. Additionally, nanopore sensors often require the use of high salt concentrations to improve the signal-to-noise ratio, which further limits their ability to study a wide range of nanoparticles that are unstable at high ionic strength.Here, we report the development of nanopore sensors enhanced by a polymer electrolyte system, enabling the analysis of heterogenous nanoparticle mixtures at low ionic strength. We present a finite element model to explain the anomalous conductive/resistive pulse signals observed and compare these results with experiments. Furthermore, we demonstrate the wide applicability of the method by characterizing metallic nanospheres of varied sizes, plasmonic nanostars with various degrees of branching, and protein-based spherical nucleic acids with different oligonucleotide loadings.Our system will complement the toolbox of nanomaterials characterization techniques and will enable real-time optimization workflow for engineering a wide range of nanomaterials.
The adaptability of the ion binding site by the Ag(I)/Cu(I) periplasmic chaperone SilF
Authors: Lithgo Ryan M. , Hanževački Marko , Harris Gemma , Kamps Jos J. A. G. , Holden Ellie , Benesch Justin LP , Jäger Christof M. , Croft Anna K. , Hobman Jon L. , Orville Allen M. , Quigley Andrew , Carr Stephen B. , Scott David J. 
Published: April 2023

ABSTRACTThe periplasmic chaperone SilF has been identified as part of an Ag(I) detoxification system in Gram negative bacteria. Sil proteins also bind Cu(I), but with reported weaker affinity, therefore leading to the designation of a specific detoxification system for Ag(I). Using isothermal titration calorimetry we show that binding of both ions is not only tighter than previously thought, but of very similar affinities. We investigated the structural origins of ion binding using molecular dynamics and QM/MM simulations underpinned by structural and biophysical experiments. The results of this analysis showed that the binding site adapts to accommodate either ion, with key interactions with the solvent in the case of Cu(I). The implications of this are that Gram negative bacteria do not appear to have evolved a specific Ag(I) efflux system but take advantage of the existing Cu(I) detoxification system. Therefore, there are consequences for how we define a particular metal resistance mechanism and understand its evolution in the environment.
Polygenic predictions of occupational status GWAS elucidate genetic and environmental interplay for intergenerational status transmission, careers, and health
Authors: Akimova Evelina T. , Wolfram Tobias , Ding Xuejie , Tropf Felix C. , Mills Melinda C. 
Published: April 2023

AbstractSocioeconomic status (SES) impacts health and the life course. This GWAS on sociologically informed occupational status measures (ISEI, SIOPS, and CAMSIS) using the UKBiobank (N=273,157) identified 106 genetic variants of which 8 are novel to the study of SES. Genetic correlation analyses point to a common genetic factor for SES. Within-family prediction and its reduction was attributable in equal parts to genetic nurture and assortative mating. Using polygenic scores from population predictions of 5-8%, we, firstly, showed that cognitive and non-cognitive traits – including scholastic and occupational motivation and aspiration – link genetic scores to occupational status. Second, 62% of the intergenerational transmission of occupational status can be ascribed to non-genetic inheritance (e.g., family environment). Third, the link between genetics, occupation, and health are interrelated with parental occupational status confounding the genetic prediction of general health. Finally, across careers, genetic prediction compresses during mid-career with divergence in status at later stages.
High-affinity biomolecular interactions are modulated by low-affinity binders
Authors: Mukundan S. , Deshpande Girish , Madhusudhan M.S. 
Published: April 2023

AbstractMolecular interactions play a central role in all biological processes. The strength of these interactions is often characterized by their dissociation constants (KD). The high affinity interactions (KD≤ 10-8M) are crucial for the proper execution of cellular processes and are thus extensively investigated. Detailed molecular and biochemical analyses of such high affinity interactions have lent considerable support to the concept of binary on/off switches in different biological contexts. However, such studies have typically discounted the presence of low-affinity binders (KD> 10-5M) in the cellular environment. In this study, we have assessed the potential influence of such low affinity binders on high affinity interactions. By employing Gillespie stochastic simulations as well as continuous methods, we demonstrate that the presence of low-affinity binders can indeed alter the kinetics and the steady state of high-affinity interactions. We refer to this effect as ‘herd regulation’ and have evaluated its possible impact in two different contexts including sex determination inDrosophila melanogasterand in signalling systems that employ molecular thresholds. Lastly, we suggest an ‘in vitro’ experimental strategy to validate herd regulation. Based on these analyses, we propose that low-affinity binders are likely prevalent in different biological contexts where the outcomes are contingent upon threshold value determinants and thus potentially impact their homeostatic regulation.
Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low dose treatment of high-grade serous ovarian carcinoma
Authors: Benada Jan , Bulanova Daria , Azzoni Violette , Petrosius Valdemaras , Ghazanfar Saba , Wennerberg Krister , Sørensen Claus Storgaard 
Published: April 2023

AbstractOvarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially, when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low dose approach utilising joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. In the present study, we found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and ovarian organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted activation of CDK1 by decreasing the phosphorylation levels of T14 and Y15 residues. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. Finally, the multiple low dosing was well tolerated in mice. These findings suggest a new multiple low dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.
A comprehensive transcriptional signature in pancreatic ductal adenocarcinoma reveals new insights into the immune and desmoplastic microenvironment
Authors: Pérez-Díez Irene , Andreu Zoraida , Hidalgo Marta R. , Perpiñá-Clérigues Carla , Fantín Lucía , Fernandez-Serra Antonio , de la Iglesia-Vaya María , Lopez-Guerrero José A , García-García Francisco 
Published: April 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) prognosis and treatment response remains devastatingly poor due partly to the highly heterogeneous, aggressive, and immunosuppressive nature of this tumor type. The intricate relationship between stroma, inflammation, and immunity remains vaguely understood in the PDAC microenvironment. Here, we performed a meta-analysis of stroma-, and immune-related gene expression in the PDAC microenvironment to improve disease prognosis and therapeutic development. We selected twenty-one PDAC studies from the Gene Expression Omnibus and ArrayExpress databases, including 922 samples (320 controls and 602 cases). Differential gene enrichment analysis identified 1153 significant dysregulated genes in PDAC patients that contribute to a desmoplastic stroma and an immunosuppressive environment (the hallmarks of PDAC tumors). The results highlighted two gene signatures related to the immune and stromal environments that cluster PDAC patients in high- and low-risk groups, impacting patient stratification and therapeutic decision-making. Moreover,HCP5, SLFN13, IRF9, IFIT2, andIFI35 immune geneswere related to prognosis value in PDAC patients, for the first time.Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with few curative options. Desmoplastic stroma and immune system evasion in PDAC represent challenges to the success of therapeutic strategies that function well in other tumor types. Characterizing the PDAC microenvironment (including the immune environment) remains critical to developing safe and efficient therapies. Here, we present a comprehensive meta-analysis identifying 1153 significantly dysregulated genes, which mainly impact extracellular matrix remodeling and the immune system. We identify two signatures of twenty-eight immune-related genes and eleven stroma-related genes influencing PDAC patient survival. Additionally, five immune genes are associated with PDAC prognosis for the first time.
Induced neural phase precession through exogeneous electric fields
Authors: Wischnewski M. , Tran H. , Zhao Z. , Shirinpour S. , Haigh Z.J. , Rotteveel J. , Perera N.D. , Alekseichuk I , Zimmermann J. , Opitz A. 
Published: April 2023

AbstractThe gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ∼90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (∼30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.
Combined effects of climate warming and pharmaceuticals on a tri-trophic freshwater food web
Authors: Duchet Claire , Grabicová Kateřina , Kolar Vojtech , Lepšová Olga , Švecová Helena , Csercsa Andras , Zdvihalová Barbora , Randák Tomáš , Boukal David S. 
Published: April 2023

AbstractMultiple anthropogenic stressors influence the functioning of ponds and lakes, but their combined effects are often little understood. We ran two mesocosm experiments to evaluate the effects of warming (+4°C above ambient) and environmentally relevant concentrations of a mixture of commonly used pharmaceuticals, an emerging class of chemical contaminants, on tri-trophic food webs representative of pelagic communities in ponds and other small standing waters. We quantified the main and interactive effects of warming and pharmaceuticals on each trophic level and attributed them to the direct effects of both stressors and the indirect effects arising through biotic interactions. Warming and pharmaceuticals had stronger effects in the summer experiment, altering zooplankton community composition and causing delayed or accelerated emergence of top insect predators. In summer, both stressors and top predators reduced filter-feeding zooplankton biomass, while warming and pharmaceuticals had opposing effects on phytoplankton. In the winter experiment, the effects were much weaker and primarily limited to a positive effect of warming on phytoplankton biomass. Overall, we show that pharmaceuticals can exacerbate the effects of climate warming in freshwater ecosystems, especially during the warm season. Our results demonstrate the utility of community-level studies across different seasons for the risk assessment of multiple emerging stressors in freshwater ecosystems.
Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis
Authors: Patel K , Barter MJ , Soul J , Clark P , Proctor CJ , Clark IM , Young DA , Shanley DP 
Published: April 2023

AbstractChanges in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA-mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work demonstrated alteration of miR-199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targetsFZD6, ITGA3andCAV1were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterize a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs.
Background environment modulates motor contagions in humans
Authors: Saito Hiroto , Fukuchi Kentaro , Inami Masahiko , Ganesh Gowrishankar 
Published: April 2023

ABSTRACTMotor contagions refer to implicit effects in one’s actions induced by the observation of actions made by others. A plethora of studies over the last two decades have exhibited that observed, as well as predicted, actions can induce various kinds of motor contagions in a human observer. However, motor contagion has always been investigated in regard to different features of an observed action and it remains unclear whether the environment, in which an observed action takes place, modulates motor contagions as well. Here we investigated the effect of the observed environment on motor contagions using an empirical hand steering task in which the participants were required to move a cursor through visual channels of different shapes. We observed the movement time of observers to be influenced by both the movement of the cursor they observed, as well as the background (channel shape) in which the cursor movement was observed. Observers consistently made faster movements after observing steering movements in a ‘narrowing’ channel compared to a ‘widening’ channel. These results show a distinct effect of the environment, in which an observed action occurs, on one’s own movement.
Rethinking data treatment: The sucrose preference threshold for anhedonia in stress-induced rat models of depression
Authors: Berrio Jenny P. , Kalliokoski Otto 
Published: April 2023

AbstractExposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this method, as it measures a rat’s preference for a sweet solution as an indicator of its ability to experience pleasure. Typically, if stressed rats show a lower preference compared to unstressed rats, it is concluded they are experiencing stress-induced anhedonia. While conducting a systematic review, we identified 18 studies that used thresholds to define anhedonia and to distinguish “susceptible” from “resilient” individuals. Based on their definitions, researchers either excluded “resilient” animals from further analyses or treated them as a separate cohort. We performed a descriptive analysis to understand the rationale behind these criteria, and found that the methods used for characterizing the stressed rats were largely unsupported. Many authors failed to justify their choices or relied exclusively on referencing previous studies. When tracing back the method to its origins, we converged on a pioneering article that, although employed as a universal evidence-based justification, cannot be regarded as such. What is more, through a simulation study, we provided evidence that removing or splitting data, based on an arbitrary threshold, introduces statistical bias by overestimating the effect of stress. Caution must be exercised when implementing a predefined cut-off for anhedonia. Researchers should be aware of potential biases introduced by their data treatment strategies and strive for transparent reporting of methodological decisions.