bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretable XGBoost-SHAP model predicts the nanoparticles delivery and reveals its interaction with tumor genomic profiles
Authors: Tang Yuxia , Ma Xingqun , Wang Shouju 
Published: June 2022

AbstractUnderstanding the complex interaction between nanoparticles (NPs) and tumors in vivo and how it dominates the delivery efficacy of NPs is critical for the translation of nanomedicine. Herein, we proposed an interpretable XGBoost-SHAP model by integrating the information of NPs physicochemical properties and tumor genomic profile to predict the delivery efficacy. The correlation coefficients were > 0.99 for all training sets, and 0.830, 0.839, and 0.741 for the prediction of maximum delivery efficacy (DEmax), delivery efficacy at 24 h (DE24), and delivery efficacy at 168 (DE168) for test sets. The analysis of the feature importance revealed that the tumor genomic mutations and their interaction with NPs properties played an important role in the delivery of NPs. The functional profile of the NP-delivery-related genes was further explored through gene ontology enrichment analysis. Our work provides a method to accurately predict the delivery efficacy of NPs to heterogeneous tumors and highlights the power of simultaneously using omics data and interpretable machine learning algorithms for discovering the interaction between NPs and tumors, which is important for the development of precision nanomedicine.
Estimating causality between smoking and abdominal obesity by Mendelian randomization
Authors: Carrasquilla Germán D. , García-Ureña Mario , Romero Lado María José , Kilpeläinen Tuomas O. 
Published: June 2022

AbstractBackground and AimsSmokers tend to have a lower body weight than non-smokers, but also more abdominal fat. It remains unclear whether the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization studies have investigated this relationship by relying on a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to assess causality between smoking and abdominal obesity using multiple genetic instruments.MethodsWe used GWAS results for smoking initiation (n=1,232,091), lifetime smoking (n=462,690) and smoking heaviness (n=337,334) as exposure traits, and waist-hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697,734), with and without adjustment for body mass index (adjBMI), as outcome traits. We implemented Mendelian randomization using the CAUSE and LHC-MR methods that instrument smoking using genome-wide data.ResultsBoth CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95%CI 0.10, 0.16] and 0.49 [0.41, 0.57], respectively) and WHRadjBMI(0.07 [0.03, 0.10] and 0.31 [0.26, 0.37]). Similarly, they indicated a positive causal effect of lifetime smoking on WHR (0.35 [0.29, 0.41] and 0.44 [0.38, 0.51]) and WHRadjBMI(0.18 [0.13, 0.24] and 0.26 [0.20, 0.31]). In follow-up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones.ConclusionsSmoking initiation and higher lifetime smoking may lead to abdominal fat distribution. The increase in abdominal fat due to smoking was characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat.
Ifit2 regulates murine-coronavirus spread to the spinal cord white matter and its associated myelin pathology
Authors: Sharma Madhav , Chakravarty Debanjana , Zalavadia Ajay , Burrows Amy , Rayman Patricia , Sharma Nikhil , Kenyon Lawrence C. , Bergmann Cornelia , Sen Ganes C. , Sarma Jayasri Das 
Published: June 2022

AbstractIfit2, an interferon-induced protein with tetratricopeptide repeats 2, plays a critical role in restricting neurotropic murine β-coronavirus RSA59 infection. RSA59 intracranial injection of Ifit2 deficient (-/-) compared to wild type (WT) mice results in impaired acute microglial activation, associated with reduced CX3CR1 expression, which consecutively limits migration of peripheral lymphocytes into the brain, leading to impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence on demyelination during the chronic phase of RSA59 infection. Our current study demonstrates that Ifit2 deficiency causes extensive RSA59 viral spread throughout both the spinal cord grey and white matter and is associated with impaired CD4+ T cell infiltration. Cervical lymph nodes of RSA59 infected Ifit2-/- mice showed reduced activation of CD4+ T cells and impaired IFNγ expression during acute encephalomyelitis. Furthermore, blood-brain-barrier integrity was preserved in the absence of Ifit2 as evidenced by integral, tight junction protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake. In contrast to WT mice exhibiting only sparse myelin loss, the chronic disease phase in Ifit2-/- mice was associated with severe demyelination and persistent viral load, even at low infection doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe demyelination.Author SummaryThe role of interferons in providing protective immunity against viral spread and pathogenesis is well known. Interferons execute their function by inducing certain genes collectively called as interferon stimulated genes (ISGs) among which Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread in the brain. So far, not much has been investigated about its role in viral spread to the spinal cord and its associated myelin pathology. Towards this our study using neurotropic murine-β-coronavirus and Ifit2 deficient mice demonstrate that Ifit2 deficiency causes extensive viral spread throughout grey and white matter of spinal cord accompanied by impaired microglial activation and CD4+ T cell infiltration. Furthermore, infected Ifit2 deficient mice showed impaired activation of T cells in cervical lymph node and Blood-Brain-Barrier was relatively intact. Ifit2 deficient mice developed viral induced severe chronic neuroinflammatory demyelination accompanied by the presence of ameboid shaped phagocytotic microglia/macrophages.
PLK4 drives centriole amplification and apical surface area expansion in multiciliated cells
Authors: LoMastro Gina M , Drown Chelsea G , Maryniak Aubrey L , Jewett Cayla E , Strong Margaret A , Holland Andrew J 
Published: June 2022

AbstractMulticiliated cells (MCCs) are terminally differentiated epithelia that assemble multiple motile cilia used to promote fluid flow. To template these cilia, MCCs dramatically expand their centriole content during a process known as centriole amplification. In cycling cells, the master regulator of centriole assembly Polo-like kinase 4 (PLK4) is essential for centriole duplication; however recent work has questioned the role of PLK4 in centriole assembly in MCCs. To address this discrepancy, we created genetically engineered mouse models and demonstrated that both PLK4 protein and kinase activity are critical for centriole amplification in MCCs. Tracheal epithelial cells that fail centriole amplification accumulate large assemblies of centriole proteins and do not undergo apical surface area expansion. These results show that the initial stages of centriole assembly are conserved between cycling cells and MCCs and suggest that centriole amplification and surface area expansion are coordinated events.
Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin
Authors: Jakhar Shailja , Lenz Kiersten D. , Jacobsen Daniel E. , Kocheril Philip A. , Klosterman Katja E. , Mukundan Harshini , Kubicek-Sutherland Jessica Z. 
Published: June 2022

AbstractMycobacterium ulceransis the causative agent of the chronic and debilitating neglected tropical disease Buruli ulcer (BU) which mostly affects children. The early detection and treatment ofM. ulceransinfections can significantly minimize life-long disability resulting from surgical intervention. However, the disease is characterized by relatively few systemic systems as a result of complex host-pathogen interactions that have yet to be fully characterized, which has limited the development of both diagnostic and therapeutic approaches to treat BU. In this work, we study the interactions of the host immune system with two principleM. ulceransvirulence factors: mycolactone, an amphiphilic macrolide toxin, and lipoarabinomannan (LAM), a cell wall component of most mycobacterial pathogens. We observe that human lipoproteins have a profound effect on the interaction of both mycolactone and LAM with the immune system. Individually, both molecules are pro-inflammatory in the absence of serum and immunosuppressive in the presence of serum. When combined, mycolactone and LAM are immunosuppressive regardless of serum conditions. We also show that Toll-like receptor 2 (TLR2), a macrophage pathogen pattern recognition receptor, is critical for LAM immune stimulation but aids in mycolactone immunosuppression. These findings are a first step towards unraveling mycolactone-mediated immunosuppression during BU disease and may facilitate the development of effective diagnostics and therapeutics in the future.Author SummaryBuruli ulcer (BU) is a neglected tropical disease caused by the pathogenMycobacterium ulcerans. The principal virulence factors associated with it are the macrolide toxin mycolactone and the major cell wall component lipoarabinomannan (LAM). Here, we examine the impact of the amphiphilic biochemistry of mycolactone and LAM on their interaction with the human immune system. We show that both mycolactone and LAM associate with serum lipoproteins, and that this association is critical for the immune evasion seen in early-stageM. ulceransinfections. In the absence of serum, mycolactone is pro-inflammatory. Immunosuppression occurs only in the presence of human serum lipoproteins. In the presence of LAM, mycolactone is immunosuppressive, regardless of serum conditions. Immunosuppression is a hallmark of BU disease, and understanding the mechanisms of this immunosuppression can support the development of effective diagnostic and therapeutic strategies.
PCP and Septins govern the polarized organization of the actin cytoskeleton during convergent extension
Authors: Devitt Caitlin C , Weng Shinuo , Bejar-Padilla Vidal D , Alvarado José , Wallingford John B 
Published: June 2022

SummaryActin is generally required for cell movement but must be brought under the control of distinct developmental systems to drive specific morphogenetic processes, such as convergent extension (CE)1. This evolutionarily conserved collective cell movement elongates the body axis of all vertebrates and is governed by the Planar Cell Polarity (PCP) signaling system1,2. Here, we sought to understand the interplay of PCP and actin duringXenopusCE. Our data provide new insights into the organization and emergence of polarity in this network and reveal new roles for the actin organizing Septins3, thereby shedding light on the mechanisms by which developmental signaling systems exploit the ubiquitous machinery of cells to drive morphogenesis.
Integrating environmental DNA monitoring to inform eel (Anguilla anguilla) status in freshwaters at their easternmost range - A case study in Cyprus
Authors: Griffiths Nathan P. , Wright Rosalind M. , Hänfling Bernd , Bolland Jonathan D. , Drakou Katerina , Sellers Graham S. , Zogaris Stamatis , Tziortzis Iakovos , Dörflinger Gerald , Vasquez Marlen I. 
Published: June 2022

AbstractAimDespite significant population declines and targeted EU regulations aimed at A. anguilla conservation, little attention has been given to their status at their easternmost range. This study applies wide scale integrated monitoring to uncover the present-day eel distribution in Cyprus’ inland freshwaters. These are subject to increasing pressures from water supply requirements and dam construction, as seen throughout the Mediterranean.LocationCyprus.MethodsWe applied environmental DNA metabarcoding of water samples to determine A. anguilla distribution in key freshwater catchments. In addition, we present this alongside ten years of electrofishing/netting data. Refuge traps were also deployed to establish the timing of glass eel recruitment. These outputs are used together, alongside knowledge of the overall fish community and barriers to connectivity, to provide eel conservation and policy insights.ResultsWe confirm the presence of A. anguilla in Cyprus’ inland freshwaters, with recruitment occurring in March. Eel distribution is restricted to lower elevation areas, and is negatively associated with distance from coast and barriers to connectivity. Many barriers to connectivity are identified, though eels were detected in 2 reservoirs upstream of dams. The overall fish community varies between freshwater habitat types.Main ConclusionsEels are much more widespread in Cyprus than previously thought, yet mostly restricted to lowland intermittent systems. This makes for a case to reconsider the requirement for eel management plans. Environmental DNA based data collected in 2020 indicate that ‘present-day’ eel distribution is representative of 10-year survey trends. Suggesting that inland freshwaters may act as an unrealised refuge at A. anguilla’s easternmost range. Conservation efforts in Mediterranean freshwaters should focus on improving connectivity, therefore enabling eels to access inland perennial refugia. Thus, mitigating the impact of climate change and the growing number of fragmented artificially intermittent river systems.
Plasticity of transmembrane helix interactions in EphA2 dimers and oligomers
Authors: Wirth Daniel , Ozdemir Ece , Wimley William C. , Pasquale Elena B. , Hristova Kalina 
Published: June 2022

AbstractLateral interactions can stabilize different EphA2 receptor assemblies in the plasma membrane in response to different ligands. Here we use two fluorescent techniques, Forster Resonance Energy Transfer (FRET) and Fluorescence Intensity Fluctuations (FIF) spectrometry, to investigate how mutations in the EphA2 transmembrane (TM) helix affect the association between full-length EphA2 molecules in the absence of ligand and in the presence of three ligands: ephrinA1-Fc, m-ephrinA1, and the YSA peptide. The EphA2 mutations we studied have been previously characterized in the context of the isolated EphA2 TM helix. Working with full-length EphA2, we observed modest effects of the mutations on receptor-receptor interaction. Our data do not support the currently accepted model of a switch between two discrete TM helix dimerization motifs corresponding to active or inactive receptor states. Instead, we propose that different dimeric/oligomeric arrangements of the EphA2 extracellular region couple to an ensemble of TM helix dimer interfaces. Plasticity in the arrangements of receptor tyrosine kinase TM helices in active dimers and oligomers may serve to facilitate the cross-phosphorylation of multiple tyrosines in different positions of the intracellular regions.
Behavioral Phenotyping From deleted CB1 Receptors on Cholinergic Neuron Terminals
Authors: Wu S , Tsutsui K , Fitoussi AY 
Published: June 2022

SummaryMarijuana is the most widely used illicit drug in the Western Hemisphere and affects physiological processes and cognition. Clear deficits are observed in working memory (WM) that involve the temporary storage and online manipulation of information to solve complex tasks. Marijuana-induced WM deficits have been ascribed to the primary psychoactive compound in marijuana, Δ9-tetrahydrocannabinol, which acts at CB1 cannabinoid receptors (CB1r). Recent work emphasized the role of CB1r and cholinergic interaction across this cognitive domain without formal anatomical demonstration. We generated mice with a conditional deletion of CB1r on cholinergic neuron terminals, and WM was evaluated in operant chambers. Control of physiological variables (temperature, nociception, neuromuscular function) was also performed, and additional motor, motivation, time estimation behavior, and effort-based decision-making. Discrete WM enhancement measured in a novel Delay-Non-Matching-To-Position task was evidenced that incorporates early acquisition during randomized delays (mixed procedure), and remarkably, improved performance when these (2s, 8s, 16s, 20s) were kept constant (same procedure) across a testing block of trials. We reported higher motivation in an exponential progressive ratio schedule whilst locomotor activity did not differ between genotypes in the rotarod and open field. However, timing behavior was modified as indicated by higher discriminated motor responses for the shortest interval in conditional deleted mice in the Fixed-Interval time task (10s, 30s). We reported no effect on effort-based decision-making. Our work outlines presynaptic CB1r-cholinergic neuron function(s), and the hippocampus, neocortex, and amygdala brain regions as critical loci through known basal forebrain efferent projections possibly involved in WM and motivation in marijuana intoxication.
Relative roles of genetic variation and phenotypic plasticity in the invasion of monkeyflower Erythranthre gutatta in New Zealand
Authors: Williamson Michelle , Gerhard Daniel , Hulme Philip , Chapman Hazel 
Published: June 2022

AbstractEvolutionary processes which increase the probability of an introduced plant species becoming invasive include high levels of genetic diversity and phenotypic plasticity. Naturalised in New Zealand, monkeyflower, (Erythranthre gutatta), a clonally spreading herb of waterways and seepage areas native to the Western USA, shows marked variation in a range of vegetative, reproductive and inflorescence traits. We used two common gardens differing in elevation to explore the relative contribution of genetic versus plastic variation within nine traits among 34 monkeyflower clones from across the New Zealand South Island. We looked for evidence of clinal variation across elevation gradients and for home site advantage. We found both high genetic diversity and trait plasticity explain the observed variation, although less evidence for adaptive plasticity. Most genetic variation was observed in the lowland garden (9m a.s.l.), where the overall trend was for above ground dry weight to be lower, and horizontal shoot length greater, than at the montane garden (560m a.s.l). We found no evidence of local adaptation to any of the measured environmental variables. However, we observed a pattern of higher biomass and higher plasticity at lower versus higher elevations and in clones originating from lower elevation sites.
TANKBind: Trigonometry-Aware Neural NetworKs for Drug-Protein Binding Structure Prediction
Authors: Lu Wei , Wu Qifeng , Zhang Jixian , Rao Jiahua , Li Chengtao , Zheng Shuangjia 
Published: June 2022

AbstractIlluminating interactions between proteins and small drug molecules is a longstanding challenge in the field of drug discovery. Despite the importance of understanding these interactions, most previous works are limited by hand-designed scoring functions and insufficient conformation sampling. The recently-proposed graph neural network-based methods provides alternatives to predict protein-ligand complex conformation in a one-shot manner. However, these methods neglect the geometric constraints of the complex structure and weaken the role of local functional regions. As a result, they might produce unreasonable conformations for challenging targets and generalize poorly to novel proteins. In this paper, we propose Trigonometry-Aware Neural networKs for binding structure prediction, TANKBind, that builds trigonometry constraint as a vigorous inductive bias into the model and explicitly attends to all possible binding sites for each protein by segmenting the whole protein into functional blocks. We construct novel contrastive losses with local region negative sampling to jointly optimize the binding interaction and affinity. Extensive experiments show substantial performance gains in comparison to state-of-the-art physics-based and deep learning-based methods on commonly-used benchmark datasets for both binding structure and affinity predictions with variant settings.
Quantitative proteomic analysis reveals apoE4-dependent phosphorylation of the actin-regulating protein VASP
Authors: Cakir Zeynep , Lord Samuel J. , Zhou Yuan , Jang Gwendolyn M. , Polacco Benjamin J. , Eckhardt Manon , Jimenez-Morales David , Newton Billy W. , Orr Adam L. , Johnson Jeffrey R. , da Cruz Alexandre , Mullins R. Dyche , Krogan Nevan J. , Mahley Robert W. , Swaney Danielle L. 
Published: June 2022

AbstractApolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s Disease (AD). While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in VASP S235 phosphorylation in a PKA-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.
Rapid binding to protofilament edge sites facilitates tip tracking of EB1 at growing microtubule plus-ends
Authors: Gonzalez Samuel J. , Goldblum Rebecca R. , Vu Katherine T. , Shoemaker Rachel , Reid Taylor , McClellan Mark , Gardner Melissa K. 
Published: June 2022

AbstractEB1 is a key cellular protein that delivers critical regulatory molecules throughout the cell via the tip-tracking of growing microtubule plus-ends. Thus, it is important to understand the mechanism for how EB1 efficiently tracks growing microtubule plus-ends. It is widely accepted that EB1 binds with higher affinity to GTP-tubulin subunits at the growing microtubule tip, relative to GDP-tubulin along the microtubule length. However, it is unclear whether this difference in affinity alone is sufficient to explain the tip-tracking of EB1 at growing microtubule tips. Previously, we found that EB1 binds to exposed microtubule protofilament-edge sites at a ∼70-fold faster rate than to closed-lattice sites, due to diffusional steric hindrance to binding. Thus, we asked whether rapid protofilament-edge binding could contribute to efficient EB1 tip tracking. A computational simulation with differential EB1 on-rates based on closed-lattice or protofilament-edge binding, and with EB1 off-rates that were dependent on tubulin hydrolysis state, recapitulated experimental EB1 tip tracking. To test this model, we used cell-free biophysical assays, as well as live-cell imaging, in combination with the chemotherapy drug Eribulin. We found that Eribulin blocked EB1 protofilament-edge binding, which led to a dramatic decrease in EB1 tip tracking on dynamic microtubules. We conclude that rapid EB1 binding to microtubule protofilament-edge sites increases the efficiency of EB1 tip tracking at the growing microtubule plus end.