bluuebunny/crossref_metadata_2025_split huggingface dataset:
PplD is a de-N-acetylase of the cell wall linkage unit of streptococcal rhamnopolysaccharides
Authors: Rush Jeffrey S. , Parajuli Prakash , Ruda Alessandro , Li Jian , Pohane Amol A. , Zamakhaeva Svetlana , Rahman Mohammad M. , Chang Jennifer C. , Gogos Artemis , Kenner Cameron W. , Lambeau Gérard , Federle Michael J. , Korotkov Konstantin V. , Widmalm Göran , Korotkova Natalia 
Published: September 2021

AbstractThe cell wall of the human bacterial pathogen Group A Streptococcus (GAS) consists of peptidoglycan decorated with the Lancefield group A carbohydrate (GAC). GAC is a promising target for the development of GAS vaccines. In this study, employing chemical, compositional, and NMR methods, we show that GAC is attached to peptidoglycan via glucosamine 1-phosphate. This structural feature makes the GAC-peptidoglycan linkage highly sensitive to cleavage by nitrous acid and resistant to mild acid conditions. Using this characteristic of the GAS cell wall, we identify PplD as a protein required for deacetylation of linkage N-acetylglucosamine (GlcNAc). X-ray structural analysis indicates that PplD performs catalysis via a modified acid/base mechanism. Genetic surveys in silico together with functional analysis indicate that PplD homologs deacetylate the polysaccharide linkage in many streptococcal species. We further demonstrate that introduction of positive charges to the cell wall by GlcNAc deacetylation protects GAS against host cationic antimicrobial proteins.
Batch effects removal for microbiome data via conditional quantile regression (ConQuR)
Authors: Ling Wodan , Zhao Ni , Lulla Anju , Plantinga Anna M. , Fu Weijia , Zhang Angela , Liu Hongjiao , Li Zhigang , Chen Jun , Randolph Timothy , Koay Wei Li A. , White James R. , Launer Lenore J. , Fodor Anthony A. , Meyer Katie A. , Wu Michael C. 
Published: September 2021

AbstractBatch effects in microbiome data arise from differential processing of specimens and can lead to spurious findings and obscure true signals. Most existing strategies for mitigating batch effects rely on approaches designed for genomic analysis, failing to address the zero-inflated and over-dispersed microbiome data. Strategies tailored for microbiome data are restricted to association testing, failing to allow other analytic goals such as visualization. We develop the Conditional Quantile Regression (ConQuR) approach to remove microbiome batch effects using a two-part quantile regression model. It is a fundamental advancement in the field because it is the first comprehensive method that accommodates the complex distributions of microbial read counts, and it generates batch-removed zero-inflated read counts that can be used in and benefit all usual subsequent analyses. We apply ConQuR to real microbiome data sets and demonstrate its state-of-the-art performance in removing batch effects while preserving or even amplifying the signals of interest.
Arterial vasodilation drives convective fluid flow in the brain: a poroelastic model
Authors: Kedarasetti Ravi Teja , Drew Patrick J. , Costanzo Francesco 
Published: September 2021

AbstractThe movement of fluid into, through, and out of the brain plays an important role in clearing metabolic waste. However, there is controversy regarding the mechanisms driving fluid movement, and whether the movement metabolic waste is primarily driven by diffusion or convection. The dilation of penetrating arterioles in the brain in response to increases in neural activity (neurovascular coupling) is an attractive candidate for driving fluid circulation, as it drives deformation of the brain tissue and of the paravascular space around arteries, resulting in fluid movement. We simulated the effects of vasodilation on fluid movement into and out of the brain using a novel poroelastic model of brain tissue. We found that arteriolar dilations could drive convective flow through the brain radially outward from the arteriole, and that this flow is sensitive to the dynamics of the dilation. Simulations of sleep-like conditions, with larger vasodilations and increased extracellular volume in the brain showed enhanced movement of fluid from the paravascular space into the brain. Our simulations suggest that both sensory-evoked and sleep-related arteriolar dilations can drive convective flow of cerebrospinal fluid from the paravascular space into the brain tissue around arterioles.
Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject
Authors: Salahshoor Hossein , Guo Hongsun , Shapiro Mikhail G. , Ortiz Michael 
Published: September 2021

AbstractUltrasound neuromodulation (UNM), where a region in the brain is targeted by focused ultrasound (FUS), which, in turn, causes excitation or inhibition of neural activity, has recently received considerable attention as a promising tool for neuroscience. Despite its great potential, several aspects of UNM are still unknown. An important question pertains to the off-target sensory effects of UNM and their dependence on stimulation frequency. To understand these effects, we have developed a finite-element model of a mouse, including elasticity and viscoelasticity, and used it to interrogate the response of mouse models to focused ultrasound (FUS). We find that, while some degree of focusing and magnification of the signal is achieved within the brain, the induced pressure-wave pattern is complex and delocalized. In addition, we find that the brain is largely insulated, or ‘cloaked’, from shear waves by the cranium and that the shear waves are largely carried away from the skull by the vertebral column, which acts as a waveguide. We find that, as expected, this waveguide mechanism is strongly frequency dependent, which may contribute to the frequency dependence of UNM effects. Our calculations further suggest that off-target skin locations experience displacements and stresses at levels that, while greatly attenuated from the source, could nevertheless induce sensory responses in the subject.
Computational study on Strontium ion modified Fibronectin-Hydroxyapatite interaction
Authors: Basu Subhadip , Basu Bikramjit , Maiti Prabal K 
Published: September 2021

AbstractProtein adsorption is the first key step in cell-material interaction. The initial phase of such adsorption process can only be probed using modelling approaches like molecular dynamics (MD) simulation. Despite a large number of studies on the adsorption behaviour of proteins on different biomaterials including hydroxyapatite (HA); little attention has been paid towards quantitative assessment of the effects of various physicochemical influencers like surface modification, pH, and ionic strength. Among these factors, surface modification through isomorphic substitution of foreign ions inside the apatite structure is of particular interest in the context of protein-HA interaction as it is widely used to tailor the biological response of HA. Given this background, we present here the molecular-level understanding of fibronectin (FN) adsorption mechanism and kinetics on Sr2+-doped HA (001) surface, at 300K by means of all-atom molecular dynamics simulation. Electrostatic interaction involved in adsorption of FN on HA was found to be significantly modified in presence of Sr2+ doping in apatite lattice. In harmony with the published experimental observations, the Sr-doped surface was found to better support FN adhesion compared to pure HA, with 10 mol% Sr-doped HA exhibiting best FN adsorption. Sr2+ ions also influence the stability of the secondary structure of FN, as observed from the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. The presence of Sr2+ enhances the flexibility of specific residues (residue no. 20-44, 74-88) of the FN module. Rupture forces to disentangle FN from the biomaterials surface, obtained from steered molecular dynamics (SMD) simulations, were found to corroborate well with the results of equilibrium MD simulations. One particular observation is that, the availability of RGD motif for the interaction with cell surface receptor integrin is not significantly influenced by Sr2+ substitution. Summarizing, the present work establishes a quantitative foundation towards the molecular basis of the earlier experimentally validated better cytocompatibility of Sr-doped HA.
Structures of plasmepsin X from P. falciparum reveal a novel inactivation mechanism of the zymogen and molecular basis for binding of inhibitors in mature enzyme
Authors: Kesari Pooja , Deshmukh Anuradha , Pahelkar Nikhil , Suryawanshi Abhishek B. , Rathore Ishan , Mishra Vandana , Dupuis John H. , Xiao Huogen , Gustchina Alla , Abendroth Jan , Labaied Mehdi , Yada Rickey Y. , Wlodawer Alexander , Edwards Thomas E. , Lorimer Donald D. , Bhaumik Prasenjit 
Published: September 2021

AbstractPlasmodium falciparum plasmepsin X (PfPMX), involved in the invasion and egress of this deadliest malarial parasite, is essential for its survival and hence considered as an important drug target. We report the first crystal structure of PfPMX zymogen containing a novel fold of its prosegment. A unique twisted loop from the prosegment and arginine 244 from the mature enzyme are involved in zymogen inactivation; such mechanism, not previously reported, might be common for apicomplexan proteases similar to PfPMX. The maturation of PfPMX zymogen occurs through cleavage of its prosegment at multiple sites. Our data provide thorough insights into the mode of binding of a substrate and a potent inhibitor 49c to PfPMX. We present molecular details of inactivation, maturation, and inhibition of PfPMX that should aid in the development of potent inhibitors against pepsin-like aspartic proteases from apicomplexan parasites.
Knowledge-driven perceptual organization reshapes information sampling via eye movements
Authors: Pedziwiatr Marek A. , von dem Hagen Elisabeth , Teufel Christoph 
Published: September 2021

AbstractHumans constantly move their eyes to explore the environment and obtain information. Competing theories of gaze guidance consider the factors driving eye movements within a dichotomy between low-level visual features and high-level object representations. However, recent developments in object perception indicate a complex and intricate relationship between features and objects. Specifically, image-independent object-knowledge can generate objecthood by dynamically reconfiguring how feature space is carved up by the visual system. Here, we adopt this emerging perspective of object perception, moving away from the simplifying dichotomy between features and objects in explanations of gaze guidance. We recorded eye movements in response to stimuli that appear as meaningless patches on initial viewing but are experienced as coherent objects once relevant object-knowledge has been acquired. We demonstrate that gaze guidance differs substantially depending on whether observers experienced the same stimuli as meaningless patches or organized them into object representations. In particular, fixations on identical images became object-centred, less dispersed, and more consistent across observers once exposed to relevant prior object-knowledge. Observers’ gaze behaviour also indicated a shift from exploratory information-sampling to a strategy of extracting information mainly from selected, object-related image areas. These effects were evident from the first fixations on the image. Importantly, however, eye-movements were not fully determined by object representations but were best explained by a simple model that integrates image-computable features and high-level, knowledge-dependent object representations. Overall, the results show how information sampling via eye-movements in humans is guided by a dynamic interaction between image-computable features and knowledge-driven perceptual organization.
Solvent Precipitation SP3 (SP4) enhances recovery for proteomics sample preparation without magnetic beads
Authors: Johnston Harvey E. , Yadav Kranthikumar , Kirkpatrick Joanna M. , Biggs George S. , Oxley David , Kramer Holger B. , Samant Rahul S. 
Published: September 2021

Complete, reproducible extraction of protein material is essential for comprehensive and unbiased proteome analyses. A current gold standard is single-pot, solid-phase-enhanced sample preparation (SP3), in which organic solvent and magnetic beads are used to denature and capture proteins, with subsequently washes allowing contaminant removal. However, SP3 is dependent on effective protein immobilisation onto beads, risks losses during wash steps, and experiences a drop-off in protein recovery at higher protein inputs. Magnetic beads may also contaminate samples and instruments, and become costly for larger scale protein preparations. Here, we propose solvent precipitation SP3 (SP4) as an alternative to SP3, omitting magnetic beads and employing brief centrifugation—either with or without low-cost inert glass beads—as the means of aggregated protein capture. SP4 recovered equivalent or greater protein yields for 1–5000 µg preparations and improved reproducibility (median protein R2 0.99 (SP4) vs. 0.97 (SP3)). Deep proteome profiling (n = 9,076) also demonstrated improved recovery by SP4 and a significant enrichment of membrane and low-solubility proteins vs. SP3. The effectiveness of SP4 was verified in three other labs, each confirming equivalent or improved proteome characterisation over SP3. This work suggests that protein precipitation is the primary mechanism of SP3, and reliance on magnetic beads presents protein losses, especially at higher concentrations and amongst hydrophobic proteins. SP4 represents an efficient and effective alternative to SP3, provides the option to omit beads entirely, and offers virtually unlimited scalability of input and volume—all whilst retaining the speed and universality of SP3.BRIEFSolvent precipitation SP3 (SP4) captures aggregated protein for proteomics sample clean-up by omitting magnetic beads, instead employing brief centrifugation—with or without low-cost inert glass beads. SP4 offers improvements to protein yields, higher reproducibility, and greater recovery of membrane proteins, with verifications from three labs. Protein precipitation appears to be the primary mechanism of SP3, with reliance on magnetic beads presenting protein losses, especially at higher concentrations. SP4 presents an effective alternative to SP3 with improved scalability and equal speed and universality.GRAPHICAL ABSTRACT
A method to enrich and purify centromeric DNA from human cells
Authors: Gamba Riccardo , Mazzucco Giulia , Wilhelm Therese , Chardon Florian , Velikovsky Leonid , Picotto Julien , Doksani Ylli , Fachinetti Daniele 
Published: September 2021

AbstractCentromeres are key elements for chromosome segregation. Canonical centromeres are built over long-stretches of tandem repetitive arrays. Despite being quite abundant compared to other loci, centromere sequences overall still represent only 2 to 5% of the human genome, therefore studying their genetic and epigenetic features is a major challenge. Furthermore, sequencing of centromeric regions requires high coverage to fully analyze length and sequence variations, which can be extremely costly. To bypass these issues, we have developed a technique based on selective restriction digestion and size fractionation to enrich for centromeric DNA from human cells. Combining enzymes capable of cutting at high frequency throughout the genome, except within most human centromeres, with size-selection of >20 kb fragments resulted in over 25-fold enrichment in centromeric DNA. Sequencing of the enriched fractions revealed that up to 60% of the enriched material is made of centromeric DNA. This approach has great potential for making sequencing of centromeric DNA more affordable and efficient and for single DNA molecule studies.
Self-Administration of entactogen psychostimulants dysregulates GABA and Kappa Opioid Receptor signaling in the central nucleus of the amygdala of female Wistar rats
Authors: Khom Sophia , Nguyen Jacques D. , Vandewater Sophia A. , Grant Yanabel , Roberto Marisa , Taffe Michael A. 
Published: September 2021

AbstractMale rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-hour sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature postsynaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats) however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (postsynaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1mM U50488) and KOR antagonism (200nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.
A global meta-analysis reveals higher variation in breeding phenology in urban birds than in their non-urban neighbours
Authors: Capilla-Lasheras Pablo , Thompson Megan J. , Sánchez-Tójar Alfredo , Haddou Yacob , Branston Claire J. , Réale Denis , Charmantier Anne , Dominoni Davide M. 
Published: September 2021

AbstractCities pose a major ecological challenge for wildlife worldwide. Phenotypic variation, which can result from underlying genetic variation or plasticity, is an important metric to understand eco-evolutionary responses to environmental change. Recent work suggests that urban populations might have higher levels of phenotypic variation than non-urban counterparts. This prediction, however, has never been tested across species nor over a broad geographical range. Here, we conduct a meta-analysis of the avian literature to compare urbanversusnon-urban means and variation in phenology (i.e., lay date) and reproductive effort (i.e., clutch size, number of fledglings). First, we show that urban populations reproduce earlier and have smaller broods than non-urban conspecifics. Second, we show that urban populations have higher phenotypic variation in laying date than non-urban populations. This result arises from differences between populations within breeding seasons, conceivably due to higher landscape heterogeneity in urban habitats. These findings reveal a novel effect of urbanisation on animal life-histories with potential implications for species adaptation to urban environments (which will require further investigation). Higher variation in phenology in birds subjected to urban disturbance could result from plastic responses to a heterogeneous environment, or from higher genetic variation in phenology, possibly linked to higher evolutionary potential.
Early anteroposterior regionalisation of human neural crest is shaped by a pro-mesodermal factor
Authors: Gogolou Antigoni , Souilhol Celine , Granata Ilaria , Wymeersch Filip J , Manipur Ichcha , Wind Matthew , Frith Thomas JR , Guarini Maria , Bertero Alessandro , Bock Christoph , Halbritter Florian , Takasato Minoru , Guarracino Mario R , Tsakiridis Anestis 
Published: September 2021

AbstractThe neural crest (NC) is an important multipotent embryonic cell population and its impaired specification leads to various developmental defects, often in an anteroposterior (A-P) axial level-specific manner. The mechanisms underlying the correct A-P regionalisation of human NC cells remain elusive. Recent studies have indicated that trunk NC cells, the presumed precursors of the childhood tumour neuroblastoma, are derived from neuromesodermal-potent progenitors of the postcranial body (NMPs). Here we employ human embryonic stem cell differentiation to define how NMP-derived NC cells acquire a posterior axial identity. We show that TBXT, a pro-mesodermal transcription factor, mediates early posterior NC regionalisation together with WNT signalling effectors. This occurs by TBXT-driven chromatin remodelling via its binding in key enhancers within HOX gene clusters and other posterior regulator-associated loci. In contrast, posteriorisation of NMP-derived spinal cord cells is TBXT/WNT-independent and takes place under the influence of FGF signalling. Our work reveals a previously unknown role of TBXT in influencing posterior NC fate and points to the existence of temporally discrete, cell type-dependent modes of posterior axial identity control.
Targeting of MCL-1 in breast cancer associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties
Authors: Bonneaud TL , Nocquet L , Basseville A , Weber H , Campone M , Juin PP , Souazé F 
Published: September 2021

AbstractCancer associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFS) typically express MCL-1. We show here that targeting this regulator of mitochondrial integrity using a specific BH-3 mimetic promotes fragmentation of these organelles without inducing cell death. MCL-1 antagonism in primary bCAFs directly derived from human samples mitigates myofibroblastic features and decreases expression of genes involved in actomyosin organization and contractility, associated with a cytoplasmic retention of the transcriptional regulator, Yes-Associated Protein(YAP). Such treatment decreases bCAFs ability to promote cancer cells invasion in 3D co-culture assays. These effects are counteracted by an inhibitor of the mitochondrial fission protein DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve.The authors declare no conflict of interest.