bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-body Microbiota of Newborn Calves and Their Response to Prenatal Vitamin and Mineral Supplementation
Authors: Luecke Sarah M. , Holman Devin B. , Schmidt Kaycie N. , Gzyl Katherine E. , Hurlbert Jennifer L. , Menezes Ana Clara B. , Bochantin Kerri A. , Kirsch James D. , Baumgaertner Friederike , Sedivec Kevin K. , Swanson Kendall C. , Dahlen Carl R. , Amat Samat 
Published: March 2023

ABSTRACTHere, we investigated whether initial microbial colonization at seven different anatomical locations in newborn calves and their blood cytokines are influenced by prenatal vitamin and mineral (VTM) supplementation. Samples were collected from the hoof, liver, lung, nasal cavity, eye, rumen (tissue and fluid), and vagina of beef calves that were born from dams that received diets with or without VTM supplementation throughout gestation (n=7/group). Calves were separated from their dams immediately after birth and fed colostrum and milk replacer until euthanasia at 30 h post-initial colostrum feeding. The microbiota of all samples was assessed using 16S rRNA gene sequencing and qPCR. 15 cytokines and chemokines were quantified in their serum. The hoof, ocular, liver, respiratory, and reproductive sites of newborn calves were colonized by site-specific microbiota that differed from that of the rumen (0.64 ≥ R2≥ 0.12,P≤ 0.003). Only the ruminal fluid microbiota was differed by on prenatal VTM supplementation (P<0.01 Differences (P<0.05) were detected in microbial richness (vagina), diversity (ruminal tissue and fluid, eye), composition at the phylum and genus level (ruminal tissue and fluid, and vagina), and total bacterial abundance (ocular and vagina) between VTM and control calves. The cytokine IP-10 was higher (P=0.02) in VTM calves. Overall, our results suggest that despite immediate separation from the dam upon birth, whole-body of 32-h old calves are colonized by relatively rich, diverse and site-specific bacterial communities, and that initial microbial colonization of the rumen, vagina and oculus seem to be influenced by the prenatal VTM supplementation.IMPORTANCEIncreased appreciation of maternal nutrition and microbiome’s involvement in developmental programming and evidence supportingin uteromicrobial colonization highlight that maternal nutrition factors could impact offspring microbial colonization. Here, we investigated whether initial microbial colonization in any of 7 different anatomical sites of newborn calves was influenced by maternal vitamin and mineral (VTM) supplementation. We identified changes in ruminal, vaginal, and ocular microbiota in newborn calves in response to prenatal VTM supplementation. We provided a “holistic” view on the whole-body calf microbiota. Our data was obtained from calves of the same sex and age, and who were immediately separated from dams, and hence provides novel insights on taxonomic composition of initial bacterial microbiota colonization in those anatomical sites examined. Combined, this study provides direction for future work targeting the manipulation of early life microbiome via alteration of maternal nutrition and harnessing early life microbiota for improved cattle health and production.
Resistance to host antimicrobial peptides mediates resilience of gut commensals during infection and aging inDrosophila
Authors: Arias-Rojas Aranzazu , Frahm Dagmar , Hurwitz Robert , Brinkmann Volker , Iatsenko Igor 
Published: March 2023

AbstractResilience to short-term perturbations, like inflammation, is a fundamental feature of microbiota, yet the underlying mechanisms of microbiota resilience are incompletely understood. Here we show thatLactiplantibacillus plantarum, a majorDrosophilacommensal, stably colonizes the fruit fly gut during infection and is resistant toDrosophilaantimicrobial peptides (AMPs). By transposon screening, we identifiedL. plantarummutants sensitive to AMPs. These mutants were impaired in peptidoglycan O-acetylation or teichoic acid D-alanylation, resulting in increased negative cell surface charge and higher affinity to cationic AMPs. AMP-sensitive mutants were cleared from the gut after infection and aging-induced gut inflammation in wild-type, but not in AMP-deficient flies, suggesting that resistance to host AMPs is essential for commensal resilience in an inflamed gut environment. Thus, our work reveals that in addition to the host immune tolerance to the microbiota, commensal-encoded resilience mechanisms are necessary to maintain the stable association between host and microbiota during inflammation.
ODF2 negatively regulates CP110 levels at centrioles/basal bodies to control biogenesis of primary cilia
Authors: Otto Madeline , Hoyer-Fender Sigrid 
Published: March 2023

AbstractPrimary cilia are essential sensory organelles that develop when an inhibitory cap consisting of CP110 and other proteins is eliminated. Degradation of CP110 by the ubiquitin-dependent proteasome pathway mediated by NEURL4 and HYLS1 removes the inhibitory cap. Here, we investigated the suitability of rapamycin-mediated dimerization for centriolar recruitment and asked whether the induced recruitment of NEURL4 or HYLS1 to the centriole promotes primary cilia development and CP110 degradation. We used rapamycin-mediated dimerization with ODF2 to induce their targeted recruitment to the centriole. We found decreased CP110 levels in transfected cells, but independent of rapamycin-mediated dimerization. By knocking down ODF2, we show that ODF2 controls CP110 levels. Overexpression of ODF2 is not sufficient to promote the formation of primary cilia, but overexpression of NEURL4 or HYLS1 is. Co-expression of ODF2 and HYLS1 resulted in the formation of tube-like structures, indicating an interaction. Thus, ODF2 controls primary cilia formation by negatively regulating the concentration of CP110 levels. Our data suggest that ODF2 most likely acts as a scaffold for the binding of proteins such as NEURL4 or HYLS1 to mediate CP110 degradation.SummaryNEURL4 and HYLS1 mediate the degradation of CP110 to allow cilium formation. We used rapamycin-mediated dimerization with ODF2 to recruit NEURL4 and HYLS1 to the centriole and show that ODF2 controls CP110 levels.
Native RNA nanopore sequencing reveals antibiotic-induced loss of rRNA modifications in the A- and P-sites
Authors: Delgado-Tejedor Anna , Medina Rebeca , Begik Oguzhan , Cozzuto Luca , Ponomarenko Julia , Novoa Eva Maria 
Published: March 2023

ABSTRACTThe biological relevance and dynamics of mRNA modifications have been extensively studied in the past few years, revealing their key roles in major cellular processes, such as cellular differentiation or sex determination. However, whether rRNA modifications are dynamically regulated, and under which conditions, remains largely unclear. Here, we performed a systematic characterization of bacterial rRNA modification dynamics upon exposure to diverse antibiotics using native RNA nanopore sequencing. To identify significant rRNA modification changes, we developedNanoConsensus, a novel pipeline that integrates the estimates from multiple RNA modification detection algorithms, predicting differentially modified rRNA sites with very low false positive rates and high replicability. We showed thatNanoConsensusis robust across RNA modification types, stoichiometries and coverage, and outperforms all individual algorithms tested. Using this approach, we identified multiple rRNA modifications that are lost upon the presence of antibiotics, showing that rRNA modification profiles are altered in an antibiotic-specific manner. We found that significantly altered rRNA modified sites upon antibiotic exposure are located in the vicinity of the A and P-sites of the ribosome, possibly contributing to antibiotic resistance. We then systematically examined whether loss of ‘antibiotic-sensitive’ rRNA modifications may be sufficient to confer antibiotic resistance, finding that depletion of some rRNA modification enzymes guiding dysregulated rRNA modifications confers increased antibiotic resistance. Altogether, our work reveals that rRNA modification profiles can be rapidly altered in response to environmental exposures, and that nanopore sequencing can accurately identify dysregulated rRNA modifications, contributing to the mechanistic dissection of antibiotic resistance. Moreover, we provide a novel, robust workflow to study rRNA modification dynamics in any species using nanopore sequencing in a scalable and reproducible manner.
Effects of alertness on perceptual detection and discrimination
Authors: Xu Yanzhi , Wokke Martijn , Noreika Valdas , Bareham Corinne , Jagannathan Sridhar , Georgieva Stanimira , Trentin Caterina , Bekinschtein Tristan 
Published: March 2023

AbstractThe level of alertness fluctuates throughout the day, exerting modulatory effects on human cognitive processes at any moment. However, our knowledge of how alertness level interacts with specific cognitive demands and perceptual rules of the task is still limited. Here we use perceptual decision-making paradigms to understand how alertness modulates the detection of a stimulus and the capacity to discriminate one stimulus from another. We analyzed data from four different experiments (113 participants in total): 1 - auditory masking detection; 2 - sensorimotor detection; 3 - auditory spatial discrimination; and 4 - auditory phoneme discrimination, and examined the performance of participants during the natural transition from awake (high alertness) to drowsy (low alertness). First, we fitted psychometric functions to the hit rates across different conditions of difficulty for EEG-defined high and low alertness metastable states, respectively. Second, we performed modelling of slope and threshold for the fitted curves as well as signal detection theory measures of perceptual sensitivity (d’) and response bias (criterion). We found lower detection and discrimination sensitivity to stimuli as alertness level decreases, signalled by a shallower slope of the sigmoidal curve and a lower d’, while the threshold increases slightly and equivalently across experiments during lower alertness. There was no change in the criterion to make the decision during the transition. These results suggest that reduced alertness generally decreases the quality of perceptual decision-making. Zooming in, we observed that the decrease in sensitivity measured by slope was stronger for discrimination than for detection decisions, indicating that lower alertness impairs the precision of decisions in discriminating alternatives more than identifying the presence of a stimulus around the threshold. Taken together, these results suggest that alertness has a common effect on perceptual decision-making and differentially modulates detection and discrimination decisions.
Distinct Electrophysiological Signatures of Intentional and Unintentional Mind-Wandering Revealed by Low-Frequency EEG Markers
Authors: Martel Adrien , Bruno Nicolas , Robertson Ian H , Dockree Paul M , Sitt Jacobo D , Valero-Cabré Antoni 
Published: March 2023

AbstractMind-wandering is typically characterized by the common experience wherein attention veers off into thoughts unrelated to the task at hand. Recent research highlights the intentionality dimension of mind-wandering as a key predictor of adverse functional outcomes with intentional and unintentional task-unrelated thought (TUT) differentially linked to neural, behavioral, clinical, and functional correlates. We here aimed to elucidate the electrophysiological underpinnings of intentional and unintentional TUT by systematically examining the individual and collective discriminative power of a large set of EEG markers to distinguish between attentional states. Univariate and multivariate analyses were conducted on 54 predefined markers belonging to four conceptual families: ERP, spectral, information theory and connectivity measures, extracted from scalp EEG recordings prior to multidimensional reports of ongoing thought from participants performing a sustained attention task. We report here that on-task, intentional and unintentional TUT exhibit distinct electrophysiological signatures in the low frequency range. More specifically, increased features of the theta frequency range were found to be most discriminative between on-task and off-task states, while features within the alpha band were characteristic of intentional TUT when compared to unintentional TUT. This result is theoretically well aligned with contemporary accounts describing alpha activity as an index of internally oriented attention and a potential mechanism to shield internal processes from sensory input. Our study verifies the validity of the intentionality dimension of mind-wandering and represents a step forward towards real-time detection and mitigation of maladaptive mind-wandering.
ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer’s disease
Authors: Bartosch Anne Marie W. , Youth Elliot H. H. , Hansen Shania , Kaufman Maria E. , Xiao Harrison , Koo So Yeon , Ashok Archana , Sivakumar Sharanya , Soni Rajesh K. , Dumitrescu Logan C. , Lam Tiffany G. , Ropri Ali S. , Lee Annie J. , Klein Hans-Ulrich , Vardarajan Badri N. , Bennett David A. , Young-Pearse Tracy L. , De Jager Philip L. , Hohman Timothy J. , Sproul Andrew A. , Teich Andrew F. 
Published: March 2023

AbstractZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer’s Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17’s binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4 dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17’s role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology.SignificanceAbnormal RNA processing is an important component of AD pathophysiology. We show here that ZCCHC17, a previously identified putative master regulator of synaptic dysfunction in AD, plays a role in neuronal RNA processing, and illustrate that ZCCHC17 dysfunction is sufficient to explain some of the splicing abnormalities seen in AD brain tissue, including synaptic gene splicing abnormalities. Using data from human patients, we demonstrate that ZCCHC17 mRNA levels correlate with cognitive resilience in the setting of AD pathology. These results suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for supporting cognitive function in AD patients, and motivate future work examining a possible role of abnormal RNA processing in AD-related cognitive decline.
Unrecognized Potent Activities of Colistin Against Clinically Importantmcr+ Enterobacteriaceae Revealed in Synergy with Host Immunity
Authors: Kumaraswamy Monika , Riestra Angelica , Flores Anabel , Uchiyama Satoshi , Dahesh Samira , Bondsäter Gunnar , Nilsson Victoria , Chang Melanie , Seo Hideya , Sakoulas George , Nizet Victor 
Published: March 2023

ABSTRACTColistin (COL) is a cationic cyclic peptide that disrupts negatively-charged bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity againstmcr+patients based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients withmcr+infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we report previously unrecognized bactericidal activities of COL againstmcr-1+isolates ofEscherichia coli(EC),Klebsiella pneumoniae(KP), andSalmonella enterica(SE) in standard tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on themcr-1+Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killedmcr-1+EC, KP, and SE in freshly isolated human blood proved effective as monotherapy in a murine model ofmcr-1+EC bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients withmcr-1+Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high risk patients with limited therapeutic options.
Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes
Authors: Verkhivker Gennady , Alshahrani Mohammed , Gupta Grace 
Published: March 2023

AbstractThe evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, protein stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of non-additive epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.
Reliable Particle Sizing in Vaccine Formulations using Advanced Dynamic Light Scattering
Authors: Bretz Coline , Jauslin Andrea , Leumann Dario , Koch Marius , Vaccaro Andrea 
Published: March 2023

AbstractUnderstanding the impact of lipid nanoparticles’ size on immunogenicity represents an important step for enabling the rapid development of novel vaccines against known or emergent diseases. Dynamic light scattering, also known as quasi-elastic light scattering or photon correlation spectroscopy, has established itself as an optimal analytical method to determine particle size due to its in-situ approach and fast measurements. However, its application to many systems of industrial relevance has been limited due to artifacts arising from multiple scattering. Results interpretation becomes severely compromised depending on the concentration of the system and the size of the particles. In this context, strong sample dilution is often required, bringing additional uncertainties to the formulation development process. Here, we show how advanced dynamic light scattering technology can filter out multiple scattering from the signal and yield fully accurate sizing measurements, regardless of the sample concentration. We illustrate this in a comparative study with standard dynamic light scattering using polystyrene beads as model suspension as well as a concentrated commercial lipid nanoparticle adjuvant (AddaVax™).