bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bordetella spp. block eosinophil recruitment to suppress lung iBALT formation
Authors: First Nicholas J. , Martínez Amparo , González-Fernández África , Bharrham Sushma , Roan Connor , Cox Emily , Wang Jian , Scott Rona , Woolard Matthew , Gestal Monica C. 
Published: September 2022

ABSTRACTA characteristic that differentiates pathogenic and opportunistic bacteria is that pathogens have been selected by their ability to suppress host inflammatory responses allowing colonization and persistence. Bordetella spp. are respiratory pathogens characterized for the arsenal of mechanisms they use to manipulate host immune responses. We have previously characterized a B. bronchiseptica mutant, RB50ΔbtrS, that is not able to suppress host immune responses, resulting not only in rapid clearance of the infection but also long-term lung sterilizing immunity against reinfection with the three classical Bordetella spp. Interestingly, this strong immune response requires eosinophils. In this work our results indicate that wildtype B. bronchiseptica, RB50, blocks eosinophil pro-inflammatory functions to prevent the rapid recruitment of B and T cells to the lung that results in iBALT formation. Moreover, eosinophils promote a TH17 microenvironment within the iBALT that might be responsible for the long-term robust protective immunity generated by infection with this mutant. Overall, this work provides a novel role for eosinophils as promoters of adaptive immune responses and protective immunity, while also indicating that bacteria actively manipulate those cells to promote long-term persistence and reinfection.
Tinamou egg color displacement at eco-geographical and song space overlap
Authors: Li Qin , Chen Dahong , Wang Silu 
Published: September 2022

AbstractThe divergence of reproductive traits frequently underpins the evolution of reproductive isolation. Here we investigated the hypothesis that tinamou (Tinamidae) egg coloration functions as a mating signal and its diversification was driven by reinforcement. For many tinamou species, the male guards the nest that is sequentially visited and laid eggs in by multiple females. The colorations of the existing eggs in the nest could signal mate quality and species identities to both the incubating male and the upcoming females, preventing costly hybridization, thus were selected to diverge among species (Mating Signal Character Displacement Hypothesis). If so, two predictions should follow: (1) egg colors should coevolve with known mating signals as the tinamou lineages diverged; (2) species that partition similar eco-geography should display different egg colors. The tinamou songs are important mating signals and are highly divergent among species. We found that the egg color was significantly associated with the first principal component of the song variables. In addition, tinamou species with similar eco-geography tend to display different egg colors, while controlling for song variation among species. Mating signal evolution could be opportunistic and even exploit post-mating trait as premating signals that undergo character displacement in sympatry.
Yeast mtDNA transcription initiation in single nucleotide addition steps
Authors: Goovaerts Quinten , Shen Jiayu , De Wijngaert Brent , Basu Urmimala , Patel Smita S. , Das Kalyan 
Published: September 2022

AbstractTranscription initiation catalyzed by the RNA polymerase is a multistep process involving promoter binding, transcription bubble formation, abortive RNA synthesis, and transition into elongation following promoter escape. We report cryo-EM structures of yeast mitochondrial RNA polymerase initiation complexes (ICs) with transcription factor MTF1 catalyzing RNA synthesis from de novo initiation to 6-mer synthesis at single-nucleotide steps on fully-resolved transcription bubbles. The growing RNA:DNA hybrid is accommodated by continuous scrunching of the template strand while the non-template and MTF1 C-tail in the polymerase cleft are structurally reorganized. Each nucleotide addition accumulates stress energy, which drives abortive RNA synthesis during early transcription initiation steps and promoter release later. The non-template scrunches as loops in IC2/IC3, and unscrunching assists abortive synthesis of 2-/3-mer RNAs. Subsequently, in IC5 and IC6, the non-template strand assumes a stable structure by stacking its bases into a spiral staircase-like structure that supports processive synthesis. In IC6, the template scrunches to the maximum and places the -1 nucleotide in a pocket near the thumb domain. Subsequently, the -1 nucleotide acts as a pivot point for promoter escape ushering the IC into the elongation phase. The structural snapshots visualize the interplay between abortive and productive synthesis regulating transcription initiation.
DNA methylation of the endothelin receptor B makes blue fish yellow
Authors: Fang W. , Blakkan D. , Lee G. , Bashier R. , Fernald R.D. , Alvarado S.G. 
Published: September 2022

ABSTRACTNatural selection shapes traits during evolution including animal coloration known to be important for concealment and communication and color has been particularly salient in the explosive radiation of cichlid fish species in the rift valley lakes of East Africa. Though selection can produce variation in color via genetic substrates during early development, plasticity in coloration can occur through endocrine, neural and transcriptional cues in response to various environmental stimuli. It is well known that some animals often change color to match their visual ecology. Adult male cichlid fish (Astatotilapia burtoni, Lake Tanganyika) can switch between blue and yellow body colors. Different colors result from the expression of pigment-bearing cells, which differ in density and function between these two color morphs. We show that A. burtoni switches from yellow to blue depending on their visual environment by downregulating endothelin receptor B (EdnRB) mRNA via DNA hypermethylation at a single cytosine residue within its promoter. EdnRB functions in yellow chromatophores to signal the aggregation of yellow pigments, making yellow less visible. Taken together, the regulation of EdnRB through DNA methylation in yellow chromatophores, in part, contributes to pigmentation changes from blue to yellow, depending on visual environment.
Exploring protein sequence similarity with Protein Language UMAPs (PLUMAPs)
Authors: Jinich Adrian , Nazia Sakila Z. , Rhee Kyu 
Published: September 2022

AbstractVisualizing relationships and similarities between proteins can reveal insightful biology. Current approaches to visualize and analyze proteins based on sequence homology, such as sequence similarity networks (SSNs), create representations of BLAST-based pairwise comparisons. These approaches could benefit from incorporating recent protein language models, which generate high-dimensional vector representations of protein sequences from self-supervised learning on hundreds of millions of proteins. Inspired by SSNs, we developed an interactive tool - Protein Language UMAPs (PLUMAPs) - to visualize protein similarity with protein language models, dimensionality reduction, and topic modeling. As a case study, we compare our tool to Sequence Similarity Network (SSN) using the proteomes of two related bacterial species, Mycobacterium tuberculosis and Mycobacterium smegmatis. Both SSNs and PLUMAPs generate protein clusters corresponding to protein families and highlight enrichment or depletion across species. However, only in PLUMAPs does the layout distance between proteins and protein clusters meaningfully reflect similarity. Thus in PLUMAPs, related protein families are displayed as nearby clusters, and larger-scale structures correlate with cellular localization. Finally, we adapt techniques from topic modeling to automatically annotate protein clusters, making them more easily interpretable and potentially insightful. We envision that as large protein language models permeate bioinformatics and interactive sequence analysis tools, PLUMAPs will become a useful visualization resource across a wide variety of biological disciplines. Anticipating this, we provide a prototype for an online, open source version of PLUMAPs.
Initial and ongoing tobacco smoking elicits vascular damage and distinct inflammatory response linked to neurodegeneration
Authors: Garza Alejandra P. , Morton Lorena , Pállinger Éva , Buzás Edit I. , Schreiber Stefanie , Schott Björn H. , Dunay Ildiko Rita 
Published: September 2022

AbstractTobacco smoking is strongly linked to vascular damage contributing to the development of hypertension, atherosclerosis, as well as an increased risk for neurodegeneration. Still, the contribution of the innate immune system to the development of vascular damage upon chronic tobacco use before the onset of clinical symptoms is not fully elucidated. Notably, our data provide evidence that a single acute exposure to tobacco in never smokers elicits a secretion of extracellular vesicles by endothelial cells expressing CD105 and CD49e, granting further recognition of early preclinical biomarker of vascular damage. Further, we investigated the effects of smoking on the immune system of healthy asymptomatic chronic smokers compared to never-smokers and focused on the innate immune system. Our data reveal a distinct immune landscape representative for early stages of vascular damage before tobacco smoking related disease develop in clinically asymptomatic chronic smokers. These results indicate a dysregulated immuno-vascular axis in chronic tobacco smokers that are considered healthy individuals. The distinct alterations are characterized by increased CD36 expression by blood monocyte subsets, neutrophilia, increased plasma IL-18 and reduced levels of IL-33, IL-10 and IL-8. Further, the detection of lower circulating BDNF and elevated sTREM2, specific markers for neurodegeneration, suggests a considerable pre-clinical impact of tobacco smoking on CNS function in clinically healthy individuals. These findings provide further insight into the initial and ongoing effects of tobacco smoking and the potential vascular damage contributing to the progression of neurodegenerative disorders, specifically cerebrovascular dysfunction and dementia.
A Single-Cell Level Comparison of Human Inner Ear Organoids and the Human Cochlea and Vestibular Organs
Authors: van der Valk Wouter H. , van Beelen Edward S.A. , Steinhart Matthew R. , Nist-Lund Carl , de Groot John C.M.J. , van Benthem Peter Paul G. , Koehler Karl R. , Locher Heiko 
Published: September 2022

SummaryGenetic inner ear disorders are among the most common congenital abnormalities and lead to hearing loss and balance disorders. Ideally, tissue culture models of the inner ear should contain a functional unit combining otic sensory and nonsensory cell types to recapitulate the varied etiologies of inner ear disorders. Here, we evaluated cell type diversity of late-stage human pluripotent stem cell-derived inner ear organoids using single-cell transcriptomic analysis, electron microscopy and immunohistochemistry. We observed the induction of on-target inner ear-related periotic mesenchymal cells alongside off-target induction of skeletal myocytes, endothelial cells, and ependymal cells. By constructing a single-cell transcriptomic atlas of the human fetal and adult inner ear, we show that epithelium in the inner ear organoids contains cochlear and vestibular identities similar to the developing human inner ear. Moreover, the inner ear organoids contain immature type I and type II vestibular hair cells. Within these putative inner ear cell types, we confirmed the expression of genes and proteins linked to sensorineural hearing loss. This approach using human inner ear organoids would allow for disease modeling of specific genetic inner ear pathologies in the sensory and nonsensory domains of the inner ear.
Accurate and efficient constrained molecular dynamics of polymers through Newton’s method and special purpose code
Authors: López-Villellas Lorién , Mikkelsen Carl Christian Kjelgaard , Galano-Frutos Juan José , Marco-Sola Santiago , Alastruey-Benedé Jesús , Ibáñez Pablo , Moretó Miquel , Sancho Javier , García-Risueño Pablo 
Published: September 2022

AbstractIn molecular dynamics simulations we can often increase the time step by imposing constraints on internal degrees of freedom, such as bond lengths and bond angles. This allows us to extend the length of the time interval and therefore the range of physical phenomena that we can afford to simulate. In this article we analyse the impact of the accuracy of the constraint solver. We present ILVES-PC, an algorithm for imposing constraints on proteins accurately and efficiently.ILVES-PC solves the same system of differential algebraic equations as the celebrated SHAKE algorithm, but uses Newton’s method for solving the nonlinear constraint equations. It solves the necessary linear systems of equations using a specialised linear solver that utilises the molecular structure. ILVES-PC can rapidly solve the nonlinear constraint equations to nearly the limit of machine precision. This eliminates the spurious forces introduced to simulations through the very common use of inaccurate approximations. The run-time of ILVES-PC is proportional to the number of constraints.We have integrated ILVES-PC into GROMACS and simulated proteins of different sizes. Compared with SHAKE, we have achieved speedups of up to 4.9× in single-threaded executions and up to 76× in shared-memory multi-threaded executions. Moreover, we find that ILVES-PC is more accurate than the P-LINCS algorithm. Our work is a proof-of-concept of the utility of software designed specifically for the simulation of polymers.Author summaryMolecular dynamics simulates the time evolution of molecular systems. It has become a tool of extraordinary importance for e.g. understanding biological processes and designing drugs and catalysts. This article presents an algorithm for computing the forces needed to impose constraints in molecular dynamics, i.e., the constraint forces; moreover, it analyses the effect of the accuracy of the constraint solver. Presently, it is customary to calculate the constraint forces with a relative error that that is not tiny. This is due to the high computational cost associated with the available software. Accurate calculations are possible, but they are very time-consuming. The algorithm that we present solves this problem: it computes the constraint forces accurately and efficiently. Our work will improve the accuracy and reliability of molecular dynamics simulations beyond the present state-of-the-art. The results that we present are also a proof-of-concept that special-purpose code can increase the performance of software for the simulation of polymers. The algorithm is implemented into a popular molecular simulation package, and is now available for the research community.
Correction for participation bias in the UK Biobank reveals non-negligible impact on genetic associations and downstream analyses
Authors: Schoeler Tabea , Speed Doug , Porcu Eleonora , Pirastu Nicola , Pingault Jean-Baptiste , Kutalik Zoltán 
Published: September 2022

AbstractWhile large-scale volunteer-based studies such as the UK Biobank (UKBB) have become the cornerstone of genetic epidemiology, the study participants are rarely representative of their target population.Here, we aim to evaluate the impact of non-random participation in the UKBB, and to pin down areas of research that are particularly susceptible to biases when using non-representative samples for genome-wide discovery. By comparing 14 harmonized characteristics of the UKBB participants to that of a representative sample, we derived a model for participation probability. We then conducted inverse probability weighted genome-wide association analyses (wGWA) on 19 UKBB traits. Comparing the output obtained from wGWA (Neffective=94,643 – 102,215) to standard GWA analyses (N=263,464 – 283,749), we assessed the impact of participation bias on three estimated quantities, namely 1) genotype-phenotype associations, 2) heritability and genetic correlation estimates and 3) exposure-outcome causal effect estimates obtained from Mendelian Randomization. Participation bias can lead to both overestimation (e.g., cancer, education) and underestimation (e.g., coffee intake, depression/anxiety) of SNP effects. Novel SNPs were identified in wGWA for 12 of the included traits, highlighting SNPs missed as a result of participation bias. While the impact of participation bias on heritability estimates was small (average change in h2: 1.5%, maximum: 5%), substantial distortions were present for genetic correlations (average absolute change in rg: 0.07, maximum: 0.31) and Mendelian Randomization estimates (average absolute change in standardized estimates: 0.04, maximum: 0.15), most markedly for socio-behavioural traits including education, smoking and BMI. Overall, the bias mainly affected the magnitude of effects, rather than direction. In contrast, genome-wide findings for more molecular/physical traits (e.g., LDL, SBP) exhibited less bias as a result of selective participation.Our results highlight that participation bias can distort genomic findings obtained in non-representative samples, and we propose a viable solution to reduce such bias. Moving forward, more efforts ensuring either sample representativeness or correcting for participation bias are paramount, especially when investigating the genetic underpinnings of behaviour, lifestyles and social outcomes.
Global diversification of the common moonwort ferns (Botrychium lunariagroup, Ophioglossaceae) was mainly driven by Pleistocene climatic shifts
Authors: Mossion Vinciane , Koenen Erik , Grant Jason , Croll Daniel , Farrar Donald R. , Kessler Michael 
Published: September 2022

AbstractThe cosmopolitanBotrychium lunariagroup belong to the most species rich genus of the family Ophioglossaceae and was considered to consist of two species until molecular studies in North America and northern Europe led to the recognition of multiple new taxa. Recently, additional genetic lineages were found scattered in Europe, emphasizing our poor understanding of the global diversity of theB. lunariagroup, while the processes involved in the diversification of the group remain unexplored. We conducted the first global phylogenetic study of the group including 513 ingroup accessions sequenced for four non-coding plastid loci. We recovered ten well-supported clades, although relationships between clades were inconsistent between Bayesian and Maximum Likelihood analyses. We treated each clade at the species level, except for one clade including two ploidy levels, resulting in the recognition of 11 species, 5 of which are unnamed. In contrast to previous studies, we found species diversity to be equally distributed across the northern hemisphere, with 7-8 species per continent. We estimated the stem age of theB. lunariagroup at 2.4-5.1 million years, with most species 1.8-2.6 million years old, and subspecies 0.5-1.0 million years old. Diversification thus coincided with Pleistocene climatic fluctuations that strongly affected the areas inhabited by the group, suggesting that diversification was driven by climatically induced cycles of extinction, dispersal, and migration. Furthermore, ecological differentiation between species suggests these complex population dynamics were associated with adaptations to specific environmental conditions. We found limited evidence that speciation is driven by polyploidization and hybridization. We show that theB. lunariagroup has greater species level diversity than previously assumed and suspect that further cryptic species may await discovery, especially in theB. neolunariaclade.
Development of Comprehensive Ultraperformance Liquid Chromatography-High Resolution Mass Spectrometry Assays to Quantitate Cisplatin-Induced DNA-DNA Cross-Links
Authors: Groehler Arnold S. , Maratova Asema , Dao Nhat Mai , Mahkmut Anuar , Schärer Orlando D. 
Published: September 2022

ABSTRACTCisplatin (CP) is a common anti-tumor drug used to treat many solid tumors. The activity of CP is attributed to the formation of DNA-DNA cross-links, which consist of 1,2-intra-, 1,3-intra-, and interstrand cross-links. To better understand how each intrastrand cross-link contributes to the activity of CP, we have developed comprehensive ultraperformance liquid chromatography-selective ion monitoring (UPLC-SIM) assays to quantify 1,2-GG, 1,2-AG, 1,3-GCG, and 1,3-GTG-intrastrand cross-links. The limit of quantitation for the developed assays ranged from 5 – 50 fmol, or as low as 6 cross-links per 108 nucleotides. To demonstrate the utility of the UPLC-SIM assays, we first performed in vitro cross-link formation kinetics experiments. We confirmed 1,2-GG-intrastrand cross-links were the most abundant intrastrand cross-link and formed at a faster rate compared to 1,2-AG- and 1,3-intrastrand cross-links. Furthermore, we investigated the repair kinetics of intrastrand cross-links in CP-treated wild type and nucleotide excision repair (NER)-deficient U2OS cells. We observed slow repair of both 1,2- and 1,3-intrastrand cross-links in wild type cells, and no evidence of repair in the NER-deficient cells. Taken together, we have demonstrated that our assay is capable of accurately quantifying intrastrand cross-links in CP-treated samples and can be utilized to better understand the activity of CP.
Ester-linked ubiquitin sites formed by HOIL-1 in TLR7 signaling include four novel ubiquitin dimers
Authors: McCrory Elisha H. , Akimov Vyacheslav , Cohen Philip , Blagoev Blagoy 
Published: September 2022

AbstractThe E3 ligase HOIL-1 forms ester bonds in vitro between ubiquitin and serine/threonine residues in proteins. Here, we exploit UbiSite technology to identify serine and threonine residues undergoing HOIL-1 catalysed ubiquitylation in macrophages stimulated with R848, an activator of the TLR7/8 heterodimer. We identify Thr12, Thr14, Ser20 and Thr22 of ubiquitin as amino acid residues forming ester bonds with the C-terminal carboxylate of another ubiquitin molecule, increasing from 8 to 12 the different types of ubiquitin dimer formed in cells. We also identify Ser175 of IRAK4, Ser136, Thr163 and Ser168 of IRAK2 and Thr141 of MyD88 as further sites of HOIL-1-catalysed ubiquitylation together with lysine residues in these proteins that also undergo R848-dependent ubiquitylation. These findings establish that the ubiquitin chains attached to components of myddosomes are initiated by both ester and isopeptide bonds. Ester bond formation takes place within the proline, serine, threonine-rich (PST) domains of IRAK2 and IRAK4 and the intermediate domain of MyD88. The ubiquitin molecules attached to Lys162, Thr163 and Ser168 of IRAK2 are attached to different IRAK2 molecules.