bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping the potential distribution of the principal vector of Crimean-Congo hemorrhagic fever virus Hyalomma marginatum in Europe
Authors: Celina Seyma S. , Černý Jiří , Samy Abdallah M. 
Published: October 2022

AbstractCrimean-Congo haemorrhagic fever (CCHF) is the most widely distributed tick-borne viral disease in humans. The virus is widely expanded across western China, South Asia, and the Middle East to southeastern Europe and Africa. Its causative agent, Crimean-Congo haemorrhagic fever virus (CCHFV), is among the deadliest human pathogens in Africa and Eurasia. The historical known distribution of the CCHFV vector Hyalomma marginatum in Europe included most of the Mediterranean and the Balkan countries, Ukraine, and southern Russia. Further expansion of its potential distribution is possibly occurred in and out of the Mediterranean region. This study updated the map of the principal vector of CCHFV, H. marginatum, in the Old World. The model estimated the environmental suitability of H. marginatum in the Old World, including Europe. On the continental European scale, the model anticipated a widespread potential distribution, covering southern, western, central, and eastern Europe, as far north as southern parts of Scandinavian countries. The distribution of H. marginatum also covered the countries across the central part of Europe where the species is not autochthonous. All models were statistically robust and performed better than random (p < 0.001). Based on the results of the model, climatic conditions could hamper the successful overwintering of H. marginatum and their survival as adults in many areas of the region. Regular updates of the models, using updated occurrence, current, and future climatic data are recommended to regularly assess the areas at risk.SummaryHyalomma marginatum is a vector of numerous highly important human and animal pathogens. It is the main vector of Crimean-Congo haemorrhagic fever virus (CCHFV) in Europe. This study updated the potential distribution of H. marginatum on a global scale, including Europe, with a particular focus on Central Europe. The model predicted a widespread potential distribution of H. marginatum on the continental European scale, anticipating occurrences of H. marginatum in southern, western, central, and eastern Europe, as far north as southern parts of Scandinavian countries. In Central Europe, H. marginatum populations have not been established in any of the countries yet, but the presence of the species has been reported from all countries in the region. Their potential spread northwards and establishment of permanent populations of H. marginatum in the north are therefore of great importance, in particular since the immature stages of H. marginatum are frequently found on migratory birds flying northwards to temperate Europe. Our ecological niche model of H. marginatum in Central Europe anticipated its distribution in all countries of the region. Our prediction for current global potential distribution of this tick species can help in understanding disease risk areas associated with this vector.
Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection
Authors: Ghorbani Peyman , Kim Sang Yong , Smith Tyler K.T. , Minarrieta Lucía , Robert-Gostlin Victoria , Kilgour Marisa K. , Ilijevska Maja , Alecu Irina , Snider Shayne A. , Margison Kaitlyn D. , Nunes Julia R.C. , Woo Daniel , Pember Ciara , O’Dwyer Conor , Ouellette Julie , Kotchetkov Pavel , St-Pierre Julie , Bennett Steffany A.L. , Lacoste Baptiste , Blais Alexandre , Nair Meera G. , Fullerton Morgan D. 
Published: October 2022

AbstractType 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably,Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded byRetnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with intestinal helminthsHeligmosomoides polygyrusorNippostrongylus brasiliensiswere treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolismin vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity toH. polygyruswith increased egg burden, but there were no differences in intestinal worm count nor differences inN. brasiliensisparasite burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.Abstract Figure
Two opposing effects of monovalent cations on the stability of i-motif structure
Authors: Kim Sung Eun , Hong Seok-Cheol 
Published: October 2022

ABSTRACTAt acidic pH, cytosine-rich single-stranded DNA can be folded into a tetraplex structure called i-motif (iM). In recent studies, the effect of monovalent cations on the stability of iM structures has been addressed, but a consensus about the issue has not been reached yet. Thus, we investigated the effects of various factors on the stability of iM structures using fluorescence resonance energy transfer (FRET)-based analysis for three types of iM derived from human telomere sequences. We confirmed that the iM structure is destabilized as the concentration of monovalent cations (Li+, Na+, K+) increases and that Li+ has the greatest tendency of destabilization. This cation-induced destabilization is rather unexpected and specific to the iM structure, considering the cation’s electrostatic effect of supporting DNA folding. Monovalent cations of different kinds promote the flexibility of single-stranded DNA (ssDNA) and the stability of folded DNA structures to different degrees, suggesting that the size of cation be a key factor in its function. All taken together, we conclude that the stability of iM structures is controlled by the subtle balance of the two counteractive effects of monovalent cations, electrostatic screening and disruption of cytosine base pairing.
Endogenous GFP tagging in the diatomThalassiosira pseudonana
Authors: Nam Onyou , Grouneva Irina , Mackinder Luke C. M. 
Published: October 2022

AbstractThe regulated abundance and spatial distribution of proteins determines cellular structure and function. The discovery of green fluorescent protein (GFP) and fusing it to a target protein to determine subcellular localization revolutionized cell biology. Most localization studies involve introducing additional copies of a target gene genetically fused to GFP and under the control of a constitutive promoter, resulting in the expression of the GFP-fusion protein at non-native levels. Here we have developed a single vector CRISPR/Cas9 guided GFP knock-in strategy in the diatomThalassiosira pseudonana. This enables precise and scarless knock-in of GFP at the endogenous genomic location to create GFP fusion proteins under their nativecisandtransregulatory elements with knock-in efficiencies of over 50%. We show that a previously uncharacterized bestrophin-like protein localizes to the CO2-fixing pyrenoid and demonstrate that by measuring GFP fluorescence we can track relative protein abundance in response to environmental change. To enable endogenous tagging, we developed a Golden Gate Molecular Cloning system for the rapid assembly of episomes for transformation intoThalassiosira pseudonanavia bacterial conjugation. In addition, this versatile toolbox enables CRISPR/Cas9 gene editing, provides a broad range of validated fluorophores and enables future large-scale functional studies in diatoms.Significance statementFluorescent protein (FP) tagging is a widely utilized technique for understanding the spatial distribution of proteins. However, introducing extra gene copies under constitutive promoters that randomly integrate into the genome can result in non-biologically relevant expression levels, unwanted genomic mutations and localization artefacts. To overcome this, we developed a novel single vector system capable of CRISPR/Cas9-guided endogenous GFP tagging in a globally important model diatom. This allows scarless GFP knock-in at precise genomic locations resulting in GFP fusions regulated by native promoters/terminators, which facilitates accurate localization and determination of relative protein abundance. Moreover, the developed modular cloning framework is user-friendly and opens the door for high throughput large-scale studies, including FP tagging, knock-out, and knock-in.
Integrated signaling and transcriptome analysis reveals Src-family kinase individualities and novel pathways controlled by their constitutive activity
Authors: Koutras Nikolaos , Morfos Vasileios , Konnaris Kyriakos , Kouvela Adamantia , Shaukat Athanasios-Nasir , Stathopoulos Constantinos , Stamatopoulou Vassiliki , Nika Konstantina 
Published: October 2022

AbstractThe Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns, the two kinases share common functions, the most pronounced one, being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T-lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting open question of mechanisms granting selectivity amongst SFK members. In this work we sought to investigate the mechanistic basis of ectopic Lck function in B-cells and compare it to events elicited by the predominant B-cell SFK, Lyn. Our results reveal substrate promiscuity displayed by the two SFKs, which however, is buffered by their differential susceptibility towards regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, we show that Lck- and Lyn-generated signals suffice to induce transcriptome alterations, reminiscent of B-cell activation, in the absence of receptor/co-receptor engagement. Finally, our analyses revealed a yet unrecognized role of SFKs in tipping the balance of cellular stress responses, by promoting the onset of ER-phagy, an as yet completely uncharacterized process in B-lymphocytes.SignificanceThe Src-family-kinases Lck and Lyn are mandatory for lymphocyte function. However, several aspects of their regulation and critical pathways they control remain elusive. Using signaling and transcriptome analysis we show that the two kinases share substrate preferences; yet they display differential susceptibility towards regulatory mechanisms, revealing a so far unappreciated aspect of SFK member-specific fine-tuning. Furthermore, overexpression of both kinases suffices to induce receptor-ligation independent signaling responses. Finally, our analyses reveal a novel role of SFKs in tipping the balance of cellular stress responses, by promoting ER-phagy, in the expense of proteasomal degradation and the Unfolded Protein Response. These data advance our understanding of molecular individualities amongst SFK members, and identifies novel networks significant for lymphocyte activation and effector function.
HY5 regulates GLK transcription factors to orchestrate photomorphogenesis inArabidopsis thaliana
Authors: Zhang Ting , Zhang Rui , Zeng Xi-Yu , Lee Sanghwa , Ye Lu-Huan , Tian Shi-Long , Zhang Yi-Jing , Busch Wolfgang , Zhou Wen-Bin , Zhu Xin-Guang , Wang Peng 
Published: October 2022

AbstractLight induced de-etiolation is an important aspect of seedling photomorphogenesis. GOLDEN2 LIKE (GLK) transcriptional regulators are involved in chloroplast development, but to what extent they participate in photomorphogenesis is not clear. Here we show that ELONGATED HYPOCOTYL5 (HY5) binds toGLKpromoters to activate their expression, and also interacts with GLK proteins. Chlorophyll content in the de-etiolating Arabidopsis seedlings of thehy5 glk2double mutants was lower than that inhy5single mutant.GLKsinhibited hypocotyl elongation, and the phenotype could superimpose on thehy5phenotype. Correspondingly, GLK2 regulates the expression of photosynthesis and cell elongation genes partially independent of HY5. Before exposed to light, the accumulation of GLK proteins was regulated by DE-ETIOLATED 1 (DET1), while also affected (especially for GLK1) transcriptionally by HY5. The enhanced etioplast development and photosystem gene expression observed indet1mutant were attenuated indet1 glk2double mutant. Our study reveals that GLKs act down-stream of HY5 and likely cooperate with HY5 and DET1, to orchestrate multiple developmental traits during the light-induced skotomorphogenesis to photomorphogenesis transition in Arabidopsis.One-sentence summaryGLK and GNC act downstream of HY5, and cooperate with HY5 and DET1, to regulate both chloroplast development and hypocotyl elongation during the transition from skotomorphogenesis to photomorphogenesis.
Genetic basis of a seasonal life-history polyphenism
Authors: Caplins Serena A 
Published: October 2022

AbstractSeasonal polyphenisms are common across the animal and plant kingdom yet we understand the explicit interactions between genetics and environment for only a few taxa. Are the genomic regions and their variants associated with the trait the same or different across environments? Is the response to selection shared or different across different “background” selection environments? Offspring type in the sacoglossan sea slug Alderia willowi is a seasonally modulated interaction between genotype and phenotype that results in offspring of wildly different developmental trajectories. In a genome-wide association test I found 41 SNPs associated with offspring type. In an evolve and resequence experiment I found thousands of loci changed in frequency following selection. These loci were partially shared (37%) between low and high salinity. Of the 41 candidate SNPs identified in the GWAS only seven also showed significant allele frequency change across replicates in the selection experiments with four in high salinity, two in low and one in both. This reveals a broad pattern of allele frequency change that is largely unique to the environment in which selection for the same phenotype occurs. The results presented in this paper showcase the ability of phenotypic plasticity to move the phenotype independent of the genotype and thus maintain the polyphenism that is so striking in this species.
Establishing the contribution of active histone methylation marks to the aging transcriptional landscape of Drosophila photoreceptors
Authors: Jauregui-Lozano Juan , Bakhle Kimaya M. , Hagins Arrianna C. , Weake Vikki M. 
Published: October 2022

ABSTRACTStudies in multiple organisms have shown that aging is accompanied by several molecular phenotypes that include dysregulation of chromatin. Since chromatin regulates DNA-based processes such as transcription, alterations in chromatin modifications could impact the transcriptome and function of aging cells. In flies, as in mammals, the aging eye undergoes changes in gene expression that correlate with declining visual function and increased risk of retinal degeneration. However, the causes of these transcriptome changes are poorly understood. Here, we profiled chromatin marks associated with active transcription in the agingDrosophilaeye to understand how chromatin modulates transcriptional outputs. We found that both H3K4me3 and H3K36me3 globally decrease across all actively expressed genes with age. However, we found no correlation with changes in differential gene expression. Downregulation of the H3K36me3 methyltransferase Set2 in young photoreceptors revealed significant changes in splicing events that overlapped significantly with those observed in aging photoreceptors. These overlapping splicing events impacted multiple genes involved in phototransduction and neuronal function. Since proper splicing is essential for visual behavior, and because agingDrosophilaundergo a decrease in visual function, our data suggest that H3K36me3 plays a role in maintaining visual function in the aging eye through regulating alternative splicing.
Actin cytoskeleton dynamics affect replication of Human Metapneumovirus
Authors: Rodríguez Pamela Elizabeth , Gil Pedro Ignacio , Cámara Jorge Augusto , Cámara Alicia , Paglini María Gabriela 
Published: October 2022

ABSTRACTHuman Metapneumovirus (hMPV) is responsible for viral respiratory infection with clinical and epidemiological relevance in pediatric, immunocompromised, and elderly populations. Little is known about hMPVin vitroreplication processes and their relationship with cellular structures such as the cytoskeleton. Our goal was to evaluate the role of the actin cytoskeleton in hMPV replication at different stages of viral growth. hMPV was isolated in Vero cells from a clinical sample and identified as A2genotype. The cytopathic effect was detected by the appearance of cell rounding and refractory cell clusters. The growth curve showed that viral replication maximum level was between 48 and 72 hpi. The highest percentage of infected cells and intracellular hMPV-protein were detected at the early stages of the replication cycle. Disruption of actin microfilaments with Cytochalasin D during the early events provoked an increase in both intracellular and extracellular viruses. We demonstrate that the early phase of the hMPV curve is crucial for viral replication; and the disruption of microfilaments during this time increments both viral protein expression and release of viruses to the extracellular space. This study contributes to elucidate wild-type hMPV growth kinetics, providing new insights on the actin cytoskeleton role in viral replication mechanisms.
Ultra-weak protein-protein interactions can modulate proteome-wide searching and binding
Authors: Hofmann Jennifer L. , Maheshwari Akshay J. , Sunol Alp M. , Endy Drew , Zia Roseanna N. 
Published: October 2022

AbstractResearch on protein-protein interaction (PPIs) tends to focus on high affinity interactions. Weaker interactions (Kd >1μM) recently understood as contributing to intracellular phase separation suggest that even-weaker PPIs might also matter in as-yet unknown ways. However, ultra-weak PPIs (Kd >1mM) are not readily accessible by in vivo techniques. Here we use protein electrostatics to estimate PPI strengths and spatially-resolved dynamic simulations to investigate the potential impacts of ultra-weak PPIs within dense protein suspensions. We find that ultra-weak PPIs can drive formation of transient clusters that last long enough to enable enzyme-catalyzed reactions and accelerate the sampling of protein associations. We apply our method to Mycoplasma genitalium, finding that ultra-weak PPIs should be ubiquitous among cytoplasmic proteins. We also predict that the proteome-wide interactome can be shifted to favor ‘binding-dominant’ ultra-weak PPIs via the introduction of a few charged protein complexes. We speculate that ultra-weak PPIs could contribute to cellular fitness by facilitating sampling and colloidal-scale transport of proteins involved in biological processes, including protein synthesis.
RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes
Authors: Subramanian Megha , McIninch James , Zlatev Ivan , Schlegel Mark K. , Kaittanis Charalambos , Nguyen Tuyen , Agarwal Saket , Racie Timothy , Alvarado Martha Arbaiza , Wassarman Kelly , Collins Thomas S. , Chickering Tyler , Brown Christopher R. , Schmidt Karyn , Castoreno Adam B. , Shulga-Morskaya Svetlana , Stamenova Elena , Buckowing Kira , Berman Daniel , Barry Joseph D. , Bisbe Anna , Maier Martin A. , Fitzgerald Kevin , Jadhav Vasant 
Published: October 2022

ABSTRACTAdeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein AAV transgene expression is silenced using the clinically validated modality of chemically modified short interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies.