bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contact-number-driven virus evolution: a multi-level modeling framework for the evolution of acute or persistent RNA virus infection
Authors: Sunagawa Junya , Komorizono Ryo , Hart William S. , Thompson Robin N. , Makino Akiko , Tomonaga Keizo , Iwami Shingo , Yamaguchi Ryo 
Published: December 2022

AbstractViruses evolve in infected host populations, and host population dynamics affect viral evolution. RNA viruses with a short duration of infection and a high peak viral load, such as and SARS-CoV-2, are maintained in human populations. By contrast, RNA viruses characterized by a long infection duration and a low peak viral load (e.g., borna disease virus) can be maintained in nonhuman populations, and why the persistent viruses evolved has been rarely explored. Here, using a multi-level modeling approach including both individual-level virus infection dynamics and population-scale transmission, we consider virus evolution based on the host environment, specifically, the effect of the contact history of infected hosts. We found that, with a highly dense contact history, viruses with a high virus production rate but low accuracy are likely to be optimal, resulting in a short infectious period with a high peak viral load. In contrast, with a low-density contact history, viral evolution is toward low virus production but high accuracy, resulting in long infection durations with low peak viral load. Our study sheds light on the origin of persistent viruses and why acute viral infections but not persistent virus infection tends to prevail in human society.
Pheromone-based animal communication influences the production of somatic extracellular vesicles
Authors: Szczepańska Agata , Olek Katarzyna , Kołodziejska Klaudia , Yu Jingfang , Ibrahim Abdulrahman Tudu , Adamkiewicz Laura , Schroeder Frank C. , Pokrzywa Wojciech , Turek Michał 
Published: December 2022

AbstractExtracellular vesicles (EVs) are involved in multiple biological processes; however, there is limited knowledge of the influence of environmental factors or other individuals in a population on EV-regulated systems. The largest evolutionarily conserved EVs, exophers, are a component of theC. elegansmaternal somatic tissue resource management system induced by embryos developingin utero, and thus progeny of individuals with active exopher biogenesis (exophergenesis) appear to be privileged. Using this model, we investigated the inter-tissue and social regulatory mechanisms of exophergenesis. We found that the predominant male pheromone, ascr#10, increases exopher production in hermaphrodites via the G-protein-coupled receptor STR-173 in the ASK sensory neurons. In contrast, pheromones from other hermaphrodites in the population temper exophergenesis. Within the hermaphrodite, an increase in embryo accumulation drives pro-exopher signals, and the internal sensory neurons AQR, PQR, and URX play a central role in modulating exopher levels. This intricate process is regulated partly via the neuropeptides FLP-8 and FLP-21, which originate from the URX and AQR/PQR/URX neurons, respectively. Our results reveal a regulatory network integrating internal and external cues, including control of somatic EVs production by the nervous system in response to social signals.
Understanding the effects of moisture content and temperature on dormancy release in sunflower (Helianthus annuusL) achenes
Authors: Arata Gonzalo Joaquín , Batlla Diego , Demkura Patricia Verónica , Rodríguez María Verónica 
Published: December 2022

AbstractThe effects of moisture content (MC) and storage temperature (ST) on seed longevity have been modeled for many species. In contrast, our understanding on the combined effects of MC and ST on dormancy release (DR) in “dry” orthodox seeds is still insufficient to build robust predictive models. We used freshly harvested, dormant sunflower achenes to explore the effects of MC (4-10%) in combination with a wide range of ST (−18°C to +30°C) on DR dynamics, embryo responsiveness to abscisic acid (ABA) and deterioration indicators. Storage temperatures allowing full DR were inversely related to achene MC, ranging from >25°C for MC4% to sub-zero temperatures for MC10%, resembling a phase diagram. Rates of DR were plotted along a RH gradient. Combinations of MCxST optimal for DR were betweenca. 40-60%RH. Increasing RH from 60 to 80% inhibited DR. Higher RH>80-85% promoted partial DR together with rapid ageing. We suggest that reactions promoting full DR are favored alongside a physical (glassy) transition and are not oxidative. We propose biophysical coordinates to guide future studies on the mechanisms involved in DR, but also to develop predictive models useful to define post-harvest conditions that maximize sunflower seed quality.Highlights□The effects of moisture content (MC) and storage temperature (ST) on dormancy release and deterioration were investigated in sunflower achenes using a factorial design.□Dormancy release was promoted by MCxST combinations in equilibrium with a RH between 40 and 60% and was delayed outside this range.□Storage temperatures optimal for dormancy release were inversely related to achene MC, ranging from >25°C for MC4% to sub-zero temperatures for MC10%, resembling a phase diagram.□Dormancy release and ageing are promoted within distinct, non-overlapping regions along the RH gradient supporting different types of reactions for each process.
Disrupting central carbon metabolism increases antibiotic susceptibility inVibrio cholerae
Authors: Keller Megan , Han Xiang , Dörr Tobias 
Published: December 2022

AbstractAntibiotic tolerance, the ability of bacteria to sustain viability in the presence of typically bactericidal antibiotics for extended time periods, is an understudied contributor to treatment failure. The Gram-negative pathogenVibrio cholerae, the causative agent of cholera disease, becomes highly tolerant to β-lactam antibiotics (penicillin and related compounds) in a process requiring the two-component system VxrAB. VxrAB is induced by exposure to cell wall damage conditions, which results in the differential regulation of >100 genes. While the effectors of VxrAB are relatively well-known, VxrAB environment-sensing and activation mechanisms remain a mystery. Here, we used transposon mutagenesis to screen for mutants that spontaneously upregulate VxrAB signaling. This screen was answered by genes known to be required for proper cell envelope homeostasis, validating the approach. Unexpectedly, we also uncovered a new connection between central carbon metabolism and antibiotic tolerance. Inactivation ofpgi(vc0374, coding for Glucose-6-phosphate isomerase) resulted in an intracellular accumulation of glucose-6-phosphate and fructose-6-phosphate, concomitant with a marked cell envelope defect, resulting in VxrAB induction. Deletion ofpgialso increased sensitivity to β-lactams and conferred a growth defect on salt-free LB; phenotypes that could be suppressed by deleting sugar uptake systems and by supplementing cell wall precursors in the growth medium. Our data suggest an important connection between central metabolism and cell envelope integrity and highlight a potential new target for developing novel antimicrobial agents.ImportanceAntibiotic tolerance (the ability to survive exposure to antibiotics) is a stepping-stone towards antibiotic resistance (the ability to grow in the presence of antibiotics), an increasingly common cause of antibiotic treatment failure. The mechanisms promoting tolerance are poorly understood. Herein, we discovered central carbon metabolism as a key contributor to antibiotic tolerance and resistance. A mutant in a sugar utilization pathway accumulates metabolites that likely shut down the synthesis of cell wall precursors, which weakens the cell wall and thus increases susceptibility to cell wall-active drugs. Our results illuminate the connection between central carbon metabolism and cell wall homeostasis inV. choleraeand suggest that interfering with metabolism may be a fruitful future strategy for development of antibiotic adjuvants.
Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma
Authors: Barras David , Ghisoni Eleonora , Chiffelle Johanna , Orcurto Angela , Dagher Julien , Fahr Noémie , Benedetti Fabrizio , Crespo Isaac , Zimmermann Stefan , Duran Rafael , Imbimbo Martina , de Olza Maria Ochoa , Navarro Blanca , Homiscko Krisztian , Bobisse Sara , Labes Danny , Tsourti Zoe , Andriakopoulou Charitini , Herrera Fernanda , Grimm Alizée , Morotti Matteo , Pétremand Rémy , Dummer Reinhard , Berthod Gregoire , Bassani-Sternberg Michal , Schaefer Niklaus , Prior John O , Matter Maurice , Demartines Nicolas , Aedo Veronica , Dromain Clarisse , Corria-Osorio Jesus , Tissot Stephanie , Kandalaft Lana E. , Gottardo Raphael , Pittet Mikael , Sempoux Christine , Michielin Olivier , Dafni Urania , Trueb Lionel , Harari Alexandre , Laniti Denarda Dangaj , Coukos George 
Published: December 2022

AbstractAdoptive cell therapy (ACT) usingex vivoexpanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+TIL-myeloid cell networks
Combination of Expert Guidelines-based and Machine Learning-based Approaches Leads to Superior Accuracy of Automated Prediction of Clinical Effect of Copy Number Variations
Authors: Sládeček Tomáš , Gažiová Michaela , Kucharík Marcel , Zaťková Andrea , Pös Zuzana , Pös Ondrej , Krampl Werner , Tomková Erika , Hýblová Michaela , Minárik Gabriel , Radvanszky Ján , Budiš Jaroslav , Szemes Tomáš 
Published: December 2022

AbstractClinical interpretation of copy number variants (CNVs) is a complex process that requires skilled clinical professionals. General recommendations have been recently released to guide the CNV interpretation based on predefined criteria to uniform the decision process. Several semiautomatic computational methods have been proposed to recommend appropriate choices, relieving the clinicians from the tedious search in vast genomic databases. We have developed and evaluated such a tool called MarCNV and tested it on CNV records collected from the ClinVar database. Alternatively, the emerging machine learning-based tools, such as the recently published ISV (Interpretation of Structural Variants), showed promising ways of even fully automated predictions using wider characterization of affected genomic elements. Such tools utilize features that are additional to ACMG criteria, thus, they have the potential to significantly improve and/or provide supportive evidence for accurate CNV classification. Since both approaches contribute to evaluation of CNVs clinical impact, we propose a combined solution in the form of adecision support toolbased on automated ACMG guidelines (MarCNV) supplemented by a machine learning-based pathogenicity prediction (ISV) for classification of CNVs. We provide evidence that such a combined approach is able to reduce the number of uncertain classifications and reveal potentially incorrect classifications using automated guidelines. CNV interpretation using MarCNV, ISV, and combined approach is available for non-commercial use athttps://predict.genovisio.com/.
Structural perspective on the design of selective DYRK1B inhibitors
Authors: Grygier Przemyslaw , Pustelny Katarzyna , Menezes Filipe , Jemiola-Rzeminska Malgorzata , Suder Piotr , Dubin Grzegorz , Czarna Anna 
Published: December 2022

AbstractDYRK1B, has been recently recognized as a critical therapeutic target in oncology, metabolic syndrome, and non-alcoholic fatty liver disease. However, the development of selective inhibitors for DYRK1B, has been constrained by the lack of structural information. In this study, we employed recombinant protein production, activity assays, and crystallization to elucidate the structure of DYRK1B. We present a crystal structure of DYRK1B in complex with a known inhibitor, AZ191. For comparative analysis, we provide the crystal structure of the closely related DYRK1A kinase in complex with AZ191. Our analysis identifies a distinct binding site in the hinge region of DYRK1B, which is pivotal for the design of selective inhibitors. Quantum mechanical calculations reveal a notable difference in the accessibility of the catalytic lysine between DYRK1B and DYRK1A, suggesting a potential avenue for selective inhibitor design. These findings mark a significant advancement in the quest for specific DYRK1B inhibitors, potentially offering focused efficacy compared to the current dual-specificity inhibitors targeting both DYRK1B and DYRK1A.
Neuronal-immune Axis Alters Pain and Sensory Afferent Damage During Dental Pulp Injury
Authors: Erdogan Ozge , Michot Benoit , Xia Jinya , Alabdulaaly Lama , Rubi Pilar Yesares , Chiu Isaac , Gibbs Jennifer L. 
Published: December 2022

ABSTRACTDental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occur, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuro-immune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin-gene related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using calca knock out (calca−/−) and wild type (calca+/+) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. While CGRP did not contribute to facial mechanical hypersensitivity, at an early time point, it did contribute to spontaneous pain-like behavior. We also found that CGRP contributed to recruitment of neutrophils and monocytes, while not clearly affecting the progression of pulpal pathology histologically. When we depleted neutrophils and monocytes, we found that there was more sensory afferent loss, tissue damage and deeper spread of bacteria into the pulp tissue, while there was a reduction in facial mechanical hypersensitivity compared to control animals at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease.
Detection of A-to-I microRNA editing with miRmedon reveals widespread co-editing of mature microRNA in the human brain
Authors: Mordechai Amitai , Eran Alal 
Published: December 2022

ABSTRACTmicroRNA (miRNA), key regulators of gene expression, are prime targets for adenosine deaminase acting on RNA (ADAR) enzymes. Although ADAR-mediated adenosine-to-inosine (A-to-I) miRNA editing has been shown to be essential for orchestrating complex processes, including neurodevelopment and cancer progression, only few human miRNA editing sites have been reported. Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of ‘G’ at primary adenosine sites in known miRNA sequences. However, these methods have several limitations, including their ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), their focus on uniquely mapping reads (even though 20% of human miRNA are transcribed from multiple loci), and their inability to detect editing in miRNA harboring genomic variants (though 73% of human miRNA loci include a reported SNP or indel). To overcome these limitations, we developed miRmedon, that leverages large-scale human variation data, a combination of local and global alignments, and a comparison of the inferred editing and error distributions, for confident detection of miRNA editing in small RNAseq data. We demonstrate the improved performance of miRmedon as compared to currently available methods and describe its advantages. We further use miRmedon to discover editing haplotypes of mature human brain miRNA for the first time. We find that doubly edited mature miRNA are common in the adult human prefrontal cortex, most include a frequently edited site within the miRNA seed region, and are predicted to maintain a stable pre-miRNA structure. These results suggest that co-editing of mature miRNA could enable efficient shifting of gene expression programs.
Generation and characterization of two immortalized dermal fibroblast cell lines from the spiny mouse (Acomys)
Authors: Dill Michele N. , Tabatabaei Mohammad , Kamat Manasi , Basso Kari B. , Simmons Chelsey S. 
Published: December 2022

AbstractThe spiny mouse (Acomys) is gaining popularity as a research organism due to its phenomenal regenerative capabilities.Acomysrecovers from injuries to several organs without fibrosis. For example,Acomysheals full thickness skin injuries with rapid re-epithelialization of the wound and regeneration of hair follicles, sebaceous glands, erector pili muscles, adipocytes, and dermis without scarring. Understanding mechanisms ofAcomysregeneration may uncover potential therapeutics for wound healing in humans. However, access toAcomyscolonies is limited and primary fibroblasts can only be maintained in culture for a limited time. To address these obstacles, we generated immortalizedAcomysdermal fibroblast cell lines using two methods: transfection with the SV40 large T antigen and spontaneous immortalization. The two cell lines (AcoSV40 and AcoSI-1) maintained the morphological and functional characteristics of primaryAcomysfibroblasts, including maintenance of key fibroblast markers and ECM deposition. The availability of these cells will lower the barrier to working withAcomysas a model research organism, increasing the pace at which new discoveries to promote regeneration in humans can be made.
Discovery of prevalent naturalWolbachiainAedes aegyptiin Metropolitan Manila, Philippines using locally designed primers: bacterial density is influenced by strain and host sex
Authors: Reyes Jerica Isabel L. , Suzuki Takahiro , Suzuki Yasutsugu , Watanabe Kozo 
Published: December 2022

AbstractWolbachiaare maternally transmitted bacteria that are utilized for arboviral disease prevention. Cytoplasmic incompatibility (CI) and viral blocking, two characteristics that makeWolbachiasuitable for vector control, both depend on bacterial infection prevalence and density. Although numerous mosquito species naturally harborWolbachia, the prevalence ofWolbachiainAedes aegyptivaries from minimal to absent. The absence of naturalWolbachiainAe. aegyptiis considered advantageous for novelWolbachiatransinfection because interference caused by incompatibleWolbachiastrains will not occur. In this study, we screened forWolbachiadensity in 429 individualAe. aegypticollected from Metropolitan Manila, Philippines using locally designed primers to determine whether primer compatibility improvesWolbachiadetection in naturally infectedAe. aegypti. We also investigated the effects of host sex andWolbachiastrain onWolbachiadensity. We found a highWolbachiaprevalence for16S rRNA(40%) andwsp(62%) markers. RelativeWolbachiadensities ranged from −3.840 to 2.710 for16S rRNAand from −4.020 to 1.810for wsp, and these relative densities were higher among male mosquitoes than female mosquitoes. Phylogenetic analysis revealed that most of theAe. aegyptiwere clustered into supergroup B, with 63% (142/226) of these sequences representing a unique strain referred to here as “wAegML,” which exhibited a significantly lower density inAe. aegyptithan the other twoWolbachiastrains detected (wAegB/wAlbB andwAlbA) as well as a higher density in maleAe. aegyptithan in females. Overall, locally designed primers improvedWolbachiadetection in naturally infectedAe. aegypti. The unique strainwAegML occurs at a low density and is related to the use ofwAlbB in mass-release programs; therefore, it is unlikely to interfere with such programs. Further studies on naturalWolbachiainfection inAe. aegypticombining methodological and biological factors are warranted to help resolve current conflicts in the field.
Single-cell analysis maps distinct cellular responses to rhizobia and identifies the novel infection regulator SYMRKL1 inLotus japonicus
Authors: Frank Manuel , Fechete Lavinia Ioana , Tedeschi Francesca , Nadzieja Marcin , Malekzadeh Nørgaard Malita Malou , Montiel Jesus , Andersen Kasper Røjkjær , Schierup Mikkel H. , Reid Dugald , Andersen Stig Uggerhøj 
Published: December 2022

AbstractLegume-rhizobium signaling during establishment of symbiotic nitrogen fixation restricts rhizobium colonization to specific cells. A limited number of root hair cells allow infection threads to form, and only a fraction of the epidermal infection threads progress to cortical layers to establish functional nodules. Here we use single-cell analysis to define the epidermal and cortical cell populations that respond to and facilitate rhizobium infection. We then identify high-confidence nodulation gene candidates based on their specific expression in these populations, pinpointing genes stably associated with infection across genotypes and time points. We show that one of these, which we nameSYMRKL1, encodes a protein with an ectodomain predicted to be nearly identical to that of SYMRK and is required for normal infection thread formation. Our work disentangles cellular processes and transcriptional modules that were previously confounded due to lack of cellular resolution, providing a more detailed understanding of symbiotic interactions.
Combination of transcriptomic, proteomic and degradomic profiling reveals common and distinct patterns of pathogen-induced cell death in maize
Authors: Barghahn Sina , Saridis Georgios , Mantz Melissa , Meyer Ute , Mellüh Jaqueline C , Misas Villamil Johana C , Huesgen Pitter F , Doehlemann Gunther 
Published: December 2022

AbstractRegulated cell death (RCD) is crucial for plant development, as well as in decision-making in plant-microbe interactions. Previous studies revealed components of the molecular network controlling RCD, including different proteases. However, the identity, the proteolytic network as well as molecular components involved in the initiation and execution of distinct plant RCD processes, still remain largely elusive. In this study, we analyzed the transcriptome, proteome and N-terminome ofZ. maysleaves treated with the Xanthomonas effector avrRxo1, the mycotoxin Fumonisin B1 (FB1), or the phytohormone salicylic acid (SA) to dissect plant cellular processes related to cell death and plant immunity. We found highly distinct and time-dependent biological processes being activated on transcriptional and proteome levels in response to avrRxo1, FB1 and SA. A correlation analysis of the transcriptome and proteome identified general, as well as trigger-specific markers for cell death inZ. mays. We found that proteases, particularly papain-like cysteine proteases, are specifically regulated during RCD. Collectivley, this study characterizes distinct RCD responses inZ. maysand provides a framework for the mechanistic exploration of components involved in the initiation and execution of cell death.