bluuebunny/crossref_metadata_2025_split huggingface dataset:
An explanation for SARS-CoV-2 rebound after Paxlovid treatment
Authors: Perelson Alan S. , Ribeiro Ruy M. , Phan Tin 
Published: June 2023

AbstractIn a fraction of SARS-CoV-2 infected individuals treated with the oral antiviral Paxlovid, the virus rebounds following treatment. The mechanism driving rebound is not understood. Here, we show that viral dynamic models based on the hypothesis that Paxlovid treatment near the time of symptom onset halts the depletion of target cells, but may not fully eliminate the virus, which can lead to viral rebound. We also show that the occurrence of viral rebound is sensitive to model parameters, and the time treatment is initiated, which may explain why only a fraction of individuals develop viral rebound. Finally, the models are used to test the therapeutic effects of two alternative treatment schemes. These findings also provide a possible explanation for rebounds following other antiviral treatments for SARS-CoV-2.SignificancePaxlovid is an effective treatment for SARS-CoV-2. In some patients treated with Paxlovid, the initial reduction in viral load is followed by a rebound once treatment is stopped. Understanding the mechanisms of the rebound may help us develop better treatment strategies to minimize this possibility. We hypothesize that early treatment with Paxlovid stops viral growth, but may not fully clear the virus, thus preserving host resources that would have otherwise been used by the virus. Once treatment ends, the remaining viruses can utilize the available resources to grow, leading to the observed transient viral rebound. We built standard viral dynamic models based on this hypothesis and fit the models to data to show its feasibility. We further examined the effect of two alternative treatment schemes.
Comparison of caffeine consumption behavior with plasma caffeine levels as exposures in drug-target Mendelian randomization and implications for interpreting effects on obesity
Authors: Woolf Benjamin , Cronjé Héléne T. , Zagkos Loukas , Larsson Susanna C. , Gill Dipender , Burgess Steve 
Published: June 2023

AbstractDrug-target Mendelian randomization (MR) is a popular approach for exploring the effects of pharmacological targets.Cis-MR designs select variants within the gene region that code for a protein of interest to mimic pharmacological perturbation. An alternative uses variants associated with behavioral proxies of target perturbation, such as drug usage. Both have been employed to investigate the effects of caffeine but have drawn different conclusions. We use the effects of caffeine on body mass index (BMI) as a case study to highlight two potential flaws of the latter strategy in drug-target MR: misidentifying the exposure and using invalid instruments. Some variants associate with caffeine consumption because of their role in caffeine metabolism. Since people with these variants require less caffeine for the same physiological effect, the direction of the caffeine-BMI association is flipped depending on whether estimates are scaled by caffeine consumption or plasma caffeine levels. Other variants seem to associate with caffeine consumption via behavioral pathways. Using multivariable-MR, we demonstrate that caffeine consumption behavior influences BMI independently of plasma caffeine. This implies the existence of behaviorally mediated exclusion restriction violations. Our results support the superiority ofcis-MR study designs in pharmacoepidemiology over the use of behavioral proxies of drug targets.
Opposing implications of co-evolutionary lineages and traits of gut microbiome on human health status
Authors: Li Hao , He Junliang , Liang Jieping , Liang Yiting , Zheng Wei , Qu Qingming , Guo Feng 
Published: June 2023

AbstractLittle is known about the co-evolutionary history of the human gut microbe and its relevance to host physiology. Here, we constructed a gut prokaryotic genomic database of wild primates (pSGBs) and compared it with the human gut prokaryotic database (hSGBs) to define shared co-evolutionary clusters (SCEC-hSGBs) and co-evolutionary traits of hSGBs. We analyzed the evolutionary trends of specific functions like carbohydrate-active enzymes and antibiotic resistance in hSGBs and uncovered host-jumping events and genome reduction tendencies in SCEC-hSGBs. Intriguingly, the SCEC-hSGBs and the super enrichers of the traits (SUEN-hSGBs), which are putatively partially derived from carnivores, showed opposite implications for host health status. Specifically, SUEN-hSGBs are enriched in various diseases, showing a negative correlation with gut biodiversity and disproportionate contributions to the known health-negative marker taxa and metabolite. Our study provides insight into the origin and adaptability of human gut microbes and references for developing probiotics and microbiome-based host health prediction.
Modulation of antigen discrimination by duration of immune contacts in a kinetic proofreading model of T cell activation with extreme statistics
Authors: Morgan Jonathan , Lindsay Alan E. 
Published: June 2023

AbstractT cells form transient cell-to-cell contacts with antigen presenting cells (APCs) to facilitate surface interrogation by membrane bound T cell receptors (TCRs). Upon recognition of molecular signatures (antigen) of pathogen, T cells may initiate an adaptive immune response. The duration of the T cell/APC contact is observed to vary widely, yet it is unclear what constructive role, if any, such variations might play in immune signaling. Modeling efforts describing antigen discrimination often focus on steady-state approximations and do not account for the transient nature of cellular contacts. Within the framework of a kinetic proofreading (KP) mechanism, we develop a stochasticFirst Receptor Activation Model(FRAM) describing the likelihood that a productive immune signal is produced before the expiry of the contact. Through the use of extreme statistics, we characterize the probability that the first TCR triggering is induced by a rare agonist antigen and not by that of an abundant self-antigen. We show that defining positive immune outcomes as resilience to extreme statistics and sensitivity to rare events mitigates classic tradeoffs associated with KP. By choosing a sufficient number of KP steps, our model is able to yield single agonist sensitivity whilst remaining non-reactive to large populations of self antigen, even when self and agonist antigen are similar in dissociation rate to the TCR but differ largely in expression. Additionally, our model achieves high levels of accuracy even when agonist positive APCs encounters are rare. Finally, we discuss potential biological costs associated with high classification accuracy, particularly in challenging T cell environments.Author summaryPhysical contact between the T cell and antigen presenting cell (APC) is essential for productive immune signaling. Wide variations in this contact time have been observed yet little is known of mechanisms controlling this crucial timescale, nor how its duration may impact antigen discrimination. We develop and analyze a probabilistic mathematical model of T cell activation which combines kinetic proofreading (KP) with a finite contact duration. Our model is capable of suppressing large populations of self ligands while remaining sensitive to only a single agonist in T cell/APC cellular contacts. Additionally, we explored two challenging cases, one in which self and agonist antigen are similar and one in which agonist positive APCs are rare. We found that our model could overcome these environmental challenges by increasing the number of kinetic proofreading steps. Finally, we discuss the potential biological costs of achieving such accuracy. Our work demonstrates the extreme effectiveness of kinetic proofreading in a temporal context while also demonstrating the possible challenges in biological implementation of such a model.
P-DOR, an easy-to-use pipeline to reconstruct outbreaks using pathogen genomics
Authors: Batisti Biffignandi Gherard , Bellinzona Greta , Petazzoni Greta , Sassera Davide , Zuccotti Gian Vincenzo , Bandi Claudio , Baldanti Fausto , Comandatore Francesco , Gaiarsa Stefano 
Published: June 2023

SummaryBacterial Healthcare Associated Infections (HAIs) are a major threat worldwide, which can be counteracted by establishing effective infection control measures, guided by constant surveillance and timely epidemiological investigations. Genomics is crucial in modern epidemiology but lacks standard methods and user-friendly software, accessible to users without a strong bioinformatics proficiency. To overcome these issues we developed P-DOR, a novel tool for rapid bacterial outbreak characterization. P-DOR accepts genome assemblies as input, it automatically selects a background of publicly available genomes using k-mer distances and adds it to the analysis dataset before inferring a SNP-based phylogeny. Epidemiological clusters are identified considering the phylogenetic tree topology and SNP distances. By analyzing the SNP-distance distribution, the user can gauge the correct threshold. Patient metadata can be inputted as well, to provide a spatio-temporal representation of the outbreak. The entire pipeline is fast and scalable and can be also run on low-end computers.Availability and implementationP-DOR is implemented in Python3 and R and can be installed using conda environments. It is available from GitHubhttps://github.com/SteMIDIfactory/P-DORunder the GPL-3.0 license.
The road to restoration: Identifying and conserving the adaptive legacy of American chestnut
Authors: Sandercock Alexander M , Westbrook Jared W , Zhang Qian , Holliday Jason A 
Published: June 2023

AbstractThe American chestnut (Castanea dentata) is a functionally extinct tree species that was decimated by an invasive fungal pathogen in the early 20thcentury. Disease resistant chestnuts have been developed through hybridization and genetic modification, but these populations may lack the adaptive genomic diversity necessary to restore the species across its climatically diverse historical range. An understanding of the genomic architecture of local adaptation in wild American chestnut and identification of seed zones for germplasm conservation are necessary in order to deploy locally adapted, disease-resistant American chestnut populations. Here, we characterize the genomic basis of climate adaptation in remnant wild American chestnut, define seed zones based on climate envelopes and adaptive diversity, and make sampling recommendations for germplasm conservation. Whole genome re-sequencing of 384 trees coupled with genotype-environment association methods suggest the species range can be most parsimoniously subdivided into three seed zones characterized by relatively homogeneous allele frequencies relative to rangewide adaptive diversity. Using these data, we developed a method to estimate the number of samples required from each seed zone to recapitulate standing adaptive diversity in each seed zone, and found that on average, 21-29 trees will need to be conserved to capture 95% of the wild adaptive diversity. Taken together, these results will inform the development of anex situgermplasm conservation and breeding plan to develop locally adapted blight-resistant American chestnut populations, and provide a blueprint for developing restoration plans for other imperiled tree species.
Multi-target genome editing reduces polyphenol oxidase activity in wheat (Triticum aestivumL.) grains
Authors: Wold-McGimsey Forrest , Krosch Caitlynd , Reverte Rocío Alarcón , Ravet Karl , Katz Andrew , Stromberger John , Mason Richard Esten , Pearce Stephen 
Published: June 2023

SUMMARYPolyphenol oxidases (PPO) are dual activity metalloenzymes that catalyse the production of quinones. In plants, PPO activity may contribute to biotic stress resistance and secondary metabolism but is undesirable for food producers because it causes the discolouration and changes in flavour profiles of products during post-harvest processing. In wheat (Triticum aestivumL.), PPO released from the aleurone layer of the grain during milling results in the discolouration of flour, dough, and end-use products, reducing their value.Loss-of-function mutations in thePPO1andPPO2paralogous genes on homoeologous group 2 chromosomes confer reduced PPO activity in the wheat grain but limited natural variation and small intergenic distances between these genes complicates the selection of extremely low-PPO wheat varieties by recombination.In the current study, a CRISPR/Cas9 construct with one single guide RNA (sgRNA) targeting a conserved copper binding domain was used to edit all sevenPPO1andPPO2genes in the spring wheat cultivar ‘Fielder’. Five of the seven edited T1lines exhibited significant reductions in PPO activity, and T2lines had PPO activity up to 86.7% lower than wild-type controls. In the elite winter wheat cultivars ‘Guardian’ and ‘Steamboat’, which have fivePPO1andPPO2genes, PPO activity was reduced by >90% in both T1and T2lines. This study demonstrates that multi-target editing at late stages of variety development could complement selection for beneficial alleles in crop breeding programmes by inducing novel variation in loci inaccessible to recombination.
Colonial ground nesting byArchaeopteryxsuggests wing evolution in primal association with nesting and the ground up evolution of flight
Authors: Guimarães M. Jorge 
Published: June 2023

ABSTRACTFollowing an investigation into the hypothesis that the iconic Berlin specimen ofArchaeopteryxfossilized in nesting position, which led to the discovery not only of its association with soft eggs and several hatchlings, but also similar findings in a secondArchaeopteryxspecimen, an attempt to characterize the entire Berlin specimen nest and estimate its number of eggs is reported here.The Berlin specimen arranged and brooded its eggs on the ground. Its clutch size appears to have exceeded one hundred eggs. Egg littering found not only in its fossil bed but also in the sediment layer immediately above it, inclusively with evidence that a subsequent generation nested over the specimen, is consistent with repeated usage of a ground nesting site.AllArchaeopteryxspecimens fossilized in different views of a similar pose that is compatible with a nesting posture, and evidence of eggs of consistent size with the 2D outlines of 3D flattened eggs is present not only in the Berlin, Teylers, Thermopolis and Maxberg specimens, but also in the isolatedArchaeopteryxfeather fossil.In addition, egg and hatchling littering are present in the Berlin, Teylers and isolatedArchaeopteryxfeather fossils.Taken together, these findings are indicative of colonial ground nesting behavior byArchaeopteryxin Solnhofen.Egg littering, eggs dorsal to the Berlin specimen torso and limb rotations in the London and ThermopolisArchaeopteryxspecimens can all be explained by nesting in reentrances located at the margins or in sand banks of marine lagoons in Solnhofen, which would have been flooded, causing the subsequent collapse of the nest and the still-life preservation of its content.The discovery of colonial ground nesting in a winged Jurassic bird relative favors the evolution of birds from the ground up and suggests that wings and their elongated feathers were primarily associated with ground nest protection and only secondarily with flight.
Yeast Ixr1 mediates the DNA replication stress response through it HMGB DNA binding domains and interaction with checkpoint Mrc1
Authors: Teng Siying , wang Yi , Jiang Jingyuan , Li Mengyuan , Liu Yingxin , Guan Yangying , Wei Anhui , Cong Zhongyi , Zhang Xinmin 
Published: June 2023

AbstractBackgroundHigh mobility group box (HMGB) family protein Ixr1 has been shown to be involved in DNA damage repair, however, its role and mechanism remain largely unclear.MethodsGenes ofS. cerevisiaewere deleted or tagged with myc, GFP, or mcherry using the lithium acetate method. Sensitivity of strains to hydroxyurea (HU), methyl methanesulfonate (MMS), camptothe-cin (CPT), 4-nitroquinoline N-oxide (4-NQ), or Zeocin was tested. Distribution of GFP or mcherry fusion proteins was visualized with laser scanning confocal microscopy. RNA-seq was used to determine differential gene expression between mutant and control strains.ResultsIxr1 deletion (ixr1Δ) mutant strain was sensitive to HU. Additionally, phosphorylation of effector of DNA damage checkpoint kinase Rad53 was lower in ixr1Δ than WT. Deletion of DNA damage checkpoint mediators ixr1Δ Rad9Δ was more sensitive to HU than ixr1Δ or Rad9Δ, and ixr1Δ mrc1Δ had similar sensitivity to HU as mrc1Δ but stronger than ixr1Δ. Deletion of ribonucleotide reductase inhibitors sml1Δ or crt10Δ didn’t reduce the sensitivity of ixr1Δ induced by HU. Repli-cation fork nuclease exo1Δ ixr1Δ or helicase sgs1Δ ixr1Δ double deletions were more sensitive to HU than single deletion. In addition, laser scanning confocal microscopy imaging indicated that in response to HU, Ixr1 may be in the same pathway as Mrc1, possibly downstream. Gene Ontol-ogy enrichment analysis of differentially expressed genes (DEGs) between ixr1Δ and wildtype, untreated and treated with HU, confirmed that Ixr1 plays an important role in regulating the transcription of genes related to DNA replication or DNA damage repair. We also found that, re-gardless of HU exposure, Ixr1 localized to the nucleus and may bind DNA through its two HMG-boxes.ConclusionIxr1 participates in the DNA replication stress response through a DNA damage checkpoint pathway mediated by Mrc1, and regulates expression of genes related to DNA damage repair.
PERK-mediated antioxidant response is key for pathogen persistence in ticks
Authors: Rosche Kristin L. , Hurtado Joanna , Fisk Elis A. , Vosbigian Kaylee A. , Warren Ashley L. , Sidak-Loftis Lindsay C. , Wright Sarah J. , Ramirez-Zepp Elisabeth , Park Jason M. , Shaw Dana K. 
Published: June 2023

ABSTRACTA crucial phase in the lifecycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force shaping how transmissible pathogens interact with the vector. How pathogens remain in the tick despite immunological pressure remains unknown. In persistently infectedIxodes scapularis, we found thatBorrelia burgdorferi(Lyme disease) andAnaplasma phagocytophilum(granulocytic anaplasmosis) activate a cellular stress pathway mediated by the endoplasmic reticulum receptor PERK and the central regulatory molecule, eIF2α. Disabling the PERK pathway through pharmacological inhibition and RNAi significantly decreased microbial numbers.In vivoRNA interference of the PERK pathway not only reduced the number ofA. phagocytophilumandB. burgdorfericolonizing larvae after a bloodmeal, but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed thatA. phagocytophilumandB. burgdorferiinduce activity of the antioxidant response regulator, Nrf2. Tick cells deficient fornrf2expression or PERK signaling showed accumulation of reactive oxygen and nitrogen species in addition to reduced microbial survival. Supplementation with antioxidants rescued the microbicidal phenotype caused by blocking the PERK pathway. Altogether, our study demonstrates that theIxodesPERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment.
Culturable approach to rice-root associated bacteria in Burkina Faso: diversity, plant growth-promoting rhizobacteria properties and cross-comparison with metabarcoding data
Authors: Sondo Moussa , Wonni Issa , Koïta Kadidia , Rimbault Isabelle , Barro Mariam , Tollenaere Charlotte , Moulin Lionel , Klonowska Agnieszka 
Published: June 2023

ABSTRACTPlant-associated bacteria are essential partners in plant health and development. In addition to taking advantage of the rapid advances recently achieved in high-throughput sequencing approaches, studies on plant-microbiome interactions require experiments with culturable bacteria. A study on the rice root microbiome was recently initiated in Burkina Faso. As a follow up, the aim of the present study was to develop a collection of corresponding rice root-associated bacteria covering maximum diversity so as, to be able to assess the diversity of the collection based on the culture medium used, and to describe the taxonomy, phenotype and abundance of selected isolates in the rice microbiome. More than 3,000 isolates were obtained using five culture media (TSA, NGN, NFb, PCAT, Baz). The 16S rRNA fragment sequencing of 1,013 selected working collection isolates showed that our working collection covered four bacterial phyla (Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes) and represented 33% of the previously described diversity of the rice root microbiome at the order level. Phenotypicin vitroanalysis of the plant growth promoting capacity of the isolates revealed an overall ammonium production and auxin biosynthesis capacity, while siderophore production and phosphate solubilisation were enriched inBurkholderia,Ralstonia,AcinetobacterandPseudomonasspecies. Of 45 representative isolates screened for growth promotion on seedlings of two rice cultivars, five showed an ability to improve the growth of both cultivars, while five others were effective on only one cultivar. The best results were obtained withPseudomonas taiwanensisABIP 2315 andAzorhizobium caulinodansABIP 1219, which increased seedling growth by 158% and 47%, respectively. Among the 14 best performing isolates, eight appeared to be abundant in the rice root microbiome dataset from previous study. The findings of this research contribute to the functional description of rice root-associated bacteria and their potential importance for plants by providing, for the first time, insight into their prevalence in the rice root microbiome.
Single cell-guided prenatal derivation of primary epithelial organoids from the human amniotic and tracheal fluids
Authors: Gerli Mattia Francesco Maria , Calà Giuseppe , Beesley Max Arran , Sina Beatrice , Tullie Lucinda , Panariello Francesco , Michielin Federica , Yunyan Kylin Sun , Davidson Joseph R , Russo Francesca Maria , Jones Brendan C , Lee Dani , Savvidis Savvas , Xenakis Theodoros , Simcock Ian , Straatman-Iwanowska Anna A , Hirst Robert A , David Anna L , O’Callaghan Christopher , Olivo Alessandro , Eaton Simon , Loukogeorgakis Stavros P , Cacchiarelli Davide , Deprest Jan , Li Vivian SW , Giobbe Giovanni Giuseppe , Coppi Paolo De 
Published: June 2023

ABSTRACTDespite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define individual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem/progenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To confirm this, we derived lung organoids from AF and tracheal fluid (TF) cells of Congenital Diaphragmatic Hernia (CDH) fetuses and found that they show differences to non-CDH controls and can recapitulate some pathological features of the disease. Amniotic Fluid Organoids (AFO) allow investigation of fetal epithelial tissues at clinically relevant developmental stages and may enable the development of therapeutic tools tailored to the fetus, as well as to predicting the effects of such therapies.