bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies
Authors: Zou Peng 
Published: January 2023

AbstractThere has been an increasing trend towards subcutaneous (SC) delivery of fusion proteins and monoclonal antibodies (mAbs) in recent years versus intravenous (IV) administration. The prediction of bioavailability is one of the major barriers in clinical translation of SC administered therapeutic proteins due to a lack of reliable in vitro and preclinical in vivo predictive models. In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 20 Fc-or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and human intravenous clearance (CL) or isoelectric point (pI). The bioavailability of fusion proteins is more correlated with pI while the bioavailability of mAbs is more correlated with CL. A mAbs with intravenous CL < 4 mL/day/kg is likely to have SC bioavailability > 60%. Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models were validated with an independent test set (N = 33). A linear regression model resulted in 27 among 33 (82%) predictions within 0.8-to 1.2-fold deviations. Overall, this study demonstrated that CL- and pI-based multivariate regression models could be used to predict human SC bioavailability of fusion proteins and mAbs.
Dynamics of Innate Immune Response Due to Bacteria-Induced Pulpitis
Authors: Erdogan Ozge , Xia Jingya , Chiu Isaac M. , Gibbs Jennifer L. 
Published: January 2023

ABSTRACTIntroductionPulpitis is associated with dental carries and can lead to irreversible pulp damage. As bacteria penetrate deeper into dentin and pulp tissue, a pulpal innate immune response is initiated. However, an understanding of the types of immune cells in the pulp, how this relates to bacterial infiltration, and the dynamics of the immune response during pulpitis is limited. As conserving the vitality of the pulp tissue through conservative therapies becomes an important part of dental practice, there is a greater need to understand the kinetics and composition of the immune response during pulpitis.MethodsDental pulp exposure in molars of mice was used as an animal model of pulpitis. To investigate the kinetics of immune response, pulp tissue was collected from permanent molars at different time points after injury (baseline, day 1, and day 7). Flow cytometry analysis of CD45+ leukoctyes including macrophages, T cells, neutrophils and monocytes was performed. 16S in situ hybridization captured bacterial invasion of the pulp, and immunohistochemistry for F4/80 investigated spatial and morphological changes of macrophages during pulpitis. Data were analyzed using two-way ANOVA with Tukey’s multiple comparisons.ResultsBacteria mostly remained close to the injury site, with some expansion towards non-injured pulp horns. We found that F4/80+macrophages were the main immune cell population in healthy pulp. Upon injury, CD11b+Ly6Ghighneutrophils and CD11b+Ly6GintLy6Cintmonocytes constituted 70-90% of all immune populations up to 7 days after injury. Even though there was a slight increase in T cells at day 7, myeloid cells remained the main drivers of the immune response.ConclusionsAs bacteria proliferate within the pulp chamber, innate immune cells including macrophages, neutrophils and monocytes predominate as the major immune populations, with minimal signs of transitioning to an adaptive immune response.
Resolving the haplotypes of arbuscular mycorrhizal fungi highlights the role of two nuclear populations in host interactions
Authors: Sperschneider Jana , Yildirir Gokalp , Rizzi Yanina , Malar C Mathu , Sorwar Essam , Chen Eric CH , Iwasaki Wataru , Brauer Elizabeth K. , Bosnich Whynn , Gutjahr Caroline , Corradi Nicolas 
Published: January 2023

AbstractArbuscular mycorrhizal fungi (AMF) are prominent root symbionts with a multinucleate cytoplasm that can carry thousands of nuclei deriving from two parental strains and varying in relative abundance in a large syncytium. Here, we set out to improve our understanding of such remarkable genetics by resolving the nuclear genomes of all publicly available AMF heterokaryons using PacBio HiFi and Hi-C sequencing. We find that all AMF heterokaryons carry two sets of homologous chromosomes, where genes associated with plant colonization reside in gene-sparse, repeat-rich compartments. The co-existing nuclear genomes are phylogenetically related but differ significantly in content and epigenetics, resulting in nucleus-specific regulatory programs during mycorrhizal interactions. AMF heterokaryons carry signatures of past genetic exchange indicative of sexual reproduction, followed by clonal haplotype evolution. This work uncovers the contribution and origin of nuclear genomes present in AMF heterokaryons and opens avenues for improvement and environmental application of these strains.
Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats
Authors: Truckenbrod Leah M. , Betzhold Sara M. , Wheeler Alexa-Rae , Shallcross John , Singhal Sarthak , Harden Scott , Schwendt Marek , Frazier Charles J. , Bizon Jennifer L. , Setlow Barry , Orsini Caitlin A. 
Published: January 2023

AbstractDecision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.
AliSim-HPC: parallel sequence simulator for phylogenetics
Authors: Ly-Trong Nhan , Barca Giuseppe M.J. , Minh Bui Quang 
Published: January 2023

AbstractMotivationSequence simulation plays a vital role in phylogenetics with many applications, such as evaluating phylogenetic methods, testing hypotheses, and generating training data for machine-learning applications. We recently introduced a new simulator for multiple sequence alignments called AliSim, which outperformed existing tools. However, with the increasing demands of simulating large data sets, AliSim is still slow due to its sequential implementation; for example, to simulate millions of sequence alignments, AliSim took several days or weeks. Parallelization has been used for many phylogenetic inference methods but not yet for sequence simulation.ResultsThis paper introduces AliSim-HPC, which, for the first time, employs high-performance computing for phylogenetic simulations. AliSim-HPC parallelizes the simulation process at both multi-core and multi-CPU levels using the OpenMP and MPI libraries, respectively. AliSim-HPC is highly efficient and scalable, which reduces the runtime to simulate 100 large alignments from one day to 9 minutes using 256 CPU cores from a cluster with 6 computing nodes, a 162-fold speedup.Availability and implementationAliSim-HPC is open source and available as part of the new IQ-TREE version v2.2.2.2 athttps://github.com/iqtree/iqtree2/releaseswith a user manual athttp://www.iqtree.org/doc/AliSim.Contactm.bui@anu.edu.au
Using a self-attention architecture to automate valence categorization of French teenagers’ free descriptions of their family relationships. A proof of concept
Authors: Sedki Mohammed , Vidal Nathan , Roux Paul , Barry Caroline , Speranza Mario , Falissard Bruno , Brunet-Gouet Eric 
Published: January 2023

AbstractThis paper proposes a proof of concept of using natural language processing techniques to categorize valence of family relationships described in free texts written by french teenagers. The proposed study traces the evolution of techniques for word embedding. After decomposing the different texts in our possession into short texts composed of sentences and manual labeling, we tested different word embedding scenarios to train a multi-label classification model where a text can take several labels : labels describing the family link between the teenager and the person mentioned in the text and labels describing the teenager’s relationship with them positive/negative/neutral valence). The natural baseline for word vector representation of our texts is to build a TF-IDF and train classical classifiers (Elasticnet logistic regression, gradient boosting, random forest, support vector classifier) after selecting a model by cross validation in each class of machine learning models. We then studied the strengths of word-vectors embeddings by an advanced language representation technique via the CamemBERT transformer model, and, again, used them with classical classifiers to compare their respective performances. The last scenario consisted in augmenting the CamemBERT with output dense layers (perceptron) representing a classifier adapted to the multi-label classification and fine-tuning the CamemBERT original layers. The optimal fine-tuning depth that achieves a bias-variance trade-off was obtained by a cross-validation procedure. The results of the comparison of the three scenarios on a test dataset show a clear improvement of the classification performances of the scenario with fine-tuning beyond the baseline and of a simple vectorization using CamemBERT without fine-tuning. Despite the moderate size of the dataset and the input texts, fine-tuning to an optimal depth remains the best solution to build a classifier.
Differences Between Reported COVID-19 Deaths and Estimated Excess Deaths in Counties Across the United States, March 2020 to February 2022
Authors: Paglino Eugenio , Lundberg Dielle J. , Zhou Zhenwei , Wasserman Joe A. , Raquib Rafeya , Hempstead Katherine , Preston Samuel H. , Elo Irma T. , Stokes Andrew C. 
Published: January 2023

ABSTRACTAccurate and timely tracking of COVID-19 deaths is essential to a well-functioning public health surveillance system. The extent to which official COVID-19 death tallies have captured the true toll of the pandemic in the United States is unknown. In the current study, we develop a Bayesian hierarchical model to estimate monthly excess mortality in each county over the first two years of the pandemic and compare these estimates to the number of deaths officially attributed to Covid-19 on death certificates. Overall, we estimated that 268,176 excess deaths were not reported as Covid-19 deaths during the first two years of the Covid-19 pandemic, which represented 23.7% of all excess deaths that occurred. Differences between excess deaths and reported COVID-19 deaths were substantial in both the first and second year of the pandemic. Excess deaths were less likely to be reported as COVID-19 deaths in the Mountain division, in the South, and in nonmetro counties. The number of excess deaths exceeded COVID-19 deaths in all Census divisions except for the New England and Middle Atlantic divisions where there were more COVID-19 deaths than excess deaths in large metro areas and medium or small metro areas. Increases in excess deaths not assigned to COVID-19 followed similar patterns over time to increases in reported COVID-19 deaths and typically preceded or occurred concurrently with increases in reported COVID-19 deaths. Estimates from this study can be used to inform targeting of resources to areas in which the true toll of the COVID-19 pandemic has been underestimated.
Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study
Authors: Zhang Shijia , Tang Kimberly , Wan Guihong , Nguyen Nga , Lu Chenyue , Ugwu-Dike Pearl , Raval Neel , Seo Jayhyun , Alexander Nora A. , Jairath Ruple , Phillipps Jordan , Leung Bonnie W. , Roster Kathleen , Chen Wenxin , Zubiri Leyre , Boland Genevieve , Chen Steven T. , Tsao Hensin , Demehri Shadmehr , LeBoeuf Nicole R. , Reynolds Kerry L. , Yu Kun-Hsing , Gusev Alexander , Kwatra Shawn G. , Semenov Yevgeniy R. 
Published: January 2023

AbstractBackgroundCutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear.ObjectiveTo investigate the association of cirAEs with survival among ICI recipients.MethodsICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival.ResultsOf the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,p<0.001), psoriasiform eruption (HR=0.52,p=0.005), vitiligo (HR=0.29,p=0.007), isolated pruritus without visible manifestation of rash (HR=0.71,p=0.007), acneiform eruption (HR =0.34,p=0.025), and non-specific rash (HR=0.68, p<0.001) were significantly associated with better survival after multiple comparisons adjustment.LimitationsRetrospective design; single geography.ConclusionCirAE development is associated with improved survival among ICI recipients, especially melanoma patients.Capsule SummaryPatients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.
Patulin contamination of hard apple cider by Paecilomyces niveus and other postharvest apple pathogens: assessing risk factors
Authors: Wang Tristan W. , Wilson Amanda G. , Peck Gregory M. , Gibney Patrick A. , Hodge Kathie T. 
Published: January 2023

AbstractHard apple cider is considered to be a low-risk product for food spoilage and mycotoxin contamination due to its alcoholic nature and associated food sanitation measures. However, the thermotolerant mycotoxin-producing fungusPaecilomyces niveusmay pose a significant threat to hard cider producers.Pa. niveusis known to infect apples (Malusxdomestica), and previous research indicates that it can survive thermal processing and contaminate finished apple juice with the mycotoxin patulin. To determine if hard apple cider is susceptible to a similar spoilage phenomenon, cider apples were infected withPa. niveusor one of three patulin-producingPenicilliumspecies and the infected fruits underwent benchtop fermentation. Cider was made with lab inoculated Dabinett and Medaille d’Or apple cultivars, and patulin was quantified before and after fermentation. Results show that all four fungi can infect cider apples and produce patulin, some of which is lost during fermentation. OnlyPa. niveuswas able to actively grow throughout the fermentation process. To determine if apple cider can be treated to hinderPa. niveusgrowth, selected industry-grade sanitation measures were tested, including chemical preservatives and pasteurization. High concentrations of preservatives inhibitedPa. niveusgrowth, but apple cider flash pasteurization was not found to significantly impact spore germination. This study confirms that hard apple cider is susceptible to fungal-mediated spoilage and patulin contamination.Pa. niveusshould be of great concern to hard apple cider producers due to its demonstrated thermotolerance, survival in fermentative environments, and resistance to sanitation measures.HighlightsApple fruits of traditional cider cultivars Dabinett and Medaille d’Or were found to be susceptible to infection by three patulin-producingPenicilliumspp. andPaecilomyces niveusPa. niveuscan grow in finished fermented hard cider at 5.22% ethanolPatulin levels in cider were reduced by fermentation but still exceeded 50 µg/kg, a maximum limit set by various regulatory agenciesPa. niveuswas observed to be able to grow in low concentrations of three preservatives: potassium sorbate, sulfur dioxide, and sodium benzoate
Antibody-drug conjugates to treat bacterial biofilms
Authors: Tvilum Anne , Johansen Mikkel I. , Glud Lærke N. , Ivarsen Diana M. , Khamas Amanda B. , Carmali Sheiliza , Mhatre Snehit Satish , Søgaard Ane B. , Faddy Emma , de Vor Lisanne , Rooijakkers Suzan H.M. , Østergaard Lars , Jørgensen Nis P. , Meyer Rikke L. , Zelikin Alexander N. 
Published: January 2023

AbstractImplant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms,in vitroandin vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms,in vitroandin vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatmentin vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.
Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators
Authors: Kline Gabriel M. , Paxman Ryan J , Lin Chung-Yon , Madrazo Nicole , Grandjean Julia M. , Lee Kyunga , Nugroho Karina , Powers Evan T. , Wiseman R. Luke , Kelly Jeffery W. 
Published: January 2023

SUMMARYPharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino-p-cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino-p-cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.
Isoginkgetin and Madrasin are poor splicing inhibitors
Authors: Tellier Michael , Ansa Gilbert , Murphy Shona 
Published: January 2023

AbstractThe production of eukaryotic mRNAs requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation. Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7, and pol II elongation rate can regulate splicing. Splicing, in turn, can also affect transcriptional activity and transcription elongation defects are caused by some splicing inhibitors. Multiple small molecule inhibitors of splicing are now available, some of which specifically target SF3B1, a U2 snRNP component. SF3B1 inhibition results in a general downregulation of transcription elongation, including premature termination of transcription caused by increased use of intronic poly(A) sites. Here, we have investigated the effect of Madrasin and Isoginkgetin, two non-SF3B1 splicing inhibitors, on splicing and transcription. Surprisingly, we found that both Madrasin and Isoginkgetin affect transcription before any effect on splicing, indicating that their effect on pre-mRNA splicing is likely to be indirect. Both small molecules promote a general downregulation of transcription. Based on these and other published results, we conclude that these two small molecules should not be considered as primarily pre-mRNA splicing inhibitors.