bluuebunny/crossref_metadata_2025 huggingface dataset:
A survey on retracted articles in the field of health sciences from 2001 to 2022 from Iran
Authors: Soltani Parisa , Sadeghizade Shakiba , Nikbakht Mohammad Hossein , Malaz Arghavan
Published: December 2023

Background

Retraction is the process of correcting literature and warning readers of publications that contain such serious flaws or erroneous data. A variety of reasons may lead to retraction of published articles.

Objectives

This study aimed to investigate the characteristics of retracted articles from Iran in the field of health sciences.

Design

Retrospective study

Setting

This study was conducted on retracted articles in the field of health published by authors affiliated with Iranian organizations from 2001 to 2022. The Retraction Watch Database was used to extract the information from these articles. The following information was extracted: journal name, article type, institutions, country(s), date published, date retracted, authors number, and reasons for retraction. This data was evaluated using descriptive statistics.

Results

Between 2001 and 2022, our search identified 348 retracted articles. The highest number of retractions belongs to Diagnostic Pathology and Tumor Biology journals. The highest numbers of retractions belong to 2016 and 2020, respectively. The highest number of retracted articles were published in 2015 and 2018, respectively. Different types of articles have been assigned different percentages: Research article (52.9%), clinical study (29.9%), conference abstract/paper (5.2%), review article (4.6%), case report (3.7%), and others (3.7%). The main reasons that led to retraction were investigation by journal/publisher, fake peer review, and concerns/issues about data. Malaysia, Bahrein, and India had the most cooperation with Iran in the retracted articles. The mean time between publication and retraction was 2.44 years and ranged between less than a year and 16 years. Institutions with the highest record of retraction are Kashan University of Medical Sciences, Shaheed Beheshti University of Medical Sciences, and Tabriz University of Medical Sciences.

Conclusions

Investigation by journal/publisher, fake peer review, and concerns/issues about data were the most common reasons for retraction. The results of this study indicate that more attention is required from research ethics authorities in order to protect the integrity of published research.
Patient-derived PixelPrint phantoms for evaluating clinical imaging performance of a deep learning CT reconstruction algorithm
Authors: Im Jessica Y. , Halliburton Sandra S. , Mei Kai , Perkins Amy E. , Wong Eddy , Roshkovan Leonid , Sandvold Olivia F. , Liu Leening P. , Gang Grace J. , Noël Peter B.
Published: December 2023

Objective

Deep learning reconstruction (DLR) algorithms exhibit object-dependent resolution and noise performance. Thus, traditional geometric CT phantoms cannot fully capture the clinical imaging performance of DLR. This study uses a patient-derived 3D-printed PixelPrint lung phantom to evaluate a commercial DLR algorithm across a wide range of radiation dose levels.

Approach

The lung phantom used in this study is based on a patient chest CT scan containing ground glass opacities and was fabricated using PixelPrint 3D-printing technology. The phantom was placed inside two different sized extension rings to mimic a small and medium sized patient and was scanned on a conventional CT scanner at exposures between 0.5 and 20 mGy. Each scan was reconstructed using filtered back projection (FBP), iterative reconstruction, and DLR at five levels of denoising. Image noise, contrast to noise ratio (CNR), root mean squared error (RMSE), structural similarity index (SSIM), and multi-scale SSIM (MS SSIM) were calculated for each image.

Main Results

DLR demonstrated superior performance compared to FBP and iterative reconstruction for all measured metrics in both phantom sizes, with better performance for more aggressive denoising levels. DLR was estimated to reduce dose by 25-83% in the small phantom and by 50-83% in the medium phantom without decreasing image quality for any of the metrics measured in this study. These dose reduction estimates are more conservative compared to the estimates obtained when only considering noise and CNR with a non-anatomical physics phantom.

Significance

DLR has the capability of producing diagnostic image quality at up to 83% lower radiation dose which can improve the clinical utility and viability of lower dose CT scans. Furthermore, the PixelPrint phantom used in this study offers an improved testing environment with more realistic tissue structures compared to traditional CT phantoms, allowing for structure-based image quality evaluation beyond noise and contrast-based assessments.
Enhancing the accuracy of register-based metrics: Comparing methods for handling overlapping psychiatric register entries in Finnish healthcare registries
Authors: Suokas Kimmo , Gutvilig Mai , Lumme Sonja , Pirkola Sami , Hakulinen Christian
Published: December 2023

Objectives

Healthcare registers are invaluable resources for research. Partly overlapping register entries and preliminary diagnoses may introduce bias. We compare various methods to address this issue and provide fully reproducible open-source R scripts.

Methods

We used all Finnish healthcare registers 1969-2020, including inpatient, outpatient and primary care. Four distinct models were formulated based on previous reports to identify actual admissions, discharges, and discharge diagnoses. We calculated the annual number of treatment episodes and patients, and the median length of hospital stay (LOS). We compared these metrics to non-processed data. Additionally, we analyzed the lifetime number of individuals with registered mental disorders.

Results

Overall, 2 130 468 individuals had a registered medical contact related to mental disorders. After processing, the annual number of inpatient episodes decreased by 5.13– 10.41% and LOS increased by up to 3 days (27.27%) in years 2011–2020. The number of individuals with lifetime diagnoses reduced by more than 1 percent point (pp) in two categories: schizophrenia spectrum (3.69–3.81pp) and organic mental disorders (1.2– 1.27pp).

Conclusions

The methods employed in pre-processing register data significantly impact the number of treatment episodes and LOS. Regarding lifetime incidence of mental disorders, schizophrenia spectrum disorders require a particular focus on data pre-processing.
Risk Factors for Non-Communicable Diseases among Bangladeshi Adults: An Application of Generalized Linear Mixed Model on Multilevel Demographic and Health Survey Data
Authors: Nahin Kazi Sabbir Ahmad , Jannatul Tabita
Published: December 2023

Objective

The research effort addresses the impact of non-communicable diseases (NCDs), particularly diabetes mellitus (DM) and hypertension (HTN), on Bangladesh, a lower-middle-income country. Due to their higher incidences and associated risks, DM and HTN present substantial concerns. The paper clarifies the need for specific public health initiatives and emphasizes the socioeconomic and lifestyle-related factors of NCDs.

Methods

A mixed-model technique is employed to conduct a multivariate analysis of the cross sectional data from the Bangladesh Demographic and Health Survey (BDHS) 2017-18, with the aim of identifying possible risk factors. We have two outcome variables under consideration in the study, namely Diabetes, and Hypertension, each having binary categories. The adjusted odds ratios (AORs) in addition to their corresponding p-values and 95% confidence intervals (CIs) to assess and evaluate the relative strength of covariates.

Results

Those with hypertension have a 28% (OR = 1.28, 95% CI: 1.14, 1.43) higher risk of developing diabetes. Likewise, individuals with diabetes have a 24% (OR = 1.24, 95% CI: 1.11, 1.39) increased probability of developing hypertension. People over 40 years old are 66.4% more likely to have diabetes. Also, rich people are more likely to be diabetic and hypertensive.

Conclusion

The prevalence of diabetes is significantly elevated among individuals aged 40 years and older, particularly among those who have hypertension, are overweight, and possess a higher socioeconomic status. In contrast, there is a notable increase in the likelihood of developing hypertension among male individuals who are diabetic, above the age of 40, who already have hypertension, are overweight and have a higher socioeconomic class. There is a good chance that presenting these risk factors to policymakers could contribute to the amelioration of the NCDs crisis in Bangladesh.
Length of hospital stay and associated factors among adult surgical patients admitted to a surgical ward in Amhara Regional State Comprehensive Specialized Hospitals, Ethiopia
Authors: Dadi Habtamu Hurisa , Habte Netsanet , Mulu Yenework , Asfaw Yabibal
Published: December 2023

Introduction

Hospitals across the country are experiencing a rise in the length of hospital stays, ranging from 2% to 14%. As a result, patients who remain hospitalized for a prolonged period are three times more likely to suffer in-hospital deaths. Therefore, identifying contributing factors for prolonged hospital stays enhances the ability to improve services and the quality of patient care. However, there is limited documented evidence in Ethiopia as well as in the study area about factors associated with prolonged hospital stays among surgical inpatients.

Objective

This study aimed to assess the length of hospital stay and associated factors among adult surgical patients admitted to a surgical ward in Amhara Regional State Comprehensive Specialized Hospitals, Ethiopia, 2023.

Methods

An institutional-based cross-sectional study was conducted among 452 adult surgical patients from April 17 to May 22, 2023. Data were collected based on a pretested, structured interviewer-administered questionnaire, patient chart review, and direct measurement. Study participants were selected using a systematic random sampling technique. The collected data were cleaned, entered into EpiData 4.6.0 and exported to STATA version 14 for analysis. Binary logistic regression analysis was used. Variables with a p value < 0.05 in the multivariable logistic regression analysis were considered statistically significant.

Results

In the current study, the prevalence of prolonged hospital stay was 26.5% (95% CI: 22.7–30.8). Patients referred from another public health institution (AOR = 2.46; 95% CI: 1.09, 5.57), hospital-acquired pneumonia (AOR = 3.18; 95% CI: 1.28, 7.89), duration of surgery ≥110 minutes (AOR = 2.48; 95% CI: 1.25, 4.91), and preoperative anemia (AOR = 3.37; 95% CI: 1.88, 6.04) were factors associated with prolonged hospital stays.

Conclusion

This study found a significant proportion of prolonged hospital stays. Source of referral, preoperative anemia, duration of surgery, and hospital-acquired pneumonia were factors associated with a prolonged hospital stay. Strengthening the established information system among hospitals when referring patients and early screening and treating anemia upon admission to hospitals can reduce the length of stays.
MLL3/MLL4 enzymatic activity shapes DNA replication timing
Authors: Gökbuget Deniz , Boileau Ryan M. , Lenshoek Kayla , Blelloch Robert
Published: December 2023

Mammalian genomes are replicated in a precise order during S phase, which is cell-type-specific1–3and correlates with local transcriptional activity2,4–8, chromatin modifications9and chromatin architecture1,10,11,12. However, the causal relationships between these features and the key regulators of DNA replication timing (RT) are largely unknown. Here, machine learning was applied to quantify chromatin features, including epigenetic marks, histone variants and chromatin architectural factors, best predicting local RT under steady-state and RT changes during early embryonic stem (ES) cell differentiation. About one-third of genome exhibited RT changes during the differentiation. Combined, chromatin features predicted steady-state RT and RT changes with high accuracy. Of these features, histone H3 lysine 4 monomethylation (H3K4me1) catalyzed by MLL3/4 (also known as KMT2C/D) emerged as a top predictor. Loss ofMll3/4(but notMll3 alone) or their enzymatic activity resulted in erasure of genome-wide RT dynamics during ES cell differentiation. Sites that normally gain H3K4me1 in a MLL3/4-dependent fashion during the transition failed to transition towards earlier RT, often with transcriptional activation unaffected. Further analysis revealed a requirement for MLL3/4 in promoting DNA replication initiation zones through MCM2 recruitment, providing a direct link for its role in regulating RT. Our results uncover MLL3/4-dependent H3K4me1 as a functional regulator of RT and highlight a causal relationship between the epigenome and RT that is largely uncoupled from transcription. These findings uncover a previously unknown role for MLL3/4-dependent chromatin functions which is likely relevant to the numerous diseases associated with MLL3/4 mutations.
Hypoxia alters the effects of hypomethylating agents in acute myeloid leukaemia cells
Authors: Humphries Sam , Burnard Sean M. , Keely Simon , Bond Danielle R. , Lee Heather J.
Published: December 2023

Background

Acute myeloid leukaemia (AML) is a deadly haematological malignancy that originates from mutated myeloid progenitor cells that lie quiescent in the hypoxic bone marrow. Elderly patients who cannot tolerate standard chemotherapies are administered low-dose hypomethylating agents (HMA) which act in a replication-dependent manner to reprogram the epigenome. Relapse is common following HMA treatment and may arise from quiescent leukaemia cells in the hypoxic bone marrow. Therefore, the effects of hypoxia on HMA efficacy may influence AML progression.

Results

AML cell lines (MOLM-13, MV-4-11, HL-60) were treated with decitabine (100nM) or azacitidine (500-2000nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Exposure to hypoxia significantly reduced AML cell growth across all cell lines, with no additional effects observed upon HMA treatment. This was associated with distinct effects on DNA methylation. The extent of hypomethylation induced by AZA treatment was reduced in hypoxia, whereas DAC-induced hypomethylation was maintained in low oxygen conditions. Transcriptional response to HMA treatment were also altered in hypoxia, with HMAs failing to up-regulate antigen presentation pathways in hypoxia. In particular, human leukocyte antigens (HLAs) such as HLA-DR were increased upon HMA treatment in normoxia, but not hypoxia.

Conclusion

Our results suggest that HMA-induced antigen presentation may be impaired in hypoxic tissues such as the bone marrow. This study highlights the need to consider microenvironmental factors when designing co-treatment strategies to improve HMA therapeutic efficacy.
DNA-terminus-dependent transcription by T7 RNA polymerase and its C-helix mutants
Authors: Yu Bingbing , Chen Yifan , Yan Yan , Zhu Bin
Published: December 2023

The remarkable success of mRNA-based vaccines has underscored their potential as a novel biotechnology platform for vaccine development and therapeutic protein delivery. However, the single-subunit RNA polymerase from bacteriophage T7 widely used for in vitro transcription is well known to generate double-stranded RNA (dsRNA) byproducts that strongly stimulate the mammalian innate immune response. The dsRNA was reported to be originated from self-templated RNA extension or promoter-independent transcription. Here, we identified that the primary source of the full-length dsRNA during in vitro transcription is the DNA-terminus-initiated transcription by T7 RNA polymerase. Guanosines or cytosines at the end of DNA templates enhance the DNA-terminus-initiated transcription. Moreover, we found that aromatic residues located at position 47 in the C-helix interfere with the binding of T7 RNA polymerase to DNA termini, leading to a significant reduction in the production of full-length dsRNA. As a result, the mRNA synthesized using the T7 RNA polymerase G47W mutant exhibits higher expression efficiency and lower immunogenicity compared to the mRNA produced using the wild-type T7 RNA polymerase.
Improved mRNA electroporation into immature oocytes to examine protein dynamics during development
Authors: Satouh Yuhkoh , Suzuki Emiko , Sasaki Keisuke , Sato Ken
Published: December 2023

One of the major cause of oocyte quality deterioration along with aging, chromosome segregation abnormalities occur mainly during meiosis I. However, currently, there is a technical limitation in the introduction of mRNA into premature oocytes without impairing embryonic developmental ability. In this study, we established a low-invasive electroporation (EP) method to introduce mRNA into pre-ovulatory, germinal vesicle (GV) mouse oocytes in an easier manner than the traditional microinjection method. The EP method with an optimized impedance value resulted in the efficient introduction of mRNAs encoding enhanced green fluorescent protein (EGFP) into the GV oocytes surrounded by cumulus cells at a survival rate of 95.0%. Furthermore, the introduction of histone H2B-EGFP mRNA into the GV oocytes labeled most of the oocytes without affecting the blastocyst development rate, indicating the feasibility of the visualization of oocyte chromosomal dynamics that enable us to assay chromosomal integrity in oocyte maturation and cell count in embryonic development. The establishment of this EP method offers extensive assays to select pre-implantation embryos and enables the surveying of essential factors for mammalian oocyte quality determination.

Summary blurb

This study introduces a low-invasive electroporation method with high survival rate and developmental ability, offering a potential breakthrough in preimplantation embryo treatment and assessment.
Lithocholic acid targets TULP3 to activate sirtuins and AMPK to retard ageing
Authors: Qu Qi , Chen Yan , Wang Yu , Long Shating , Wang Weiche , Yang Heng-Ye , Wu Jianfeng , Li Mengqi , Tian Xiao , Wei Xiaoyan , Liu Yan-Hui , Xu Shengrong , Yang Chunyan , Wu Zhenhua , Huang Xi , Xie Changchuan , Wu Yaying , Xu Zheni , Zhang Cixiong , Zhang Baoding , Feng Jin-Wei , Chen Junjie , Lin Liyun , Xie ZK , Sun Beibei , Yu Yong , Piao Hai-Long , Xie Xiao-Song , Deng Xianming , Zhang Chen-Song , Lin Sheng-Cai
Published: December 2023

Lithocholic acid (LCA), accumulated in the body during calorie restriction (CR), can confer administered metazoans with the ability to activate AMP-activated protein kinase (AMPK) and retard ageing. However, how LCA is signalled to activate AMPK and elicit the biological effects is unclear. Here, we show that LCA can enhance sirtuins (SIRTs) to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), thereby triggering AMPK activation via the lysosomal glucose-sensing pathway. Through proteomic analysis of SIRT1-coimmunoprecipitated proteins, we identify and validate that TUB like protein 3 (TULP3) is a constitutive component of SIRTs. Surprisingly, we found that TULP3 is an LCA receptor, and that the LCA-bound TULP3 activates SIRTs. The activated SIRTs in turn deacetylate the V1E1 subunit of v-ATPase on K52, K99 and K191 residues. Muscle-specific expression of the 3KR mutant of V1E1, mimicking the deacetylated state, dominantly activates AMPK and rejuvenates muscles in aged mice. Moreover, LCA once administered also activates AMPK and extends lifespan and healthspan in nematodes and flies, depending on the TULP3 homologuestub-1andktub, respectively. Our study thus elucidates that LCA triggers the TULP3-sirtuin-v-ATPase- AMPK route to manifest benefits of calorie restriction.
Evidence based Unification of poTato gene models with UniTato collaborative genome browser
Authors: Zagorščak Maja , Zrimec Jan , Bleker Carissa , Nolte Nadja , Ramšak Živa , Gruden Kristina , Petek Marko
Published: December 2023

Potato (Solanum tuberosum) is the most popular tuber crop and model organism. Though its gene models are frequently updated, they are not unified, leading to missing or wrongly annotated genes. Here, we thus unify the recent potato double monoploid v4 and v6 gene models by automatic merging. We established an Apollo web server that enables access to the Unified poTato genome annotation database (UniTato) as well as further community-based manual curation atunitato.nib.si. We demonstrate how the web server interface can help to resolve problems with missing or misplaced genes and can be used to further update them or consolidate a wider set of gene models or genome information. Genome annotation files and a comprehensive translation table are provided atgithub.com/NIB-SI/unitato.
GeneMAP: A discovery platform for metabolic gene function
Authors: Khan Artem , Unlu Gokhan , Lin Phillip , Liu Yuyang , Kilic Ece , Kenny Timothy C. , Birsoy Kıvanç , Gamazon Eric R.
Published: December 2023

Organisms maintain metabolic homeostasis through the combined functions of small molecule transporters and enzymes. While many of the metabolic components have been well-established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Associations Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions, even pinpointing genes that are distant from the variants implicated by GWAS. In particular, our work identifiedSLC25A48as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite, betaine. Rare variant testing and polygenic risk score analyses have elucidated choline-relevant phenomic consequences of SLC25A48 dysfunction. Altogether, our study proposes SLC25A48 as a mitochondrial choline transporter and provides a discovery platform for metabolic gene function.
Maintenance and evolution of individual differences in a prey defence trait examined with a dynamic predator-prey model
Authors: Eigentler L. , Reinhold K.
Published: December 2023

Predator-prey systems often feature periodic population cycles. In an empirical system with a heritable prey defence trait, ecological oscillations were previously shown to cause evolution of prey defence on the timescale of the population cycles. In this paper, we develop an eco-evolutionary mathematical model comprising partial differential equations to investigate the evolutionary dynamics of prey defence during population cycles. We reveal that ecological population cycles induce evolutionary oscillations of the mean prey defence trait. In contrast to existing continuum modelling frameworks, our model allows for the evolution of individual variability. We show that eco-evolutionary oscillations select for increased individual variability close to the transition from stable to oscillatory states. We also reveal that evolution of prey defence requires both high efficiency and low cost of prey defence and highlight that more information on trade-offs between cost and efficiency is required.
A common cortical basis for variations in visual crowding
Authors: Greenwood John A , Jerotic Katarina , Danter Joseph E , Finnie Rhiannon J , Schwarzkopf D. Sam
Published: December 2023

Peripheral vision is limited by crowding, the disruptive effect of clutter on object recognition. Crowding varies markedly around the periphery, with e.g. stronger performance decrements with increasing eccentricity and in the upper vs. lower visual field. Although a number of neural substrates have been proposed for crowding, none to date can explain the full pattern of these variations. Here we examine the effects of crowding on object appearance. These effects are central to many models of crowding, and also vary markedly, causing target objects to appear more similar to flanker objects (assimilation) in some instances and dissimilar (repulsion) in others. We took 3 manipulations known to vary crowded performance (flankers in the same vs. different hemifield, the upper-lower visual field anisotropy, and the radial-tangential flanker anisotropy) and examined whether the effects on appearance vary similarly. In all cases, manipulations that increased performance impairments also increased assimilative errors, e.g. flankers on the radial axis around fixation gave high threshold elevation and assimilation, with reduced elevation and repulsion errors for tangential flankers. These linked variations in performance and appearance are well described by a population-coding model of crowding that varies the weighted combination of target vs. flanker population responses. We further demonstrate that this pattern is inconsistent with crowding being driven by either the cortical distance between elements or receptive-field size variations on their own. Instead, using a series of models we show that crowding could be driven by receptive field overlap - the intermixing of the spatial distribution of target/flanker population responses. Crowding is strong (with high performance decrements and assimilative biases) when the degree of spatial overlap in population responses is high and reduced (with low threshold elevation reduced assimilation or repulsion) when these responses are separable.
EEG microstate transition cost correlates with task demands
Authors: Barzon Giacomo , Ambrosini Ettore , Vallesi Antonino , Suweis Samir
Published: December 2023

The ability to solve complex tasks relies on the adaptive changes occurring in the spatio-temporal organization of brain activity under different conditions. Altered flexibility in these dynamics can lead to impaired cognitive performance, manifesting for instance as difficulties in attention regulation, distraction inhibition, and behavioral adaptation. Such impairments result in decreased efficiency and increased effort in accomplishing goal-directed tasks. Therefore, developing quantitative measures that can directly assess the effort involved in these transitions using neural data is of paramount importance. In this study, we propose a framework to associate cognitive effort during the performance of tasks with electroencephalography (EEG) activation patterns. The methodology relies on the identification of discrete dynamical states (EEG microstates) and optimal transport theory. To validate the effectiveness of this framework, we apply it to a dataset collected during a spatial version of the Stroop task. The Stroop task is a cognitive test where participants must respond to one aspect of a stimulus while ignoring another, often conflicting, aspect. Our findings reveal an increased cost linked to cognitive effort, thus confirming the framework's effectiveness in capturing and quantifying cognitive transitions. By utilizing a fully data-driven method, this research opens up fresh perspectives for physiologically describing cognitive effort within the brain.
Structural connectivity predicts individual perceived stress
Authors: Amos Toluwani Joan , Bamisile Olusola , Jin Zhenlan , Zhang JunJun , Ling Li
Published: December 2023

Many previous studies have investigated the neural mechanisms of perceived stress using either task or resting-state functional connectomes. However, to date, the structural connectivity predictors of individual perceived stress remain unknown. In this study, using connectome-based predictive modeling with a leave-one-out cross-validation framework in a sample of 100 unrelated healthy young adults, we show that individual differences in perceived stress can be reliably predicted from their structural connectivity. The obtained results show that perceived stress could be predicted from the interaction of visual association, and motor and sub-cortical networks. This present work highlights that structural connectivity can be used to investigate the neural mechanism of PS in healthy populations.
The Ptk2-Pma1 pathway enhances tolerance to terbinafine inTrichophyton rubrum
Authors: Ishii Masaki , Yamada Tsuyoshi , Monod Michel , Ohata Shinya
Published: December 2023

The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment.Trichophyton rubrumis the most commonly isolated fungus in dermatophytosis. InT. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeastSaccharomyces cerevisiaepolyamine transport kinase 2 (Ptk2) and found thatT. rubrumPtk2 (TrPtk2) is involved in terbinafine tolerance. In bothT. rubrumandS. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared to the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. TheT. rubrumPtk2 knockout strain (ΔTrPtk2) was sensitive to omeprazole, an inhibitor of plasma membrane proton pump Pma1, which is activated through phosphorylation by Ptk2 inS. cerevisiae. Overexpression ofT. rubrumPma1 (TrPma1) in ΔTrPtk2 suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine- resistant dermatophytes.
Estimating butterfly population trends from sparse monitoring data using Generalized Additive Models
Authors: Edwards Collin , Schultz Cheryl , Sinclair David , Marschalek Daniel , Crone Elizabeth
Published: December 2023

Concerns of declines in insects and population level responses to climate change have highlighted the importance of estimating trends in abundance and phenology from existing monitoring data. As the taxa with the most systematic monitoring data, butterflies are a frequent focus for understanding trends in insects. Even so, ecologists often have only sparse monitoring data for at-risk butterfly populations. As existing statistical techniques are typically poorly suited to such data, these at-risk populations are frequently excluded from analyses of butterfly trends. Here we present guidelines for estimating population trends from sparse butterfly monitoring data using generalized additive models (GAMs), based on extensive simulations and our experiences fitting hundreds of butterfly species. These recommendations include pre-processing steps, model structure choices, and post-hoc analysis decisions that reduce bias and prevent or mitigate biologically implausible model fits. We also present the ButterflyGamSim package for the programming language R, available athttps://github.com/cbedwards/butterflyGamSims. This open source software provides tools for ecologists and applied statisticians to simulate realistic butterfly monitoring data and test the efficacy of different GAM model choices or monitoring schemes.
Temporal dynamics and representational consequences of the control of processing conflict between visual working memory and visual perception
Authors: Teng Chunyue , Fulvio Jacqueline M. , Pietrelli Mattia , Jiang Jiefeng , Postle Bradley R.
Published: December 2023

Visual working memory (WM) extensively interacts with visual perception. When information between the two processes is in conflict, cognitive control can be recruited to effectively mitigate the resultant interference. The current study investigated the neural bases of the control of conflict between visual WM and visual perception. We recorded the electroencephalogram (EEG) from 25 human subjects (13 male) performing a dual task combining visual WM and tilt discrimination, the latter occurring during the WM delay. The congruity in orientation between the memorandum and the discriminandum was manipulated. Behavioral data were fitted to a reinforcement-learning model of cognitive control to derive trial-wise estimates of demand for proactive and reactive control, which were then used for EEG analyses. The level of proactive control was associated with sustained frontal-midline theta activity preceding trial onset, as well as with the strength of the neural representation of the memorandum. Subsequently, discriminandum onset triggered a control prediction error signal that was reflected in a left frontal positivity. On trials when an incongruent discriminandum was not expected, reactive control that scaled with the prediction error acted to suppress the neural representation of the discriminandum, producing below-baseline decoding of the discriminandum that, in turn, exerted a repulsive serial bias on WM recall on the subsequent trial. These results illustrate the flexible recruitment of two modes of control and how their dynamic interplay acts to mitigate interference between simultaneously processed perceptual and mnemonic representations.

Significance Statement

One hallmark of human cognition is the context dependent, flexible control of behavior. Here we studied the “mental juggling” required when, while holding information in mind, we have to respond to something that “pops up in front of us” before returning to the interrupted task. Using parameter estimates from a reinforcement-learning model, we analyzed EEG data to identify neural correlates of two discrete modes of cognitive control that act to minimize interference between perception and WM. Proactive control, indexed by frontal midline theta power, increased prior to trial onset when a high level of conflict was expected. Reactive control acted to suppress the representation of items likely to interfere with performance, a processing step with consequences for the subsequent trial.
The dysregulated IL-23/TH17 axis in endometriosis pathophysiology
Authors: Sisnett Danielle J. , Zutautas Katherine B. , Miller Jessica E. , Lingegowda Harshavardhan , Ahn Soo Hyun , McCallion Alison , Bougie Olga , Lessey Bruce A. , Tayade Chandrakant
Published: December 2023

Endometriosis is a chronic inflammatory disease where endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. Interleukin (IL)-23 is established as a key contributor in the development and differentiation of a subset of T cells known as T-helper 17 (TH17) cells, driving TH17 cells towards a pathogenic profile. In a variety of inflammatory and autoimmune disorders, such as psoriasis and rheumatoid arthritis, TH17 cells secrete proinflammatory cytokines including IL-17, contributing to the disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. Here we address whether IL-23 driven TH17 cells contribute to the cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. Our results indicate significantly dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared to healthy controls.In-vitrostudies using primary human THcells determined that IL-23 cocktail treatment significantly increased the frequency of pathogenic TH17 cells. Similarly, treatment with recombinant human (rh)IL-23 on cell lines (12Z, EECC, HUVEC, and hESC) representative of the endometriotic lesion microenvironment led to a significant increase in cytokines and growth factors known to play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, treatment with recombinant mouse (rm)IL-23 led to significant alterations in numbers of myeloid and T cell subsets in peritoneal fluid and significantly increased numbers of giant cells within the lesion. Endometriotic lesions from rmIL-23 mice did not reveal significant alterations in proliferation and vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on the pathophysiology of endometriosis.
Adapting to changing methodology in a long-term experiment
Authors: Manning Katherine McNamara , Perrone Julia , Petrycki Stephanie , Landis Douglas A. , Bahlai Christie A.
Published: December 2023

Long-term experiments are critical for understanding ecological processes, but their management comes with unique challenges. As time passes, projects may encounter unavoidable changes due to external factors, like availability of materials, affecting aspects of their research methodology. At the Kellogg Biological Station Long-Term Ecological Research Site, one of many National Science Foundation-funded long-term research stations, a three-decade project recently experienced a supply-chain-induced change in insect sampling methodology in their lady beetle observation study. Since 1989, lady beetles (Coleoptera: Coccinellidae) have been sampled weekly over the growing season using yellow sticky cards. In 2021, the original sticky traps were discontinued by the manufacturer and replaced with a similar, but not identical trap. We conducted a 3-year study while the new traps were phased in to examine how the trap change would impact the observed biodiversity patterns at the site. We examined community metrics and individual taxa captures to examine within year and between year differences in performance between the card types. Overall, we noted several small but statistically detectable differences in capture patterns between the two trap types. After accounting for other sources of variation, we observed a difference in Shannon diversity of insects captured on the two card types, but not richness or abundance, in the overall insect community. Yet, these differences were dwarfed by the magnitude of difference observed between years within card types. For individual taxa, similar patterns held: between trap differences could be detected statistically, but the number of differences between capture rates of traps was less than the number of differences observed for the same trap, between years. Thus, we conclude that while subtle changes in methodology could impact data produced in long-term experiments, in this case the magnitude of this change is smaller than other factors such as time and plant treatment. However, if sustained changes in the capture rates of focal taxa are observed, future data users may use our observations to specifically quantify and correct for these shifting patterns related to the protocol change.
A semi-automated cell tracking protocol for quantitative analyses of neutrophil swarming to sterile andS. aureuscontaminated bone implants in a mouse femur model
Authors: Lekkala Sashank , Ren Youliang , Weeks Jason , Lee Kevin , Tay Allie Jia Hui , Liu Bei , Xue Thomas , Rainbolt Joshua , Xie Chao , Schwarz Edward M. , Yeh Shu-Chi A.
Published: December 2023

Implant-associated osteomyelitis remains a major orthopaedic problem. As neutrophil swarming to the surgical site is a critical host response to prevent infection, visualization and quantification of this dynamic behavior at the native microenvironment of infection will elucidate previously unrecognized mechanisms central to understanding the host response. We recently developed longitudinal intravital imaging of the bone marrow (LIMB) to visualize fluorescentS. aureuson a contaminated transfemoral implant and host cells in live mice, which allows for direct visualization of bacteria colonization of the implant and host cellular responses using two-photon laser scanning microscopy. To the end of rigorous and reproducible quantitative outcomes of neutrophil swarming kinetics in this model, we developed a protocol for robust segmentation, tracking, and quantifications of neutrophil dynamics adapted from Trainable Weka Segmentation and TrackMate, two readily available Fiji/ImageJ plugins. In this work,Catchupmice with tdTomato expressing neutrophils received a transfemoral pin with or without ECFP-expressing USA300 methicillin-resistantStaphylococcus aureus(MRSA) to obtain 30-minute LIMB videos at 2-, 4-, and 6-hours post-implantation. The developed semi-automated neutrophil tracking protocol was executed independently by two users to quantify the distance, displacement, speed, velocity, and directionality of the target cells. The results revealed high inter-reader reliability for all outcomes (ICC > 0.98; p > 0.05). Consistent with the established paradigm on increased neutrophil swarming during active infection, the results also demonstrated increased neutrophil speed and velocity at all measured time points, and increased displacement at later time points (6 hours) in infected versus uninfected mice (p < 0.05). Neutrophils and bacteria also exhibit directionality during migration in the infected mice. The semi-automated cell tracking protocol provides a streamlined approach to robustly identify and track individual cells across diverse experimental settings and eliminates inter-observer variability.
Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation
Authors: Meehan Gavin R , Gunes Utku , Scales Hannah E , Finney George , Deehan Ross , Sintoris Sofia , Athanasiadou Aegli , Brewer James M
Published: December 2023

Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in Dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced. To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism. Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent. Taken together this data demonstrates that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilised by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.
Exploring the preservation of a parasitic trace in decapod crustaceans using finite elements analysis
Authors: Wright Nathan , Klompmaker Adiël A. , Petsios Elizabeth
Published: December 2023

The fossil record of parasitism is poorly understood, due largely to the scarcity of strong fossil evidence of parasites. Understanding the preservation potential for fossil parasitic evidence is critical to contextualizing the fossil record of parasitism. Here, we present the first use of X-ray computed tomography (CT) scanning and finite elements analysis (FEA) to analyze the impact of a parasite-induced fossil trace on host preservation. Four fossil and three modern decapod crustacean specimens with branchial swellings attributed to an epicaridean isopod parasite were CT scanned and examined with FEA to assess differences in the magnitude and distribution of stress between normal and swollen branchial chambers. The results of the FEA show highly localized stress peaks in reaction to point forces, with higher peak stress on the swollen branchial chamber for nearly all specimens and different forces applied, suggesting a possible shape-related decrease in the preservation potential of these parasitic swellings. Broader application of these methods as well as advances in the application of 3D data analysis in paleontology are critical to understanding the fossil record of parasitism and other poorly represented fossil groups.
Tic-related behaviors inCelsr3mutant mice are contributed by alterations of striatal D3dopamine receptors
Authors: Cadeddu Roberto , Branca Caterina , Braccagni Giulia , Musci Teresa , Piras Ignazio S , Anderson Collin J , Capecchi Mario R , Huentelman Matthew J , Moos Philip J , Bortolato Marco
Published: December 2023

The geneCELSR3(Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally,Celsr3mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile ofCelsr3mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed thatCelsr3mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum ofCelsr3mutants. Single-nucleus transcriptomics also showed significant upregulation of theDrd3gene, encoding the dopamine D3receptor, in striosomal D1-positive neurons.In situhybridization and immunofluorescence confirmed dysregulated D3receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3receptors amplified or decreased tic-like jerks and stereotypiesin Celsr3-deficient mice, respectively. These findings suggest that modifications of D3receptor distribution contribute to the tic-like responses associated withCelsr3deficiency.
A Computational Framework for the Administration of 5-Aminovulinic Acid before Glioblastoma Surgery
Authors: Zeng Jia , Moore Nicholas J.
Published: December 2023

5-Aminolevulinic Acid (5-ALA) is the only fluorophore approved by the FDA as an intraoperative optical imaging agent for fluorescence-guided surgery in patients with glioblastoma. The dosing regimen is based on rodent tests where a maximum signal occurs around 6 hours after drug administration. Here, we construct a computational framework to simulate the transport of 5-ALA through the stomach, blood, and brain, and the subsequent conversion to the florescent agent protoporphyrin IX at the tumor site. The framework combines compartmental models with spatially-resolved partial differential equations, enabling one to address questions regarding quantity and timing of 5-ALA administration before surgery. Numerical tests in two spatial dimensions indicate that, for tumors exceeding the detectable threshold, the time to peak flouresent concentration is 2-7 hours, broadly consistent with the current surgical guidelines. Moreover, the framework enables one to examine the specific effects of tumor size and location on the required dose and timing of 5-ALA administration before glioblastoma surgery.