bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic remodeling of centrioles and the microtubule cytoskeleton in the lifecycle of chytrid fungi
Authors: Long Alexandra F. , Vasudevan Krishnakumar , Swafford Andrew J.M. , Venard Claire M. , Stajich Jason E. , Fritz-Laylin Lillian K. , Feldman Jessica L. , Stearns Tim
Published: January 2025

Cells reorganize in space and time to move and divide – complex behaviors driven by their internal cytoskeleton. While we have substantial knowledge of the molecular parts and rules of cytoskeletal assembly, we know less about how structures are remodeled, for example to interconvert centrioles from the ciliary base to the centrosome. To study this in an evolutionary context we use the chytrid fungus,Rhizoclosmatium globosum, a member of the zoosporic fungi which have centrioles and cilia, lost in other fungal lineages. Chytrids undergo reorganization of their microtubule cytoskeleton as they cycle from zoospore to multinucleated coenocyte. We use comparative bioinformatics, RNA sequencing, and expansion microscopy to map the microtubule cytoskeleton over the chytrid lifecycle. We find that when zoospores encyst, cilia are retracted into the cytoplasm and degraded, and centrioles detach but are protected from degradation. A shortened proximal centriole then forms the mitotic centrosome and ultimately elongates to form cilia at the end of the mitotic cycles, driven by a conserved transcriptional program. Thus, structural remodeling of the chytrid centriole is coupled temporally to ciliated stages rather than mitotic cycles, which may serve as a mechanism to tune microtubule organization to meet the needs of different lifecycle stages.
Mechanism of nascent chain removal by the Ribosome-associated Quality Control complex
Authors: Li Wenyan , Cahoon Talia , Shen Peter S.
Published: January 2025

Errors during translation can cause ribosome stalling, leaving incomplete nascent chains attached to large ribosomal subunits1–5. Cells rely on the Ribosome-associated Quality Control (RQC) complex to recognize, process, and remove these partially synthesized proteins to maintain proteostasis. Despite its central role, the mechanisms by which the RQC complex orchestrates nascent chain processing and extraction have remained unclear. Here, we present a cryo-EM structure of the RQC complex from budding yeast, revealing how its core eukaryotic components function in nascent chain removal. We show that the Cdc48 protein extracting enzyme, along with its Ufd1-Npl4 adaptor, is recruited by the Ltn1 E3 ubiquitin ligase to extract ubiquitylated stalled peptides from the 60S ribosome. Additionally, we find that the Rqc1 component bridges the 60S ribosome with ubiquitin and Ltn1, facilitating the specific formation of K48-linked polyubiquitin chains on stalled peptides. These findings provide a structural and mechanistic framework for understanding how components of the RQC complex work together to remove faulty translation products from the ribosome, advancing our understanding of cellular protein quality control.
RBPscan: A Quantitative, In Vivo Tool for Profiling RNA-Binding Protein Interactions
Authors: Kretov Dmitry A. , Sanborn Owen , McIssac Thora , Park Elaine , Imrat  , Wu Samuel , Cifuentes Daniel
Published: January 2025

RNA-binding proteins (RBPs) are essential regulators of gene expression at post-transcriptional level, yet obtaining quantitative insights into RBP-RNA interactionsin vivoremains a challenge. Here we developed RBPscan, a method that integrates RNA editing with massively parallel reporter assays (MPRAs) to profile RBP bindingin vivo. RBPscan fuses the catalytic domain of ADAR to the RBP of interest, using RNA editing of a recorder mRNA as a readout of binding events. We demonstrate its utility in zebrafish embryos, human cells, and yeast, where it quantifies binding strength, resolves dissociation constants, identifies high-specificity motifs for a variety of RBPs, and links binding affinities to their impact on mRNA stability. RBPscan also provides positional information of conserved and novel Pumilio-binding sites in lncRNANORAD. With its simplicity, scalability, and compatibility across systems, RBPscan offers a versatile tool for investigating RBP-RNA interactions and complements established methods for studying post-transcriptional regulatory networks.

GRAPHICAL ABSTARCT
Tension-area relationship in compartmentalized crumpled plasma membrane: a mechanistic model and its implications
Authors: Tsaturyan Andrey K.
Published: January 2025

The plasma membrane is a liquid lipid bilayer containing both dissolved proteins and proteins anchoring the membrane to the underlying actin cortex. Membrane tension, a 2D analog of pressure in a 3D liquid, is believed to play a crucial role in organizing essential processes within cells and tissues. This, along with recent, conflicting data on the speed of membrane tension propagation, highlights the need for a comprehensive mechanical model to describe tension in the cortex-anchored plasma membrane as a function of transmembrane hydrostatic pressure difference and excess membrane area due to cortex contraction. In this study, we present a mechanical model of plasma membrane compartments, separated by “picket fences” of cortex-anchoring proteins permeable to lipids. Beyond hydrostatic pressure, the model incorporates the 2D osmotic pressure exerted by membrane-dissolved proteins. Our findings reveal that the tension-area relationship within a membrane compartment exhibits a seemingly paradoxical feature: in a specific range of membrane surface area, an increase in area leads to a rise in tension. We further model the tension-area relationship for an ensemble of membrane compartments, which exchange membrane area through shared borders, and discuss potential biological implications of this model.
Does white matter structure relate to hemispheric language lateralisation? A systematic review
Authors: Andrulyte Ieva , Demirkan Eszter , Branzi Francesca M. , Bonnett Laura J. , Keller Simon S.
Published: January 2025

The relationship between functional language lateralisation and diffusion MRI-based white matter metrics remains a subject of considerable interest and complexity. This systematic review aims to synthesise existing diffusion MRI studies examining white matter correlates of functional language dominance. Twenty-five studies were identified through searches of Web of Science, Scopus, and Ovid MEDLINE (search period: inception to 16th March 2023) involving adults with epilepsy, tumours, or healthy controls. The results suggest that while the arcuate fasciculus, particularly its fractional anisotropy (FA), is commonly associated with language lateralisation in clinical populations, the findings in healthy individuals are more variable, often influenced by factors such as handedness. Other white matter tracts, including the corpus callosum and uncinate fasciculus, showed less consistent associations with language dominance across studies. Interestingly, temporal lobe regions, especially those involved in semantic processing, exhibited stronger correlations with diffusion measures compared to areas associated with phonological tasks. Methodological inconsistencies, such as variability in sample selection, task design, and analytical techniques, were identified as significant challenges in comparing findings across studies. Future research should aim for larger, more diverse sample sizes, whole- brain approaches, and a wider range of fMRI tasks to better elucidate the role of white matter in language lateralisation. If regions of interest (ROI)-based studies are utilised, a more standardised approach to tract segmentation should be adopted to ensure consistency and improve comparability across studies.
Multi-center improvement in screening for pain that affects activities in adults with cerebral palsy
Authors: Bailes Amy F. , Noritz Garey H. , Wyeth Duncan O. , Lucas Elizabeth J. , Bates Elisabeth B. , Azizi Hana , Sarmiento Cristina A. , Thorpe Deborah E. , Nichols Stephen A. , Kreschmer Jodi , Wisniewski Stephen , Gannotti Mary ,   Cerebral Palsy Research Network
Published: January 2025

Purpose

Increase screening for pain in adults with cerebral palsy (CP) across three centers and examine factors associated with pain that affect activities.

Materials and Methods

Using the quality improvement (QI) infrastructure of the Cerebral Palsy Research Network (CPRN), we implemented interventions to improve screening at clinic visits for pain that affects activities for adults with CP. Three physicians from two CPRN centers performed interventions August 2021- June 2023 before spreading to a fourth physician at a third CPRN center October 2022. To track progress, we collected visit data cross sectionally every two weeks. Descriptive statistics, analysis of variance, and logistic regression evaluated relationships in a sample cohort of all visits after screening practices had been established.

Results

Screening improved from 42% at baseline to over 90%. After three months of sustained screening, we assessed 423 unique visits. Pain was reported at 185/423 (44%) of the visits. Of the 185 with pain reported, 100 (54%) reported pain that affected activities. Increasing age, female gender, and motor function were associated with pain (p<.001) and pain that affects activities (p<.01). Females reported pain 3.4 and pain that affects activity 2.2 times more than males.

Conclusion

QI methodology was successful at improving screening for pain that affects activities in adults with CP at clinic visits. Lower rates of pain were found (44%) than previous reports, with similar findings about pain affecting activities and associated characteristics. We propose continued screening with improvement in differentiating proxy vs self-report and including other domains of pain important to guide care such as location and chronicity.
First Measurement: Proactive Immune Cell Sparing in Radiation Therapy
Authors: Wijesooriya Krishni , Nguyen Cam , Conaway Mark R , Read Paul W , Romano Kara , Lum Lawrence G , Thakur Archana , Lain David W , McLaughlin Christopher M , Luminais Christopher K , Wood Song , Williams Grant , Chen Joe , Walker Bryant , Sprouts Damon , Muller Donald , Ward Kristin , Datta Sunil , Sanders Jason , Cousins David , Asare Ebenezer , Nesbit Emily , Chavis Yhana C , Walker Kristin V , Janowski Einsley , Showalter Timothy , Larner James M
Published: January 2025

Purpose Radiation Therapy (RT) can modulate the immune system and generate anti-tumor T cells. However, this anti-tumor-activity is countered by radiation-induced immunosuppression (RIIS). Clinical advantages of proactively sparing RT dose to immune rich organs have not previously been evaluated. Methods We conducted a phase II randomized trial from 2020 to 2023, enrolling 51 early-stage lung cancer patients treated with SBRT, to evaluate the effect of dose reduction to immune rich organs on RIIS. Two groups were: RIIS-optimized-treatment (lowering the dose to blood, bone-marrow and lymph-node-stations) and standard-treatment. All treatments followed national protocol guidelines. Peripheral blood was collected at baseline, immediately, 4-weeks and 6-months post-treatment. Results ALC changes from baseline immediately, 4-weeks and 6-months post-SBRT are: optimized-arm: -16%, -22%, -16%, standard-arm: -31%, -34%, -26%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 13.4 (5.3) % (95% CI, 2.8 to 24.0; p = 0.01). Central tumors had the largest improvement in ALC from baseline: optimized-arm: -8%, -18%, -14%, standard-arm: -39%, -43%, -47%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 29.5 (9.6) % (95% CI, 10.1 to 48.9; p = 0.004). Grade 3 lymphopenia occurred in 15.4% of standard arm patients but was absent in the optimized arm. Additionally, 2.8 times more patients in the optimized arm experienced an ALC increase post-SBRT. Dose to organs such as the heart, great vessels, thoracic spine, and lymph nodes significantly correlated with RIIS. A trend towards increased Event-Free-Survival (two-year: 75.0% (SE = 10.8%) versus 59.8% (SE = 11.2%), p=0.10) and Overall Survival (two-year: 93.4% (SE=6.1%) versus 69.4% (SE=10.5%), p=0.14) was observed with optimized-planning compared to standard-planning in treatment naive patients. Conclusion Reducing RT dose to immune rich organs significantly reduces RIIS compared to standard-of-care. This has implications in enhancing immune system mediated anti-tumor-activity. (Funded by National Cancer Institute and others. ClinicalTrials.gov number,NCT04273893)
Association between body roundness index and myopia among US adolescents: a cross-sectional study of NHANES 2001-2006
Authors: Wang Dongfang , Sha Fang , Feng JiaoJiao , Su Weihua , Tang Guodong , Song Jike , Bi Hongsheng
Published: January 2025

Background

This study analyzed the association between body roundness index (BRI) and myopia in adolescents in the United States.

Methods

This cross-sectional study analyzed the data of a nationally representative survey, the National Health and Nutrition Examination Survey (NHANES) conducted from 2001 to 2006. Among the 7078 adolescents aged 12 to 19 years, 3915 participants were selected for review. BRI, a new obesity assessment index that evaluates visceral fat, was classified into four groups: Q1,< 2.083; Q2, 2.083 to 2.724; Q3, 2.725 to 4.004; Q4, ≥ 4.005. Myopia was defined as SE≤-0.50 diopters (D). Weighted multivariate logistic regression analysis and smooth curve fitting were performed to evaluate the association between BRI and myopia. Additionally, subgroup and sensitivity analysis was applied.

Results

The prevalence of myopia was 39.4%. Adolescents who are older, have a larger waist circumference, a lower level of vitamin D, a relatively low PIR level, and a higher waist-height ratio (WHtR) are more likely to have a higher BRI. We found a positive association between BRI and myopia before and after adjusting for confounders (odds ratio [OR] = 1.057, 95% confidence interval [CI]: 1.016-1.100,P< 0.01; OR = 1.049, 95%CI: 1.009-1.090,P=0.022). Specifically, after full adjustment for age, sex, race/ethnicity, PIR, guardians’ education, Vitamin D, physical activity, screen time, adolescents in Q4 were 26.1% more likely to develop myopia compared to adolescents in Q1 (OR=1.261, 95% CI:1.046-1.521,P=0.022). There was a general linear trend between BRI and myopia (allPvalues for trend <0.001) and nonlinear association (allPfor nonlinear < 0.05). Subgroup analysis conducted after full adjustment demonstrated positive associations between BRI and myopia in Mexican American adolescents (OR=1.11, 95% CI: 1.05-1.19,P=0.001), women (OR=1.10, 95% CI: 1.05-1.15,P<0.001), those guardians with educational levels lower than high school (OR=1.09, 95% CI: 1.03-1.14,P=0.004), those with PIR < 1.30 (OR=1.07, 95% CI:1.01-1.14,P=0.037) and those with high physical activity (OR=1.08, 95% CI: 1.04-1.13,P<0.001). Sensitivity analysis was applied using weighted ordinal logistic regressions to explore the relationship of BRI with degrees of myopia. The results remained stable after adjusting for potential confounding factors, consistent with the results of BRI and myopia.

Conclusions

This study assessed that in adolescents, an increase in BRI was associated with an increased risk of myopia, especially in women. Additionally, there was a nonlinear association between BRI and myopia. This study aimed to increase public awareness of BRI values, a novel measure of obesity, and that maintaining a moderate BRI can help reduce the risk of myopia.
Development and Validation of a Nomogram for Predicting False Negative IGRA Results in Pulmonary Tuberculosis Patients Using Propensity Score Matching
Authors: Zhang Feng , Gao Yong , Li Tuantuan , Zhang Wei
Published: January 2025

Objective Exploration of Factors Influencing False-Negative Results in Interferon-Gamma Release Assay (IGRA) for Patients with Pulmonary Tuberculosis (PTB), and Development of a Nomogram Model to Predict IGRA False Negatives, to Optimize Clinical Diagnosis and Treatment Decisions. Methods A total of 143 patients diagnosed with Pulmonary Tuberculosis (PTB) were selected for this study. Among them, 63 patients who were IGRA negative but positive for pathogen detection formed the observation group, while 80 patients who were both IGRA positive and pathogen positive constituted the control group. After balancing potential confounding factors between the two groups using Propensity Score Matching (PSM), clinical characteristics and laboratory indicators of the two groups were compared. Logistic regression analysis was then employed to identify independent risk factors affecting IGRA results. Based on significantly associated factors, a nomogram model was constructed, and its predictive performance was evaluated. Results After propensity score matching, each group consisted of 55 patients. Compared to the control group, the observation group showed significant differences in white blood cell count (WBC), neutrophil count (NEUT), lymphocyte count (LYM), red blood cell count (RBC), hemoglobin (HGB), and albumin (ALB) levels (P < 0.05). Logistic regression analysis revealed that RBC and ALB were influencing factors for false-negative IGRA results. The constructed nomogram model demonstrated a good fit (χ²=6.444, P=0.598), with an area under the receiver operating characteristic curve (AUC) of 0.703 (95% CI: 0.605-0.800), accuracy of 0.682 (95% CI: 0.586-0.767), sensitivity of 0.691 (95% CI: 0.569-0.813), specificity of 0.673 (95% CI: 0.549-0.797), positive predictive value (PPV) of 0.679 (95% CI: 0.556-0.801), and negative predictive value (NPV) of 0.685 (95% CI: 0.561-0.809). Decision curve analysis indicated that the net benefit of predicting false-negative IGRA results using this nomogram model was greater than 0 when the threshold probability ranged from 0.15 to 0.75. Conclusion Lower levels of RBC and ALB may be significant factors contributing to false-negative IGRA results in PTB patients. The constructed nomogram model, incorporating these factors, holds considerable clinical application value for predicting IGRA false negatives, aiding in the improvement of early diagnosis and management strategies for PTB.
Psychometric validation of an Arabic version of the WHO-5 wellbeing scale among Lebanese Adolescents
Authors: Doumit Rita , Hallit Souheil , Sanchez-Ruiz Maria-Jose , El Khoury-Malhame Myriam
Published: January 2025

Introduction

Wellbeing in adolescence is frequently associated with positive developmental outcomes. The WHO-5 is widely recognized for its brevity, clarity, robust reliability, and cultural validity. In this study, we aimed to assess the psychometric properties of an Arabic version of the WHO-5 scale among Lebanese adolescents.

Methods

This cross-sectional study involved 681 Lebanese school students aged 15-18 years. Participants were assessed using WHO-5 (wellbeing), PHQ-9 (depression), and GAD-7 (anxiety) Arabic questionnaires at two-time points, 3 months apart.

Results

We found that the 5 items of the WHO-5 converged into a single factor. Composite reliability of scores was adequate in the total sample (ω = .83 / α = .83). The convergent validity for this model was satisfactory. We were able to show the invariance across gender at the configural, metric, and scalar levels, with males showing a higher level of wellbeing compared to females. The pre-posttest assessment for the WHO-5 scale was conducted on 358 participants; the intraclass correlation coefficient was adequate = 0.78 [95% CI .73; .82]. Our analyses also show that wellbeing was negatively correlated with depression (r = −.54; p < .001) and anxiety (r = −.52; p < .001).

Conclusion

The Arabic WHO-5 among Lebanese adolescents displayed highly satisfactory psychometric properties, which are evidence of its validity. It could be used to better track positive mental health in this vulnerable age group and could highlight efficiency in interventions aiming to promote wellbeing in adolescents. It could also potentially identify at risk individuals.
Understanding the Relational Aspects of Networks of Care for Maternal and Newborn Health: A Revised Operational Framework
Authors: Fasawe Olufunke , Jenny Alisa , Churchill Robyn , Kalaris Katherine , Bertozzi Stefanp , Prata Ndola , Carmone Andy , Mulwa Dennis Matheka , Vergara Marite , Moran Allisyn , Walker Dilys
Published: January 2025

Objective: We investigated the relational aspects of the “Networks of Care” (NOC) approach to better define their role and highlight their importance.  These relational aspects distinguish NOC from other health system strengthening approaches that aim to enhance the quality of MNH care. NOCs include functional and relational aspects, as defined in the WHO NOC for MNH framework, and offer a promising strategy for enhancing maternal and newborn health (MNH) by strengthening care coordination at an operational level.   Methods: We conducted a cross-disciplinary (healthcare, business, military, aviation, education) scoping review of 90 papers and consulted with key stakeholders to identify and synthesize insights about relational aspects and the associated barriers and facilitators for implementation. We then used the literature review findings and stakeholder feedback to define the relational aspects and revise the Networks of Care Operational framework.   Results: The revised framework highlights teamwork with its attributes—trust, mutual respect, shared goals, shared values, and psychological safety and behaviors - leadership, shared decision making, situation monitoring and communication. Organizational enablers underlie a NOC to mitigate barriers and strengthen facilitators to teamwork, which include conflict management, complexity of targets, systemic challenges, social ties, formalization of NOC, and roles like boundary spanners. The study identified relational coordination theory as the basis for refining the NOC operational framework.   Conclusion: The resulting framework centers relational coordination including teamwork supported by organizational enablers, in enhancing care coordination between health workers, system administrators, and other users and non-health actors in the network. By targeting relational elements in intervention design and evaluation, the revised Operational NOC Framework for MNH may be valuable in strengthening NOC effectiveness and driving quality improvements leading to improved MNH outcomes, and resilient health systems.
The Role of Self-efficacy Towards Health-promoting Lifestyle among Patients with Non-communicable Disease: A Systematic Literature Review
Authors: Shamsuddin Sharifah Maziah Syed , Ahmad Norfazilah , Sutan Rosnah , Ibrahim Roszita
Published: January 2025

Background

Non-communicable diseases (NCDs) will be a major cause of death worldwide by 2023. One effective strategy for preventing and managing NCDs is the implementation of health-promoting lifestyle intervention programs. Self-efficacy is a key factor associated with the adoption of health- promoting lifestyle practices. This review aims to examine the role of self-efficacy in fostering health-promoting lifestyles among patients with NCDs.

Method

A literature search was conducted across three scientific databases — Scopus, PubMed, and Web of Science —targeting original articles published in English between 2015 and 2024 that identified health-promoting lifestyle as an outcome. The quality of the eligible articles was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools, and the findings were synthesized through content analysis.

Results

The initial search identified 308 citations. A total of eight studies meeting the criteria of the JBI Critical Appraisal Tools were included, highlighting the direct effects of self-efficacy. Self- efficacy was demonstrated as a positive predictor of health-promoting lifestyle as a whole construct, as well as the physical activity dimension, among patients with NCDs, particularly those with hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease (COPD), and acute stages of cancer.

Limitation

All included studies were cross-sectional design. Therefore, the evidence quality was relatively low and exhibited a high risk of bias. Furthermore, there was language bias as only English- language publications were selected.

Conclusion

The findings of this review will guide healthcare providers in enhancing self-efficacy as a crucial positive predictor of health-promoting lifestyles among patients with non-communicable diseases. This approach can be integrated into clinic consultations and intervention programs. Future studies are warranted to evaluate the effectiveness of self-efficacy in improving a health-promoting lifestyle.
Reasons and Challenges of Adopting Flexitarian Diet: A Mixed-Methods Approach Using Natural Language Processing
Authors: Teixeira Carla Djaine , De Lima Djackson Garcia , de Menezes Neto Elias Jacob , Gomes Sávio Marcelino , Jacob Michelle Cristine Medeiros
Published: January 2025

In this study, we analyzed data from a large sample (n = 778) of individuals who identified as flexitarians, using Brazil as a case study. We applied Natural Language Processing (NLP) to characterize the reasons why individuals self-identify as flexitarians. We explored how these self-perceptions contribute to the construction of a flexitarian identity and identified the challenges this group faces in adopting a flexitarian diet. Our results indicate that there is no homogeneous flexitarian identity, but rather a diversity of categories, organized into five distinct clusters: ethical flexitarians (those who express greater concern for the environment and animals), flexible vegetarians (those who often express the desire to become vegetarian but still consume meat), meat lovers (those who enjoy meat but do not feel compelled to consume it), moderate consumers (those who refrain from meat on certain days of the week), and meat reducers (those who actively reduce their meat consumption). The latter three groups are more similar, as they tend to reduce their meat intake due to the belief that meat is not essential in their diet, although they still enjoy its taste. Additionally, we found that the main challenge faced by our participants is directly related to the social environment, specifically the difficulty in finding alternatives to meat, which makes the love for meat’s taste and meat-centric eating habits secondary challenges.
Catalyzing computational biology research at an academic institute through an interest network
Authors: Zak Jaroslav , Newman Ian , Montiel Garcia Daniel J. , Parisi Daniele , Joy Janet , Head Steven R. , Ducom Jean-Christophe , Natarajan Padma , Cui Haissi , Ul-Hasan Sabah
Published: January 2025

Biology has been transformed by the rapid development of computing and the concurrent rise of data-rich approaches such as -omics or high-resolution imaging. However, there is a persistent computational skills gap in the biomedical research workforce. Inherent limitations of classroom teaching and institutional core support highlight the need for accessible ways for researchers to explore developments in computational biology. An analysis of the Scripps Research Genomics Core revealed an increasingly diverse set of experiments: the share of experiments other than bulk RNA- or DNA-seq increased from 34% to 60% within 10 years, requiring more tailored computational analyses. These challenges were tackled by forming a volunteer-led affinity group of over 300 academic biomedical researchers interested in computational biology referred to as the Computational Biology and Bioinformatics (CBB) affinity group. This adaptive group has provided continuing education and networking opportunities through seminars, workshops and coding sessions while evolving along with the needs of its members. A survey of CBB’s impact confirmed the group’s events increased the members’ exposure to computational biology educational and research events (79% respondents) and networking opportunities (61% respondents). Thus, volunteer-led affinity groups may be a viable complement to traditional institutional resources for enhancing the application of computing in biomedical research.
T cell plasticity in systemic lupus erythematosus revealed by large-scale T cell receptor repertoire and transcriptome studies
Authors: Nagafuchi Yasuo , Nakano Masahiro , Lagattuta Kaitlyn A. , Ota Mineto , Hatano Hiroaki , Takahashi Haruka , Itamiya Takahiro , Inokuchi Hajime , Raychaudhuri Soumya , Okamura Tomohisa , Fujio Keishi , Ishigaki Kazuyoshi
Published: January 2025

CD4+ T cell plasticity plays a pivotal role in immune homeostasis. However, evidence of T cell plasticity and its pathological role in human systemic lupus erythematosus (SLE) is missing due to the lack of a reporter system. Here we utilized T cell receptor (TCR) repertoire data as a molecular signatures alongside transcriptomic dataset. Using a large-scale ImmuNexUT database of autoimmune disease patients including 117 SLE cases, we quantified T cell plasticity across 13 fine-grained T cell-types. We analyzed 6,392 samples in total and identified two orthogonal signatures of repertoire and transcriptome, the cell-type and disease signatures, allowing us to investigate CD4+ T cell plasticity comprehensively. Among all possible patterns, the plasticity level was the highest in effector regulatory T cells (eTreg) to Th1 plasticity, which was replicated in an independent cohort. Moreover, eTreg-to-Th1 plasticity positively correlated with SLE disease activity. Our study provides novel evidence that Treg plasticity is involved in SLE pathology.
Sex and education differences in trajectories of physiological ageing: longitudinal analysis of a prospective English cohort study
Authors: Bloomberg Mikaela , Steptoe Andrew
Published: January 2025

Background

Physiological age (PA) derived from clinical indicators including blood-based biomarkers and tests of physiological function can be compared with chronological age to examine disparities in health between older adults of the same age. Though education interacts with sex to lead to inequalities in healthy ageing, their combined influence on longitudinally-measured PA has not been explored. We derived PA based on longitudinally-measured clinical indicators and examined how sex and education interact to inform PA trajectories.

Methods

Three waves of clinical indicators (2004/05-2012/13) drawn from the English Longitudinal Study of Ageing (ages 50-100 years) were used to estimate PA, which was internally validated by confirming associations with incident chronic conditions, functional limitations, and memory impairment after adjustment for chronological age and sex. Joint models were used to construct PA trajectories in 8,891 ELSA participants to examine sex and educational disparities in PA.

Findings

Among the least educated participants, there were negligible sex differences in PA until age 60 (sex difference [men-women] age 50=-0.6 years [95% confidence interval=-2.2-0.6]; age 60=0.4 [-0.6-1.4]); at age 70, women were 1.5 years (0.7-2.2) older than men. Among the most educated participants, women were 3.8 years (1.6-6.0) younger than men at age 50, and 2.7 years (0.4-5.0) younger at age 60, with a non-significant sex difference at age 70.

Interpretation

Higher education provides a larger midlife buffer to physiological ageing for women than men. Policies to promote gender equity in higher education may contribute to improving women’s health across a range of ageing-related outcomes.
RENOVO-NF1 accurately predicts NF1 missense variant pathogenicity
Authors: Bonetti Emanuele , Pellegatta Serena , Rosati Nayma , Eoli Marica , Mazzarella Luca
Published: January 2025

The identification of a pathogenic variant in the NF1 gene is an important step in the diagnosis of the tumor-predisposing and developmental syndrome neurofibromatosis, and is increasingly important in the characterization of sporadic tumors, in which NF1 loss identifies specific biologic subtypes. However, NF1 variant interpretation is complicated by multiple factors including allelic heterogeneity, sequence homology, and the lack of functional assays to confirm loss of function. Computational tools able to predict variant pathogenicity may represent an ideal complement to the lengthy process of clinical validation, often impossible within an adequate time frame.

Here, we present RENOVO-NF1, an evolution of our previously published tool RENOVO algorithm, optimized for the interpretation of NF1 variants. RENOVO-NF1 has an accuracy of 98.6% on (likely) pathogenic/(likely) benign (P/LP/B/LB) variants, and importantly shows high accuracy on P/LP/B/LB variants that were initially classified as of unknown significance (VUS), in particular missense. Based on this, we predict reclassification for 79% of the variants currently classified as missense VUS in ClinVar. Since missense VUS are the most represented and problematic variant class, RENOVO-NF1 may significantly aid in diagnostic challenges in neurofibromatosis and in precision oncology for putatively NF1-mutated patients.
Assessing food acquisition, preparation, and consumption practices in South Asia: A systematic review of assessment tools
Authors: Patwardhan Sharvari , Boncyk Morgan , Avula Rasmi , Blake Christine , Akter Fahmida , Das Jai K , Silva Renuka , Menon Purnima , Scott Samuel
Published: January 2025

Assessing behaviors related to food choice at individual- and household-levels is essential for improving household diets, but assessment tools are limited. We conducted a systematic review to identify gaps in existing assessment tools for food acquisition, preparation, and household consumption practices in South Asia, wherein diets are rapidly changing, and triple burden of malnutrition is emerging.

Systematic search of three academic databases (PubMed, Scopus, and Web of Science Core Collection) using pre-defined keywords were undertaken to identify studies assessing food acquisition, food preparation, and household consumption practices in South Asia, published in English between 2000 and December 2023. Following PRISMA guidelines, two reviewers independently screened titles, abstracts, and full texts based on the inclusion criteria, and extracted data on study characteristics and the assessment tools used to examine the food choice behaviors.

Of 11,288 unique articles identified, 46 were included for synthesis. Food acquisition behaviors were assessed by 25 studies, food preparation by eight studies and household consumption practices by 26 studies. Most studies used quantitative methods (n=30), some used qualitative (n=13), and few used mixed methods (n=3), and varied by type of behavior assessed. Likert scales were the most widely used tools of quantitative assessments, while semi-structured interviews were the most common for qualitative assessments. Across the 46 studies, 59 different tools were used to assess food-related behaviors and only 14 studies claimed using validated tools and many studies did not include the full tool in the text or supplement (n=22).

Our review highlights the need for expanding food choice behavior assessments to include the less-studied populations such as exploring young children and adolescents’ food choice behaviors and developing a contextually adaptable repository of validated tools to advance our understanding of food choice behaviors in various settings.

Registry: Open Science Framework Registries

Registration DOI:https://doi.org/10.17605/OSF.IO/5GPEF
Correlates of asymmetric venous drainage in resting state functional magnetic resonance imaging data
Authors: Schwarz Nastaran , Sundermann Benedikt , Mathys Christian
Published: January 2025

Functional magnetic resonance imaging (fMRI) is an indirect technique for measuring cerebral neural activity. It depends on the local cerebral vasculature and perfusion. It has thus been suggested that pathologies and normal variants of the cerebral vasculature can bias conclusions drawn from fMRI. The purpose of this study was to assess whether frequently observed asymmetries of the transverse sinuses are associated with apparent asymmetries of fMRI data timecourses. We re-analysed a publicly available resting state fMRI dataset (n = 135 healthy human subjects included in the main analysis). Voxel-mirrored homotopic connectivity (VMHC) was calculated as a measure of fMRI timecourse symmetry, reflecting the correlation of signal fluctuations in mirroring voxels in both cerebral hemispheres. Transverse sinus (TS) cross-sectional areas were measured in structural MRI data. In the main analysis, we assessed whether VMHC and TS asymmetry exhibited a negative linear association in brain areas near the transverse sinus. This was supplemented by exploratory whole brain analyses, including mapping of subthreshold effects. In the main hypothesis test, VMHC was not significantly associated with TS asymmetry in brain regions close to the transverse sinuses. In the whole brain analyses, VMHC was significantly negatively associated with TS asymmetry in more distant brain areas, and subthreshold effects resembled venous drainage patterns. The results suggest that part of the variance in resting state fMRI signal fluctuations might be explained by asymmetrical venous drainage. Thus, fMRI results might be confounded by the normal variability of the human intracranial venous system.
NutriSighT: Interpretable Transformer Model for Dynamic Prediction of Hypocaloric Enteral Nutrition in Mechanically Ventilated Patients
Authors: Jangda Mateen , Patel Jayshil , Gill Jaskirat , McCarthy Paul , Desman Jacob , Gupta Rohit , Patel Dhruv , Kavi Nidhi , Bakare Shruti , Klang Eyal , Freeman Robert , Manasia Anthony , Oropello John , Chan Lili , Suarez-Farinas Mayte , Charney Alexander W , Kohli-Seth Roopa , Nadkarni Girish N , Sakhuja Ankit
Published: January 2025

Achieving adequate enteral nutrition among mechanically ventilated patients is challenging, yet critical. We developed NutriSighT, a transformer model using learnable positional coding to predict which patients would achieve hypocaloric nutrition between days 3-7 of mechanical ventilation. Using retrospective data from two large ICU databases (3,284 patients from AmsterdamUMCdb – development set, and 6,456 from MIMIC-IV – external validation set), we included adult patients intubated for at least 72 hours. NutriSighT achieved AUROC of 0.81 (95% CI: 0.81 – 0.82) and an AUPRC of 0.70 (95% CI: 0.70 – 0.72) on internal test set. External validation with MIMIC-IV data yielded a AUROC of 0.76 (95% CI: 0.75 – 0.76) and an AUPRC of (95% CI: 0.69 – 0.70). At a threshold of 0.5, the model achieved a 75.16% sensitivity, 60.57% specificity, 58.30% positive predictive value, and 76.88% negative predictive value. This approach may help clinicians personalize nutritional therapy among critically ill patients, improving patient outcomes.
Racial/Ethnic Differences in Neuropsychological Test Performance in Frontotemporal Degeneration
Authors: Matyi Melanie A. , Rhodes Emma , Emrani Sheina , Jin Hannah A. , Irwin David J. , McMillan Corey T. , Massimo Lauren
Published: January 2025

Racial disparities in neuropsychological test performance are well documented in Alzheimer’s Disease (AD) but have received little attention in frontotemporal degeneration (FTD). Identification of potential disparities in neuropsychological performance is critical to identify ways to improve inclusivity in clinical research and care of representative FTD populations. We evaluated disparities in neuropsychological performance among individuals with clinically diagnosed FTD (behavioral variant FTD [bvFTD] or primary progressive aphasia [PPA]) using data from the National Alzheimer’s Coordinating Center (NACC) collected between September 2005 and November 2023. Only 10% of NACC FTD cases are from racially/ethnically minoritized groups. Black (n=56), Hispanic (n=77) and White (n=1301) individuals were evaluated in the cognitive domains of episodic memory, working memory, processing speed, cognitive flexibility, attention, category fluency and lexical retrieval, in addition to global cognition across Uniform Data Set versions 1 to 3. Linear regressions examined the association between racial/ethnic group and cognitive scores covarying for disease stage, age, sex, and education. After adjusting for age, sex, and education using NACC established normative correction, binary logistic regression examined group differences in the proportion of participants classified as impaired (<=-1.5 normative z-score) for each cognitive test. Minoritized individuals, on average, had lower scores and/or greater likelihood of impairment (odds ratio; OR) on measures of global cognition (Black: β = -3.63; OR = 2.74; Hispanic: β = -2.50), lexical retrieval (Black: β = -4.31; OR = 3.28; Hispanic: β = -2.90; OR = 3.81), processing speed (Black: β = 26.80; OR = 4.07; Hispanic: β = 21.31; OR = 2.37), cognitive flexibility (Black: β = 46.65; OR = 3.35), attention (Hispanic: β = -0.39), working memory (Black: β = -0.79; Hispanic: β = -0.42), episodic memory (Hispanic: β = -1.67), and category fluency (Hispanic: β = -1.28). We did not identify any neuropsychological tests where White individuals performed worse than minoritized individuals. These findings indicate racial/ethnic differences in neuropsychological test performance on measures of global cognition, executive function, and lexical retrieval. Critically, these tests are used in diagnosis and monitoring of FTD. Future efforts must focus on increasing research participation in underrepresented populations with FTD to support the diverse needs of individuals, and an understanding of social determinants of health in FTD to evaluate potential sources of the observed differences across racial and ethnic groups.
Metastatic spine disease alters spinal load-to-strength ratios in patients compared to healthy individuals
Authors: Anderson Dennis E. , Keko Mario , James Joanna , Allaire Brett T. , Kozono David , Doyle Patrick F , Kang Heejoo , Caplan Sarah , Balboni Tracy , Spektor Alexander , Huynh Mai Anh , Hackney David B. , Alkalay Ron N.
Published: January 2025

Pathologic vertebral fractures (PVF) are common and serious complications in patients with metastatic lesions affecting the spine. Accurate assessment of cancer patients’ PVF risk is an unmet clinical need. Load-to-strength ratios (LSRs) evaluated in vivo by estimating vertebral loading from biomechanical modeling and strength from computed tomography imaging (CT) have been associated with osteoporotic vertebral fractures in older adults.

Here, for the first time, we investigate LSRs of thoracic and lumbar vertebrae of 135 spine metastases patients compared to LSRs of 246 healthy adults, comparable by age and sex, from the Framingham Heart Study under four loading tasks. Findings include: (1) Osteolytic vertebrae have higher LSRs than osteosclerotic and mixed vertebrae; (2). In patients’ vertebrae without CT observed metastases, LSRs were greater than healthy controls. (3) LSRs depend on the spinal region (Thoracic, Thoracolumbar, Lumbar). These findings suggest that LSRs may contribute to identifying patients at risk of incident PVF in metastatic spine disease patients. The lesion-mediated difference suggests that risk thresholds should be established based on spinal region, simulated task, and metastatic lesion type.
Intrastriatal delivery of a zinc finger protein targeting the mutant HTT gene obviates lipid phenotypes in zQ175DN HD mice
Authors: Iwanowicz Andrew , Boudi Adel , Seeley Connor , Sapp Ellen , Miller Rachael , Liu Sophia , Chase Kathy , Shing Kai , Batista Ana Rita , Siena-Esteves Miguel , Aronin Neil , DiFiglia Marian , Kegel-Gleason Kimberly B.
Published: January 2025

Reducing the burden of mutant Huntingtin (mHTT) protein in brain cells is a strategy for treating Huntington’s disease (HD). However, it is still unclear what pathological changes can be reproducibly reversed by mHTT lowering. We previously found that lipid changes that occur with HD progression could be prevented by attenuating HTT transcription of the mutant allele in a genetic mouse model (LacQ140) with inducible whole body lowering. Here, we tested whether intrastriatal injection of a therapeutic capable of repressing the mutantHTTallele with expanded CAG can provide similar protection against lipid changes in HD mice with a deletion of neo cassette (zQ175DN).

Methods

Wild-type or zQ175DN mice were injected with AAV9 bearing a cDNA for a zinc finger protein (ZFP) which preferentially targets mutant HTT (ZFP-HTT) to repress transcription (Zeitler et al., 2019). Proteins were analyzed using western blot, capillary electrophoresis, and nitrocellulose filtration methods. Lipid analyses were conducted by liquid chromatography and mass spectrometry (LC-MS). Somatic expansion index was assessed using capillary gel electrophoresis of PCR products.

Conclusions

Lowering mHTT levels by 43% for 4 months prevented numerous changes in lipids of caudate-putamen in zQ175DN mice. Our data support the idea that mHTT lowering can provide meaningful benefits and support brain health. Furthermore, our data demonstrate that analyzing lipid signatures is a valuable method for evaluating potential therapies in a preclinical model of HD.
Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi
Authors: Chen Xuefei , Duan H. Diessel , Hoy Michael J. , Koteva Kalinka , Spitzer Michaela , Guitor Allison K. , Puumala Emily , Hu Guanggan , Yiu Bonnie , Chou Sommer , Bian Zhuyun , Guo Amelia Bing Ya , Sun Sheng , Robbins Nicole , Cook Michael A. , Truant Ray , MacNeil Lesley T. , Brown Eric D. , Kronstad James W. , Cowen Leah E. , Heitman Joseph , Li Huilin , Wright Gerard D.
Published: January 2025

Fungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, whileCandida auris, a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin againstCryptococcus neoformansH99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, includingC. auris. Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1–Cdc50, blocking phospholipid transport. Cryoelectron-microscopy analysis of the Apt1●butyrolactol A complex revealed that the flippase is locked in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.