bluuebunny/crossref_metadata_2025 huggingface dataset:
Secreted small RNAs ofNaegleria fowleriare biomarkers for diagnosis of primary amoebic meningoencephalitis
Authors: Russell A. Cassiopeia , Dainis Joseph , Alexander Jose , Ali Ibne Karim M. , Kyle Dennis E.
Published: January 2025

Rapid and accurate diagnostics are needed to effectively detect and treat primary amoebic meningoencephalitis (PAM) caused byNaegleria fowleri(Nf). Delayed diagnosis and similarities to other causes of meningitis contribute to a case mortality rate of >97%. Thus, there is an unmet medical need for a non-invasive liquid biopsy diagnostic method. We sequencedNfextracellular vesicles (EVs) and identified microRNAs, tRNAs and other small RNAs inNf-EVs. From these data we selected two prevalent small RNAs as biomarker candidates. We developed an RT-qPCR assay and both small RNAs were detected inNf-EVs and amoeba-conditioned media. In the mouse model of PAM both small RNA biomarkers were detected in 100% of mouse plasma samples at the end-stage of infection. Notably, smallRNA-1 was detected in the urine of infected mice at timepoints as early as 24h post infection (18/23 mice) and in the plasma as early as 60h post infection (8/8 mice). Additionally, smallRNA-1 was detected in 100% (n=6) of CSF samples from human PAM cases, and in whole blood samples, but not in human plasma from PAM cases. In this study, we discovered small RNAs as biomarkers ofNfinfection, one which can be detected reliably in CSF, urine, and whole blood. The RT-qPCR assay is a highly sensitive diagnostic assay that can be conducted in ∼3h after receipt of liquid biopsy. The data suggest detection of smallRNA-1 biomarker could provide earlier diagnosis of PAM and be used to monitor biomass of amoebae during treatment.

One Sentence Summary

Small RNAs ofNaegleria fowlerican be detected in liquid biopsies and serve as early diagnostic biomarkers of primary amoebic meningoencephalitis.
A specific, stable, and accessible LAMP assay targeting the HSP70 gene ofTrypanosoma cruzi
Authors: Guarnizo Sneider Alexander Gutierrez , Basma Luciana , Equilia Shirley , Condori Beth Jessy , Malaga Edith , Defazio Siena , Arteaga Emily , Velarde Jean Karla , Obregón Martín , Takyar Anshule , Duque Carolina , Hakim Jill , Tinajeros Freddy , Gilman Robert H , Bowman Natalie , Mugnier Monica R.
Published: January 2025

Diagnostic delays prevent most Chagas disease patients from receiving timely therapy during the acute phase when treatment is effective. qPCR-based diagnostic methods provide high sensitivity during this phase but require specialized equipment and complex protocols. More simple and cost-effective tools are urgently needed to optimize early Chagas disease diagnosis in low-income endemic regions. Here, we present a loop-mediated isothermal amplification (LAMP) that targets a highly conserved region in the HSP70 gene ofTrypanosoma cruzi,the causative agent of Chagas disease. This assay demonstrates species-specific amplification across multiple parasite genetic lineages while maintaining stability after 2 hours of incubation and at least 8 months of storage at −20°C. Moreover, the assay is at least 12 times less expensive than the TaqMan qPCR that is currently routinely used for acute Chagas diagnostics. Population-based validation in 100 infants born to Chagas-positive mothers in Santa Cruz, Bolivia, yielded a specificity of 100% and sensitivity exceeding 77% when compared to a TaqMan qPCR that targets satellite DNA. This cost-effective assay holds promise for large-scale diagnosis of Chagas disease in endemic regions with limited resources.
Prevalence of skin disorders and associated factors among patients with celiac disease: a cross-sectional study
Authors: Tajabadi Zohreh , Ekhlasi Golnaz , Daneshpazhooh Maryam , Fakheri Hafez , Tavakoli Tahmine , Ahmadi Bizhan , Ganji Azita , Niknam Ramin , Pashaei Mohammad Reza , Ghadir Mohammad Reza , Shahbazi Shaahin , Ghanaei Fariborz Mansour , Alavinejad Pezhman , Shirmohamadi Masoud , Aflatoonian Majid , Bakhshipour Alireza , Masoudi Sahar , Shahbazkhani Bijan
Published: January 2025

Background

While celiac disease (CD) ordinarily presents with gastrointestinal manifestations, extraintestinal appearances may also happen. Although cutaneous manifestations are one of the most common extraintestinal manifestations of CD, little is known about their prevalence and associated factors. This study aims to determine the prevalence of cutaneous manifestations and related factors in CD patients.

Methods

This cross-sectional study enrolled CD patients referred to the National Celiac Registry, for whom a diagnosis of CD was confirmed through clinical examination, serological testing, and intestinal biopsy. Data on demographic characteristics, CD staging, clinical manifestations, underlying comorbidities, and family history (FH) of diseases were collected. Data were analyzed using SPSS version 25.0. Ap-value less than 0.05 was considered significant.

Results

Of the 4357 enrolled CD patients (male 65.7%), 18.20% had cutaneous manifestations, with eczema (3.73%), dermatitis herpetiformis (3.46%), and psoriasis (0.71%) being the most common disorders. The FH of skin disorders (Odds ratio (OR)=7.99, 95% confidence interval (CI) 2.44-26.13,p=0.00), osteoarthritis (OR=6.15, 95% CI 1.15-32.78,p=0.03), Sjögren syndrome (OR=4.82, 95% CI 1.98-11.73,p=0.00), mouth aphthae (OR=3.10, 95% CI 1.80-5.32,p=0.00), thalassemia (OR=2.78, 95% CI 1.19-6.50,p=0.01), constipation (OR =1.62, 95% CI 1.10-2.38,p=0.01), and iron deficiency anemia (IDA) (OR=1.54, 95% CI 1.05-2.24,p=0.02) were independent predictors, and type I diabetes mellitus (OR=0.20, 95% CI 0.05-0.81,p=0.02) was a protective factor for skin diseases.

Conclusion

Considering the higher probability of cutaneous manifestations in CD patients, regular clinical evaluation of these patients is recommended for timely diagnosis and management of underlying skin diseases.
Upper extremity joint tenderness as a practical indicator for assessing presenteeism in rheumatoid arthritis patients
Authors: Naito Ryota , Taniguchi Masashi , Onizawa Hideo , Nakajima Tomoya , McCracken Kayo , Mori Masato , Hiwa Ryosuke , Nakamura Takuji , Onishi Akira , Matsuda Shuichi , Morinobu Akio , Hirose Shinji , Shinkawa Yutaka , Umehara Hisanori , Tanaka Masao
Published: January 2025

Objective

Rheumatoid arthritis (RA) causes chronic polyarthritis and joint dysfunction, reducing work productivity. This reduction is mainly due to presenteeism, characterized by impaired work performance despite being present at work. This study aims to investigate the impact of specific joint involvement, particularly in the upper extremities, on work disability in RA patients.

Methods

Annual surveys assessing work disability were conducted among RA outpatients enrolled in the Nagahama Riumachi Cohort at Nagahama City Hospital, using the Work Productivity and Activity Impairment Questionnaire (WPAI). A multivariate regression analysis was performed to examine the cross-sectional and longitudinal associations between presenteeism and the tender joint count (TJC) in the extremities across two WPAI surveys.

Results

The analysis included 201 patients, 52% of whom reported presenteeism. Cross-sectional analysis revealed a significant positive correlation between three or more TJCs of the upper extremity and presenteeism, with a regression coefficient (β) = 17.9 (95% confidence interval [CI]: 9.85–25.9). Among the joints evaluated, the sum of TJCs in the shoulder area (β = 9.55, CI: 5.39–13.7) and the fingers (β = 1.60, CI: 0.35–2.85) were significantly correlated with presenteeism. Additionally, change in presenteeism were significantly correlated with change in upper extremity TJCs (β = 1.41, CI: 0.05–2.77).

Conclusions

The upper extremity TJC is strongly associated with presenteeism in RA patients. The TJC of the upper extremities serves as a valuable indicator for clinicians, helping them effectively assess a patient’s underlying work disability.
Smooth pursuit eye movements contribute to long-latency reflex modulation in the lower extremity
Authors: Sinha Oindrila , Bertucco Matteo , Kurtzer Isaac , Singh Tarkeshwar
Published: January 2025

Somatosensory mediated reactions play a fundamental role in adapting to environmental changes, particularly through long-latency responses (LLRs). We investigated how smooth pursuit eye movements (SPEM), which are slow eye movements used to track moving objects, influence LLRs of the upper and lower limb during mechanical interactions with moving objects. Seventeen participants stabilized their limb in anticipation of a collision with a virtual object approaching at 25 cm/s while standing. This task occurred while subjects either visually pursued the object or fixated a central location. Mechanical perturbations were applied at two time points: approximately 200ms and 60ms before the anticipated collision. On a random subset of trials, the robot applied a mechanical perturbation either 200ms (early) or 60ms (late) before the anticipated collision. As in previous studies LLRs were observed in leg muscles to upper limb displacement. Moreover, the leg LLRs were modulated by gaze, being larger during pursuit than fixation but only during late perturbations. This timing-specific modulation aligns with previous reports of policy transitions in feedback control roughly 60ms before impact. Upper limb LLRs were not impacted by gaze indicating a prioritization on postural control circuits. This work extends our understanding of the neural mechanisms underlying sensorimotor integration and highlights the sophisticated nature of the human motor control system in coordinating eye movements with whole-body postural responses.

NEW and NOTEWORTHY

We show for the first time that smooth pursuit eye movements contribute to modulation of long-latency reflexes in the lower limb during virtual object interactions in upright stance. Smooth pursuit eye movements are used to track moving objects. These findings suggest a neurophysiological link between control of eye movements and posture stabilization.
Explainable artificial intelligence for neuroimaging-based dementia diagnosis and prognosis
Authors: Martin Sophie A. , Zhao An , Qu Jiongqi , Imms Phoebe , Irimia Andrei , Barkhof Frederik , Cole James H. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

INTRODUCTION: Artificial intelligence and neuroimaging enable accurate dementia prediction, but ‘black box’ models can be difficult to trust. Explainable artificial intelligence (XAI) describes techniques to understand model behaviour and the influence of features, however deciding which method is most appropriate is non-trivial. Vision transformers (ViT) have also gained popularity, providing a self-explainable, alternative to traditional convolutional neural networks (CNN). METHODS: We used T1-weighted MRI to train models on two tasks: Alzheimer’s disease (AD) classification (diagnosis) and predicting conversion from mild-cognitive impairment (MCI) to AD (prognosis). We compared ten XAI methods across CNN and ViT architectures. RESULTS: Models achieved balanced accuracies of 81% and 67% for diagnosis and prognosis. XAI outputs highlighted brain regions relevant to AD and contained useful information for MCI prognosis. DISCUSSION: XAI can be used to verify that models are utilising relevant features and to generate valuable measures for further analysis.
Metabolomic insight into the link of Intermuscular Fat with Cognitive Performance: The Health ABC Study
Authors: Xu Richard , Tian Qu , Marron Megan M. , Ferrucci Luigi , Yao Shanshan , Kim Seyoung , Shah Ravi V. , Murthy Venkatesh L. , Newman Anne B. , Miljkovic Iva , Rosano Caterina
Published: January 2025

There is growing evidence that higher intermuscular fat (IMF) is associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, the underlying biological mechanisms are not well understood. Considering that both muscle and the brain are metabolically active organs, we sought to identify metabolites that may explain the IMF-DSST association. We assessed 613 plasma metabolites in 2388 participants from the Health, Aging and Body Composition Study (mean age ± SD: 74.7 ± 2.9 years, 50% men, 63% white), using liquid chromatography-mass spectrometry. We found that higher IMF was associated with worse DSST scores (standardized beta (95% CI): -0.08 (-0.12, -0.03), p<0.001). Sixty-six metabolites were significantly associated with both IMF and DSST. Four of the 66 metabolites attenuated the association by ≥10%: higher levels of adrenic acid (polyunsaturated fatty acid), and lower levels of C20:5 lysophosphatidylcholine (lysophospholipid), 1-methylnicotinamide (vitamin B3-related myokine), and maslinic acid (triterpene) were associated with higher IMF and worse DSST. Together, they explained 41% of the IMF-DSST association. Pathway enrichment analyses identified two significant shared pathways: unsaturated fatty acid metabolism and the citrate (TCA) cycle. This study provides hypothesis-generating evidence that a set of circulating metabolites related to unsaturated fatty acids, energy metabolism, and myokines may partially explain the inverse association of IMF with processing speed. The findings, if further confirmed by independent studies, advance our understanding of molecular pathways underlying muscle-brain crosstalk and raise the possibility of metabolites as potential predictive biomarkers and/or therapeutic targets.
The engineered monoclonal antibody tobevibart enhances HBsAg capture by Fc receptor positive cells leading to activation of HBV-specific T cells
Authors: Vincenzetti Lucia , Wong Rachel , Marzi Roberta , Guarino Barbara , Stefanutti Erin , Gupta Sneha V. , Rosen Laura E. , Belnap David M. , Wang Li , Chen Yi-Pei , di Iulio Julia , Momin Amin , Tracy Karen E. , Deshpande Sharvari , Errico John M. , Sprugasci Nicole , Peter Alessia , Seu Lillian , Cloutier Daniel , Tay Chin H. , Snell Gyorgy , Czudnochowski Nadine , Lempp Florian A. , Havenar-Daughton Colin , Benigni Fabio , Lanzavecchia Antonio , Agarwal Kosh , Yuen Man-Fung , Wedemeyer Heiner , Gane Ed , Arvin Ann , Corti Davide , Schmid Michael A.
Published: January 2025

Background & Aims

Immune targeting is likely required for functional cure of chronic hepatitis B (CHB). Tobevibart, a human monoclonal antibody against hepatitis B virus (HBV) surface antigen (HBsAg), neutralizes HBV and hepatitis delta virus (HDV). This study aimed to characterize effects of the engineered GAALIE Fc of tobevibart on HBV immune responses.

Methods

We studied tobevibart and its equivalent HBC34*-GAALIEin vitrousing electron microscopy, FcγR reporter cells, and primary human or mouse immune cells to assess HBsAg binding, dendritic cell (DC) activation, and T cell stimulation. Tobevibart-mediated binding of HBsAg to immune cells was evaluated also in a phase 1 clinical trial in patients with CHB.

Results

The GAALIE Fc of tobevibart mediated gain of function in FcγR signaling in immune complexes (ICs) with HBsAg compared to wild-type (WT) Fc and increased binding of HBsAg to neutrophils and monocytesin vitro. Similarly, dosing of 300 mg tobevibart in patients with CHB mediated binding of HBsAg to these cellsin vivo, concomitant with reducing HBsAg in circulation.In vitro, ICs of HBC34*-GAALIE and HBsAg activated human DCs significantly more than HBC34*-WT. These DCs presented antigen and stimulated HBsAg-specific human T cells. Similarly, ICs of HBC34*-GAALIE and HBsAg activated DCs from mice transgenic for human FcγRs and stimulated CD4+ T cells from immunized animals more than ICs with HBC34*-WT.

Conclusions

We demonstrate that tobevibart combines the advantages of potent neutralization of HBV and HDV, FcγR-mediated reduction of HBsAg, and Fc-dependent enhancement of T cell responses. Tobevibart is currently under clinical investigation alone or in combination with other agents to treat patients with chronic hepatitis delta and to induce functional cure of patients with CHB.

Impact and Implications

Chronic infection with hepatitis B virus (HBV) or co-infection with hepatitis delta virus (HDV) can cause severe liver disease and cancer. We previously showed that the monoclonal antibody tobevibart potently neutralizes HBV and HDV. Here we show that the engineered Fc region of tobevibart effectively interacted with several immune cell typesin vitro, which may support the rapid removal of damaging virus proteins from circulation, potentially activating T cell responses that may control HBV infection long term.
The quarantine hospital strategy as a way to reduce both community and nosocomial transmission in the context of a COVID-like epidemic
Authors: Pinettes Théo , Leclerc Quentin J. , Jean Kévin , Temime Laura
Published: January 2025

Nosocomial infections of both patients and healthcare workers (HCWs) in hospitals may play an important part in the overall dynamics of a viral pandemic, as evidenced by the recent COVID-19 experience. A strategy to control this risk consists in dedicating some hospitals to the care of infected patients only, with HCWs alternating between shifts of continuous stay within these hospitals and periods of isolation. This strategy has been implemented locally in various settings and generalized in Egypt. Here, using a mathematical model coupling hospitals and community, we assess the impact of this strategy on overall epidemic dynamics. We find that quarantine hospitals may significantly reduce the number of cumulative cases, as well as the peak incidence. These benefits are highest when effective control strategies are in place in the community and symptomatic HCWs comply with self-isolation recommendations. Our results, which are robust to variations in assumed biological characteristics of the virus, suggest that the quarantine hospital strategy should be considered in future pandemic contexts to best protect the entire population.
Facilitators and Barriers to Patient-Caregiver Dyadic Recruitment in Transplantation
Authors: Koons Brittany , Lehman Rachel , Riegel Barbara , Buck Harleah
Published: January 2025

Background

Despite growing awareness of the dyadic role in transplant care and a mandate for patient–caregiver dyads for transplant listing, the integration of dyadic science into transplantation research is lacking. Recruiting transplant patient-caregiver dyads has unique challenges that need to be considered when designing and conducting dyadic studies in transplantation.

Objectives

To present 1) the barriers and facilitators to dyadic recruitment in a patient-caregiver transplant population that we encountered and 2) strategies developed to overcome these challenges.

Methods

We used the Social Marketing Mix framework to guide this methodological report of patient-care dyadic recruitment strategies employed during a post-lung transplant psychometric study of 50 patient-caregiver dyads.

Results

We identified several facilitators of dyadic recruitment in the lung transplant population including: 1) conducting a study of high relevance to both patients and caregivers, which helped to facilitate maximum engagement of participants, 2) using remote recruitment and data collection strategies to improve accessibility to participation and to minimize the amount of time or energy required to participate, 3) conducting patient and caregiver study visits independently from one another, which allowed for scheduling flexibility, and helped improve participation among dyad members who do not live together, and 4) establishing clinical partnerships and having acquired clinical experience with the target population. We also identified barriers to dyadic recruitment that require careful planning in future studies including: 1) high health care utilization, which can delay the recruitment timeline, 2) recruiting patients and caregivers independently within relevant timeframes, 3) gatekeeping, when the patient or the caregiver block researcher access to the other dyad member, 4) establishing contact with the participant via the phone, and 5) limited study staffing that reduced recruitment and study visit scheduling flexibility.

Discussion

To our knowledge, this is the first methodological report to present the barriers and facilitators to dyadic recruitment in a patient-caregiver transplant population. Our experience and lessons learned can be used to inform future research teams to successfully design and conduct much needed dyadic research in organ transplantation.
The emergence of the fractal bronchial tree
Authors: Mederacke Malte , Yamauchi Kevin A. , Doumpas Nikolaos , Schaumann Laura , Sperl Jonathan , Weikert Thomas , Dane D. Merrill , Hsia Connie C. W. , Pradella Maurice , Bremerich Jens , Vetter Roman , Iber Dagmar
Published: January 2025

The fractal design of the bronchial tree, as described by the Hess–Murray law, facilitates energy-efficient lung ventilation, yet its developmental origins remain unclear. Here, we quantify the rearrangement of the embryonic bronchial tree into its fractal architecture, using SkelePlex, a new neural network-based image processing pipeline, and elucidate the biophysical principles governing its formation. We find that the branch shapes are such that pressure drop, shear, axial and hoop stress are equal across all branches. The seemingly random diameter of sister branches reflects the different number of tips they connect to in the asymmetric lung tree. By analysing lungs after pneumonectomy and those affected by chronic obstructive pulmonary disease (COPD), we show the same principles to persist in adulthood and disease, potentially providing quantitative biomarkers for disease progression and therapeutic guidance.
Ptpn14Knockout Mice Reveal Critical Female-Specific Roles for the Hippo Pathway
Authors: McCrea Edel M. , Makrides Neoklis , Tabata Takako , Vogel Hannes , Howitt Brooke , Reineking Wencke , Vilches-Moure José G. , Wang Mengxiong , Zhang Xin , Attardi Laura D.
Published: January 2025

The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine-phosphatase that inhibits YAP/TAZ. While an established tumor suppressor, PTPN14’s role in tissue homeostasis has remained unclear. We thus generatedPtpn14-deficient mice and found that only ∼60% ofPtpn14-/-mice survived postnatally, highlighting the importance of PTPN14 for viability, while also enabling the discovery of PTPN14 physiological functions.Ptpn14-/-mice developed debilitating corneal lesions and the uterus defect, hydrometra, as well as heart and kidney abnormalities.Ptpn14-deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in the uterus. Notably, these phenotypes were female-specific, revealing sexually-dimorphic Hippo pathway function through PTPN14. Finally, analysis of humanPTPN14variants suggested that PTPN14’s essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve women’s health.
Development of FAP-targeted theranostics discovered by next-generation sequencing-augmented mining of a novel immunized VNAR library
Authors: Gunaratne Gihan S. , Gallant Joseph P. , Ott Kendahl L. , Broome Payson L. , Celada Sasha , West Jayden L. , Mixdorf Jason C. , Aluicio-Sarduy Eduardo , Engle Jonathan W. , Boros Eszter , Meimetis Labros , Lang Joshua M. , Zhao Shuang G. , Hernandez Reinier , Kosoff David , LeBeau Aaron M.
Published: January 2025

Cancer-associated fibroblasts (CAFs) in the stroma of solid tumors promote an immunosuppressive tumor microenvironment (TME) that drives resistance to therapies. The expression of the protease fibroblast activation protein (FAP) on the surface of CAFs has made FAP a target for development of therapies to dampen immunosuppression. Relatively few biologics have been developed for FAP and none have been developed that exploit the unique engagement properties of Variable New Antigen Receptors (VNARs) from shark antibodies. As the smallest binding domain in nature, VNARs cleverage unique geometries and recognize epitopes conventional antibodies cannot. By directly immunizing a nurse shark with FAP, we created a large anti-FAP VNAR phage display library. This library allowed us to identify a suite of anti-FAP VNARs through traditional biopanning and also by anin silicoapproach that did not require any prior affinity-based enrichmentin vitro. We investigated four VNAR-Fc fusion proteins for theranostic properties and found that all four recognized FAP with high affinity and were rapidly internalized by FAP-positive cells. As a result, the VNAR-Fc constructs were effective antibody-drug conjugatesin vitroand were able to localize to FAP-positive xenograftsin vivo. Our findings establish VNAR-Fc constructs as a versatile platform for theranostic development that could yield innovative cancer therapies targeting the TME.
dlmoR: An open-source R package for the dim-light melatonin onset (DLMO) hockey-stick method
Authors: Thalji Salma M. , Spitschan Manuel
Published: January 2025

The dim-light melatonin onset (DLMO) is a commonly used circadian phase marker indicating the start time of evening melatonin synthesis in humans. Several quantitative techniques have been developed to determine DLMO from melatonin time-series, including fixed- or variable-threshold techniques and the hockey-stick method developed by Danilenko and colleagues (2014). Here, we introducedlmoR, an open-source implementation of the hockey-stick method implemented in the R programming language and licensed under the permissive MIT License. Our clean-room implementation followed the algorithm description from the original article, supported by iterative validation against the existing binary executable software. We benchmark our implementation using a total of 112 melatonin time-series data sets from two different studies (Blume et al, 2024; Heinrichs and Spitschan, 2024), and find high agreement between our implementation and the reference implementation. The mean DLMO point discrepancy between implementations was −2.1 ± 11.1 minutes for the Blume et al. (2024) dataset and −1.482 ± 21.7 for the Heinrichs and Spitschan (2024) dataset. Circular correlation coefficients were 0.986 and 0.964, respectively, and paired t-tests (p >0.05) were not significant, suggesting no systematic difference or bias between the methods.dlmoRallows for the programmatic and batchable analysis of evening melatonin concentration data, enabling transparency and reproducibility of analytic techniques.
Spatially-divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates
Authors: Lesani Mahbobeh , Middleton Caitlyn E. , Feng Tzu-Yu , Arroyo Jan Carlos Urban , Casarez Eli , Ewald Sarah E. , McCall Laura-Isobel
Published: January 2025

Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of local parasite burden, local tissue inflammation and the microbiome in shaping local tissue metabolism during acute and chronic infection. Toxoplasmosis is a zoonotic disease caused by the parasiteToxoplasma gondii. This protozoan infects the small intestine and then disseminates to nearly every organ in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle and brain. We compared metabolism in eleven sampling sites in C57BL/6 mice during the acute and chronic stage ofT. gondiiinfection. Strikingly, significant metabolic changes were observed in the large intestine and colon during chronic infection, organs not associated withT. gondiipersistence. Overall, major spatial mismatches were observed between metabolic perturbation and local parasite burden for both disease stages. In contrast, a stronger association with indicators of type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity, than with local parasite burden. In addition, we observed significant changes in microbiota composition with infection, and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs, and their regulators.

Importance

Inflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across eleven sampling sites following systemic murine infection with the parasiteToxoplasma gondii. Results revealed relationships between differential metabolite enrichment and variables including inflammatory signals, pathogen burden and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.
Global DNA signatures of temperature and nutrient limitation in prokaryotes
Authors: Antman Tomer , Lewin-Epstein Ohad , Yerushalmi Tamir , Broder Yonatan , Zeevi David
Published: January 2025

Microorganisms adapt to their environment through changes in both their genes and overall genome composition. However, identifying universal principles of genomic adaptation remains challenging because different environments present multiple, overlapping selective pressures. To overcome this challenge, we analyzed DNA composition patterns across diverse environments using machine learning. By examining tetranucleotide frequencies from 1,112 marine and soil metagenomic samples, we discovered that environmental temperature can be accurately predicted from DNA composition alone (R2=0.82). This temperature signal remained robust even when analyzing individual bacterial phyla and classes, suggesting a fundamental adaptive response. To examine this adaptation mechanism, we analyzed GC content relationships with temperature and found opposing relationships in different environments: positive correlations in soil but negative correlations in marine samples. We show that this inverse relationship in marine environments is driven by nutrient availability, as GC content increases with nutrient levels while nutrients decrease with temperature in marine ecosystems. Despite these contrasting GC patterns, we identified specific tetranucleotides composed of equal numbers of GC and AT bases (50% GC content) that showed consistent temperature correlations across all environments. These findings reveal a complex interplay between temperature adaptation and nutrient limitation in shaping microbial genomes.
Cytoneme-mediated signalling coordinates the development of glial cells and neurons in theDrosophilaeye
Authors: García-Arias Juan Manuel , Girón Gonzalo G. , Foronda David , Guerrero Isabel , Baonza Antonio
Published: January 2025

Effective cell communication is essential for the development and maintenance of the nervous system, where neurons and glial cells must interact closely. While cytoneme-mediated signalling is well-documented in various biological contexts, its role in coordinating neuron-glia development remains poorly understood. In this study, we investigated the function of cytonemes in neuron-glia coordination using theDrosophilaeye imaginal disc as a model. This is a well-established system for examining the orchestrated development of glial and neuronal cells. Our results reveal that glial cells produce two distinct types of cytonemes based on their spatial orientation: one set extends toward nascent photoreceptors, while the other targets the morphogenetic furrow (MF). We have characterised the dynamics of glial cytonemes and demonstrated that disrupting these structures has a significant impact on glial cell migration and differentiation. This highlights the critical role of cytoneme-mediated signalling in regulating glial behaviour. Our findings also demonstrate that cytoneme function is essential for activating the Hedgehog (Hh) pathway in glial cells, with Hh ligand produced by photoreceptors. This pathway is necessary for glial differentiation, uncovering a previously unrecognised role for Hh signalling in this process. Overall, our results suggest that cytoneme-mediated Hh signalling is key to coordinating the development of both glial and neuronal populations.
Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity
Authors: Zhao Qing , De Nardo William , Wang Ruoyu , Zhong Yi , Keles Umur , Zhao Li Na , Tay Huiyi , Youhanna Sonia , Yan Mengchao , Xie Ye , Kim Youngrae , Lee Sungdong , Lim Rachel Liyu , Teo Guoshou , Narayanaswamy Pradeep , Burton Paul R. , Lauschke Volker M. , Choi Hyungwon , Watt Matthew J. , Kaldis Philipp
Published: January 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is generally asymptomatic in the early stages but, without appropriate intervention, it can progress to severe liver morbidities. To elucidate the molecular mechanisms of early development of MASLD, we performed transcriptomic analysis on liver biopsies and metabolomic analysis on liver and plasma samples from 109 obese individuals with no liver pathology or early stages of MASLD. The liver metabolome is remodeled by the parenchymal accumulation of neutral lipids, whereas the plasma metabolome displayed little differences. The liver transcriptome revealed that the progression of steatosis and fibrosis is characterized by distinct gene expression signatures. While metabolic remodeling characterizes steatosis, global rewiring of gene expression underpins fibrosis progression. Importantly, GTPases and their regulators were identified as a novel signature for the transition from steatosis to fibrosis. GTPase genes and their regulators were associated with hepatic fibrosis grades and co-expressed with TGF-β signaling. We further verified the involvement of GTPase regulation in fibrogenesis in HSC-like LX-2 cells and a 3D liver spheroid model of primary human hepatocytes and non-parenchymal cells. Our study suggests that modulation of GTPase signaling is a potential therapeutic entry point for the treatment of early liver fibrosis in MASLD.

Graphical abstract

Highlights

Liver metabolome remodeling is marked by accumulation of neutral lipids and relative reduction of glycerophospholipids and sphingolipids. Changes in the plasma metabolome were poorly correlated with the changes in the liver metabolome in early-stage MASLD.

Steatosis is closely linked to metabolic remodeling, whereas fibrosis progression is associated with global rewiring of gene expression.

Over 200 genes were identified as progressive markers for fibrosis progression.

GTPase signaling emerged as the top enriched pathway involved in the transition from non-fibrotic steatosis to the onset of fibrosis. The involvement of GTPase and its regulation in liver fibrogenesis was validated in a 3D spheroid MASH model. Pharmacological-mediated GTPase inhibition hindered collagen production in HSC-like LX-2 cells.
Spinal Cord Ultrasound Stimulation Modulates Corticospinal Excitability
Authors: Hou Lin , Lei Yuming
Published: January 2025

Background

Low-intensity focused ultrasound (LIFU) offers superior tissue penetration and enables precise neuromodulation of cortical and subcortical circuits. However, its effects on neural activity in the human spinal cord remain largely unexplored.

Objective

To investigate the effects of LIFU on spinal cord neuromodulation under varying conditions of intensity (spatial-peak pulse-average intensity, ISPPA), duty cycle (DC), and pulse repetition frequency (PRF).

Methods

Thirty-six healthy human volunteers participated in the study. A 500 kHz ultrasound transducer with a focal depth exceeding 100 mm was used to target the C8 spinal cord. Transcranial magnetic stimulation (TMS) was applied to the primary motor cortex (M1) hotspot corresponding to the first dorsal interosseous (FDI) muscle, innervated by the C8 nerve. A 500 ms-duration LIFU was delivered to the C8 spinal cord 400 ms prior to single-pulse TMS over the FDI hotspot. Spinal cord ultrasound stimulation (SCUS) was administered with varying acoustic parameters: intensities (ISPPA: 2.5 and 10 W/cm²), DCs (10% and 30%), and PRFs (500 and 1000 Hz). Changes in corticospinal excitability were assessed by comparing TMS-elicited motor-evoked potentials (MEPs) between active and sham SCUS conditions.

Results

SCUS with an ISPPAof 10 W/cm², a DC of 30%, and a PRF of 1000 Hz significantly reduced MEP amplitudes compared to sham stimulation. However, at the high intensity (ISPPAof 10 W/cm²), varying the DC between 10% and 30% did not affect MEP amplitudes. Additionally, while a PRF of 1000 Hz decreased MEP amplitudes at 10 W/cm², a PRF of 500 Hz did not produce significant changes.

Conclusions

The results indicate that ultrasound stimulation of the spinal cord can suppress corticospinal drive to muscles, especially when utilizing high intensity and high PRF parameters. This suggests that ultrasound stimulation may provide a novel method for modulating human spinal neural activity.
A reference-quality NLRome for the hexaploid sweetpotato and diploid wild relatives
Authors: Parada-Rojas C. H. , Childs K. L. , Fernández de Soto M. , Salcedo A. , Pecota K. , Yencho G. C. , Almeyda C. , Kitavi M. , Buell C. R. , Conant G. C. , Baltzegar D. , Quesada-Ocampo L. M.
Published: January 2025

Breeding for sweetpotato (Ipomea batatas) resistance requires accelerating our understanding genomic of sources of resistance. Nucleotide-binding domain leucine-rich repeat receptors (NLRs) proteins represent a key component of the plant immune system that mediate plant immune responses. We cataloged the NLR diversity in 32 hexaploid sweetpotato genotypes and three diploid wild relatives using resistance gene enrichment sequencing (RenSeq) to capture and sequence full NLRs. A custom designed NLR bait-library enriched NLR genes with an average 97% target capture rate. We employed a curated database of cloned and functionally characterized NLRs to assign sequenced sweetpotato NLRs to canonical phylogenetic clades. We identified between 800 to 1,200 complete NLRs, highlighting the expanded diversity of coiled-coil NLRs (CNLs) across all genotypes. NLRs among sweetpotato genotypes exhibited large conservation across genotypes. Phylogenetic distance between 6X (hexaploid) and 2X (diploid) genotypes revealed that a small repertoire ofI. batatasCNLs diverged from the sweetpotato wild relatives. Finally, we obtained chromosome coordinates in hexaploid (Beauregard) and diploid (Ipomoea trifida) genomes and recorded clustering of NLRs on chromosomes arms. Our study provides a catalog of NLR genes that can be used to accelerate breeding and increase our understanding of evolutionary dynamics of sweetpotato NLRs.
A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease
Authors: Chalumeau Anne , Dames Maria Bou , Antoniou Panagiotis , Loganathan Priyanka , Mombled Margaux , Corre Guillaume , Peterka Martin , Amendola Mario , Giovannangeli Carine , Maresca Marcello , Miccio Annarita , Brusson Mégane
Published: January 2025

Fetal hemoglobin (HbF) reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime editing strategy that introduces multiple mutations in the fetal γ-globin promoters of patients’ hematopoietic stem/progenitor cells (HSPCs), boosting HbF expression and offering alternative therapeutic perspectives.
Commonly used non-antibiotic medications promote mutation frequency and antimicrobial resistance inEscherichia coli
Authors: Chen Hanbiao , Sapula Sylvia A. , Turnidge John , Venter Henrietta
Published: January 2025

Antimicrobial resistance (AMR) poses a global threat to public health. The excessive use of antibiotics significantly contributed to the rise of resistance. Recent evidence suggests that non-antibiotic medications (NAMs) also play a role in antimicrobial resistance development, although this aspect remains less explored and understood. This issue is particularly relevant in residential aged care facilities (RACFs) where both NAMs and antibiotics are frequently used, and AMR is prevalent. We investigated the propensity of NAMs that are commonly used in RACFs and contribute to polypharmacy including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac, acetaminophen (antipyretic), metformin (glucose-lowering medication), atorvastatin (lipid-lowering agent), tramadol (opioid analgesic), temazepam (hypnotic), and pseudoephedrine (sympathomimetic) to promote bacterial antibiotic resistance by increasing the acquisition of mutations.Escherichia coliwas exposed to different NAMs at their gut concentration, combined with ciprofloxacin and the mutation frequency was determined. Additionally, we explored the simultaneous effect of two NAMs as a starting point for studying polypharmacy.

Ibuprofen and acetaminophen significantly increased mutation frequency, and conferred high levels of ciprofloxacin resistance, especially whenE. coliwas exposed to two NAMs. Whole genome sequencing revealed that these changes correlated with mutations in DNA gyrase GyrA, the multiple antibiotic resistance regulator, MarR, and the drug efflux pump expression suppressor, AcrR. Consequently, an increase in transcription of theacrAgene from the AcrAB-TolC drug efflux pump was observed. The combination of two NAMs increased the mutation rate. These multiple mutations caused the higher levels of ciprofloxacin resistance that were observed.

Given the risk of polypharmacy to induce AMR, and the results observed in this study, the assessment NAMs in their ability to promote bacterial resistance warrants special attention in future studies into prescribing practices.
Prolyl isomerase FKBP12 reduces axon growth and negatively regulates microtubule polymerization by inhibiting CRMP2A
Authors: Weissova Romana , Sabo Jan , Chafai Djamel Eddine , Ziak Jakub , Buran Peter , Bodakuntla Satish , Janke Carsten , Lansky Zdenek , Balastik Martin
Published: January 2025

Prolyl isomerases are enzymes catalyzing conformational change of the peptide bond between proline and the preceding amino acid, regulating the function and stability of their substrates. We have previously identified CRMP2A - the longer isoform of a microtubule-associated protein Collapsin response mediator protein 2 - as a substrate of the phospho-specific prolyl isomerase Pin1. CRMP2A is negatively regulated and destabilized by CDK5 phosphorylation in the distal axons and growth cones. Pin1 specifically binds to phosphorylated CRMP2A and stabilizes it by inducing conformational changes. However, the conformational regulation of unphosphorylated CRMP2 remains unknown. Here, we show that the prolyl isomerase FKBP12 specifically binds to unphosphorylated CRMP2A and regulates its activity. Usingin vitromicrotubule polymerization assays we demonstrate that CRMP2A promotes microtubule growth and that this function is inhibited by FKBP12. Next, using GFP-EB3 microtubule plus-end tracking assay, we demonstrate that FKBP12 inhibits CRMP2A-mediated microtubule polymerization also in cells. Furthermore, we show that FKBP12 co-localizes with unphosphorylated CRMP2A in growth cones and that expression of FKBP12 reduces axon growth in microfluidic chambers, while FKBP12 knockdown enhances it. Together, we demonstrate that FKBP12 is a negative regulator of microtubule dynamics and axon growth. Moreover, we show that two prolyl isomerases can differentially (positively or negatively) regulate activity of a common substrate depending on its phosphorylation. This provides an additional layer of phosphorylation-dependent or -independent control of protein activity, microtubule dynamics, and neuronal growth. Given the broad substrate specificity of FKBP12 and Pin1, this regulatory mechanism likely contributes to the modulation of diverse proteins and cellular processes in the nervous system and beyond.
MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases
Authors: Woods Virgil , Umansky Tyler , Russell Sean M , McGovern Briana L , Rosales Romel , Rodriguez M Luis , van Bakel Harm , Sordillo Emilia Mia , Simon Viviana , García-Sastre Adolfo , White Kris M , Brubaker William F , Smith Davey , Haders Daniel
Published: January 2025

The death toll and financial stress posed by the recent COVID-19 pandemic have highlighted the pressing need to develop safe and effective, broad-spectrum inhibitors to treat viral infections. To accelerate the antiviral drug discovery process, we developed GALILEO™, a computational platform that interfaces with a customizable bioinformatics pipeline with a geometric deep learning algorithm we named ChemPrint™ for in silico drug screening. Combining these algorithms with a large chemical repositioning library, we discovered MDL-001, which interacts with the Thumb pocket 1 subdomain of multiple single-stranded RNA viruses. For MDL-001, we demonstrate potent in vitro activity against a broad spectrum of pathogenic viruses, and we demonstrate potent in vivo efficacy in a mouse model of SARS-CoV-2 infection. In clinical trials, orally administered MDL-001 has been shown to be safe and well tolerated. These data underline both the effectiveness of the GALILEO™ platform for drug discovery and the promise of MDL-001 as a novel broad-spectrum antiviral clinical candidate.
Characterization of auditory responsive neurons in the mouse superior colliculus to naturalistic sounds
Authors: Si Yufei , Ito Shinya , Litke Alan M. , Feldheim David A.
Published: January 2025

Locating the source of a specific sound in a complex environment and determining its saliency is critical for survival. The superior colliculus (SC), a sensorimotor midbrain structure, plays an important role in sound localization and has been shown to have a topographic map of the auditory space in a range of species. In mice, previous studies using broadband white noise stimuli found that neurons use high-frequency monaural spectral cues and interaural level differences (ILDs) to compute spatially restricted receptive fields (RFs), and that these RFs are organized topographically along the azimuth. However, in a naturalistic environment, the auditory stimuli that an animal encounters may have rich spectral components; however, these sound sources can still be localized efficiently. It remains unknown whether and how the SC neurons respond to naturalistic sounds and, in turn, compute a spatially restricted RF. Here, we show results from large-scale in vivo physiological recordings of SC neurons in response to white noise, naturalistic ultrasonic pup calls and chirps. We find that mouse SC auditory neurons respond to pup calls with distinct temporal patterns and a spatial preference predominantly at ∼60 degrees in contralateral azimuth. In addition, we categorized auditory SC neurons based on their spectrotemporal receptive field patterns and demonstrated that there are at least 4 distinct subtypes of auditory responsive SC neurons.

Significance Statement

The superior colliculus (SC) receives visual and auditory information that is used to localize objects. While the organization and composition of visually responsive SC neurons is well described, much less is known about the types and response properties of auditory SC neurons. Here, we presented white noise, ultrasonic mouse pup calls, and chirp stimuli to mice while recording from SC neurons. Analysis of neuronal responses defines 4 distinct classes of auditory neurons. We also show that while auditory neurons respond to naturalistic stimuli, these responses mainly occur when presented from the side but not the front of the animal. These results lead to the hypothesis that mice use different strategies to localize sound depending on the spectral composition of the source.