bluuebunny/crossref_metadata_2025 huggingface dataset:
The benefits of palliative care follow-up combining day hospital and telemedicine
Authors: Saffon Valerie Mauries , Faya-Robles Alfonsina , Bourgouin Marie , Lamy Sebastien , Caunes-Hilary Nathalie , Couderc Bettina
Published: January 2025

The objective of the present study is to evaluate the impact of remote consultations (telemedicine) conducted on a monthly basis, in conjunction with quarterly inpatient follow-ups conducted by a team specialising in palliative care for cancer patients, in terms of anticipating potential deterioration in patients’ general condition and enhancing their quality of life. The study also investigates whether there is a specific profile of patients who could benefit from teleconsultation and identifies patients’ expectations and concerns regarding teleconsultation.

The study enrolled 36 patients on their initial admission to a palliative care day hospital (HDJ), and they completed a questionnaire regarding their demographics, expectations, and reservations concerning teleconsultation. Patients were then scheduled for two monthly teleconsultations and were advised to return to the HDJ at D = 3 months. However, only 13 out of the 36 patients enrolled were able to benefit from the two teleconsultations and return to the HDJ after 3 months. This finding underscores the critical issue of patients being referred to the mobile palliative care team at a late stage. Our study revealed that factors such as age, gender, socio-economic status, and pathology did not influence patient compliance or the efficacy of the teleconsultations. The study emphasised the benefits of monthly teleconsultations for the clinical and psychological management of patients, highlighting that patients had minimal negative preconceptions upon enrolment and expressed a strong desire to continue these monthly consultations after the initial 3-month period. The findings underscore the significance of leveraging teleconsultations for patients receiving palliative care in oncology, particularly in scenarios where face-to-face consultations are not feasible. Telemedicine holds immense potential to enhance the monitoring of a larger patient population, thereby promoting greater equity in healthcare delivery.
Rationale design of peptide inhibitors forα-Synuclein liquid condensates and fibrillar aggregates using multiscale modelling approach
Authors: Ekambaram Srinivasan , Prajapati Santosh , Srivastava Anand
Published: January 2025

α-Synuclein is an intrinsically disordered protein (IDP) whose aggregation is implicated in Parkinson’s disorder. Herein, we computationally design aα-Synuclein derived potential peptide inhibitor against the protein’s monomeric, fibrillar and liquid condensate forms using multi-scale molecular modelling approaches. Since the conventional structure-based design paradigm often is not applicable to these highly labile IDPs, we first develop a pipeline to generate an exhaustive library of small candidate peptides from an available repository ofα-Synuclein 70µs all-atom molecular dynamics (AAMD) trajectory data. We then use high throughput screening techniques such as PATCHDOCK and HPEPDOCK as well as AAMD simulations to arrive at a single candidate peptide. AAMD simulations data show thatα-Synuclein bound peptide chain leads to an expanded conformational ensemble for the chain and also reduces theβ-sheet propensity of the protein’s fibrillar amylogenic aggregates. Coarse-grained simulations using HPS-Cation forcefield with 100 chains ofα-Synuclein and varying levels of candidate peptides shows decreased density and increased apparent critical temperature of the condensate system. Our detailed molecular interactions analyses show that peptides bind to theα-Synucleins through the “dynamic shuttling mechanism” where interaction are frequently made and broken around a given set of structurally proximal residues, which likely softens the dynamic interaction network in the condensates. Together, we could illustrate the inhibitory effect of the final designed peptide against distinct forms ofα-Synuclein monomer and aggregates. Our work provides a multiscale simulation based prescription towards the futuristic development of therapeutic strategies against the disordered proteins.
Transcranial Magnetic Stimulation Depression Treatment Induces Positive Bias in Task-Related Brain Function: Results From the BRAEN-MAP Trial
Authors: Sarrazin Verena , Suen Paulo , Cavendish Beatriz , Martens Marieke , da Silva Pedro Henrique Rodrigues , Britto Anne , Rassi Matheus , Baptista Mariana , Brunoni Andre R , O’Shea Jacinta
Published: January 2025

Antidepressant treatments are theorised to act by inducing a positive bias in information processing early on during treatment. Here, we tested for the first time whether this theory generalises to transcranial magnetic stimulation (TMS) treatment, an effective therapy for treatment-resistant depression. 49 patients with major depression received 20 sessions of open-label intermittent theta-burst stimulation applied to left dorsolateral prefrontal cortex. At baseline and after eight stimulation sessions, positive bias was assessed using behavioural and functional magnetic resonance imaging tasks presenting emotional faces. Clinical improvement at the end of treatment was related to an early increase in positive bias (1) in misclassification of emotional faces, (2) in the response of the default mode network (DMN) to emotional faces including rostral anterior cingulate cortex (ACC), and (3) in connectivity between rostral ACC and DMN. These neural changes predicted clinical improvement at the end of treatment beyond early symptom reduction. The results suggest that TMS treatment increases positive bias early on during treatment, and that the neural mechanisms might differ from that of antidepressant drugs.
SYSTEMS AND NETWORK BIOLOGY ANALYSIS COMBINED WITH MACHINE LEARNING IDENTIFIES KEY IMMUNE RESPONSE PROFILES AND POTENTIAL CORRELATES OF PROTECTION FOR THE M72/AS01E TUBERCULOSIS VACCINE
Authors: Taofeek Oluwaseun oluwatosin , Alile Solomon Osarumwense , Elcanah Evans Mauta , Ezediuno Louis Odinakaose , George Ifeoluwa Adeniyi , Oyewole Olawale Moses , Owiti Peter Ngo’la , Sulaimon Lateef Adegboyega
Published: January 2025

Tuberculosis claims around 1.5 million lives annually. The M72/AS01E vaccine candidate is an innovative effort demonstrating a 50% reduction in the incidence of active TB in adults. However, optimization and effective immunization strategies against TB depends heavily on precise identification of specific molecular signatures active in vaccine protection. In this study, we employed weighted gene co-expression network analysis, machine learning and network biology to investigate the gene expression patterns of peripheral blood mononuclear cells, identifying transcriptomic markers of vaccine protection. Our comprehensive exploration of publicly available gene expression dataset comprising samples from subjects vaccinated twice with 10μg of M72/AS01E vaccine one day post-second dose (D31) and one week post-second dose (D37) in a Phase IIA clinical trial revealed intense induction of multiple gene modules, indicative of acute/immediate immune response at D31 that subsided by D37. Thirty-one hub genes with significant elevation/correlation with immune protection were identified significantly mediating key events in immunity to TB. The more selective profile at D37 involved additional adaptive immunity pathways including Th1/Th2/Th17 differentiation, T cell receptor and cytokine signaling. The functional relevance of these biomarkers in predicting vaccine response was further analyzed using the random forest classifier demonstrating high accuracy in distinguishing between vaccinated and non-vaccinated samples. Additionally, the study pinpointed a miRNAs-transcription factors (TF)-target regulatory network excavating key TF, miRNA, mRNAs mediating vaccine protection. Our results provided new insights into immune protection of M72/AS01E vaccine meriting further study aiming to advance its optimization and informing development of future TB vaccines.
Respiratory virus infection dynamics and genomic surveillance to detect seasonal influenza subtypes in wastewater: a longitudinal study in Bengaluru, India
Authors: Daroch Namrta , Subash KK , Srikantaiah Vishwanath , Mishra Rakesh , Ishtiaq Farah
Published: January 2025

Recent global pandemics have been caused by respiratory viruses found in both humans and animals with zoonotic spillover potential. Many respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), influenza A virus (IAV), and influenza B virus (IBV), have overlapping ecology and share similar symptoms. However, respiratory disease surveillance is often passive and relies on testing clinical specimens. Wastewater surveillance has been widely used as an epidemiological tool for early detection of SARS-CoV-2 variants and can differentiate between respiratory virus infections and SARS-CoV-2 peaks at a community level. In this retrospective longitudinal study covering three SARS-CoV-2 Omicron waves, we conducted a monthly sampling for 28 months (812 samples) between August 2021 and December 2023 at 28 sewershed sites in Bengaluru city (∼11 million inhabitants). Using RT-qPCR kits, we quantified SARS-CoV-2 RNA concentrations, IAV, IBV and RSV to understand community viral infection occurrences. We provide evidence of changes in the relative abundance of influenza subtypes and SARS-CoV-2 variants driving emerging peaks in wastewater data. We found 86% of samples positive for SARS-CoV-2, while the positivity rates for influenza virus and RSV were lower (37% for IAV, 16 % for IBV, and 15% for RSV). We observed an increase in influenza viruses in the post monsoon season (August to December) and remained present in January and February, while being practically absent the rest of the year. RSV showed a similar trend to IAV, with comparable quantities. Furthermore, we identified all eight segments of influenza virus genomes and emerging SARS-CoV-2 variants in wastewater samples. Wastewater surveillance provides data on the abundance of respiratory viruses in urban Bengaluru that would not be reported otherwise. Under the One Health framework, wastewater surveillance can offer early warning signs and enhance the traceability of infectious diseases in both wildlife and humans.
Estimating malaria antigen dynamics and the time to negativity of next-generation malaria rapid diagnostic tests
Authors: Sheahan William , Golden Allison , Barney Rebecca , Das Smita , Jang Ihn-Kyung , Ntuku Henry , Wu Xue , Whittemore Brooke , Dausab Lucille , Mumbengegwi Davis , Slater Hannah , Domingo Gonzalo J , Hsiang Michelle S
Published: January 2025

Background

Rapid diagnostic tests (RDTs) used to diagnosePlasmodium falciparum(Pf) predominantly target the antigen Histidine Rich Protein 2 (HRP2) exclusively. With the emergence ofhrp2/hrp3gene deletions, RDTs targeting other antigens such as the essential enzyme Lactate Dehydrogenase (LDH) are needed. The dynamics of LDH relative to HRP2 are currently not well described but are needed to inform the use of next-generation (NG-) LDH and HRP2 RDTs that are designed to addresshrp2/hrp3gene deletions.

Methods

A longitudinal cohort study conducted in a low transmission setting in Namibia was leveraged to compare HRP2 and LDH decay rates. Passive and active case detection were used to recruit individuals with positive HRP2-RDT results. Study participants were treated and subsequently followed weekly until they received two consecutive HRP2-RDT negative results. Blood specimens were characterized for antigen concentration and parasite density. Antigen decay rates were calculated and used to estimate time to negativity (TTN) of NG-RDTs: two HRP2 and LDH-based RDTs (Rapigen Pf and a WHO prequalified Pf/Pv RDT) and an LDH-only RDT (Rapigen Pf/Pv).

Results

In 135 participants, the starting geometric mean concentrations for HRP2 and LDH were 899 ng/mL and 344 ng/mL respectively. Both antigens followed a biphasic decay rate, with a faster decay rate in the first phase. For current RDTs with an analytical sensitivity of 1 ng/mL for HRP2 and 5 ng/mL for LDH, TTN was 44 and 4 days, respectively. With a NG-RDT with LDH analytical sensitivity of 0.37 ng/mL, average TTN was 9 days. Multiple levels of analytical sensitivity were also modeled.

Conclusions

In the detection of Pf malaria, LDH versus HRP2-based RDTs had a faster TTN due to a combination of lower accumulated antigen concentrations and faster decay rates, even for more sensitive LDH-based RDTs. Detection of LDH versus HRP2 by RDT is more likely to reflect a new or very recent infection. For NG-RDTs that target both antigens, HRP2 is likely to contribute more to the test signal than LDH in recently treated infections unless the infection hashrp2/hrp3gene deletions. Antigen decay data combined with analytical sensitivity of RDTs contributes to our understanding of their performance and interpretation.
Evaluation of stochastic trajectory-based epidemic models using the energy score
Authors: Bay Clara , Mu Kunpeng , St-Onge Guillaume , Chinazzi Matteo , Davis Jessica T. , Vespignani Alessandro
Published: January 2025

Scoring rules are critical for evaluating the predictive performance of epidemic models by quantifying how well their projections and forecasts align with observed data. In this study, we introduce the energy score as a robust performance metric for stochastic trajectory-based epidemic models. As a multivariate extension of the continuous ranked probability score (CRPS), the energy score provides a single, unified measure for time-series predictions. It evaluates both calibration and sharpness by considering the distances between individual trajectories and observed data, as well as the inter-trajectory variability. We provide an overview of how the energy score can be applied to assess both scenario projections and forecasts in this format, with a particular focus on a detailed analysis of the Scenario Modeling Hub results for the 2023-2024 influenza season. By comparing the energy score to the widely used weighted interval score (WIS), we demonstrate its utility as a powerful tool for evaluating epidemic models, especially in scenarios requiring integration of predictions across multiple target outcomes into a single, interpretable metric.

Author summary

Epidemic model predictions are often evaluated using scoring rules, such as the weighted interval score (WIS), which require outputs in interval or quantile formats. However, epidemic models often produce outputs as collections of stochastic trajectories, which are then summarized into quantiles for evaluation. In this study, we introduce the energy score as a scoring metric specifically designed for evaluating stochastic trajectories without requiring conversion to other formats. The energy score provides a rigorous assessment by accounting for both the variability among trajectories and their alignment with observed data. Using publicly available data, we demonstrate that the energy score is a reliable and effective metric for evaluating epidemic model predictions in their native stochastic trajectory format.
Artificial Intelligence Generated Computed Tomography Segmentation of the Thoracoabdominal Aorta
Authors: Chatterjee Devina , Obey Nicholas T. , Shou Benjamin , Singh Sangmita , Acuna Higaki Adrian R. , Ahmed Adham , Erez Ely , Cupo Michela , Price Nathaniel , Hameed Irbaz , Schneider Eric B. , Vallabhajosyula Prashanth , Ong Chin Siang
Published: January 2025

Objectives

The rising global burden of cardiovascular diseases (CV) highlights the critical need for efficiency in disease diagnosis and management. An important area for such improvement is utilization of artificial intelligence (AI) for streamlining time and resources in CV imaging workflow. We evaluate the performance of artificial intelligence (AI) segmentation for aortic segmentation on clinical computed tomography angiography (CTA) images and compare accuracy to manual methods. Such automation would markedly improve efficiency and accuracy of aortic surveillance.

Methods

This retrospective study included 27 scans from 20 patients who underwent thoracic endovascular aortic repair (TEVAR) between January 2020 and March 2022. An open-source AI model was applied to segment the aorta, and its performance was assessed by comparing AI-generated segmentations with manual segmentations using Dice similarity coefficients, volumetric analysis, and aortic dimensions. Centerline reconstructed images of thoracoabdominal aorta were processed to extract radiomic features, including maximum diameter and cross-sectional area, for analysis.

Results

The AI tool achieved a median Dice coefficient of 0.96 (0.02), indicating a high degree of concordance with manual segmentation. Multiplanar reconstruction was performed to visualize the aorta and extract measurements along its length using the automated centerline, and radiomic features, including maximum diameter and cross-sectional area, were subsequently extracted for analysis.

Conclusions

AI segmentation demonstrates strong potential for improving efficiency and consistency in thoracoabdominal aortic segmentation, achieving high accuracy compared to manual methods. These findings highlight the feasibility of AI integration into clinical practice for diagnosis and surveillance of aortopathies, warranting further validation on larger datasets to enable clinical translation.

Graphical Abstract
Genomic Resources for the Scuttle Fly Megaselia abdita: A Model Organism for Comparative Developmental Studies in Flies
Authors: Tenger-Trolander Ayse , Amiri Ezra , Gantz Valentino , Kwan Chun Wai , Sanders Sheri A , Schmidt-Ott Urs
Published: January 2025

The order Diptera (true flies) holds promise as a model taxon in evolutionary developmental biology due to the inclusion of the model organism, Drosophila melanogaster, and the ability to cost-effectively rear many species in laboratories. One of them, the scuttle fly Megaselia abdita (Phoridae) has been used in the field of evolutionary developmental biology for 30 years and is an excellent phylogenetic intermediate between fruit flies and mosquitoes but remains underdeveloped in genomic resources. Here, we present a de novo chromosome-level assembly and annotation of M. abdita and transcriptomes of 9 embryonic and 4 postembryonic stages. We also compare 9 stage-matched embryonic transcriptomes between M. abdita and D. melanogaster. Our analysis of these resources reveals extensive chromosomal synteny with D. melanogaster, 28 orphan genes with embryo-specific expression including a novel F-box LRR gene in M. abdita, and conserved and diverged features of gene expression dynamics between M. abdita and D. melanogaster. Collectively, our results provide a new reference for studying the diversification of developmental processes in flies.
Reduced Dietary Protein Induces Changes in the Dental Proteome
Authors: Burroughs Robert W. , Percival Christopher J. , Vitek Natasha S.
Published: January 2025

Experimental studies have demonstrated that nutritional changes during development can result in phenotypic changes to mammalian cheek teeth. This developmental plasticity of tooth morphology is an example of phenotypic plasticity. Because tooth development occurs through complex interactions between manifold processes, there are many potential mechanisms which can contribute to a tooth’s norm of reaction. Determining the identity of those mechanisms and the relative importance of each of them is one of the main challenges to understanding phenotypic plasticity. Quantitative proteomics combined with experimental studies allow for the identification of potential molecular contributors to a plastic response through quantification of expressed gene products. Here, we present the results of a quantitative proteomics analysis of mature upper first molars (M1s) inMus musculusfrom a controlled feeding experiment. Pregnant and nursing mothers were fed either a low-dietary protein (10%) treatment diet or control (20%) diet. Expression of tooth-related proteins, immune system proteins, and actin-based myosin proteins were significantly altered in our low-dietary protein sample. The recovery of expression change in tooth development proteins was anticipated and consistent with previous proteomic studies. We also identified differential immune protein response along with systematic reduction in actin-based myosin protein expression, which are novel discoveries for tooth proteomics studies. We propose that studies which aim to elucidate specific mechanisms of molar phenotypic plasticity should prioritize investigations into the relationships between IGF regulation and tooth development and actin-based myosin expression and tooth development.

Research Highlights

A low-protein diet during development results in significantly altered protein expression for major dental building proteins, immune system proteins, and actin-based myosin proteins withinMus musculus.

Graphical Abstract
Narrative ‘twist’ shifts within-individual neural representations of dissociable story features
Authors: Sava-Segal Clara , Grall Clare , Finn Emily S.
Published: January 2025

Given the same external input, one’s understanding of that input can differ based on internal contextual knowledge. Where and how does the brain represent latent belief frameworks that interact with incoming sensory information to shape subjective interpretations? In this study, participants listened to the same auditory narrative twice, with a plot twist in the middle that dramatically shifted their interpretations of the story. Using a robust within-subject whole-brain approach, we leveraged shifts in neural activity between the two listens to identify where latent interpretations are represented in the brain. We considered the narrative in terms of its hierarchical structure, examining how global situation models and their subcomponents–namely, episodes and characters–are represented, finding that they rely on partially distinct sets of brain regions. Results suggest that our brains represent narratives hierarchically, with individual narrative elements being distinct and dynamically updated as a part of changing interpretations of incoming information.
Krüppel-like Factors Play Essential Roles in Regulating Pluripotency and the Formation of Neural Crest Stem Cells
Authors: Rigney Sara , York Joshua R. , LaBonne Carole
Published: January 2025

The evolutionary transition from simple chordate body plans to complex vertebrate body plans was driven by the acquisition of the neural crest, a stem cell population that retains broad, multi-germ layer developmental potential long after most embryonic cells have become lineage restricted. We have previously shown that neural crest cells share significant gene regulatory architecture with pluripotent blastula stem cells. Here we examine the roles that Krüppel-like Family (Klf) transcription factors play in these stem cell populations. Although Klf4 has established roles in regulating pluripotency in mammalian stem cells cultures, we find that inXenopusit isklf2that is highly expressed in pluripotent blastula stem cells.klf2expression is down-regulated as cells transition to a neural crest state while a related klf factor, klf17, is significantly up regulated in response to neural crest induction. We used gain and loss of function studies to compare the activities of these closely related factors and found that they have both shared and distinct activities. Inhibition of either klf2 or klf17 activity led to significantly expanded expression of pluripotency, neural plate border and neural crest factors in neurula stage embryos, leading us to hypothesize that klf factors regulate the exit from pluripotency and proper establishment of the boundary of the neural crest domain. To gain further insights into the role of klf factors in the evolution of the neural crest, we examined their expression in the jawless vertebrate,Petromyzon marinus (sea lamprey). We find that lamprey have aklf2/4and aklf17gene, but that onlyklf17is expressed in blastula and neural crest stem cells. Moreover, ectopic expression of lampreyklf17inXenopusembryos phenocopiesXenopus klf17activity. These data suggest that klf17, rather than klf4, may have been the ancestral klf factor that functioned in these GRNs in stem vertebrates.
Eyes-closed resting state EEG reveals clearer and more stable group differences between autistic and neurotypical individuals than eyes-open resting state EEG
Authors: Xiao Wenyi , Jones Myles , Milne Elizabeth , Dede Adam J.O
Published: January 2025

Background

Resting-state electroencephalography (rs-EEG) has been widely used to explore neural dynamics in Autism Spectrum Condition (ASC). However, inconsistencies in findings across studies remain a challenge, partly due to variations in brain state, such as eye conditions (eyes-open vs. eyes-closed). This study aims to examine rs-EEG differences between ASC and neurotypical (NT) participants, focusing on the influence of eye condition.

Methods

A total of 300 participants (126 ASC) were included. Rs-EEG data were analysed across eyes-open, eyes-closed, and difference between eye conditions, with 726 variables assessed per participant. Linear regression and effect size (η2partial) were used to identify group differences, complemented by cluster-based permutation testing and bootstrapped split-half validation for reliability.

Results

Group differences were most pronounced in the eyes-closed condition, particularly for relative power and multiscale entropy (MSE). Compared to neurotypical participants, ASC participants exhibited reduced frontal coarse-scale MSE, increased delta power, and decreased alpha power, suggesting altered local-global neural dynamics. Cross-validation revealed greater reliability of effects in the eyes-closed condition compared to eyes-open or difference between eye conditions.

Conclusions

Eye condition plays a critical role in detecting rs-EEG differences between ASC and NT groups, with the eyes-closed condition yielding more consistent and pronounced effects. These findings highlight the importance of controlling brain state in rs-EEG studies and suggest that integrating eye condition effects with other biomarkers may improve identification of neural differences associated with ASC.
Individualized Phenotyping of Functional ALS Pathology in Sensorimotor Cortex
Authors: Kalyani Avinash , Northall Alicia , Schreiber Stefanie , Brüggemann Jascha , Vielhaber Stefan , Al Dubai Marwa , Benramadan Abrar , Mattern Hendrik , Speck Oliver , Reichert Christoph , Kuehn Esther
Published: January 2025

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in primary motor cortex (MI), leading to muscle weakness, atrophy, and death within a median of three years. Even though ALS is characterized by different disease subtypes affecting different body parts, individiualized phenotyping of functional ALS pathology has so far not been achieved. We recorded 7 Tesla functional MRI (7T-fMRI) data while ALS patients and matched controls moved affected and non-affected body parts in the MR scanner. We applied robust Shared Response Modeling (rSRM) for capturing ALS-specific shared responses for group classification, and Partial Least Squares (PLS) regression for relating the latent variables to clinical subtypes and the degree of disease progression. We show that both functional connectivity and functional activation in MI are a predictor for disease onset site. However, disease severity could best be predicted by functional connectivity rather than pure activation changes. Critically, we show that functionally disease-defining information in MI is not strongest in the area that is behaviorally first-affected, deviating from the behavioral phenotype of the patients. When computing the model’s weight distribution of the King stage classification and projecting them back into voxel space, the highest mean weights are present in the foot and tongue/face regions that seem to drive disease progress. Our data highlight the importance of 7T-fMRI task-based functional connectivity measures for classifying ALS-patients, and provide evidence that a single 7T-MRI scan can be used for identifying a disease signature of each individual ALS patient.
ATR, a DNA damage kinase, modulates DNA replication timing inLeishmania major
Authors: da Silva Gabriel L. A. , Damasceno Jeziel D. , Black Jennifer A. , McCulloch Richard , Tosi Luiz R. O.
Published: January 2025

All cells possess mechanisms to maintain and replicate their genomes, whose integrity and transmission are constantly challenged by DNA damage and replication impediments. In eukaryotes, the protein kinase Ataxia-Telangiectasia and Rad3-related (ATR), a member of the phosphatidylinositol 3-kinase-like family acts as a master regulator of the eukaryotic response to DNA injuries, ensuring DNA replication completion and genome stability. Here we aimed to investigate the functional relevance of the ATR homolog in the DNA metabolism ofLeishmania major, a protozoan parasite with a remarkably plastic genome. CRISPR/cas9 genome editing was used to generate a Myc-tagged ATR cell line (mycATR), and a Myc-tagged C-terminal knockout of ATR (mycATRΔC-/-). We show that the nuclear localisation of ATR depends upon its C-terminus. Moreover, its deletion results in single-stranded DNA accumulation, impaired cell cycle control, increased levels of DNA damage, and delayed DNA replication restart after replication stress. In addition, we show that ATR plays a key role in maintainingL. major’sunusual DNA replication program, where larger chromosomes duplicate later than smaller chromosomes. Our data reveals loss of the ATR C-terminus promotes the accumulation of replication signal around replicative stress fragile sites, which are enriched in larger chromosomes. Finally, we show that these alterations to the DNA replication program promote chromosome instability. In summary, our work shows that ATR acts to moderate DNA replication timing thus limiting the plasticity of theLeishmaniagenome.
ATG-3 limits Orsay virus infection inC. elegansthrough regulation of collagen pathways
Authors: Kalugotla Gowri , Marmerstein Vivien , Schriefer Lawrence A. , Wang Leran , Morrison Stephanie , Perez Luis Casorla , Schedl Tim , Pak Stephen C. , Baldridge Megan T.
Published: January 2025

Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay virus infection ofCaenorhabditis elegans. Orsay virus infection does not modulate autophagic flux, and re-feeding after starvation limits Orsay virus infection and blocks autophagic flux, suggesting that the role of ATG-3 in Orsay virus susceptibility is independent of its role in maintaining autophagic flux.atg-3mutants phenocopyrde-1mutants, which have a defect in RNA interference (RNAi), in susceptibility to Orsay virus infection and transcriptional response to infection. However,atg-3mutants do not exhibit defects in RNAi. Additionally,atg-3limits viral infection at a post-entry step, similar torde-1mutants. Differential expression analysis using RNA sequencing revealed that antiviralsqt-2, which encodes a collagen trimer protein, is depleted in naïve and infectedatg-3mutants, as well as in infected WT animals, as are numerous other collagen genes. These data suggest that ATG-3 has a role in collagen organization pathways that function in antiviral defense inC. elegans.
Interindividual differences in caries potential of the salivary microbiome after mouthwash exposure
Authors: Mermans Fabian , Poelman Britt , Saghi Mehraveh , Teughels Wim , Boon Nico
Published: January 2025

Prevention and treatment of dental caries is often achieved by fluoride mouthwashes. The most common forms of fluoride are Stannous fluoride (SnF2), amine fluoride (AmF) and sodium fluoride (NaF), each with differing activities against oral bacteria. Additionally, differences in oral microbiome between individuals are linked to differences in response to treatment and the phenotype of the microbiome can provide information on this response. Flow cytometry can successfully track microbial phenotypic heterogeneity and may prove useful for capturing the response to treatment. In this study, we compared the effect of three fluoride-containing mouthwashes, Elmex Anti Caries (AmF/NaF), Listerine Anticaries (NaF) and Meridol (AmF/SnF2), on the salivary microbiome and assessed their anticaries potential. Furthermore, we investigated if the flow cytometric fingerprint could be used to capture the response to treatment. Saliva samples of different donors were treated with the mouthwashes and the intact salivary community composition was assessed using 16S rRNA gene amplicon sequencing. Treated saliva samples were incubated in sucrose-rich medium to assess the organic acid production of the remaining microbiota. Moreover, flow cytometric fingerprints of the intact microbial population were used to track the response to treatment and to train a random forest classifier predicting the most suitable mouthwash for the donor. We found a mouthwash-dependent shift in the salivary microbiome composition and found different anticaries potential of the mouthwashes. Meridol affected more bacterial taxa and had the best overall anticaries potential, followed by Elmex. Finally, the response to treatment could be captured in the flow cytometric fingerprint of the initial intact salivary microbiota and a random forest classifier predicting the most suitable mouthwash for the donor was successfully trained.
CO2-dependent opening of Connexin 43 hemichannels
Authors: Dospinescu Valentin-Mihai , Mascarenhas Alexander , Butler Jack , Nijjar Sarbjit , de Oliveira Taborda Kyara , Connors Sean , Huang Lumei , Dale Nicholas
Published: January 2025

Sequence and structure comparisons between alpha and beta connexins, Cx43 and Cx26, revealed that Cx43 has a motif, the carbamylation motif, that confers CO2-sensitivity on a subset of beta connexins. By using a fluorescent dye loading assay, whole cell patch clamp recordings and real time measurement of ATP release via GRABATPwe have demonstrated that Cx43 hemichannels open in a highly CO2sensitive manner over the range 20 to 70 mmHg. Mutational analysis confirms that the equivalent residues to those in Cx26 that have been shown to be involved in mediating the effects of CO2on gating of hemichannels and gap junction channels, also mediate Cx43 hemichannel gating. Our data predicts that Cx43 will be partially open and able to release ATP at resting physiological levels of PCO2. We have tested this prediction in acute hippocampal slices, by showing that CO2-dependent enhancement of synaptic transmission can be blocked by the Cx43-selective mimetic peptide Gap26. Our data resolves an inconsistency in the literature betweenin vivostudies suggesting that Cx43 hemichannels are at least partially open at rest, andin vitrostudies, performed in the absence of HCO3−/CO2buffering that show Cx43 hemichannels are shut. Our evidence suggests that the ancestral gene that duplicated to give the alpha and beta connexin clades must have possessed the carbamylation motif. CO2sensitivity is thus a fundamental ancient characteristic of several connexins that has been lost in more recently derived members of this gene family.
Cerebellar transcranial alternating current stimulation in the theta band facilitates extinction of learned fear responses
Authors: Thieme Andreas , Spisak Zsofia , Zeidan Philippe , Klein Michael , Nio Enzo , Ernst Thomas M. , Diekmann Nicolas , Göricke Sophia , Cheng Sen , Merz Christian J. , Yavari Fatemeh , Nitsche Michael A. , Batsikadze Giorgi , Timmann Dagmar
Published: January 2025

Fear extinction is a major component of exposure therapy for anxiety disorders. There is initial evidence that the cerebellum contributes to fear extinction learning, i.e., the ability to learn that certain stimuli are no longer associated with an aversive outcome. So far, however, knowledge of the cerebellum’s role in extinction is scarce. In the present study, 6 Hz cerebellar transcranial alternating current stimulation (ctACS) was used to modulate cerebellar function during extinction learning in young and healthy human participants in an MRI study. A two- day differential fear conditioning paradigm was used with acquisition and extinction training being performed on day 1, and fear extinction recall being tested on day 2. 6 Hz ctACS reduced spontaneous recovery of the initial fear association during recall, stabilizing extinction effects compared to sham ctACS. fMRI data during recall revealed significantly reduced activation in cortical areas involved in initial fear acquisition, such as the anterior cingulate and insula, in the verum ctACS group compared to the sham group. During extinction training, on the other hand, the verum group exhibited more widespread cerebral activation compared to the sham group. Group differences were significant in occipital cortical areas. Although direct stimulation effects cannot be excluded, increased activation in the visual cortex may reflect enhanced encoding and processing of visual information during fear extinction learning. The findings suggest that theta-range oscillatory interactions between the cerebellum and cortical areas support extinction processes and provide causal evidence of the cerebellar role in the human fear extinction network.

Significance Statement

While the cerebellum is well known for its role in associative learning, its contribution to fear extinction learning remains underexplored. This study used 6 Hz cerebellar transcranial alternating current stimulation (ctACS) to modulate cerebellar function during extinction training in healthy participants. The present data demonstrate that ctACS enhances cerebral cortical activation during extinction training which is followed by enhanced recall of the extinction memory and subsequently reduced activation of cerebral cortical areas associated to spontaneous recovery of fear memory. These findings provide causal evidence for the cerebelluar involvement in the human fear extinction network and suggest that enhancing cerebellar theta oscillations may be useful to support exposure therapy.
Life as a Function: Why Transformer Architectures Struggle to Gain Genome-Level Foundational Capabilities
Authors: Hassan Hassan , Puhger Kyle , Saadat Ali , Sprang Maximilian
Published: January 2025

Recent years have seen a flurry of generative nucleotide models, mostly of limited utility. In this paper, we use the functional representation of DNA as a complex, composite function on the plane of evolution to extend the theoretical unification of ecological and evolutionary change to the problem of synthetic DNA models. Through experiments on synthetic and real DNA sequences we show that next-token prediction decoder transformer architectures are limited in their capacity to learn such functions.
Continual familiarity decoding from recurrent connections in spiking networks
Authors: Zemliak Viktoria , Pipa Gordon , Nieters Pascal
Published: January 2025

Familiarity memory enables recognition of previously encountered inputs as familiar without recalling detailed stimuli information, which supports adaptive behavior across various timescales. We present a spiking neural network model with lateral connectivity shaped by unsupervised spike-timing-dependent plasticity (STDP) that encodes familiarity via local plasticity events. We show that familiarity can be decoded from network activity using both frequency (spike count) and temporal (spike synchrony) characteristics of spike trains. Temporal coding demonstrates enhanced performance under sparse input conditions, consistent with the principles of sparse coding observed in the brain. We also show how connectivity structure supports each decoding strategy, revealing different plasticity regimes. Our approach outperforms LSTM in temporal generalizability on the continual familiarity detection task, with input stimuli being naturally encoded in the recurrent connectivity without a separate training stage.
Courtship vocalizations in male ducks: spectral composition and resonance of the syringeal bulla
Authors: Mishkind Darcy , Lester Michael , Tabin Clifford J. , Goller Franz
Published: January 2025

Ducks display a unique and dramatic sexual dimorphism in their vocal organ, the syrinx. Males have a left-sided bulla that is not present in females and that has been long hypothesized to play a role in courtship vocalizations, though this connection has never been tested. The large, hollow morphology of the bulla and its proximity to the sound-producing vocal folds introduce the possibility that it may work as a Helmholtz resonator, which makes it possible to predict the resonance frequencies enhanced by this structure. We find that during early ontogeny, the distribution of energy across the harmonic spectrum of contact calls is not different between males and females. We then used micro-CT scans of duck syrinxes to estimate resonance frequencies of the bullae and compared these to spectral features of their vocalizations. This comparison overall supports the idea that the bulla resonance may specifically enhance aspects of courtship vocalizations, especially in species that have a tonal courtship whistle. We also see potential influence in non-courtship vocalizations, which could be explored further with a greater understanding of the input of other vocal tract features that influence vocalization. We observed that bulla size is positively correlated with bird body mass with the largest exception in the Common Eider, which had a small bulla for its body mass and for which we saw no evidence of bulla-input to its vocalizations. This study found support for the long-held hypothesis that the adult male duck bulla influences resonance frequencies, in particular in courtship vocalizations.
Insights into the FOXE3 Transcriptional Network and Disease Mechanisms from the Investigation of a Regulatory Variant Driving Complex Microphthalmia
Authors: Plaisancié Julie , Angée Clémentine , Erjavec Elisa , Raymond-Letron Isabelle , Douet Jean-Yves , Goetz Mathilde , Vincent-Delorme Catherine , Karemaker Ino D. , Baltissen Marijke , Vermeulen Michiel , Valdivia Leonardo , Jabot-Hanin Fabienne , David Pierre , Hadjadj Djihad , Monsef Yanad Abou , Lyazrhi Faouzi , Calvas Patrick , Rozet Jean-Michel , Chassaing Nicolas , Fares-Taie Lucas
Published: January 2025

FOXE3encodes a conserved, lens-specific transcription factor essential for eye development. Biallelic mutations inFOXE3lead to a spectrum of ocular anomalies, from cataracts to complex microphthalmia (CM), with clinical severity correlating to genotype. In a CM case with a truncating mutation (p.Cys240*), we identified a regulatory variant (rv, rs745674596 G>A) 3 kb upstream ofFOXE3. Mouse models harboring either the rv or a frameshift mutation were generated in homozygosity (Foxe3rv/rv, Foxe3-/-) and compound heterozygosity (Foxe3rv/Foxe3-). Phenotypic analysis revealed progressive severity: Foxe3rv/rv mice exhibited cataracts and anterior segment dysgenesis, Foxe3rv/Foxe3-displayed more severe anomalies, andFoxe3-/-mice consistently developed CM. These findings align with human genotype-phenotype relationships. Notably, a direct correlation between protein levels and ocular phenotype was observed, with no association to mRNA levels. In Foxe3-/- mice, CM resulted from early disorganization of the anterior lens epithelium, leading to degeneration and ocular involution. Transcription factor binding assays identified USF2 as a key regulator ofFOXE3expression, positioning USF2 as a promising candidate in ocular development and disease, enhancing our understanding of the FOXE3-related network. This study underscores the importance of integrated approaches to identify genetic variants and cis-regulatory elements, revealing a novel mechanism for microphthalmia through degeneration and involution.
A V-ATPase complex, required for biogenesis of a lysosome-related organelle (LRO) inTetrahymena thermophila, disassembles during LRO maturation
Authors: Pradhan Ajay , Tadasare Niraj , Sarkar Debolina , Bansal Lavan K. , Turkewitz Aaron P. , Kumar Santosh
Published: January 2025

In the ciliateTetrahymena thermophila, a subset of proteins are exocytosed via lysosome-related organelles (LROs) called mucocysts. Formation of many LROs depends on modulation of pH by vacuolar-type ATPases (V-ATPases). Here, we used expression profiling to identify a V-ATPase a-subunit that is targeted to mucocysts. Cells lacking theV-ATPase-a1gene are defective in mucocyst biogenesis and exocytosis. However, the requirement for this subunit may not be limited to the canonical role of V-ATPases in proton pumping, since we find no evidence that mature mucocysts are acidified. Consistent with this, we find that while the a1-subunit is present in both immature and mature mucocysts, several other V-ATPase subunits are absent from the latter. These data suggest that the V-ATPase complex disassembles during mucocyst maturation, and that the a1-subunit performs roles independent of the holo-complex. Cells lacking the a1-subunit are defective in the targeting of both structural and enzymatic mucocyst proteins, and moreover appear deficient in fusion between vesicles from the secretory and endocytic pathways that is a feature of normal mucocyst maturation.
DUSP12 promotes cell cycle progression and protects cells from cell death by regulating ZPR9
Authors: Abdusamad Mai , Guo Xiao , Ramirez Ivan , Velasquez Erick F. , Cohn Whitaker , Gholkar Ankur A. , Whitelegge Julian P. , Torres Jorge Z.
Published: January 2025

Protein phosphatases are critical for regulating cell signaling, cell cycle, and cell fate decisions, and their dysregulation leads to an array of human diseases like cancer. The dual specificity phosphatases (DUSPs) have emerged as important factors driving tumorigenesis and cancer therapy resistance. DUSP12 is a poorly characterized atypical DUSP widely conserved throughout evolution. Although no direct substrate has been firmly established, DUSP12 that has been implicated in protecting cells from stress, regulating ribosomal biogenesis, and modulating cellular DNA content. In this study, we used affinity- and proximity-based biochemical purification approaches coupled to mass spectrometry to identify the zinc finger protein ZPR9 as a novel DUSP12 interactor, which was validated by in-cell andin-vitroIP assays. Interestingly, ZPR9 binds to the unique zinc-binding domain of DUSP12, which previous reports indicated was important for many of DUSP12’s functions within the cell. Prior studies had implicated ZPR9 as a modulator of apoptosis, but it remained unclear if and how ZPR9 participated in the cell cycle and, more so, how it promoted cell death. Using mass spectrometry analyses, we found that overexpression of DUSP12 promoted de-phosphorylation of ZPR9 at Ser143. Overexpression of ZPR9, but not Ser143phosphomimetic and phosphorylation-deficient mutants, led to an increase in pre-metaphase mitotic defects while knockdown of DUSP12 also showed mitotic defects in metaphase. Furthermore, knockdown of DUSP12 promoted, while knockdown of ZPR9 suppressed, stress-induced apoptosis. Our results support a model where DUSP12 protects cells from stress-induced apoptosis by promoting de-phosphorylation of ZPR9.