bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate Neural Markers of Individual Differences in Thought Control Difficulties
Authors: DeRosa Jacob , Smolker Harry R. , Kim Hyojeong , Groff Boman , Peacock Jarrod Lewis- , Banich Marie T.
Published: February 2025

Difficulties in controlling thought, including pathological rumination, worry, and intrusive thoughts, occur in a range of mental health disorders. Here we identify specific patterns of brain activity distributed within and across canonical brain networks that are associated with self-reported difficulties in controlling one’s thoughts. These activity patterns were derived using multivariate pattern analysis on fMRI data recorded while participants engaged in one of four operations on an item in working memory: maintaining it, replacing it with another, specifically suppressing it, or clearing the mind of all thought. Individuals who reported greater difficulties exhibited brain activation patterns that were more variable and less differentiated across the four operations in frontoparietal and default mode networks, and showed less distinct patterns of connectivity within the default mode network. These activity profiles were absent during rest but serve as promising task-based neural markers, explaining over 30% of the variance in thought control difficulties.
Seq-Scope-eXpanded: Spatial Omics Beyond Optical Resolution
Authors: Anacleto Angelo , Cheng Weiqiu , Feng Qianlu , Cho Chun-Seok , Hwang Yongha , Kim Yongsung , Si Yichen , Park Anna , Hsu Jer-En , Schrank Mitchell , Teles Rosane , Modlin Robert L. , Plazyo Olesya , Gudjonsson Johann E. , Kim Myungjin , Kim Chang H. , Han Hee-Sun , Kang Hyun Min , Lee Jun Hee
Published: February 2025

Sequencing-based spatial transcriptomics (sST) enables transcriptome-wide gene expression mapping but falls short of reaching the optical resolution (200–300 nm) of imaging-based methods. Here, we present Seq-Scope-X (Seq-Scope-eXpanded), which empowers submicrometer-resolution Seq-Scope with tissue expansion to surpass this limitation. By physically enlarging tissues, Seq-Scope-X minimizes transcript diffusion effects and increases spatial feature density by an additional order of magnitude. In liver tissue, this approach resolves nuclear and cytoplasmic compartments in nearly every single cell, uncovering widespread differences between nuclear and cytoplasmic transcriptome patterns. Independently confirmed by imaging-based methods, these results suggest that individual hepatocytes can dynamically switch their metabolic roles. Seq-Scope-X is also applicable to non-hepatic tissues such as brain and colon, and can be modified to perform spatial proteomic analysis, simultaneously profiling hundreds of barcode-tagged antibody stains at microscopic resolutions in mouse spleens and human tonsils. These findings establish Seq-Scope-X as a transformative tool for ultra-high-resolution whole-transcriptome and proteome profiling, offering unparalleled spatial precision and advancing our understanding of cellular architecture, function, and disease mechanisms.
rplec: An R package of placental epigenetic clock to estimate aging by DNA-methylation-based gestational age
Authors: Sufriyana Herdiantri , Su Emily Chia-Yu
Published: February 2025

Background

Latest placental epigenetic clocks (PlECs) were claimed to be robust when applied to cases with either maternal or fetal adverse conditions. However, the accuracies in estimating gestational age (GA) were lower in earlier trimesters. We aimed to develop an R package of PlEC to estimate aging by DNA-methylation-based GA (DNAm-GA).

Methods

We utilized 1742 samples of placental DNA methylation, provided by the 2024 Placental Clock DREAM Challenge. Our PlEC was trained using only used beta values at the common CpG sites in either the Infinium HumanMethylation-450 (n=930)/-850 BeadChip arrays (n=912) from Illumina, in which 100 samples were used for the validation set. External validation was independently evaluated by the challenge organizer using a publicly-unavailable test set (n=384). Elastic regression was applied to develop a three-stage prediction model to estimate: (1) DNAm-GA among normal samples; (2) first residual DNAm-GA among samples with known phenotypes that were leading to earlier termination; and (3) second residual DNAm-GA depending on the estimated GA from the previous stages. An R package was developed to simplify our scikit-learn models into a single function and to utilize DNAm-GA for placental aging study.

Results

Our PlEC required beta values at 10,433 CpG sites and achieved the top performance in the validation set. Based on the test set, the root mean squared-error (RMSE) was 1.245 weeks. The RMSE for preterm samples were lower (0.558, 95% confidence interval [CI] 0.545, 0.570) compared to the two previous PlECs using the common dataset: (1) Lee et al (1.696, 95% CI 1.667, 1.724); and (2) Mayne et al (4.018, 95% CI 3.927, 4.108). We developedrplecR package with only two functions for preprocessing input and estimating DNAm-GA and two functions for conducting quality control and utilizing DNAm-GA for placental aging study. The simplified version of PlEC achieved similar performance with the original scikit-learn model with RMSE 0.102 (95% CI 0.101, 0.104), which was reasonably imperfect since Python and R handle floating/decimal numbers, differently.

Conclusions

Our R package precisely estimated DNAm-GA and our analytical framework could utilize DNAm-GA for placental aging study. Our PlEC also allows individual assessment of placental aging in clinical settings via the residual DNAm-GA. Future studies are needed to refine the first residual GA estimation and reduce the number of predictors while maintaining the accuracy.
Factors Influencing Phenomic Prediction: A Case Study on a Large Sorghum BCNAM Population
Authors: Bienvenu Clement , Garin Vincent , Salas Nicolas , Thera Korotimi , Tekete Mohamed Lamine , Sarathjith Madathiparambil Chandran , Diallo Chiaka , Berger Angelique , Catalayud Caroline , De Bellis Fabien , Rami Jean Francois , Vaksmann Michel , Segura Vincent , Pot David , De Verdal Hugues
Published: February 2025

Plant breeding efficiency is crucial to develop varieties able to cope with climate change and support food and feed value chains. Genomic prediction (GP) has been a major step in increasing this efficiency and is now routinely used in breeding programs. Recently, phenomic prediction (PP) has gained attention as a promising complementary approach to GP, further increasing the breeding programs efficiency. Factors impacting the predictive ability (PA) of PP have been studied on many species but are not fully clarified. In this context, we studied the impacts of spectra pre-processing, prediction methods, population structure, training set size, NIRS acquisition environment and wavelength selection on a large multi-parental sorghum population including 2498 genotypes. Our results show that PP can compete with GP, that it is less affected by population structure, and can reach its maximal PA with smaller training sets than GP, but its performances are trait dependant. We also show that NIRS can be acquired in a reference environment to perform prediction in other environments and that it is possible to randomly select as little as 10 wavelengths to perform predictions. Finally, we show that spectra pre-processing, and statistical methods have a limited and unclear impact on PA. Our study confirms that PP is a relevant trait prediction method that deserves attention to optimize breeding schemes. The main challenges for the future will be to better understand the information contained in the spectra and disentangle their genetic and proxy components to optimize the use of PP in breeding programs.
Flowers as fungal extended phenotypes: nectar yeasts obfuscate among-plant differences in nectar sugar concentration
Authors: Herrera Carlos M. , Alonso Conchita
Published: February 2025

Nectar-dwelling yeasts modulate the ecology of interactions between flowers and pollinators. We evaluate here the hypothesis that floral nectar traits, which are a central element in most plant-pollinator relationships, can largely represent the extended fungal phenotypes of nectar-dwelling yeasts. The following specific question is addressed, Do local genotypes of the specialist nectar yeastMetschnikowia reukaufiihave the ability to obfuscate intrinsic individual variation amongHelleborus foetidusplants in nectar sugar concentration ? An array of paired plant-yeast genotypes mimicking a natural field situation was created in the laboratory by inoculating field-collected nectar from different plant individuals with distinct yeast genotypes following a factorial design. Chemical analyses of nectar sugars before and after exposure to yeasts were performed using ion exchange high performance liquid chromatography. Plant individual, yeast genotype, and their interaction all had strong, significant effects on sucrose concentration ofH. foetidusnectar. Yeasts abolished 79% of intrinsic variance among plants in nectar sucrose concentration and profoundly reshaped patterns of intrinsic among-plant variation. Our results support the hypothesis that among-plant variation in nectar sugar concentration found by pollinators in the field can sometimes reflect the extended phenotypes of nectar yeasts more closely than intrinsic differences among the plants themselves.
Statistics in biology: a survey of the three major multidisciplinary journals
Authors: Mazoit Jean Xavier
Published: February 2025

This article presents the results of a survey of the three major multidisciplinary journals (Nature, Proceedings of the National Academy of Science, Science). Fifty articles involving experiments necessitating the agreement of an ethics committee were searched in each of the three journals to June 30th 2023. Because PNAs announced that a Statistical Review Committee was created and working since September 2023, a further set of 50 articles was retrieved and analyzed from 2024 January 1st. The following items were checked in articles: an explicit statement of approval from an animal ethics committee, the calculation of the appropriate samples size needed and how randomization and blinding were performed, the minimum sample size reported, the presence of repeats, and the methods used to limit type I and type II errors.

No clear experimental design was fully reported in any article. The major problems were 1) extremely small sample sizes (<4/group) in nearly half of the articles, 2) confusion between biological repeats and technical replications, and 3) lack of correction for multiple comparisons. These errors led to major inflation of type I and type II errors.

In conclusion, only 10 percent of the articles analyzed presented correct statistical methodology.
Near-cognate tRNAs dominate codon decoding times in simulated ribosomes
Authors: Hedayioglu Fabio , Mead Emma J. , Kurusamy Sathishkumar , Thaventhiran James E.D. , Willis Anne E. , Smales C. Mark , von der Haar Tobias
Published: February 2025

The codon sequence of messenger RNAs affects ribosome dynamics, translational control, and transcript stability. Here we describe an advanced computational modelling tool and its application to studying the effect of different tRNA species on the codon decoding process. We show that simulated codon decoding times are sensitive to the abundance of near-cognate tRNA species as well as cognate species, an aspect of the decoding system that is not fully considered in other computational modelling studies. We demonstrate that codon decoding times predicted by models that accurately define near-cognate tRNAs and that are parameterised with high-quality tRNA abundance datasets are highly similar to ribosome dwell times determined using experimental ribosome footprinting data, thereby confirming both the importance of near-cognate tRNAs for the codon decoding process and the general accuracy of our modelling tools.
ANALYSIS OF THE IMPACT OF FIVE METHANE–MITIGATING FEED ADDITIVES ON MILK PRODUCTION AND ASSOCIATED PARAMETERS ACROSS MULTIPLE COMMERCIAL DAIRY FARMS
Authors: Altshuler Yaniv , Chebach Tzruya Calvao , Cohen Shalom , Gatica Joao
Published: February 2025

The effect of methane–mitigating feed additives on dairy cows has been widely explored; however, confusing conclusions have been reached due to factors such as the inclusion of different doses and experimental conditions in which the additives are tested, or even a small sample size. We present the first extensive study assessing the effects of methane–mitigating feed additives on milk production across several commercial dairy farms. This study used a previously developed predictive AI–driven model based on microbiome samples; the model predicts farms where a significant reduction of methane emissions is expected due to the applied feed additives. Thus, in this study, each feed additive was supplied to a large number of farms, widely distributed across different climatic areas in Israel. The data analysis followed two simulated scenarios: (1) a naive approach, where feed additives are supplied indiscriminately, and (2) an optimized approach, where feed additives are supplied only to farms with a high likelihood of being positively impacted in terms of reduced enteric methane emissions (50% of the farms). The results show that each feed additive significantly increased milk production compared to the control groups. This increase in milk production was significantly higher in the optimized scenario. Other related parameters such as somatic cells were also improved. Our results suggest that the feed additives positively affect milk production, reaching a maximum expression when the AI–driven model is applied.
Integrative Analysis of Drug-Gene Expression Signatures in Human Pluripotent Stem Cells Identifies Novel Drug Candidates for ALS and Monogenic Diseases
Authors: Roussange Florine , Gide Jacqueline , Tournois Johana , Cailleret Michel , Boland Anne , Battail Christophe , Deleuze Jean-François , Polvèche Hélène , Auboeuf Didier , Brockmann Knut , Kabashi Edor , Marian Anca , El Kassar Lina , Blondel Sophie , Salachas François , Bruneteau Gaëlle , Peschanski Marc , Martinat Cécile , Baghdoyan Sandrine
Published: February 2025

The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific diseases. This issue is particularly pronounced for the thousands of diseases of genetic origin, given the abundance of databases listing disease-associated changes in gene expression and various transcripts, indicating that potential read-outs may be concealed within these resources. To remedy this, an alternative approach was tested: compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 FDA-approved drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in ALS models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries.

One Sentence Summary

A novel drug screening approach for monogenic diseases integrating human pluripotent stem cell derivatives and RNA sequencing to profile gene expression.
Lemur: A Single-Cell Foundation Model with Fine-Tuning-Free Hierarchical Cell-Type Generation forDrosophila melanogaster
Authors: Botas Jorge , Jia Johnathan , Pasupuleti Sasidhar , Chen Hu , Hu Xia , Xu Zhaozhuo , Liu Zhandong
Published: February 2025

Single-cell genomics has revolutionized our understanding of cellular heterogeneity, but automating its analysis remains an open challenge. Cell-type annotation represents a critical bottleneck, particularly as datasets grow in size and complexity. While foundation models have shown promise in addressing this challenge, existing approaches require extensive fine-tuning for effective cell-type annotation. Here, we present Lemur (LargeExpressionModel forUnderstanding scRNA-seq), a single-cell foundation model specifically designed forDrosophila melanogaster. Lemur achieves fine-tuning-free cell-type annotation through comprehensive pre-training on an integrated whole-organism atlas with a unified cell-type annotation schema. To leverage this unified schema, we developed a dedicated hierarchical cell-type decoder architecture. This approach enables Lemur to generate consistent cell-type predictions across multiple levels of granularity without requiring additional training on new datasets. The model demonstrates strong performance across diverse tissue types, experimental conditions, and sequencing technologies. It also achieves batch-effect correction without explicitly training for this task. This automated analysis capability positions Lemur as an effective tool for the fly research community. Beyond its immediate applications, Lemur establishes a framework for accelerating biological discovery. It enables rapid iteration between computational predictions and experimental validation in the highly controlledDrosophila melanogastersystem, with potential implications for translational research in human biology, particularly in aging and neurodegenerative disease studies.
Monitoring Whole-Body Inflammation with Gallium-68 Labeled Polydopamine Iron Oxide Particles via Hybrid Immuno-PET-MRI
Authors: Pedron Swannie , Guillou Amaury , Fillesoye Fabien , Jacqmarcq Charlène , Perrio Cécile , Caruso Frank , Li Shiyao , Ju Yi , Vivien Denis , Gauberti Maxime , Vigne Jonathan , Bonnard Thomas
Published: February 2025

Monitoring immune reactions via inflammation imaging provides valuable disease prognosis but remains limited by currently available probes and imaging capabilities. In this study, a bimodal imaging probe was developed from microsized polydopamine matrix-based magnetic particles (M3P) functionalized with antibodies that target vascular cell adhesion molecule-1 (VCAM-1) and that are radiolabeled with the radioisotope Gallium-68. This probe combines sensitive inflammation detection via Positron Emission Tomography (immuno-PET) and high-resolution mapping via Magnetic Resonance Imaging (immuno-MRI). The probe represents a powerful disease diagnosis tool to assess the status of systemic inflammation in sepsis as whole-body immuno-PET enables rapid evaluation of the situation, and immuno-MRI provides a more detailed characterization of the identified affected tissues. The elimination profile of the M3P probe is restricted to the mononuclear phagocyte system and does not undergo renal clearance, which is suitable for application in kidney disorders. The efficacy of the hybrid immuno-PET-MRI diagnosis protocol was tested in a murine model of rhabdomyolysis. Kidney inflammation was detected by whole-body immuno-PET, and vascular inflammation patterns could be revealed by high-resolution immuno-MRI. This bimodal PET-MRI probe could significantly improve inflammation monitoring in pathologies characterized by systemic inflammation or lung and kidney dysfunction.
Noncoding and Coding Mechanisms of Aging Heart Failure with Preserved Ejection Fraction with Thyroid Dysfunction
Authors: Chakraborty Sankalpa , Dickerson Bryce , Bounds Curren , Lemus Sophia , Hickman Caleb , Rajagopalan Viswanathan
Published: February 2025

Heart Failure with preserved Ejection Fraction (HFpEF) is a heterogeneous geriatric syndrome with complex pathophysiology and comorbidities. Long noncoding RNAs (lncRNAs) account for a large majority of the functional mammalian transcriptome and act as key regulators in complex physiological and pathological processes. However, the role of lncRNAs and the development of thyroid dysfunction in aging HFpEF is not clear. We investigated the ZSF1 model in both early and more severe stages of HFpEF (5-, 13- and 20-months old [mo]). We assessed molecular, biochemical, and pathophysiological roles involving lncRNAs, mRNAs, and inflammatory markers. Thyroid hormone (TH) immuno-sorbent assays showed significant decreases in serum T3 levels in 5-mo and serum T4 levels in 5-mo and 13-mo obese HFpEF groups compared to lean controls. Morphometric analyses showed significant increases in heart and LV weights in obese HFpEF rats indicating cardiac hypertrophy. LncRNA microarray and RT-qPCR revealed that three key lncRNAs were significantly increased in 13-mo obese HFpEF but not in 5-mo obese HFpEF left ventricles compared to the ZSF1 lean controls. Microarray analyses showed thatSik1mRNA was significantly upregulated andAnxa13 was downregulated in early obese HFpEF hearts compared to the lean controls. Additionally, we also uncovered previously unreported tissue and serum inflammatory cytokine profiles in early and late HFpEF. This study has identified key novel lncRNA and inflammatory markers in early and late hypothyroid HFpEF. Further studies may help in better understanding and development of diagnostic and therapeutic targets for HFpEF that presents with severe morbidity and mortality.
Towards a comprehensive view of the pocketome universe – biological implications and algorithmic challenges
Authors: Zillmer Hanne , Walther Dirk
Published: February 2025

With the availability of reliably predicted 3D-structures for essentially all known proteins, characterizing the entirety of protein - small-molecule interaction sites (binding pockets) has become a possibility. The aim of this study was to identify and analyze all compound-binding sites, i.e. the pocketomes, of eleven different species’ from different kingdoms of life to discern evolutionary trends as well as to arrive at a global cross-species view of the pocketome universe. All protein structures available in the AlphaFold database for each species were subjected to computational binding site predictions. The resulting set of potential binding sites was inspected for overlaps with known pockets and annotated with regard to the protein domains in which the pockets are located. 2D-projections of all pockets embedded in a 128-dimensional feature space and characterizing them with regard to selected physicochemical properties, provide informative, global pocketome maps that reveal differentiating features between pockets. Our study revealed a sub-linear scaling law of the number of unique binding sites relative to the number of unique protein structures per species. Thus, larger proteomes harbor less than proportionally more different binding sites than species with smaller proteomes. However, this relationship is mainly driven by large numbers of singletons, i.e. binding sites that are not similar to any other binding site in the same species. We discuss the significance of this finding as well as identify critical and unmet algorithmic challenges.
Consumer resilience suppresses the recovery of overgrazed ecosystems
Authors: Spindel Nathan B. , Galloway Aaron W. E. , Schram Julie B. , Mcneill Gwiisihlgaa Daniel , Vanessa Bellis Sg̱iids Ḵung , Guujaaw Niisii , Yakgujanaas Jaasaljuus , Pontier Ondine , Thompson Markus , Lee Lynn C. , Okamoto Daniel K.
Published: February 2025

Food availability is among the strongest determinants of fitness. For many systems, ecosystemwide collapse in food availability can result from overgrazing with cascading ecological impacts. Yet, the mechanisms through which the responsible consumers persist in food-poor environments and their role in suppressing productivity recovery remain uncertain. This study examines how food abundance, quality, deprivation, and reintroduction shape plastic energetic traits and nutritional assimilation in an invertebrate herbivore. To evaluate how food composition and quantity affect energetic performance and biomarker composition in herbivore tissues, we analyzed fatty acids in producer and consumer tissues bothin situand in laboratory feeding trials. Sea urchins have a history of periodic overgrazing of kelp forests, followed by their extraordinary long-term persistence in the resulting barrens. Despite a two-fold difference in baseline metabolic rates (RMR) between kelp forest and barrens urchins, both consumed algae at equivalent rates in the laboratory. Starvation and feeding of urchins from kelp forests and barrens, respectively, induced reciprocal shifts in RMR and energy reserves over one month. Urchins fed lower-quality diets consumed more calories with lower efficiency in converting food to gonadal tissue. This metabolic resilience could hinder the recovery of kelp, a foundation species critical to nearshore ecosystems.
Local Topological Structures and Global Connectivity Patterns in aTrachelospermum jasminoides: a Pilot Study
Authors: Tozzi Arturo
Published: February 2025

Topological approaches to biological systems provide insights into their growth patterns, network connectivity and spatial organization. This perspective explores how biological structures self-organize, maintain stability and adapt to environmental constraints, revealing fundamental principles of efficiency, robustness, resilience and functional optimization. In this pilot study, we analysed the local and global topological properties of aTrachelospermum jasminoidesbush (commonly known as star jasmine) using persistent homology, graph theory, spectral analysis and percolation theory. The spatial positions of individual flowers were extracted from an image of the bush and represented as a point cloud to capture their structural distribution and spatial relationships. Using Delaunay triangulation, a connectivity graph revealed a dominant connected component with minimal isolated structures. DBSCAN analysis identified a large number of small, localized clusters, reflecting biological and environmental influences. Most flowers connected to five to six neighbours, forming a uniform network with high clustering. Shortest path analysis showed efficient long-range connectivity, with paths avoiding sparse regions. Spectral analysis indicated smooth percolation without bottlenecks, while percolation analysis simulations revealed resilience up to 18% flower removal, after which connectivity broke down. In sum, we showed that the star jasmine bush topology balances local structural constraints with global connectivity, ensuring efficient resource distribution and structural integrity. By integrating topological data analysis with ecological modeling, we suggested a methodological approach to understanding natural growth networks. These insights can inform broader studies on biological pattern formation, network resilience and plant architecture modeling in ecology, agricultural sciences and biomimetic design.
Overexpression of GITRL by B cell IgD low (BDL) B cells is a therapeutic strategy to increase endogenous CD4+Foxp3+T regulatory cells for the treatment of autoimmunity
Authors: Khalil Mohamed I. , Gurski Cody J. , Burns Robert , Zander Ryan , Sommers Kelli C. , Beltrame Angela K. , Dittel Bonnie N.
Published: February 2025

Autoimmune diseases, such as multiple sclerosis (MS), are often chronic with no cures. An underlying commonality of autoimmune diseases is immune-mediated inflammation. Control of inflammation is achieved by steroids and disease-modifying therapies, which can result in severe side-effects. CD4+Foxp3+T regulatory cells (Treg), are essential to controlling autoimmune responses and are considered a strong therapeutic target with minimal side effects. To that end, we leveraged our identification of B cell IgD low (BDL) B cells that control Treg homeostatic levels in the mouse spleen in a GITRL-dependent manner to demonstrate that overexpression of GITRL by BDLusing a B cell-specific GITRL transgene (tg) was sufficient to increase endogenous Treg numbers and attenuate the disease severity of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. To determine whether increased GITRL expression by BDLcould be a therapeutic strategy, WT mice were transplanted with bone marrow from GITRLtg mice. After reconstitution, GITRL expression was increased on BDL, Treg numbers were significantly elevated, and EAE was dramatically attenuated. These cumulative data further demonstrate that GITRL is a functional receptor on BDLand its overexpression in B cells is a therapeutic strategy to increase endogenous Treg numbers for treating autoimmunity.
Gene regulatory logic of the interferon-β enhancer contains multiple selectively deployed modes of transcription factor synergy
Authors: Schiffman Allison , Cheng Zhang , Ourthiague Diana , Hoffmann Alexander
Published: February 2025

Type I interferon IFNβ is a key regulator of the immune response, and its dysregulated expression causes disease. The regulation of IFNβ promoter activity has been a touchpoint of mammalian gene control research since the discovery of functional synergy between two stimulus-responsive transcription factors (TFs) nuclear factor kappa B (NFκB) and interferon regulatory factors (IRF). However, subsequent gene knockout studies revealed that this synergy is condition-dependent such that either NFκB or IRF activation can be dispensable, leaving the precise regulatory logic of IFNβ transcription an open question. Here, we developed a series of quantitative enhancer states models of IFNβ expression control and evaluated them with stimulus-response data from TF knockouts. Our analysis confirmed that TF synergy is a hallmark of the regulatory logic but that it need not involve NFκB, as synergy between two adjacent IRF dimers is sufficient. We found that a sigmoidal binding curve at the distal site renders the dual IRF synergy mode ultrasensitive, allowing it only in conditions of high IRF activity upon viral infection. In contrast, the proximal site has high affinity and enables expression in response to bacterial exposure through synergy with NFκB. However, its accessibility is controlled by the competitive repressor p50:p50, which prevents basal IRF levels from synergizing with NFκB, such that NFκB-only stimuli do not activate IFNβ expression. The enhancer states model identifies multiple synergy modes that are accessed differentially in response to different immune threats, enabling a highly stimulus-specific but also versatile regulatory logic for stimulus-specific IFNβ expression.

SIGNIFICANCE

Precise regulation of the immune cytokine IFNβ is essential for human health. Classic studies established that the transcription factors NFκB and IRF function synergistically in activating IFNβ expression. However, more recent data revealed that either factor may be dispensable in certain conditions, leaving the regulatory logic of IFNβ transcription an open question. In this study, we evaluated several quantitative models to determine what regulatory logic can account for the available data. We found that the enhancer exhibits multiple synergy modes with specific transcription capabilities that are deployed in a condition-dependent manner. The resulting IFNβ regulatory logic model reveals how stimulus-specificity is achieved, and may be tuned, thereby overcoming a bottleneck in predictive modeling the control of innate immune responses.
Distinct Microbial Communities Within and On Seep Carbonates Support Long-term Anaerobic Oxidation of Methane and Novel pMMO Diversity
Authors: Mayr Magdalena J. , Parra Sergio A. , Connon Stephanie A. , Narayanan Aditi K. , Murali Ranjani , Cremiere Antoine , Orphan Victoria J.
Published: February 2025

At methane seeps worldwide, syntrophic anaerobic methane-oxidizing archaea and sulfate-reducing bacteria (ANME-SRB) promote carbonate precipitation and rock formation, acting as methane and carbon sink. While maintenance of active anaerobic oxidation of methane (AOM) within seep carbonates has been documented, the ANME-SRB reactivity to methane exposure remains uncertain. Surface-associated microbes may metabolize AOM-derived sulfide, maintain carbonate anoxia, and contribute to carbonate dissolution and higher trophic levels; however, these microbial communities are poorly described thus far. Here we provide new insights into microbial diversity, metabolic potential, activity, and resiliency within and on Southern Californian methane seep carbonates, by combining 16S rRNA and metagenomic sequencing, laboratory incubations, and BONCAT-FISH. Ca. Methanophaga (ANME-1) dominated the carbonate interiors across different seepage activities, based on sequencing, while the dominant SRB was Ca. Desulfaltia, potentially a new ANME partner. BONCAT-FISH revealed differences in ANME-1 cell activity, suggesting cell dormancy or DNA preservation at less active seep sites. Carbonate incubations from low activity seeps (≥24 months) showed an exponential AOM reactivation (44-day doubling time), suggesting seep carbonates remain potential methane sinks over dynamic seepage conditions. The surface-associated communities were distinct from the carbonate interior and other seep habitats, and highly heterogeneous. Surface ANME-SRB biofilms and sulfide-oxidizing bacterial mats were associated with high and intermediate AOM carbonates, potentially influencing carbonate precipitation/dissolution. Carbonate surfaces shared diverse aerobic methanotrophs with invertebrates, potentially serving as pool for animal epibionts. Besides particulate methane monooxygenases from aerobic methanotrophs, we found divergent forms including within a Methylophagaceae (GCA-002733105) MAG suggesting a new function within Methylophagaceae.
Real-world experience with switching from originator to biosimilar natalizumab
Authors: Høgestøl Einar August , Brustad Åge Winje , Celius Elisabeth Gulowsen , Meling Martine , Berg-Hansen Pål , Kro Grete Birkeland , König Marton , Warren David J. , Gehin Johanna E. , Bolstad Nils , Nygaard Gro Owren
Published: February 2025

In January 2024, all persons with multiple sclerosis (pwMS) treated with natalizumab (NTZ) at Oslo University Hospital switched from originator to biosimilar NTZ. We prospectively monitored 39 pwMS during the first year of treatment with biosimilar NTZ and evaluated change in disease activity, side effects, serum NTZ levels, anti-drug antibodies (ADAb), and anti-John Cunningham virus (JCV) antibody levels. Serum NTZ levels and ADAb were measured using in-house assays, while JCV antibody levels were evaluated using Stratify (Biogen) and Immunowell (Sandoz) platforms. One new relapse occurred during the first year and 11 pwMS (28%) reported new side effects after switching to the biosimilar; whereof fatigue, headache, and muscle pain were most frequent. Serum NTZ levels were similar between pwMS on originator (15.1 mg/L, SD 8.9) and biosimilar NTZ (14.9 mg/L, SD 9.0; p = 0.63). We identified ADAb in one pwMS, present both before and after switching. The proportion of pwMS with positive JCV antibody levels increased from 13% in 2023 (Stratify) to 52% in 2024 (Immunowell). Four pwMS discontinued NTZ due to high anti-JCV antibody levels (in the Immunowell assay) in the first 10 months.
Thalamic connectivity-based Biomarkers for Neuromodulation in Patients with Refractory Epilepsies
Authors: Aiello Giovanna , Soper Daniel J. , Hadar Peter N. , Paulk Angelique C. , Cash Sydney S. , Polania Rafael , Imbach Lukas , Salami Pariya
Published: February 2025

Thalamic electrical stimulation is being used as a treatment for drug-resistant epilepsy, yet current strategies benefit only about half the patients. Advancing patient outcomes necessitates tailored target selection for stimulation including the development of biomarkers for successful treatment. Here, we analyzed intracranial recordings of the most discussed thalamic nuclei for neuromodulation in epilepsy: anterior nucleus (ANT), centromedian nucleus (CM), pulvinar (PLV), and mediodorsal nucleus (MD) in 38 patients, to evaluate how their functional connectivity to epileptogenic areas may differ from that of non-epileptogenic areas in both sleep and wake states. We found that the thalamocortical connectivity to seizure onset areas is region and frequency-dependent. Additionally, we showed that thalamic connectivity is modulated in high versus low seizure risk conditions, further emphasizing its role in ictogenesis. Most importantly, we used the connectivity signature to predict the outcomes in patients receiving RNS within CM or PLV for neuromodulatory treatment and showed that these connectivity measures could serve as biomarkers of responsiveness to the treatment. These findings suggest that interictal connectivity data can inform patient-specific neuromodulation targeting, providing insights into the neurostimulation efficacy for specific epilepsy phenotypes.
Calibrated Functional Data Decreases Clinical Uncertainty for Tier 1 Monogenic Disease: Application to Long QT Syndrome
Authors: Ng Chai-Ann , O’Neill Matthew J. , Padigepati Samskruthi R. , Ting Yi-Lee , Facio Flavia M. , Vatta Matteo , Poll Sarah R. , Reuter Jason , Vandenberg Jamie I. , Kroncke Brett M.
Published: February 2025

Rare missense variants are often classified as variants of uncertain significance (VUS) due to insufficient evidence for classification. These ambiguous findings create anxiety and frequently lead to inappropriate workup, colloquially referred to as the ‘diagnostic odyssey’. Well-validated high-throughput experimental data have the potential to significantly reduce the number of VUS identified by clinical genetic testing, though the extent of this reduction and the optimal strategies to achieve it remain unclear.1
Prevalence of HIV history and associated factors in people affected by mpox in Colombia, 2022
Authors: Muñoz Lozada Claudia Marcela , Madero Reales Javier Alberto , Chaparro Narvaez Pablo Enrique , Prieto Alvarado Franklyn Edwin
Published: February 2025

The 2022 mpox outbreak disproportionately affected men who have sex with men (MSM) and individuals with history of HIV. This study investigated the prevalence of HIV infection and associated factors among mpox cases in Colombia. A cross-sectional analysis of 4,046 confirmed mpox cases reported to the Public Health Surveillance System between June 25 and December 31, 2022, was conducted. The prevalence of a history of HIV infection in mpox cases was determined, and associated factors were assessed using bivariate and multivariate logistic regression. Most mpox patients were male (97%), with a median age of 31 years (IQR = 27, 37). The most affected age group was 25 to 34 years (52%), and 83.7% were MSM. The prevalence of HIV history was 60%, with the highest rates in Manizales, Medellín, and Itagüí. Common symptoms included genital lesions (59.6%) and fever (67.6%). Factors associated with HIV history in mpox patients were male sex [OR = 9.6, 95% CI = 4.35, 21.31], having sexually transmitted infections: hepatitis B [OR = 2.9, 95% CI = 1.91, 4.40], hepatitis C [OR = 7.0, 95% CI = 3.50, 13.97], syphilis [OR = 2.1, 95% CI = 1.46-3.12], hospitalization [OR = 2.2, 95% CI = 1.65, 2.93], Colombian nationality [OR = 2.5, 95% CI = 1.86, 3.48] and being homosexual [OR = 2.5, 95% CI = 2.09, 3.06]. A high prevalence of HIV infection (60%) was found among mpox patients in Colombia, predominantly among MSM. This highlights the need for targeted interventions, such as priority care for people with HIV, active surveillance, and education for timely diagnosis and prevention of complications.
Sit-up Test for Assessing Blood Pressure Dysregulation in Community-Dwelling Older Adults: A Cross-Sectional Study
Authors: Oyake Kazuaki , Yokokawa Yoshiharu
Published: February 2025

Background

The sit-up test enables the assessment of orthostatic hypotension without using a tilt table in individuals at high risk of falling when standing; however, no studies have compared blood pressure responses between those with and without orthostatic hypotension during this test. The primary objective of this study was to compare blood pressure responses during the sit-up test between community-dwelling older adults with and without orthostatic hypotension. The secondary objective was to determine the associations between orthostatic hypotension detected by the sit-up test and poor health conditions in these individuals.

Methods

One hundred-two community-dwelling older adults underwent the sit-up test. Orthostatic hypotension was defined as a decrease of ≥10 mmHg in systolic blood pressure and/or ≥5 mmHg in diastolic blood pressure during the test. Supine and seated hypertension were evaluated, defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg. Blood pressure responses during the test were compared between participants with and without orthostatic hypotension. Moreover, associations of orthostatic hypotension with demographic, clinical, and geriatric outcomes were examined.

Results

Thirty-four participants (33.3%) showed orthostatic hypotension during the test. Participants with orthostatic hypotension demonstrated a greater decrease in systolic blood pressure (F(3,297)= 47.0, p < 0.001), a smaller increase in diastolic blood pressure (F(3,297)= 26.5, p < 0.001), and higher supine systolic blood pressure (t = 3.363, p = 0.005) during the test than those without orthostatic hypotension. Consequently, 52.9% of participants with orthostatic hypotension had supine hypertension. Orthostatic hypotension was associated with a higher proportion of participants with at least one comorbidity (odds ratio = 4.50, p = 0.002) and those with non-robust status (odds ratio = 3.08, p = 0.022), even after adjusting for supine and seated hypertension.

Conclusion

Community-dwelling older adults with orthostatic hypotension were characterized by an impaired orthostatic increase in diastolic blood pressure and high supine systolic blood pressure during the sit-up test. Orthostatic hypotension was associated with poor health conditions, independently of supine and seated hypertension. These findings contribute valuable insights for the application of the sit-up test in preventive health screenings for older adults.
Matrix Metalloproteinase-9 Mediates Endothelial Glycocalyx Degradation and Correlates with Severity of Hemorrhagic Fever with Renal Syndrome
Authors: Jacquet Chloé , Gustafsson Rasmus , Patel Ankit Kumar , Hansson Magnus , Rankin Gregory , Bano Fouzia , Byström Julia Wigren , Blomberg Anders , Rasmuson Johan , Satchell Simon , Thunberg Therese , Ahlm Clas , Bally Marta , Connolly Anne-Marie Fors
Published: February 2025

Hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus (PUUV) leads to vascular dysfunction contributing to acute kidney injury and pulmonary complications. The endothelial glycocalyx (eGLX) is crucial for vascular integrity, and its degradation may exacerbate disease severity. In this study, we examined the association between eGLX degradation and renal and pulmonary dysfunction in 44 patients with laboratory-confirmed PUUV infection. We measured plasma levels of eGLX degradation markers—syndecan-1, heparan sulfate, soluble thrombomodulin, and albumin— and found that these correlated with severe acute kidney injury and the need for oxygen therapy. In vitro experiments showed that matrix metalloproteinase-9 (MMP-9) and heparanase can degrade eGLX components, but albumin at physiological concentrations can mitigate this degradation and protect endothelial barrier function. These findings indicate that eGLX degradation contributes to HFRS pathogenesis and suggest that targeting the eGLX could be a therapeutic strategy to improve patient outcomes.
The MicroRNA pathway regulates obligatory aestivation in a flea beetle
Authors: Guney Gozde , Schmitt Kerstin , Zicola Johan , Toprak Umut , Rostas Michael , Scholten Stefan , Cedden Doga
Published: February 2025

Aestivation is a dormant state that allows animals to withstand hot and dry summer conditions and requires complex gene regulation. Nevertheless, the mechanisms involved in the regulation of genes necessary for aestivation remain unclear. MicroRNA (miRNA) are known to fine-tune gene expression at the post-transcriptional level and are important for various biological processes. In this study, we investigated the role of the miRNA pathway in the regulation of the obligatory aestivation stage in the cabbage stem flea beetle, a major pest of oilseed rape. Small RNA sequencing showed that ~25% of miRNAs were differentially abundant during aestivation. The inhibition of the miRNA pathway deregulated 116 proteins in aestivation, which were mainly associated with metabolism and catabolism, including peroxisome activity. Most proteins regulated by miRNA exhibited lower transcript levels during aestivation. RNA degradome sequencing confirmed the miRNA-mediated exonucleolytic decay of several transcripts. Furthermore, inhibiting the miRNA pathway resulted in altered body composition, compromised metabolic suppression, and lower resilience to high temperature during aestivation. Also, beetles could not suppress their feeding activity during the transition into aestivation. Our findings highlight the critical role of miRNA in regulating aestivation in the cabbage stem flea beetle, with important implications for climate change.
Climate versus human impacts on the marine fauna of the Mediterranean Sea during the pre-industrial period
Authors: Leal Daniela , Agiadi Konstantina , Bas Maria
Published: February 2025

Climate and human impacts have impacted the Mediterranean ecosystem for thousands of years. Still, their evidence has been incomplete, hindering a proper assessment of the marine ecosystem’s baseline state and resources. In an attempt to disentangle these impacts, we conducted a study focused on commercially important species of marine mammals, fishes, and molluscs over the last 130,000 (130 ka) years until the Industrial Revolution (the year 1850). To assess differences within the basin, we subdivided the Mediterranean Sea into three subregions – Western, Eastern and Adriatic. Our work revealed significant climatic and anthropogenic impacts on three species: the banded-dye murex, the Atlantic bluefin tuna and the gilthead sea bream. Climate change, particularly temperature changes, influenced the abundance and body size of Atlantic bluefin tuna, while subregional differences in the stable isotopic composition of archaeological skeletal material reflected shifts in the system’s primary productivity. Human activities, particularly overexploitation, impacted the abundance of both banded-dye murex and Atlantic bluefin tuna, as well as the body size of gilthead sea bream and Atlantic bluefin tuna. These results highlight the significance of studying the relationships between climate, human activities, and marine resources in this large marine ecosystem. As well as integrating past data with contemporary data to reconstruct ecological baselines and obtain longer and more comprehensive time series of ecosystem change. Understanding the history of marine ecosystems and species-specific responses to environmental and anthropogenic disturbances is essential to ensure the development of effective present and future environmental management strategies while supporting the implementation of targeted conservation measures.