bluuebunny/crossref_metadata_2025 huggingface dataset:
RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation
Authors: Mayday Madeline Y. , Biancon Giulia , Wei Manyi , Ramirez Christian , Moratti Irene , Pintado-Urbanc Andreas P. , Wang Lin , Espinosa Jether Amos , Simon Matthew D. , Ofir-Rosenfeld Yaara , Rausch Oliver , Tebaldi Toma , Halene Stephanie , Krause Diane S.
Published: February 2025

Acute megakaryoblastic leukemia driven by the RBM15-MKL1 fusion protein (RM-AMKL) is the only known recurrent mutation involving the N6-methyladenosine (m6A) writer complex. Dysregulation of m6A modification affects RNA fate and is linked to oncogenesis. Inhibition of m6A deposition via inhibition of the METTL3 writer protein has anti-tumour activity, but the mechanism underlying its efficacy and cancer specificity remains unclear. We treated murine RM-AMKL cells with a novel METTL3 inhibitor, STM3675, and showed apoptosisin vitroand prolonged survival of mice transplanted with RM-AMKL, implicating m6A as an essential component of AMKL and identifying Wnt signalling as a key driver of leukemogenesis. To elucidate the mechanism by which m6A contributes to leukemogenesis we employed a multi-omic approach, combining transcriptome-wide assessment of RNA binding, methylation and turnover. We show for the first time that RM retains the RNA-binding and m6A-modifiying functions of its RBM15 component, while also selectively regulating distinct mRNA targets, particularly genes involved in Wnt signalling including Frizzled. Frizzled genes are upregulated by RM and downregulated in RM-AMKL cells in response to METTL3 inhibition, providing an m6A-dependent explanation for their upregulation. Direct Frizzled knockdown reduced RM-AMKL growth, which was partially rescued by treatment with a β-catenin agonist, underscoring a functional role of Wnt signalling in RM-AMKL. Human AMKLs show elevated Wnt pathway and Frizzled gene expression, highlighting the relevance of our work. Together, our findings reveal that RM-specific m6A modifications and activation of Wnt signalling are critical drivers of RM-AMKL, highlighting these pathways as potential therapeutic targets.

Key Points

RM retains functional abilities of RBM15 and additionally interacts with Wnt-related transcripts to increase expression of Fzd proteins.

The METTL3 writer complex and WNT signalling pathways are essential for RM-driven leukemia.
Managing the genetic diversity of animal populations using cryobanks: optimizing the constitution ofex situcollection?
Authors: Jacques Alicia , Tixier-Boichard Michèle , Restoux Gwendal
Published: February 2025

The genetic diversity of populations is important for their long-term conservation and adaptive potential. Nevertheless, there is an erosion of genetic variability in all populations, whether a small population under conservation or a large breed under selection. Many countries have conserved animal genetic resourcesex situ, with the creation of cryopreserved collections. These cryopreserved genetic resources could open up new prospects for managing the genetic diversity of animal populations. Currently, there are as many strategies for conserving cryopreserved genetic resources as there are cryobanks. The aim of our study is to examine some parameters for optimizing the constitution of a gene bank.

Results

We performed simulations of animal populations (i.e. selection or conservation) using different types of breeding strategy and changing (i) the size and age of the cryopreserved collection or (ii) the management of cryopreserved collections (entry and exit of frozen semen).

We found that the age of genetic resources was the predominant factor for populations under selection, as this factor also quantifies the lag in breeding values. A more massive stocking of recent individuals seems to be the most relevant strategy for mobilizingex situgenetic resources in a breeding scheme. For populations in conservation, older reproductive material becomes highly relevant. A cryobank with a large number of old individuals enables better management of matings and avoids too rapid an increase in inbreeding over the long term, while the use of a more moderate number of old individuals enables some genetic progress to be maintained, but offers fewer possibilities for managing genetic diversity. Continuous collection supply is a relevant option for population management. Whatever the breeding strategy, the use of OCS can help mobilizeex situgenetic resources in animal breeding programs.

Conclusions

Cryopreserved genetic resources are an invaluable help in the management of domestic populations. It is important to continue research in order to optimize the use of cryopreserved genetic resources, and to set up collection management recommendations that are relevant and adapted to breeding programs.
Resource economics of tree communities control soil food web multifunctionality in European forests
Authors: Henneron Ludovic , Wardle David A. , Berg Matty P. , Hättenschwiler Stephan , Bauhus Jürgen , Buscot François , Coq Sylvain , Decaëns Thibaud , Fromin Nathalie , Ganault Pierre , Gillespie Lauren M. , Goldmann Kezia , Matula Radim , Milcu Alexandru , Muys Bart , Nahmani Johanne , Prada-Salcedo Luis Daniel , Scherer-Lorenzen Michael , Verheyen Kris , Wambsganss Janna , Kardol Paul
Published: February 2025

Plants affect terrestrial ecosystem functioning by performing the primary production that energetically sustains heterotrophic organisms1, and by shaping the microenvironment2. However, the influence of plant diversity and community composition on ecosystem functioning through their effects on energy flow into food webs has been little studied3,4, especially for soil food webs that channel most of the plant-derived energy1,5. Applying a food web energetics approach6,7, we show that the resource economics of dominant tree species control soil food web multifunctionality across European forests. Specifically, tree communities dominated by resource acquisitive species promoted faster rates of multiple soil trophic functions simultaneously than did those dominated by resource conservative species. This was primarily driven by their production of plant litter with higher nutritional quality and their warmer forest microclimate, leading to a higher metabolic activity of soil organisms8. Tree species mixing had rather weak and negative effects on soil food web multifunctionality, mostly due to a shift in the resource-based energy channeling from living plant fine roots to litter and a cooling effect on the forest microclimate. Tree diversity effects were largely outweighed by community compositional effects, which were of similar magnitude to the effects of biogeographic differences among locations. Our findings emphasize the importance of plant functional traits related to resource economics as drivers of plant community effects on soil food web functioning5,9and highlight the consequences that climate-driven shifts in tree community composition could have for forest soil functioning.
Predicting High-Resolution Spatial and Spectral Features in Mass Spectrometry Imaging with Machine Learning and Multimodal Data Fusion
Authors: Haque Md Inzamam Ul , Kannan Ramakrishnan , Hinkle Jacob D. , Stopka Sylwia A. , Agar Nathalie Y. R. , Ovchinnikova Olga S. , Mukherjee Debangshu
Published: February 2025

Recent advancements in molecular Mass Spectrometry Imaging (MSI) have sparked interest in integrating high spatial resolution methods with molecular mass-spectrometry-based chemical imaging. Fusion-based algorithms have proven effective in generating high spatial-resolution molecular mass spectra. However, a significant challenge stems from the differing physical mechanisms underlying image generation and data upsampling techniques, potentially leading to discrepancies in integrated information channels. Integrating physical constraints into data processing workflows is essential to tackle this issue. In this study, we propose an innovative approach that merges data from Fourier transform ion cyclotron resonance (FTICR), time- of-flight matrix-assisted laser desorption/ionization (MALDI-ToF), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging techniques. By leveraging FT-ICR’s unparalleled spectral resolution and ToF-SIMS’s exceptional spatial resolution, we achieve submicron spatial resolution, enabling the observation of intact molecular species with remarkable spectral precision. Canonical correlation analysis is employed to incorporate physical constraints. Through sophisticated image processing and machine learning techniques, the results of this fusion hold significant promise for advancing our comprehension of complex systems and unveiling concealed molecular intricacies.
Deciphering the dynamics of Cyanobacteria-Phage in a natural lake: Insights from a decade-long investigation
Authors: Stern Kiri , Vincent Jin , Taranu Zofia E , Fortin Nathalie , Martel Alexis , Robbe Andrea , Thaize Romane , Castelli Mathieu , Beckett Stephen J. , Poisot Timothee , Buckling Angus , Shapiro B. Jesse , Tromas Nicolas
Published: February 2025

Phages – viruses that infect bacteria – are often seen as key players in bacterial community dynamics and the ecosystem services those communities support. However, much of our understanding of phage-bacteria interactions comes from in vitro studies, which provide limited insights into how these interactions occur in natural environments. In this study, we used cyanobacterial blooms as a model microbial community to evaluate the potential role of phages in driving cyanobacterial populations. These blooms are characterized by massive and usually rapid accumulation of cyanobacterial biomass and occur worldwide, threatening aquatic systems. The frequency and intensity of cyanobacterial blooms are increasing over time, likely due to human activities, and, until now, the role of predators like phages has remained unclear. We used a deep amplicon sequencing approach targeting the g20 capsid gene to profile the cyanophage community in eutrophic Lake Champlain over time, comparing their dynamics and diversity with bacterial communities and examining their associations. We evaluated whether phages simply followed bacterial dynamics, with limited impact on bacterial composition, or instead whether they played an active role in drving bacterial community structure. We found that phages exhibited similar dynamics to their potential bacterial hosts and shared environmental niches. However, we also observed strong differences specific to the phage community, such as inter-annual variation and an increase in Shannon diversity over time. Phage-bacteria and phage-cyanobacteria co-variance uncovered potential interactions that resulted in strongly modular networks. However, while the network structure remained modular, the composition of the modules differed significantly between environmental and temporal conditions. Lastly, viral phylogeny partially explained phage-bacteria co-variance, but only for a small proportion of bacterial ASVs. Our results indicate that phage-bacterial interactions are partly genetically structured and vary within modules across environmental conditions.
Gestational Chlorpyrifos Exposure Imparts Lasting Alterations to the Rat Somatosensory Cortex
Authors: Koenig Jeffrey A. , Haga Catherine , Cramer Nathan , Keller Asaf
Published: February 2025

Chlorpyrifos is an organophosphorus pesticide used extensively in agricultural and residential settings for nearly 60 years. Gestational, sub-acute exposure to chlorpyrifos is linked to increased prevalence of neurodevelopmental disorders. Animal studies have modeled these neurobehavioral detriments, however, the functional alterations in the brain induced by this exposure remain largely unknown. To address this, we used a rat model of gestational chlorpyrifos exposure to interrogate the alterations in the developing somatosensory (barrel) cortex. Rat dams were exposed to chlorpyrifos (5 mg/kg) or vehicle on gestational days 18-21 via subcutaneous injection, with no overt acute toxicity. Acetylcholinesterase was modestly inhibited but returned to baseline levels by postnatal day 12. We performed whole-cell patch clamp recordings on postnatal days 12-20 in both male and female progeny of the treated dams. A spike timing dependent plasticity protocol revealed changes to the normal development of use-dependent plasticity, including interference in long-term synaptic depression. Recording inhibitory synaptic activity revealed an increase in the frequency of spontaneous postsynaptic currents and in paired pulse ratios, in conjunction with a significant decrease in miniature postsynaptic currents. These findings suggest a presynaptic mechanism of inhibited GABA release, with potential disinhibition of inhibitory neurons. Evaluation of barrel cortex development displayed disruptions to normal barrel field patterning, with increases in both the septal area and total barrel field. We provide evidence for functional and structural alterations during brain development induced byin uteroexposure to the organophosphorus pesticide chlorpyrifos that may account for the well-established behavioral outcomes.

SIGNIFICANCE STATEMENT

We demonstrate persistent alterations to synaptic function and plasticity in the somatosensory cortex following a brief, sub-acute exposure to the organophosphorus pesticide chlorpyrifos in a gestational rat model. These occur in conjunction with structural changes to cellular patterning of this brain region. These previously unknown consequences are potential causal mechanisms to the well-established neurodevelopmental detriments associated with early life exposure to chlorpyrifos. Clarifying these mechanisms could aid in ameliorating or preventing their persistent effects.
3D Bioprinted Cell-laden GrooveNeuroTube: A Multifunctional Platform for Ex Vivo Neural Cell Migration and Growth Studies
Authors: Litowczenko Jagoda , Richter Yannick , Indurkar Abhishek , Tadyszak Krzysztof , Ostrowski Adam , Popenda Lukasz , Fiedorowicz Katarzyna , Cabello Jose Carlos Rodrigez , Wychowaniec Jacek Kamil
Published: February 2025

Extensive peripheral nerve injuries often lead to the loss of neurological function due to slow regeneration and limited recovery over large gaps. Current clinical interventions, such as nerve guidance conduits (NGCs), face challenges in creating biomimetic microenvironments that effectively support nerve repair. In this study, we designed the GrooveNeuroTube, composed of a hyaluronic acid methacrylate and gelatin methacrylate (HAMA-GelMA) hydrogel, incorporating active agents (growth factors and antibacterial agent) encapsulated within an NGC conduit made of 3D-printed PCL grid fibers. This bioengineered conduit demonstrated high cytocompatibility (>90%) and extended degradability (over 60 days). In vitro studies showed that GrooveNeuroTube significantly promoted the proliferation and migration of dorsal root ganglion (DRG) neuronal cells, 3D bioprinted at the far ends of the conduit to imitate a proximal nerve injury as a novel ex vivo model. A long-term culture of up to 60 days was employed to better mimic in vivo conditions. We then used this model to test the effects of pulsed electromagnetic field (PEMF) stimulation on neural tissue development and integration. Analysis revealed that neurite length was significantly greater in cells exposed to PEMF stimulation, with more elongated neurites (38%). After 60 days in culture, GrooveNeuroTube showed cell migration reaching 7.2 mm, representing a 32% increase compared to the GF-only group and a 105% increase compared to the no-growth-factor condition. These results confirm that the GrooveNeuroTube system can effectively support sustained neural cell migration and maturation over extended periods, proving a new technology for testing peripheral nerve injury ex vivo.
Local variations in L/M ratio influence the detection and color naming of small spots
Authors: Greene Maxwell J. , Pandiyan Vimal P. , Sabesan Ramkumar , Tuten William S.
Published: February 2025

The distribution of long-wavelength sensitive (L) and middle-wavelength sensitive (M) cones in the retina determines how different frequencies of incident light are sampled across space, and has been hypothesized to influence spatial and color vision. We asked whether the detection and color naming of small, short-duration increment stimuli depend on the relative numbers of L and M cones illuminated. Stimuli were corrected for optical aberrations by an adaptive optics system, and targeted to locations in the parafovea where cone spectral types were known. We found that sensitivity to 680 nm light, normalized by sensitivity to 543 nm light, grew with the proportion of L cones at the stimulated locus, though intra- and intersubject variability was considerable. A similar trend was derived from a simple model of the achromatic (L+M) pathway, as well as from photoreceptor-level ideal observers, suggesting that small spot detection mainly relies on a non-opponent mechanism. Most stimuli were called achromatic, with red and green responses becoming more common as stimulus intensity and local L/M ratio symmetry increased. Our detection data confirm earlier reports that small spot psychophysics can reveal information about local cone topography, and our color naming findings suggest that chromatic sensitivity may improve when the L/M ratio approaches unity.
Sparse testcrossing for early-stage genomic prediction of general combining ability to increase genetic gain in maize hybrid breeding programs
Authors: González-Diéguez David O. , Atlin Gary N. , Beyene Yoseph , Wegary Dagne , Gemenet Dorcus C. , Werner Christian R.
Published: February 2025

1

Sparse testcrossing is an effective strategy for increasing both short- and long-term genetic gain in hybrid breeding programs. Maize hybrid breeding programs aim to develop new hybrid varieties by crossing genetically distinct parents from different heterotic pools, exploiting heterosis for improved performance. The programs typically consist of two main components: population improvement and product development. The population improvement component aims to enhance the heterotic pools through reciprocal recurrent selection based on general combining ability (GCA). However, especially in the early stages of testing, evaluating large numbers of hybrid combinations to estimate GCA is impractical due to considerable logistical challenges and costs. Therefore, breeders often evaluate the initial population of selection candidates using only a single tester to narrow down the candidate pool before further evaluation. Using a single tester, however, may not adequately represent the heterotic pool, leading to inaccurate GCA estimates and suboptimal selection decisions. To address this, we propose sparse testcrossing for early-stage testing, where subsets of candidate genotypes are testcrossed with different testers, connected through a genomic relationship matrix. We conducted stochastic simulations to compare various sparse testcrossing designs with a conventional testcross strategy using a single tester over 15 cycles of reciprocal recurrent genomic selection. Our results show that using 3-5 testers, sparsely distributed among full-sibs, sparse testcrossing offers breeders a practical balance between simple testcross designs, resource efficiency, and increased prediction accuracy for GCA, ultimately resulting in increased rates of genetic gain.

Key message

Sparse testcrossing with 3-5 testers enhances genetic gain in hybrid breeding programs, offering a practical balance of simple testcross designs, resource efficiency, and increased prediction accuracy for general combining ability.
Efficient Prospective Electric Field-Informed Localization of Motor Cortical Targets of Transcranial Magnetic Stimulation
Authors: Schultheiss David Luis , Turi Zsolt , Marmavula Srilekha , Reinacher Peter Christoph , Demerath Theo , Straehle Jakob , Boedecker Joschka , Mittner Matthias , Vlachos Andreas
Published: February 2025

Transcranial magnetic stimulation (TMS) is a versatile non-invasive tool for brain mapping and neu-romodulation in both healthy individuals and patients. Effective TMS-based causal brain mapping relies on precise localization of cortical targets. Current state-of-the-art approaches use statistical methods to quantify the relationship between TMS-induced electric fields (E-fields) and motor evoked potential (MEP) amplitudes. However, this method typically relies on the random selection of coil configurations, which limits its efficacy. In this study, we present a novel optimization strategy for TMS-based motor mapping by prospectively selecting coil configurations based on their E-field characteristics using an iterative sampling algorithm called farthest point sampling (FPS). Through a combination of theoretical analysis, simulation and experimental validation including 10 healthy individuals, we systematically evaluated the performance of FPS against the random sampling approach. Our results demonstrate that FPS is twice as efficient as random sampling in reducing the number of trials required for estimating the motor map, while also being more robust across participants and less susceptible to noise. These findings highlight the potential of FPS to significantly enhance the efficiency of motor mapping, paving the way for the development of more effective TMS mapping algorithms.
Hypoxia-activated fluorescent probes as markers of oxygen levels in plant cells and tissues
Authors: Perri Monica , Khan M. Shahneawz , Wallabregue Antoine L. D. , Voloboeva Viktoriia , Ridgway Amber M. , Smith Edward N. , Bolland Hannah , Hammond Ester M. , Conway Stuart J. , Weits Daan A. , Flashman Emily
Published: February 2025

Low oxygen signalling in plants is important in development and stress responses. Measurement of oxygen levels in plant cells and tissues is hampered by a lack of chemical tools with which to reliably detect and quantify endogenous oxygen availability. We have exploited hypoxia-activated fluorescent probes to visualise low oxygen (hypoxia) in plant cells and tissues.

We applied 4-nitrobenzyl (4NB-) resorufin and methyl-indolequinone (MeIQ-) resorufin toArabidopsis thalianawhole cells and seedlings exposed to hypoxia (1% O2) and normoxia (21% O2). Confocal microscopy and fluorescence intensity measurements were used to visualise regions of resorufin fluorescence.

Both probes enterA.thalianawhole cells and are activated to fluoresce selectively in hypoxic conditions. Similarly, incubation withA.thalianaseedlings resulted in hypoxia-dependent activation of both probes and observation of fluorescence in hypoxic roots and leaf tissue. MeIQ-Resorufin was used to visualise endogenous hypoxia in lateral root primordia of normoxicA.thalianaseedlings.

Oxygen measurement in plants until now has relied on invasive probes or genetic manipulation. Use of these chemical probes to detect applied and endogenous hypoxia has the potential to facilitate a greater understanding of oxygen dynamics in plant cells and tissues, allowing correlation of oxygen concentrations with adaptive and developmental responses to hypoxia.
Mutant IDH impairs chromatin binding by PDGFB to promote chromosome instability
Authors: Curry Rachel N. , McDonald Malcolm F. , He Peihao , Lozzi Brittney , Ko Yeunjung , O’Reilly Isabella , Rosenbaum Anna , Kwon Wookbong , Fahim Leyla , Marcus Joshua , Powell Noah , Wang Su , Ma Jin , Multani Asha , Choi Dong-Joo , Sardar Debo , Mohila Carrie , Lee Jason , Gallo Marco , Harmanci Arif , Harmanci Akdes Serin , Deneen Benjamin , Rao Ganesh
Published: February 2025

Non-canonical roles for growth factors in the nucleus have been previously described, but their mechanism of action and biological roles remain enigmatic. Platelet-derived growth factor B (PDGFB) can drive formation of low-grade glioma and here we show that it localizes to the nucleus of human glioma cells where it binds chromatin to preserve genome stability and cell lineage. Failure of PDGFB to localize to the nucleus leads to chromosomal abnormalities, aberrant heterochromatin architecture and accelerated tumorigenesis. Furthermore, nuclear localization of PDGFB is reliant upon the expression levels and mutation status of isocitrate dehydrogenase (IDH). Unexpectedly, we identified macrophages as the predominant source of PDGFB in human, finding that immune-derived PDGFB can localize to the nucleus of glioma cells. Collectively, these studies show that immune derived PDGFB enters the nucleus of glioma cells to maintain genomic stability, while identifying a new mechanism by which IDH mutations promote gliomagenesis.
Heightened non-testing risk mitigation blood donor screening with retrospective transcription-mediated amplification testing during a 2023 local Florida malaria cluster
Authors: Sullivan David J. , Lanteri Marion , Bres Vanessa , Hanhan Measa , Pagan Marlene , Rey Alejandro , Thomas Korena , Sasnett Betsy , Reik Rita A.
Published: February 2025

Background

Transfusion-transmitted malaria risk in the USA is estimated at less than one per ten million blood donations or about 1 case every 2 years. A total of 18 autochthonous malaria infections have been reported in the USA since 2003: eight cases in 2003 and ten cases in 2023 with fifteen reported from Florida. From May to July 2023 in Sarasota County, Florida, symptomaticP. vivaxmalaria was detected in seven individuals with no recent malaria travel history.

Study Design and Methods

In the absence of an FDA-approved blood donor screening test for malaria at the time, the local blood center responded to this 2023 cluster by implementing a non-testing risk mitigation strategy of escalating blood donor screening measures and pathogen reduction. Potential blood supply safety enhancement by use of additional nucleic acid testing (NAT) on samples from donors in impacted areas was studied retrospectively using the Procleix Plasmodium Assay, a transcription-mediated amplification detecting five humanPlasmodiumspecies 18S ribosomal RNA with a limit of detection ranging from 2-7 infected erythrocytes per mL.

Results

Among the 435 valid study samples from accepted healthy blood donors, screened with heightened non-testing measures in the 4-6 mile radius of malaria-impacted area, all samples were nucleic acid test non-reactive.

Discussion

The blood center strategy in response to the local 2023 malaria outbreak maintained the blood supply safety with no transfusion-transmitted malaria and no retrospective evidence ofPlasmodiumin the 435 valid samples collected from blood donors residing in impacted areas.
T Cell Dysfunction in Cutaneous Leishmaniasis at Single-Cell Resolution
Authors: Avila Jonathan Peña , Singh Youvika , de Souza Fernanda Mesquita , de Assunção Stella Francy , Damasceno Samara , Guedes Herbert Leonel de Matos , Cunha Thiago M. , Filho Roberto Bueno , da Silva João Santana , Nakaya Helder I.
Published: February 2025

Background

Cutaneous leishmaniasis (CL) is characterized by immune dysregulation that facilitates chronic infection.

Objective

To investigate the role of T cells in the immunopathology of CL by characterizing the immune landscape of skin lesions using single-cell RNA sequencing (scRNA-seq).

Methods

We performed scRNA-seq to profile T cells from PBMC and skin lesions of CL patients.

Results

We analyzed the transcriptional profile of distinct populations of CD4+ and CD8+ migratory T cells in CL lesions. CD8+ resident T cells displayed expression of exhaustion markers and were categorized into progenitor, transitional, and terminal stages, with HAVCR2 (TIM-3) identified as a potential driver of dysfunction. Compared to psoriasis and healthy skin, CL lesions showed a reduced frequency of regulatory T cells (Tregs), potentially linked to oxidative stress, DNA damage, and increased apoptosis. We also detected double-negative (DN) γδ T cells, suggesting their potential role in antigen presentation via MHC class II through TGF-β signaling.

Conclusion

This study provides novel insights into immune evasion mechanisms in CL, identifying TIM-3, Treg modulation, and the functional role of DN γδ T cells as distinct potential targets for future immunotherapies.
Association Between Abnormal Sleep and Mortality Risk: A Nationwide Prospective Cohort Study of All-Cause and Cardiovascular disease Mortality
Authors: Ke Li , Li Ying , Zhao Lei , Xing Wenli , Jiang Sili
Published: February 2025

Background

The American Heart Association’s Life’s Essential 8 construct of ideal cardiovascular health now includes sleep duration, emphasizing the need to understand the implications of suboptimal sleep patterns. Recent studies have demonstrated that Life’s Essential 8 is correlated with the risk of all-cause mortality and CVD-specific mortality. However, although sleep duration being one of the components of Life’s Essential 8, the relationship between an individual’s sleep patterns and the risk of all-cause and CVD- specific mortality remains unclear.

Methods

The 2005–2018 National Health and Nutrition Examination Survey (NHANES) included 38,006 adults aged ≥20 years. The definitions of normal sleep duration (7–8 hours per night), short sleep duration (< 7 hours), and long sleep duration (> 8 hours) were based on the current literature. To evaluate the association between abnormal sleep patterns and both all-cause mortality and CVD mortality, a multinomial Cox regression analysis was conducted, adjusting for demographic and clinical factors.

Results

The study utilized three models (Model I–III), first unadjusted and then adjusted for sociodemographic, lifestyle, and chronic disease factors. In the fully adjusted model, both short sleep (OR=1.25, 95% CI: 1.12–1.39, P<0.001) and long sleep (OR=1.30, 95% CI: 1.18–1.44, P<0.001) were found to be associated with an increased risk of all-cause mortality. Regarding CVD mortality, after full adjustment (Model III), only long sleep remained statistically significant (OR=1.28, 95% CI: 1.07–1.52, P=0.006), while the association for short sleep was no longer significant (OR=1.16, 95% CI: 0.94–1.43, P=0.176).

Conclusions

Abnormal sleep duration (both short and long) was independently associated with an increased risk of all-cause mortality. Long sleep duration was associated with an increased risk of CVD mortality.
Persistent Homology in Medical Image Processing: A Literature Review
Authors: Brito-Pacheco Daniel , Giannopoulos Panos , Reyes-Aldasoro Constantino Carlos
Published: February 2025

Medical image analysis has experienced significant advances with the integration of machine learning, deep learning, and other mathematical and computational methodologies into the pipelines of data analysis. One methodology that has received less attention is Persistent Homology (PH), which comes from the growing field of Topological Data Analysis and has the ability to extract features from data at different scales and build multi-scale summaries. In this work, we present a systematic review of PH applied in medical images. To illustrate the potential of PH, we introduce the main concepts of PH and demonstrate with an example of histopathology. Fifteen articles where PH was applied to medical image analysis tasks such as segmentation and classification were selected and reviewed. It was observed that PH is very versatile, as it can be applied in many different contexts and to different data types, whilst also showing great potential in increasing model accuracy in both classification and segmentation. It was also observed that image segmentation predominantly uses basic level-set filtration to calculate PH, while classification takes various approaches using filtration on more complex structures built from data. This review highlights PH as an important tool that can further advance medical image analysis.
Mapping plant-scale variation in crop physiological traits and water fluxes
Authors: Caine Robert S. , Berry Peter M. , Storer Kate E. , Croft Holly L.
Published: February 2025

Nitrogen (N) is a vital plant element, affecting plant physiological processes, carbon and water fluxes and ultimately crop yields. However, N uptake by crops can vary over fine spatiotemporal scales, and optimising the application of N-fertiliser to maximise crop performance is challenging. To investigate the potential of spatially mapping the impact of N fertiliser application on crop physiological performance and yield, we leverage both optical and thermal data sampled from drone platforms and ground-level leaf measurements, across a range of different N, Sulphur (S) and sucrose treatments in winter wheat. Using leaf level hyperspectral reflectance data, leaf chlorophyll content was accurately modelled across fertiliser treatments via partial least squares regression (PLSR;R2= 0.93,P< 0.001). Leaf photosynthetic capacity (Vcmax) exhibited a strong linear relationship with leaf chlorophyll (R2= 0.77;P< 0.001). Using drone-acquired MERIS terrestrial chlorophyll index (MTCI) values as a proxy for leaf chlorophyll (R2= 0.76;P< 0.001),Vcmaxwas spatially mapped at the centimetre-scale. Thermal drone and ground measurements demonstrated that N application leads to cooler leaf temperatures, which led to a strong relationship with ground-measured leaf stomatal conductance (R2= 0.6;P< 0.01). Final grain yield was most accurately predicted by optical reflectance (MTCI,R2= 0.94;P< 0.001). Precise retrieval of leaf-level crop performance indicators from drones establishes significant potential for optimising fertiliser application, to reduce environmental costs and improve yields.
Multiple Neural Modules Orchestrate Conflict Processing
Authors: Sabo Melinda , Varlet Manuel , Grootswagers Tijl
Published: February 2025

Cognitive conflict is a ubiquitous aspect of our daily life, yet its underlying neural mechanisms remain debated. Competing theories propose that conflict processing is governed by either a domain-general system, multiple conflict-specific modules, or both types of systems, as evidenced by hybrid accounts. The aim of the current study was to settle this debate. We analyzed electroencephalogram (EEG) data from 507 participants (ages 20–70) who completed three conflict tasks: a change detection, a Simon, and a Stroop task. A novel decoding approach was adopted to distinguish between conflict and non-conflict trials. While within-task decoding showed robust effects, decoding across tasks yielded chance-level evidence. These findings support the idea that conflict processing relies on multiple conflict specific modules tailored to task-specific demands. By leveraging a large, diverse sample and a data-driven analysis, this study provides compelling evidence for conflict-specific neural mechanisms, offering new insights into the nature of conflict resolution and cognitive control.
Modeling Pyramidal Neurons Using Bidomain BEM and Hierarchical Matrix Approximation
Authors: Hasan Nahian I. , Sabino Vanine , Gomez Luis J.
Published: February 2025

Electromagnetic brain stimulation uses electrodes or coils to induce electric fields (E-fields) in the brain and affect its activity. Our understanding of the precise effects of the device-induced E-fields on neural activity is limited. In this work, we present a novel boundary integral equation that enables the modeling of fully coupled E-fields from both neurons and stimulation devices. This boundary element approach is accelerated using fast direct solvers to allow for the analysis of realistic scenarios. We present examples, indicating the ability of our solver to analyze rat L2/3 pyramidal neurons derived from the blue brain project.
Pharmacokinetics of anti-SARS-CoV-2 monoclonal antibody SA55 injection in healthy participants
Authors: Zhou Yibo , Meng Xing , Li Jianhua , Wang Jin , Zeng Gang , Cao Yunlong , Hu Chaoying , Jin Ronghua
Published: February 2025

To explore novel treatment/prevention of COVID-19, a novel broad-spectrum neutralizing antibody injection, anti-SARS-CoV-2 antibody SA55 Injection (SA55 injection) was developed. Pharmacokinetics (PK) characteristics of SA55 injection were evaluated in a randomized, controlled, double-blind phase □ trial based on healthy participants aged 18-65 years. PK parameters (AUC0-∞, AUC0-t, and Cmax) were assessed using one-way ANOVA and the Power model. Results demonstrated that SA55 injection with a Tmaxof 12.6 days and a half-life of 103 days. In conclusion, the SA55 injection demonstrates potential for use in the prevention of COVID-19 infection.
Repetitive magnetic stimulation with iTBS600 induces persistent structural and functional plasticity in mouse organotypic slice cultures
Authors: Lu Han , Garg Shreyash , Lenz Maximilian , Vlachos Andreas
Published: February 2025

Background

Repetitive transcranial magnetic stimulation (rTMS) is well known for its ability to induce synaptic plasticity, yet its impact on structural and functional remodeling within stimulated networks remains unclear. This study investigates the cellular and network-level mechanisms of rTMS-induced plasticity using a clinically approved 600-pulse intermittent theta burst stimulation (iTBS600) protocol applied to organotypic brain tissue cultures.

Methods

We applied iTBS600 to entorhino-hippocampal organotypic tissue cultures and conducted a 24-hour analysis using c-Fos immunostaining, whole-cell patch-clamp recordings, time-lapse imaging of dendritic spines, and calcium imaging.

Results

We observed long-term potentiation (LTP) of excitatory synapses in dentate granule cells, characterized by increased mEPSC frequencies and spine remodeling over time. c-Fos expression in the dentate gyrus was transient and exhibited a clear sensitivity to the orientation of the induced electric field, suggesting a direction-dependent induction of plasticity. Structural remodeling of dendritic spines was temporally linked to enhanced synaptic strength, while spontaneous firing rates remained stable during the early phase in the dentate gyrus, indicating the engagement of homeostatic mechanisms. Despite the widespread electric field generated by rTMS, its effects were spatially and temporally precise, driving Hebbian plasticity and region-specific spine dynamics.

Conclusions

These findings provide mechanistic insights into how rTMS-induced LTP promotes targeted plasticity while preserving network stability. Understanding these interactions may help refine stimulation protocols to optimize therapeutic outcomes.
A method for identifying spatially divergent selection in structured populations
Authors: do O Isabela , Gaggiotti Oscar , de Villemereuil Pierre , Goudet Jerome
Published: February 2025

Species occupy diverse, heterogeneous environments, which expose populations to spatially varied selective pressures. Populations in different environments can diverge due to local adaptation. However, neutral evolution can also drive population divergence. Thus, testing for local adaptation requires a neutral baseline for population differentiation. The classicalQST-FSTcomparison was developed for this purpose. Yet,QST-FSTfrequently fails to account for the complexities of population structure because the theory underlying this comparison assumes that all subpopulations are equally related, resulting in inflated false positive rates in metapopulations that deviate from the island model. To address this limitation we use estimates of between- and within-population relatedness to model population structure. Using those relatedness matrices, we infer the between- and within-population ancestral additive genetic variances under a mixed-effects model. Under neutrality, these inferred variances are expected to be equal. We propose here a test to detect selection based on the comparison of these two estimates of the ancestral variance and we compare its performance with earlier solutions. We find our method is well calibrated across various population structures and has high power to detect adaptive divergence.

Author summary

Populations of the same species often face different environmental pressures, driving them to adapt locally. However, even in the absence of adaptation, subpopulations can diverge due to random genetic drift and limited migration. Distinguishing between adaptive evolution and random divergence is a central challenge in evolutionary biology. Traditional methods, such asQST–FSTcomparison, assume equal relatedness among subpopulations—a simplification that rarely holds in complex real-world scenarios, leading to flawed conclusions. To overcome this limitation, we developed a novel method that incorporates genetic relatedness among subpopulations, leveraging quantitative genetic theory to estimate ancestral additive genetic variances. Our approach provides a powerful tool for testing local adaptation, reliably distinguishing adaptive divergence from drift across a variety of population structures.
A randomised clinical trial of STAtin therapy for Reducing Events in the Elderly (STAREE): Statistical analysis plan
Authors: Wolfe Rory , Heritier Stephane , Zomer Ella , Chatterton Mary Lou , Curtis Andrea , Spark Simone , Flanagan Zachary , Chong Trever T-J , Cloud Geoffrey C , Nelson Mark R , Nicholls Stephen J , Moran Chris , Reid Christopher M , Zoungas Sophia
Published: February 2025

The STAREE randomised controlled trial of 9971 community-dwelling older adults without cardiovascular disease, diabetes or dementia is designed to compare daily 40mg atorvastatin to placebo. We present a statistical analysis plan to pre-specify the analytical approaches that will be taken when reporting the main findings from the trial. The plan describes the analysis approach for the co-primary endpoints: (a) death, dementia, and persistent physical disability; (b) major cardiovascular events; and all secondary endpoints. A pre-specified economic evaluation is also included as part of this plan.
APOEandTREM2variants differentially influence glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants
Authors: Freudenberg-Hua Yun , Giliberto Luca , D’Abramo Cristina , Li Wentian , Ma Yilong , Goate Alison , Koppel Jeremy
Published: February 2025

Plasma levels of protein biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers, but it is unclear how risk genes for Alzheimer’s disease (AD) influence levels of these biomarkers. We investigated the association of the established high-effect variants for AD inAPOEandTREM2with these biomarkers, using data from over 50,000 participants from the UK Biobank (UKB). The results show thatAPOE4is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. TheAPOE4effect on GFAP increases with age and the number ofAPOE4alleles. The risk variants R47H and R62H inTREM2are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. Higher levels of both GFAP and NEFL in midlife are significantly associated with greater risk for incident dementia. In contrast, the protectiveAPOE2allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for AD differentially affect dementia protein biomarkers across age, indicating gene specific pathways with potential therapeutic implications.
Alternative splicing broadens antiviral diversity at the humanOAS2locus
Authors: Davies Emma L. , Sowar Hanna , Balci Arda , Moorhouse Elliot , Wickenhagen Arthur , Turnbull Matthew L. , Palmarini Massimo , Wilson Sam J. , Fletcher Adam J.
Published: February 2025

Interferons (IFN) are cytokines that regulate the expression of hundreds of genes during viral infections to generate a broadly antiviral environment in the stimulated cell. Antiviral breadth is provided by the concurrent expression of many individual IFN-stimulated genes (ISG), each encoding a protein with often exquisite antiviral specificity. Here, we show that mechanistic plasticity at a single genetic locus is a novel mechanism to diversify the antiviral profile of human cells. Through alternative splicing, theOAS2gene encodes two antiviral molecules with distinct target specificities. The shorter OAS2 p69 isoform blocks the replication of seasonal human coronavirus OC43 (HCoV-OC43), while the longer p71 isoform restricts the replication of picornavirus Cardiovirus A (EMCV). The restriction profile is determined by the variable length OAS2 C-terminal tail. Remarkably, the antiviral mechanisms underlying these distinct antiviral profiles are either RNase L dependent or independent, suggesting that splicing divides ‘classic restriction’ versus ‘virus sensing’ systems across two distinct OAS2 polypeptides. Together, our data reveal that the humanOAS2locus uses alternative splicing and mechanistic plasticity to diversify antiviral profiles.
Myelin transcription factors 1 and 3 have overlapping but distinct roles in insulin secretion and survival of human β cells
Authors: Hu Ruiying , Yagan Mahircan , Wang Yu , Tong Xin , Doss Teri D. , Liu Jinhua , Xu Yanwen , Simmons Alan J. , Lau Ken S. , Stein Roland , Liu Qi , Gu Guoqiang
Published: February 2025

Islet β-cell dysfunction, loss of identity, and death, together known as β-cell failure, lead to reduced inulin output and Type 2 diabetes (T2D). Understanding how β-cells avoid this failure holds the key to preventing or delaying the development of this disease. Here, we examine the roles of two members of the Myelin transcription factor family (including MYT1, 2, and 3) in human β-cells. We have reported that these factors together prevent β-cell failure by repressing the overactivation of stress response genes in mice and human β-cell lines. Single-nucleotide polymorphisms in MYT2 and MYT3 are associated with human T2D. These findings led us to examine the roles of these factors individually in primary human β-cells. By knocking downMYT1orMYT3separately in primary human donor islets, we show here that these TFs have distinct functions. Under normal physiological conditions, highMYT1expression is required for β-cell survival, while highMYT3expression is needed for glucose-stimulated insulin secretion. Under obesity-induced metabolic stress, MYT3 is also necessary for β-cell survival. Accordingly, these TFs regulate different genes, with MYT1-KD de-regulating several in protein translation and Ca2+binding, while MYT3-KD de-regulating genes involved in mitochondria, ER, etc. These findings highlight not only the family member-specific functions of each TF but also the multilayered protective function of these factors in human β-cell survival under different levels of metabolic stress.

Highlights

MYT1-KD compromises human β-cell survival but not insulin secretion

MYT3-KD compromises human β-cell insulin secretion but not survival

MYT3-KD compromises human β-cell viability in obesity

MYT1 and MYT3 regulate overlapping but distinct sets of genes