bluuebunny/crossref_metadata_2025 huggingface dataset:
Warming increases richness and shapes assemblages of eukaryotic parasitic plankton
Authors: Rajarajan Amruta , Cerbin Sławek , Beng Kingsly C. , Monaghan Michael T. , Wolinska Justyna
Published: January 2025

Anthropogenic activities have led to a global rise in water temperatures, leading to an increased interest in how warming affects infectious disease ecology. While most studies have focused on individual host-parasite systems, there is a gap in understanding the impact of warming on multi-host, multi-parasite assemblages in natural ecosystems. To address this gap, we examined freshwater eukaryotic parasite communities in ten natural lakes near Konin, Poland: five artificially heated and five nearby non-heated “control” lakes. Since 1958, the heated lakes have experienced a mean annual temperature increase of 2°C due to hot water discharge from two adjacent power plants. We collected seasonal environmental DNA (eDNA) samples from surface waters over a two-year period and applied targeted metabarcoding to compare the richness and distribution of eukaryotic parasites across lake types, with a focus on protists and fungi. Using literature searches and sequence metadata from GenBank, we identified putative parasites which included Alveolates, Stramenopiles, basal Fungi and Ichthyosporeans, as well as their associated hosts. Heated lakes exhibited distinct parasite assemblages, with higher richness of parasitic chytrids and aphelids particularly during summer, suggesting thermal preferences among some freshwater parasite species. A general linear model suggests that increased chytrid richness in heated lakes may be partly due to higher richness of their green algal, diatom- and dinoflagellate hosts. These findings highlight how warming can drive shifts in parasite richness and assemblages, potentially altering host-parasite dynamics in freshwater ecosystems.
Statistical Analysis Plan for the manuscript reporting the primary outcome in the TESSA study
Authors: Grunnet Louise Groth , Quist Jonas Salling , Færch Kristine , Blond Martin Bæk , Kengne Andre , Dave Joel , Goedecke Julia , Mendham Amy
Published: January 2025

This paper describes the statistical analyses plan (SAP) for the following study: Exploring the effects of time-restrictedeating on body weight and associated cardiometabolic outcomes inSouthAfrican women living with HIV (TESSA): a protocol for a randomised controlled trial.

This document is a supplement to the TESSA study protocol and contains the statistical analysis plan (SAP) for the main paper of the trial in which the primary outcome will be reported. This document complies with the guidelines for the content of statistical analysis plans in clinical trials. The SAP does not cover the statistical analysis of data for outcomes to be included in secondary manuscripts.
Unveiling BPDE Induced Carcinogenic Signaling: Computational Insights into NF-κB, MAPK, and PI3K/Akt Pathway Activation
Authors: Kathpalia Karishma Vivek , Kumar Anil , Verma Awadhesh Kumar
Published: January 2025

Abstract

The Carcinogen benzo[a]pyran-7, 8 dihydrodiol 9, 10 epoxide(BaP-DNP) the active metabolite of benzo[a]pyrene has been postulated to induce carcinogenesis through formation of adduct with DNA and through alteration of critical pathways involved in signaling. Besides genotoxicity, BPDE has more recently been reported to alter the NF-κB, MAPK, and PI3K/Akt, that are involved in inflammation, cell survival and cell proliferation. From the above molecular docking analysis of BPDE binding to the potential proteins of these pathways, the mechanism of action of the compound is examined. The studies conducted on docking reveal moderate binding affinity of BPDE with NF-κB, that is, -6.11 kcal/mol, which points out its role in inflammation and oncogenic signaling. In addition, BPDE has more protein-binding affinities within the MAPK and PI3K/Akt pathway for CDK1 (-7.46 kcal/mol), LOX (-7.47 kcal/mol), and CDK6 (-6.84 kcal/mol). These indicate that influence of BPDE in tumour progression should not be only through the activation of NF-κB but would rather be supported by significant inputs of pathways that include PI3K/Akt and MAPK. This interaction would seem to favor cell survival, proliferation, and apoptosis resistance. Broader analysis of the data presented allows defining NF-κB as one of the key molecules contributing to BPDE-induced carcinogenesis; however, the data also point to the significant participation of the MAPK and PI3K/Akt pathways in this process. Future work should also more fully detail how these pathways interconnect and also evaluate the effectiveness of inhibiting NF-κB and related pathways in preventing BPDE’s carcinogenic action. This study adds to understanding of molecular mechanisms and therapeutic targets of BPDE.

Graphical Abstract
Establishing a preclinical chronic wound model to characterise the pathophysiology of snakebite envenoming
Authors: Dawson Charlotte A , Harijanto Pruistinne , Nawilaijaroen Yonlada , Casewell Nicholas R. , Cash Jenna L
Published: January 2025

Snakebite claims 138,000 lives a year with an additional 400,000 patients left permanently disabled or disfigured1. Morbidity following envenoming includes the development of chronic wounds around the bite site. The understanding of the underlying pathophysiology of chronic snakebite wounds has been severely limited by the historical reliance on a preclinical model that only captures acute local envenoming pathology. Through the application of three medically important snake venoms (Echis ocellatus, Bothrops atrox and Naja nigricollis) to a recently developed preclinical model of chronic wounds, we have been able to characterise key features of venom wounds. We have been able to show that venom wounds share consistencies with non-venom induced preclinical wounds, and also display unique characteristics such as extracellular matrix degradation and eosinophilic infiltrate. This model will not only serve to increase our understanding the underlying pathophysiology of venom wounds, but will also provide a platform for exploring therapeutic interventions to reduce or resolve snakebite wounds.
IMPORTANT: Advanced Pollen Classification of Indian Medicinal Plants through SEM and Computer Vision
Authors: Khalane Jaidev Sanjay , Gawande Nilesh D. , Raman Shanmuganathan , Sankaranarayanan Subramanian
Published: January 2025

Pollen grains of plant species have unique morphological characteristics. The variability in shape, size, and microscopic pollen surface features can be efficiently used to determine the plant species to which they belong. This approach can be instrumental in regions with rich biodiversity in plant species, specifically in medicinal plant. The creation of a pollen dataset for these species using SEM images and a computer vision application can be beneficial for their identification. We have developed a robust approach utilizing scanning electron microscopy (SEM) to generate high-resolution pollen images from 28 plant species of medicinal importance and employed computer vision techniques for accurate segmentation and classification based on diverse morphological features. In this study, a dataset comprising 269 images for segmentation and 5842 images was used for classification across 28 classes. In addition, we have created a globally accessible database named IMPORTANT (Indian Medicinal Plants Pollen Images Dataset for Research, Training, and Analysis of Neural Networks) to facilitate easy retrieval and sharing of pollen images. This study can effectively identify medicinal plant species by utilizing the microscopic features of pollen SEM images through the IMPORTANT database. Since the pollen of even closely related species vary in their morphological characteristics, this approach can efficiently determine the closely related species with accuracy and precision.
Endogenous falcarinol-type polyacetylenes in carrots and their putative influence on post-harvest fungal pathogensMycocentrospora acerinaandBotrytis cinerea
Authors: He Wanying , Dunemann Frank
Published: January 2025

Falcarinol-type polyacetylenes are a main group of natural bitter compounds synthesized in carrot taproots and putatively contribute to defence mechanisms against soil-borne fungal pathogens. In this study, we analysed the relationships between the constitutive levels of these secondary metabolites and the extent of root infection with the two main carrot storage fungal pathogensMycocentrospora acerina(liquorice rot) andBotrytis cinerea(grey mold). Taproots of eight differently colored carrot cultivars exhibiting different levels of the three main falcarinol-type polyacetylenes were inoculated with the two fungi and evaluated for diseased area with a digital image analysis system after 6-weeks incubation in a cold storage facility. After inoculation on cortex tissue and the periderm of taproots, a progressed carrot breeding line and the cultivar Bolero demonstrated the highest tolerance to bothM. acerinaandB. cinerea, while Blanche and Senta were the most susceptible cultivars. Concentrations of falcarinol-type polyacetylenes were negatively correlated, though not significantly, withM. acerinaandB. cinereadisease severity. Nevertheless, our study has provided further insights into the naturally occurring variability for the accumulation of falcarinol-type polyacetylenes in cultivated carrots and their putative contributions to resistance against post-harvest fungal pathogensM. acerinaandB. cinerea. To our knowledge, this is the first study about the pathogenicity ofB. cinereaafter inoculation of different carrot cultivars with known root PA levels.
Vascular contribution to cognitive impairment in heart failure with preserved ejection fraction: TRPV4 and KLF2 as key mediators of neurovascular dysfunction in the ZSF1 model
Authors: Lambrichts Sara M.P. , van der Taelen Laura , Pastor Irene , Leenders Peter , Bitsch Nicole , Majcher Daria , Hermes Denise , Simmonds Steven J. , van Herwijnen Marcel , Kamps Rick , Weltjens Ellen , Steinbusch Hellen P. , Caiment Florian , Kutmon Martina , Jones Elizabeth A.V. , van Oostenbrugge Robert J. , Foulquier Sebastien
Published: January 2025

Background

The development of vascular cognitive impairment (VCI) and heart failure with preserved ejection fraction (HFpEF) are strongly associated with comorbidities such as obesity, diabetes, hypertension, and aging. Microvascular dysfunction may be key a pathological step in the development of cognitive dysfunction during HFpEF. Hence, we aimed to evaluate the cerebrovascular and cognitive phenotype in ZSF1 rats and identify molecular processes central to the development of VCI during HFpEF.

Methods

Male Lean and Obese rats underwent blood pressure and glucose measurements, echocardiography and a series of behavioural tasks at three different time points. Cerebral blood flow was measured over the barrel cortex using laser speckle contrast imaging and neurovascular coupling was assessed upon whisker stimulation. Brain immunohistochemistry was performed to assess blood- brain barrier (BBB) integrity and vascular density. Lastly, isolated cortical microvessels were used for transcriptomic analysis, and selected targets were validated in brain sections via fluorescent multiplex in-situ hybridization.

Results

Obese ZSF1 rats exhibited neurovascular uncoupling, along with an impaired short- and long- term memory, as well as spatial learning. In addition, BBB permeability and cerebral vascular density were elevated in Obese vs Lean at 22-23 and 34-35 weeks of age, respectively. Transcriptomic analysis of brain microvessels revealed the regulation of processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling. Among the top regulated biological processes,Trpv4andKlf2were found to be consistently downregulated in Obese vs Lean rats and involved in many of the top regulated biological processes. This was further verified in brain sections at 22-23 weeks of age.

Conclusion

Obese ZSF1 rats develop cognitive impairment, which is related to dysfunction of the neurovascular unit. This cerebrovascular phenotype progresses along with the onset of HFpEF and is associated with downregulation ofTrpv4andKlf2in cerebral microvessels, two key genes known for their vasoprotective actions.
Balancing tumour proliferation and sustained cell cycle arrest through proteostasis remodelling drives immune niche compartmentalisation in breast cancer
Authors: Celik Cenk , Withnell Eloise , Pan Shi , Chu Tooki , Labbadia John , Secrier Maria
Published: January 2025

Uncontrolled proliferation is a hallmark of cancer, yet tumour cells can enter G0 arrest by halting the cell cycle reversibly (quiescence) or irreversibly (senescence) to survive under stress and in hostile tumour microenvironments (TME). G0 arrested cells contribute to drug tolerance, metastasis and recurrence, but their identification remains challenging due to their rarity and elusive regulatory pathways. Here, we quantify G0 arrest and proliferation decisions in single-cell and spatially profiled breast primary tumours to unveil adaptive responses driving immune compartmentalisation. We identify a genomically-constrained and prolonged G0 arrest state resembling that of dormant precursors of cancer progression. This state featured adaptive transcriptional reprogramming, including unfolded protein response stress, reduced mitochondrial translation and epithelial-mesenchymal plasticity enabled by semaphorin signalling. Spatial transcriptomics revealed G0 arrest pockets encapsulated byAPOE+ lipid-associated macrophages, myofibroblastic CAFs and immature perivascular cells, suggestive of an immunosuppressive niche contrasting with cytotoxic environments in proliferative hotspots and displaying distinct drug sensitivities. To facilitate future research, we provide a foundation model capturing G0 arrest and proliferation with 94% accuracy in single cell data, available athttps://github.com/secrierlab/G0-LM. Our findings provide new insights into the spatial organisation of cell cycle arrest in breast cancer, highlighting the role of G0 states in tumour heterogeneity and adaptation.
Learning a CoNCISE language for small-molecule binding
Authors: Erden Mert , Devkota Kapil , Varghese Lia , Cowen Lenore , Singh Rohit
Published: January 2025

Rapid advances in deep learning have improvedin silicomethods for drug-target interaction (DTI) prediction. However, current methods do not scale to the massive catalogs that list millions or billions of commercially-available small molecules. Here, we introduce CoNCISE, a method that accelerates drug-target interaction (DTI) prediction by 2-3 orders of magnitude while maintaining high accuracy. CoNCISE uses a novel vector-quantized codebook approach and a residual-learning based training of hierarchical codes. Strikingly, we find that much of binding-specificity information in the small molecule space can be compressed into just 15 bits of information per compound, characterizing all small molecules into 32,768 hierarchically-organized binding categories. Our DTI architecture, which combines these compact ligand representations with fixed-length protein embeddings in a cross-attention framework, achieves state-of-the-art prediction accuracy at unprecedented speed. We demonstrate CoNCISE’s practical utility by indexing 6.4 billion ligands in the Enamine dataset, enabling researchers to query vast chemical libraries against a protein target in seconds. A “CoNCISE + docking” pipeline screened Enamine to propose strong binders (predictedKD≈ 10-20µM) of three difficult-to-drug targets, each within two hours. CoNCISE’s advance could democratize access to largescale computational drug discovery, potentially enabling rapid identification of promising molecules for therapeutic targets and cellular perturbations.
The MAP kinase scaffold MORG1 shapes cell death in unresolved ER stress in Arabidopsis
Authors: Kim Joo Yong , Ko Dae Kwan , Brandizzi Federica
Published: January 2025

Governed by the unfolded protein response (UPR), the ability to counteract endoplasmic reticulum (ER) stress is critical for maintaining cellular homeostasis under adverse conditions. Unresolved ER stress leads to cell death through mechanisms that are yet not completely known. To identify key UPR effectors involved in unresolved ER stress, we performed an ethyl methanesulfonate (EMS) suppressor screen on the Arabidopsisbzip28/60mutant, which is impaired in activating cytoprotective UPR pathways. This screen identified MAP kinase organizer 1 (MORG1), a conserved MAP kinase scaffold protein, as a previously uncharacterized regulator of ER stress tolerance. Thecoffin1mutant, which carries a mutation inMORG1, exhibited enhanced resilience to ER stress by partially restoring UPR gene expression and promoting growth under stress conditions. Mechanistically, we found that MORG1 modulates MPK6-dependent phosphorylation of the stress-responsive transcription factor WRKY8. Loss ofWRKY8phenocopied thecoffin1mutant, highlighting WRKY8’s role as a key repressor in the UPR. Together, these findings reveal a MORG1–MPK6–WRKY8 signaling axis that fine-tunes UPR gene expression, providing new insights into ER stress regulation and strategies for improving stress tolerance in multicellular eukaryotes.
ACTIVITY IN HUMAN DORSAL RAPHE NUCLEUS SIGNALS CHANGES IN BEHAVIOURAL POLICY
Authors: Priestley Luke , Mahmoodi Ali , Reith William , Khalighinejad Nima , Rushworth Matthew
Published: January 2025

The dorsal raphe nucleus (DRN) is an important source of serotonin to the human forebrain, however there is little consensus about its behavioural function. We build on recent results from animal models to demonstrate that activity in human DRN represents changes between general behavioural policies. We use a novel behavioural task to show that human participants change their policy to pursue or reject reward opportunities as a function of the average value of opportunities in the environment. Activity in DRN – but no other neuromodulatory nucleus – signalled such policy changes. Patterns of multivariate activity in dorsal anterior cingulate cortex (dACC) and anterior insular cortex (AI), meanwhile, tracked the relative value of reward opportunities given the average value of the environment. We therefore suggest that DRN, dACC and AI form a circuit in which dACC/AI compute the relative value of reward opportunities given the current context, and DRN implements changes in behavioural policy based on context-specific values.
Integrating flowering and stress responses in Arabidopsis through KH-domain genes
Authors: Rodríguez-Cazorla Encarnación , Ripoll Juan-José , Candela Héctor , Aranda-Martínez Almudena , Zavala-González Ernesto , Martínez-Laborda Antonio , Vera Antonio
Published: January 2025

Plant reproductive success largely relies on flowering under favorable conditions. However, stress factors have forced plants to acquire adaptive strategies to coordinate floral timing and stress responses through key genetic elements. RNA-binding proteins with K-homology (KH) domains are emerging as versatile regulators of an increasing number of plant developmental processes, including flowering and stress acclimation. InArabidopsis thaliana,FLKandHOS5encode multifaceted KH-domain proteins associated with transcription and cotranscriptional operations.FLKfacilitates floral transition by repressingFLC, the central flowering inhibitor, while both KH-genes have been involved in abiotic stress and defense against pathogens. Our genetic and molecular data identify HOS5 as a novel flowering regulator that, together with FLK, repressesFLC. Our transcriptomics results reveal that, in addition,FLKandHOS5cooperatively repress numerous stress-responsive genes. Consistent with this,flk hos5double mutant plants exhibit elevated levels of stress-induced gene activities and enhanced resistance to abiotic stress and pathogenic fungi. The coordinated repression ofFLCand stress-induced genes by FLK and HOS5 suggests that these KH proteins are part of a cotranscriptional regulatory hub key for orchestrating flowering time and environmental adaptation responses.
Seeing is Feeling: How Aphantasia Alters Emotional Engagement with Stories
Authors: Abdelrahman Noha , Melcher David , Ripollés Pablo
Published: January 2025

Visual imagery is thought to act as an ‘emotional amplifier’, potentially contributing to narrative engagement. To examine this, we conducted two experiments in which participants were presented with emotionally charged audio and video story excerpts. Experiment 1 included 84 online participants from the general population, while Experiment 2 involved 25 individuals with aphantasia (the inability to generate mental images) and 25 controls. In both experiments we assessed narrative engagement behaviorally using the Narrative Engagement Questionnaire (NEQ), while for Experiment 2 we also measured physiological responses. We found a main effect of modality, with video stimuli scoring higher across all NEQ subscales in both experiments. Notably, in experiment 2, a significant group effect on emotional—but not cognitive—engagement emerged, with aphantasics reporting less emotional engagement than controls. Moreover, controls experienced higher heart rate during audio narratives, while aphantasics had a similar heart rate across both modalities. Our results suggest that the enhanced physiological response seen in non-aphantasics during audio narratives is driven by the mental effort required to generate imagery. Furthermore, this capacity for visual imagery appears to enhance emotional engagement with stories. This highlights mental imagery’s role in both subjective and physiological responses, emphasizing distinct cognitive processes during narrative engagement.
CD20+natural killer cells are polyfunctional, memory-like cells that are enriched in inflammatory disorders
Authors: Albayrak Özgür , Tiryaki Ergün , Akkaya Nazan , Burak Kızılırmak Ali , Doran Tansu , Gökmenoğlu Gökçe , Yüksel Muhammed , Ulukan Bürge , Üzülmez Mina , Baytekin Işıl , Soylu Kemal , Esendağlı Güneş , Meinl Ingrid , Köseoğlu Mesrure , Yüksel Burcu , Erus Suat , Arıkan Çiğdem , Vural Seçil , Zeybel Müjdat , Soysal Aysun , Meinl Edgar , Vural Atay
Published: January 2025

While CD20 was initially characterized as a B cell-specific marker, its expression on memory T cells has expanded our understanding of this molecule’s distribution and function. Here, we identify a previously unrecognized CD20-expressing NK cell population and demonstrate its functional significance. CD56+CD20+ NK cells exhibit hallmarks of cellular activation, including elevated NKp46, CD69, and CD137 expression, enhanced proliferative capacity, and increased production of inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-10). Functional analyses revealed enhanced cytotoxicity against K562 targets, correlating with increased expression of cytolytic mediators including granzymes A, B, and K, perforin, FASL, and TRAIL. Single-cell transcriptional profiling demonstrated that MS4A1-expressing NK cells possess a distinct molecular signature characterized by elevated granzyme K expression and memory-like features. These cells preferentially localize to secondary lymphoid organs and accumulate in inflammatory tissues. Notably, CD56+CD20+ NK cells are enriched in multiple inflammatory conditions, including multiple sclerosis, autoimmune hepatitis, hepatitis B infection, hepatocellular carcinoma, and lung cancer. Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases.

One Sentence Summary

Our study reveals expression of CD20 by NK cells, in relation with enhanced functionality, memory-like features, and inflammation.
Development of catecholaminergic neurons of Otp-lineage in the medial extended amygdala and other centers of the social behavior network
Authors: Morales Lorena , Desfilis Ester , Medina Loreta
Published: January 2025

Catecholaminergic (CA) neurons of the medial extended amygdala, preoptic region and adjacent alar hypothalamus have been involved in different aspects of social behavior. Previous data suggested that at least some CA neurons of the medial extended amygdala could originate in a hypothalamic embryonic domain that expresses the transcription factor Otp. To investigate this, we used Otp-eGFP mice to analyze coexpression of GFP and tyrosine hydroxylase (TH) throughout ontogenesis by way of double immunofluorescence. Our results showed that some TH cells coexpress GFP in the medial extended amygdala preoptic region, and alar and basal hypothalamus. However, the presence of TH/GFP double-labeled cells in the extended amygdala is transient, as they are not seen in adults. Based on previous data, the Otp-related CA cells of the medial extended amygdala might derive from the telencephalon-opto-hypothalamic domain, and those of the central paraventricular and supraoptic hypothalamic nuclei likely derive from the supraopto-paraventricular hypothalamic core domain. Taken together, these data provide new evidence for several Otp-related CA subpopulations in centers of the social brain network. The results open interesting questions about the role of these catecholaminergic subpopulations during the development and in different aspects of social behavior.
Origin of subgenomes in the circumboreal allopolyploid carnivorous plantDrosera anglica(Droseraceae)
Authors: Mohn Rebekah A. , Yang Ya
Published: January 2025

Premise of Study

The parentage of a widespread member of the carnivorous sundew genusDrosera, the allopolyploidDrosera anglica,remains uncertain despite over 100 years of morphological, cytological, and, more recently, molecular study.

Methods

Using transcriptomic and genomic data from 12 speciesDroserasect.Droseraincluding fourD. anglicapopulations and a disjunct Idaho population ofD. intermedia, we assembled genes in HybPiper and phased sequences in HybPhaser. We estimated heterozygosity and generated flow cytometry data to assess ploidy levels. We estimated species relationships with phylogenetic and pairwise genetic distance methods. Additionally, we assembledrbcL and ITS reads to compare to previous data.

Key Results

Sequences from phased subgenomes highly supportedD. anglicaas sister toD. rotundifoliaandD. linearis,differing from previous analyses based on chromosome pairing and Sanger sequencing with limited taxon sampling. Both ITS andrbcL sequences ofD. anglicawere the most similar toD. linearis.Drosera anglicais intermediate between both parents in leaf shape and microhabitat; however, acrossD.sect.Drosera, neither leaf shape nor biogeographic distribution were reliable indicators of phylogenetic relationships. Despite a range-wide sampling, we did not find evidence for multiple origins ofD. anglica. Additionally, we confirmed that the Idaho population previously identified asD. intermediaisD. anglica.

Conclusions

Drosera anglicaarose from allopolyploidy betweenD. linearis(the chloroplast donor) andD. rotundifolia. Our study demonstrates the importance of taxon sampling and careful examining complex phylogenomic data, and presents an exemplar of analyzing allopolyploid relationships in plant lineages.
Strategies to improve selection compared to selection based on estimated breeding values
Authors: Pook Torsten , Hassanpour Azadeh , Niehoff Tobias A.M. , Calus Mario P.L.
Published: January 2025

Background

Selection of individuals based on their estimated breeding values aims to maximize response to selection to the next generation in the additive model. However, when the aim is not only about short-term population-wide genetic gain but also the gain over multiple generations, an optimal strategy is not as clear-cut, as the maintenance of genetic diversity may become an important factor. This study provides an extended comparison of existing selection strategies in a unifying testing pipeline using the simulation software MoBPS.

Results

Applying a weighting factor on the estimated SNP effects based on the frequency of the beneficial allele resulted in an increase of the long-term genetic gain of 1.6% after 50 generations while reducing inbreeding rates by 16.2% compared to truncation selection based on estimated breeding values. However, this also resulted in short-term losses in genetic gain of 1.2% with the break-even point reached after 25 generations. In contrast, inclusion of the average kinship of an individual to top individuals of the population as an additional trait in the selection index with a weight of 17.5% resulted in no short-term losses and increased long-term genetic gains by 4.3% while reducing inbreeding by 15.8%, achieving very similar efficiency to the use of optimum genetic contribution selection. Combining multiple diversity management strategies, with weights for each strategy optimized using an evolutionary algorithm resulted in a breeding scheme with 5.1% increased genetic gain and 37.3% reduced inbreeding rates. The proposed strategy included the use of optimum genetic contribution, weighting of SNP effects based on allele frequency, average kinship as a trait in the selection index, avoiding matings between related individuals, and lowering the proportion of selected individuals.

Conclusions

The combination of selection strategies for the management of genetic diversity was shown to be far superior to the use of any singular method tested in this study. As an efficient use of methods for the management of genetic diversity and inbreeding does not necessarily lead to short-term losses in genetic gain and comes at no extra costs, it is critical for breeding companies to implement such strategies for long-term success.
Piezo1 activation increases the release of therapeutic extracellular vesicles after mechanical stimulation in bioreactors
Authors: Andrade André Cronemberger , Le Goas Oriane , Lemieux Shony , Grangier Alice , Nicolai Alice , Guerrera Chiara , Ribes Christopher , Suply Estelle , Volatron Jeanne , Gazeau Florence , Silva Amanda. K.A.
Published: January 2025

Enhancing protocols and methods for producing therapeutic extracellular vesicles (EVs) in bioreactors is crucial to achieve scalable production while ensuring both quality and quantity. Studies have shown that mechanical stress can promote EV release, although the underlying mechanisms remain largely unclear. Here we investigated which mechanisms are responsible for the increase of EV production under shear stress. EVs were produced from adipose tissue-derived stromal cells (ASCs), also described as mesenchymal stromal cells (MSCs) that can support the regeneration of injured tissues via several paracrine factors. The cultures were treated with GsMTx4, an inhibitor which blocks the Piezo1 ion channels, or with YODA1, its agonist, to assess if mechanical or shear forces pathways are involved in enhancing the EV release. EVs were quantified and characterized after high shear (HS) stimulation compared with no shear stress stimulation (3D) and standard cultures methods (2D). These experiments showed that, after mechanical stimulation by shear stress, EV production increased in bioreactors and this effect was blocked by the inhibition of Piezo1 ion channels with GsMTx4 (88%) with no impact on cell viability. Consistently, the agonist YODA1 increased the EV production (149%). The implications of these findings are significant, especially for regenerative medicine and cellular therapies, where the efficient production of high-quality EVs is crucial. By understanding turbulence-induced shear stress and the natural mechanotransductive pathways within cells, it may be possible to optimize the production of therapeutic EVs, paving the way for more effective treatments in the future.
Competitive elimination of ZO-1/ZO-2-deficient cells regulates epithelial barrier homeostasis
Authors: Otani Tetsuhisa , Nguyen Thanh Phuong , Kinoshita Noriyuki , Fujimori Toshihiko , Furuse Mikio
Published: January 2025

Epithelia cover the body and form a barrier to segregate the internal body from the external environment. Epithelial tissues contact the external environment and are exposed to various stresses that are potentially deleterious for the epithelial barrier1. However, how focal epithelial barrier defects are detected and repaired to maintain epithelial barrier homeostasis remains poorly understood. We co-culturedZO-1/ZO-2double-knockout (DKO) MDCK II cells, which lack tight junctions, with wild-type MDCK II cells, to understand how epithelial cells respond to focal epithelial barrier defects. When co-cultured with wild-type cells,ZO-1/ZO-2DKO cells were selectively eliminated by induction of apoptosis. The elimination depended on a purse-string-like contraction of supracellular actomyosin cables formed at the clone boundary, regulated by ROCK. Furthermore, Hippo signaling and adherens junctions in the surrounding wild-type cells were required to eliminateZO-1/ZO-2DKO cells. These results demonstrate that selective elimination of ZO-1/ZO-2-deficient cells by cell competition regulates epithelial barrier homeostasis.

In brief

Otani et al. reveal that epithelial barrier homeostasis is regulated by cell competition-mediated elimination of ZO-1/ZO-2-deficient cells. Supracellular actomyosin cables form at the clone boundary and constrict in a purse-string-like manner to eliminate the ‘loser’ cells. Mechanosensing in the winning cells is required to eliminate the ‘loser’ cells.

Highlights

ZO-1/ZO-2-deficient cells are eliminated by cell competition

Actomyosin cables form in the winning cells at the clone boundary

A purse-string-like contraction of actomyosin cables compresses the losing cells

Mechanosensing in the winning cells is important to eliminate the ‘loser’ cells
Identification of a BACH1 lung cancer signature: A novel tool for understanding BACH1 biology and identifying new inhibitors
Authors: Klenja-Skudrinja Donika , Walker David , Ali Kevin X. , Higgins Maureen , Patel Angana AH , Raj Dorota , Creelman Anna , McDowall Charlotte , Wenta Tomasz , Larsson Erik , Wiel Clotilde , Sayin Volkan I. , de la Vega Laureano
Published: January 2025

The transcription factor BACH1 is a transcriptional repressor with a central role in regulating oxidative stress and anti-inflammatory pathways, emerging as a promising therapeutic target for multiple conditions, including neoplastic malignancies, neurodegenerative disorders, ischemia-reperfusion injuries and sickle cell disease. In the field of cancer BACH1 has gained significant attention, with BACH1 overexpression correlating with poor prognosis and metastasis across various cancer types; however, despite this increasing relevance of BACH1, no universal pro-metastatic mechanism or transcriptional signature for BACH1 has been identified which is a major limitation for this growing field. To address this, we performed RNA-Seq coupled with ChIP-Seq in BACH1-proficient and BACH1-deficient lung cancer cells, identifying a set of common BACH1 directly regulated genes, which we thoroughly validated in a large panel of cancer cells. This novel lung cancer BACH1 transcriptional signature is highly sensitive and specific to BACH1 perturbations (both genetic and pharmacological) and does not respond to NRF2 modulation, underscoring its specificity. This signature not only represents a robust surrogate for BACH1 activity, but we also provide evidence of its potential value as a tool to i) identify novel BACH1 inhibitors, and ii) provide insights into BACH1’s pro-metastatic role.
Phenotypic analysis of variousClostridioides difficileribotypes reveals consistency among core processes
Authors: Beebe Merilyn A. , Paredes-Sabja Daniel , Kociolek Larry K. , Rodríguez César , Sorg Joseph A.
Published: January 2025

Clostridioides difficileinfections (CDI) cause almost 300,000 hospitalizations per year of which ∼15-30% are the result of recurring infections. The prevalence and persistence of CDI in hospital settings has resulted in an extensive collection ofC. difficileclinical isolates and their classification, typically by ribotype. While much of the current literature focuses on one or two prominent ribotypes (e.g., RT027), recent years have seen several other ribotypes dominate the clinical landscape (e.g., RT106 and RT078). Some ribotypes are associated with severe disease and / or increased recurrence rates, but why are certain ribotypes more prominent or harmful than others remains unknown. BecauseC. difficilehas a large, open pan-genome, this observed relationship between ribotype and clinical outcome could be a result of the genetic diversity ofC. difficile. Thus, we hypothesize that core biological processes ofC. difficileare conserved across ribotypes / clades. We tested this hypothesis by observing the growth kinetics, sporulation, germination, bile acid sensitivity, bile salt hydrolase activity, and surface motility of fifteen strains belonging to various ribotypes spanning each knownC. difficileclade. In viewing these phenotypes across each strain, we see that core phenotypes (growth, germination, sporulation, and resistance to bile salt toxicity) are remarkably consistent across clades / ribotypes. This suggests that variations observed in the clinical setting may be due to unidentified factors in the accessory genome or due to unknown host-factors.

Importance

C. difficileinfections impact thousands of individuals every year many of whom experience recurring infections. Clinical studies have reported an unexplained correlation between some clades / ribotypes ofC. difficileand disease severity / recurrence. Here, we demonstrate thatC. difficilestrains across the major clades / ribotypes are consistent in their core phenotypes. This suggests that such phenotypes are not responsible for variations in disease severity / recurrence and are ideal targets for the development of therapeutics meant to treatC. difficilerelated infections.
Effect of Weather and Soil Management on Medicinal Compound Concentration in East African Arid Acacias: A Simulation Study
Authors: Kinyua Esther Wairimu , Pietsch Stephan , Muli Esther , Kungurtsev Vyacheslav , Neru Sospeter , Mugo Kennedy
Published: January 2025

1

In African countries various tree spcies are a key part in Non Timber Forest Production (NTFP) economy, be it for fruit, resin collection or medicinal use. Among these species Acacias play an important role in the arid and semi-arid dry-lands over Africa. In this study we explore the potential of BioGeoChemical Modelling techniques to assess growth peformance of Acacia ocurrences within their natural environment, where they only may persist against rain-fed grassland vegetation when having access to seasonally changing groundwater tables. Within this study we assess the applicability of BGC-modeling techonologies to pastoral and AgroForestry settings within a semi-arid region in Kenya. Results show that effects of (i) changing hydrological patterns, (ii) fire and grazing regimes and (iii) plant use for resin production may be captured.
Patterns of population structure and genetic variation within the Saudi Arabian population
Authors: Malomane D.K. , Williams M. P. , Huber C.D. , Mangul S. , Abedalthagafi M. , Chiang C. W. K.
Published: January 2025

The Arabian Peninsula is considered the initial site of historic human migration out of Africa. The modern-day indigenous Arabians are believed to be the descendants who remained from the ancient split of the migrants into Eurasia. Here, we investigated how the population history and cultural practices such as endogamy have shaped the genetic variation of the Saudi Arabians. We genotyped 3,352 individuals and identified twelve genetic sub-clusters that corresponded to the geographical distribution of different tribal regions, differentiated by distinct components of ancestry based on comparisons to modern and ancient DNA references. These sub-clusters also showed variation across ranges of the genome covered in runs of homozygosity, as well as differences in population size changes over time. Using 25,488,981 variants found in whole genome sequencing data (WGS) from 302 individuals, we found that the Saudi tend to show proportionally more deleterious alleles than neutral alleles when compared to Africans/African Americans from gnomAD (e.g. a 13% increase of deleterious alleles annotated by AlphaMissense between 0.5 -5% frequency in Saudi, compared to 7% decrease of the benign alleles; P < 0.001). Saudi sub-clusters with greater inbreeding and lower effective population sizes showed greater enrichment of deleterious alleles as well. Additionally, we found that approximately 10% of the variants discovered in our WGS data are not observed in gnomAD; these variants are also enriched with deleterious annotations. To accelerate studying the population-enriched deleterious alleles and their health consequences in this population, we made available the allele frequency estimates of 25,488,981 variants discovered in our samples. Taken together, our results suggest that Saudi’s population history impacts its pattern of genetic variation with potential consequences to the population health. It further highlights the need to sequence diverse and unique populations so to provide a foundation on which to interpret medical-and pharmaco-genomic findings from these populations.
Cost-effectiveness of tuberculosis infection screening at first reception into English prisons: a model-based analysis
Authors: Mafirakureva Nyashadzaishe , Hunter Rachael , Ferraro Claire F. , Willner Steve , Finnie Thomas , Hayward Andrew , Lee Andrew , Roy Anjana , Edge Chantal , Dodd Peter J.
Published: January 2025

Background

The World Health Organization recommends systematic screening for tuberculosis in incarcerated populations, which are consistently at high risk of tuberculosis relative to the general population. In England, new receptions into prisons do not receive screening for tuberculosis infection, and evidence from economic evaluations is lacking.

Methods

We performed a cost-effectiveness analysis of introducing systematic screening for tuberculosis infection at first reception into English prisons from a health systems perspective. We used a tuberculosis transmission model calibrated to public data on prison stocks and flows. We developed decision tree models of prison-specific tuberculosis care pathways and their costs, informed by stakeholders and pilot studies. Sensitivity analyses included eliminating loss to follow-up (LTFU) in care cascades, zeroing extramural escort costs, and targeting screening to those born in countries with higher tuberculosis incidence (over 40 per 100,000 per year).

Findings

In our base case analysis, the intervention had an incremental cost-effectiveness ratio (ICER) of £78,000 per quality-adjusted life-year (QALY) gained. Reducing LTFU and avoiding prison escort costs would substantially improve cost-effectiveness, to ICERs of £70,000 and £54,000 per QALY gained, respectively. Targeting those born in higher incidence countries was predicted to be cost-saving.

Interpretation

Universal tuberculosis screening and preventive treatment for new receptions into English prisons is not cost-effective by the usual threshold of £30,000. However, targeting high-risk groups could be cost-saving. Tuberculosis interventions should explore ways to reduce LTFU and extramural healthcare in order to meet the needs of those incarcerated while minimizing costs.

Funding

UKHSA
Thyroid volume, lobe asymmetry and AP diameter classification - A preliminary study
Authors: Akter Sanjida , Sarker Azmal K , Muttakin Shahriar , Biswas Sanjoy
Published: January 2025

Objective

To assess the thyroid lobe volumes and the total thyroid volumes across the arbitrary range for AP diameter of thyroid lobes, the age and sex related variation and compare local normal sizes with those in the reference. Because assessment of thyroid gland size by visual comparison with anatomical relations or by an arbitrary category for antero-posterior (AP) diameter precludes use of management guidelines based on thyroid gland volume. Moreover, the international references for AP diameter seem larger for Bangladeshi patients and therefore deemed as inapplicable.

Methods

Patients who underwent thyroid ultrasound with thyroid volume measurements from October 2023 to October 2024 were included. The patients were classified into two groups. Group 1 consisted of children aged below 15 years while group 2 consisted of adolescents aged 15 years or more and all adults. Statistical analyses were applied to assess distribution of gland size between sexes and age groups, correlation between gland size and age, and distribution of thyroid lobe volume and total gland volume, across the arbitrary categories of AP diameter.

Results

Total 110 patients (90 females) with mean (± SD) age of 28.1 ± 13.2 were included. There was no significant difference of gland size between males and females. The AP diameter and right thyroid lobe was significantly larger than the left in group 2 consisting of adolescents and adults (p < 0.05). There was a positive correlation of thyroid size and age in group 1 consisting of pre-adolescents who had normal sized glands (R = 0.91, p < 0.01). Observation of thyroid volumes across the arbitrary AP diameter category showed AP diameter categories of right lobe tended to better classify the normal glands whereas the AP diameter categories of left lobe tended to perform better for classification of the enlarged glands.

Conclusions

This study apart from describing the interaction of age and sex with thyroid size, highlights the importance of considering the natural asymmetry between the thyroid lobes for accurate thyroid volume classification. This study points toward the void for a reference local standard of thyroid volume that can classify not only the different categories of enlargement but also the small volume glands.
Comparison of length of liver among patients with and without fatty change in liver
Authors: Muttakin Shahriar , Sarker Azmal Kabir , Adrita Farzana Rahman , Tamanna Nafisa Kaisar
Published: January 2025

Objective

The retrospective cross-sectional study was done to assess the change of length of liver across the grades of fatty change, across the ages of individual as well as between the male and female sexes.

Methods

The liver length measurement and qualitative visual grading of fatty change (from grade 0 to grade 3), obtained from patients who underwent ultrasound of liver at our institute between July and October of 2024 was retrospectively retrieved. The age of patient, length of liver and the grading of fatty change was used as the variables for the analyses.

Results

The mean lengths of liver were found to be significantly increasing with increased grades fatty change (grade 0, grade I and grade II), both in males and females (p < 0.01). Male patients were affected by fatty change in liver (both grades I and II), more in comparison to the females (Pearson’s Chi-squared value 4.53, p = 0.033). Being at older age is significantly associated with being affected by fatty change in liver (both grades I and II) in females (p<0.01). Liver with fatty changes (grade I and II combined) were significantly larger than those without fatty change both in males as well as in females (p < 0.01). A weak positive association of length of liver and advancing age was found only among females without fatty change (R 0.29, p = 0.046).

Conclusions

Findings from this study is expected to have implications in the clinical and lifestyle management of NAFLD and future research