bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remoscope: a label-free imaging cytometer for malaria diagnostics
Authors: Lebel Paul M. , Jeyakumar Ilakkiyan , Khoo Michelle W.L. , Charlton Chris , Saxena Aditi , Jacobsen Axel , James Emorut , Huynh Emily , Wu William , Courville Greg , Fu Pei-Chuan , Raghavan Madhura , Puccinelli Robert , Peter Olwoch , Dorsey Grant , Rosenthal Phil , DeRisi Joseph , Gomez-Sjoberg Rafael 
Published: November 2024

AbstractMalaria diagnostic testing in high transmission settings remains a burden on healthcare systems. Here we present Remoscope, a portable automated imaging cytometer that scans fresh, unstained whole blood using a custom neural network on low-cost hardware. By screening up to two million red blood cells, Remoscope performs label-free quantitative stage-specific detection ofPlasmodium falciparum(Pf) in 1-12 minutes without sample fixation, staining, or slide scanning. Flow is used to achieve high cellular throughput, with blood confined to a 4.5 µm monolayer in low-cost disposable flow cartridges. Remoscope performance was benchmarkedin vitroby titration of cultured parasites into uninfected whole blood at concentrations of 17.1-710,000 parasites/µL. Counts generated by Remoscope demonstrated a linear response across the entire range. Considering drug susceptibility assays, the half-maximal effective concentration (EC50) of chloroquine (CQ) for the W2 strain ofPfwas 211 nM by Remoscope, compared to 191 nM for conventional flow cytometry. Remoscope’s real-world diagnostic accuracy was evaluated in a cohort of 500 individuals in eastern Uganda, comprising 601 unique clinic visits. Parallel measurements of parasitemia were performed using Remoscope, qPCR targeting the multicopy conserved var gene acidic terminal sequence, and microscopic evaluation of Giemsa-stained thick blood smears. Remoscope’s limit of detection with respect to qPCR was 95.1 parasites/µL. At this threshold, the system had a sensitivity of 83%, specificity of 96%, Positive Predictive Value (PPV) of 91%, and a Negative Predictive Value (NPV) of 93%. Remoscope’s speed, accuracy, low cost, and ease of use address practical challenges in malaria diagnostic settings around the world. As a general imaging flow cytometer, Remoscope may also inform the development of recognition models for the diagnosis of other infectious and noninfectious blood disorders.
Mathematical Modelling of Oxygenation Dynamics using High-Resolution Perfusion Data – Part 2: Physiological Insights
Authors: Sharabiani Mansour T. A. , Mahani Alireza S. , Issitt Richard W. , Srinivasan Yadav , Bottle Alex , Stoica Serban 
Published: November 2024

AbstractBackgroundAccurate prediction of oxygen demand is essential for optimizing oxygen delivery during paediatric cardiopulmonary bypass (CPB), but traditional models may not fully account for the influences of temperature, age, and weight. We aimed to quantify these relationships and assess age-related variability in the oxygen extraction ratio (OER) response.MethodsWe analysed data from 334 paediatric patients undergoing CPB, developing an extended GARIX model (eGARIX) that incorporates age, weight, and nonparametric temperature modelling via splines. Subgroup analyses compared OER responses to changes in haemoglobin and arterial oxygen saturation across different age groups.ResultseGARIX significantly improved model fit over GARIX (p < 0.001). Oxygen demand per body surface area exhibited a nonlinear relationship with age and weight, peaking around 3 years. In neonates and infants, oxygen demand positively correlated with weight; in adolescents, the correlation was negative. The temperature dependence was more complex than constant-Q10models predict, showing reduced sensitivity of oxygen demand to mild hypothermia and increased sensitivity at deep hypothermia. Younger patients showed a diminished OER response to haemoglobin changes.ConclusionsAge and weight significantly affect oxygen demand during paediatric CPB, highlighting the need for individualized models. Our findings challenge constant-Q10assumptions, indicating that nonparametric models better capture temperature effects. Personalized oxygen delivery strategies are essential; further validation is recommended.
Bleeding Risks Associated with Antidepressant Medications Among Acute Ischemic Stroke Patients on Anticoagulation or Dual Anti-platelet Therapy
Authors: Simmonds Kent P. , Chavez Audrie , Venkatachalam Aardhra M. , Ifejika Nneka 
Published: November 2024

BackgroundSelective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitors (SSRI/SNRIs) can treat post-stroke depression and improve recovery but may be withheld for acute ischemic stroke (AIS) patients over bleeding risk concerns. Study objectives were: 1) Quantify the association between early SSRI/SNRI initiation and adverse bleeding events 2) Assess bleeding risk among patients receiving concurrent anticoagulants (AC) or dual antiplatelet therapy (DAPT) and 3) Evaluate if bleeding risks were specific to SSRI/SNRIs.MethodsAIS patients were identified from Electronic Medical Records of 76 healthcare organizations (2004-2024). Patients were assigned to one of three groups within 3 months of the indexed stroke – (1) No antidepressant (No AD), (2) SSRI/SNRI, (3) Other AD (i.e., mirtazapine, bupropion, trazodone, or tricyclic ADs). The primary outcome was 1-year risk of a major bleeding event. Secondary outcomes included hemorrhagic stroke (HS), fall/fracture and death. Baseline differences were adjusted for using 1:1 matched propensity scores.Results679,532 patients were included [No AD (n=612,868), SSRI/SNRI (n=40,136), Other AD (n=26,528)]. Early SSRI/SNRIs use (vs. No ADs) was not associated with an increased risk of a major bleed among all patients (n=36,838 pairs) or patients on anticoagulants (n=7,942 pairs). Concurrent use of SSRI/SNRIs and DAPT was associated with an 11% increased risk of a major bleed (RR: 1.11, 95% CI: 1.00 -1.24, n=7,536 pairs). Bleed risks were higher (RR: 1.10; 95 CI% 1.05, 1.14) for use of Other AD vs. SSRI/SNRI (n=22,789 pairs).DiscussionSSRI/SNRIs treat post-stroke depression, promote recovery and are generally safe, however, bleed risks among patients on current DAPT should be considered.
Development of a pipeline to evaluate YAP-TEAD inhibitor potential-direct TEAD inhibition represses cancerous growth in aNF2-mutant model of mesothelioma
Authors: Cunningham Richard , Jia Siyang , Purohit Krishna , Fairley Michaela Noskova , Lin Yue , Hui Ning Sze , Graham Rebecca E. , Rossi Adriano G. , Cholewa-Waclaw Justyna , Carragher Neil O. , Hansen Carsten Gram 
Published: November 2024

ABSTRACTAs the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true within the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors have shown great promise, but comparisons of their performances are so far limited. Here we develop a high content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer relevant assays in a clinically relevant cellular model.
Overexpression ofβTrCP1elicits cell death in cisplatin-induced senescent cells
Authors: Belmonte-Fernández Alejandro , Herrero-Ruíz Joaquín , Limón-Mortés M. Cristina , Sáez Carmen , Japón Miguel Á. , Mora-Santos Mar , Romero Francisco 
Published: November 2024

ABSTRACTSenescence is a non-proliferative cellular state derived from aging or in response to exogenous insults, such as those that cause DNA damage. As a result of cancer treatments like cisplatin, certain tumor cells may undergo senescence. However, rather than being beneficial for patients, this is detrimental because these cells might proliferate again under specific conditions and, more importantly, because they synthesize and secrete molecules that promote the proliferation of nearby cells. Therefore, to achieve complete tumor remission, it is necessary to develop senolytic compounds to eliminate senescent cells. Here, we studied the role of βTrCP1 in cell proliferation and senescence and found that lentiviral overexpression ofβTrCP1induces the death of senescent cells obtained after cisplatin treatment in both two-dimensional cell cultures and tumorspheres. Mechanistically, we demonstrated that overexpression ofβTrCP1triggers proteasome- dependent degradation of p21 CIP1, allowing damaged cells to progress through the cell cycle and consequently die. Furthermore, we identified nucleophosmin 1 (NPM1) as the intermediary molecule involved in the effect of βTrCP1 on p21 CIP1. We determined that increased amounts of βTrCP1 partially retains NPM1 in the nucleoli, preventing it from associating with p21 CIP1, thus leaving it unprotected from degradation by the proteasome. These results have allowed us to discover a potential new target for senolytic drugs, as retaining NPM1 in the nucleoli under senescent conditions induces cell death.
Lipid-driven SRC self-association modulates its transformation capacity
Authors: Mohammad Irrem-Laareb , Giannotti Marina I. , Fourgous Elise , Boublik Yvan , Fernándz Alejandro , Le Roux Anabel-Lise , Sirvent Audrey , Taulés Marta , Roche Serge , Pons Miquel 
Published: November 2024

AbstractSrc tyrosine kinase is anchored to the plasma membrane, however, the contribution of membrane lipids to its regulation remains elusive. Here we report Src self-association through a lysine cluster in the Src SH4 region mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine modulates Src self-association and its transforming function in human cells. This mechanism may also apply to other membrane-associated signaling proteins that have similar lysine clusters in their unstructured regions.Lipid-anchored micron-sized condensates of full length Src are formed in supported homogeneous lipid bilayers (i.e independently of lipid phase separation). Condensates are also formed by the purified Src N-terminal regulatory element, including the myristoylated SH4 domain, the intrinsically disordered Unique domain and the globular SH3 domain. The isolated SH4 domain forms small protein-lipid clusters, but not micron-size condensates.Our findings reveal lipid-mediated kinase self-association as an additional mechanism for Src regulation.Significance StatementCondensate formation, often associated to intrinsically disordered protein regions is emerging as a widespread regulatory mechanism. Protein phase separation has been linked to the regulation of kinases recruited to condensates formed by other proteins. Here we show i) that the N-terminal disordered region of Src kinase drives lipid-mediated self-association to form condensates on the cell surface, ii) a lysine cluster in the N-terminal SH4 domain is essential for this process, iii) mutation of these lysine residues to arginine increases self-association in vitro and in vivo, and iv) self-association of Src results in enhanced transforming capacity in human cells. Similar lysine clusters are present in juxtamembrane regions suggest a general mechanism for modulating protein-protein interactions by lipids.The article shows the formation of condensates by Src on supported lipid membranes mediated by lipids, dependent of a conserved lysine cluster in its SH4 domain, and modulating Src’s transforming capacity.Full length Src and truncated variants including its myristoylated SH4 domain self-associate on the surface of homogeneous lipid bilayers.The interaction of a lysine cluster in SH4 domain with lipids modulates Src self-associationAtomic force microscopy shows the formation of micron-size condensates and smaller clusters on the surface of supported lipid bilayers, depending on the lipid composition or the presence of mutations in the lysine clusterSrc self-association is confirmed in human cells and the Src transforming function of Src in human cells is modulated by lipid-mediated self-association
Biological Boundary Conditions Regulate the Internalization ofAspergillus FumigatusConidia by Alveolar Cells
Authors: Schiefermeier-Mach Natalia , Polleux Julien , Heinrich Lea , Lechner Lukas , Vorona Olexandra , Perkhofer Susanne 
Published: November 2024

AbstractIntroductionThe lung environment is defined by unique biological boundary conditions, including complex alveolar geometry, extracellular matrix composition and mechanical forces generated during respiration. These factors were shown to regulate alveolar permeability, surfactant secretion, cell contractility and apoptosis, but their role in fungal infections remains unknown.Aspergillus fumigatusis a critical fungal pathogen that causes severe pulmonary infections in immunocompromised individuals. Our study addresses a knowledge gap by investigating how boundary conditions affectA. fumigatusconidia interactions with alveolar epithelial cells.MethodsWe applied micropatterned substrates to confine cells into defined shapes and densities, allowing precise control over geometric conditions and extracellular matrix composition. Using cell line stably expressing the phagolysosomal protein Lamp1-NeonGreen and multiplane fluorescent microscopy, we evaluatedA. fumigatus conidiabinding and internalization efficiency.ResultsWe observed significantly faster and more efficientA. fumigatusconidia internalization in cells confined on micropatterns compared to previously reported studies using cell monolayers. Altering cell geometry, density, and extracellular matrix composition strongly affected conidia binding and localization to Lamp1+phagolysosomes. Cells on X-shaped or multicellular micropatterns showed higher internalization rates, particularly at the periphery, suggesting spatial heterogeneity in pathogen uptake. Additionally, changes in extracellular matrix composition influenced the intracellular trafficking ofA. fumigatusconidia.DiscussionOur findings emphasize the essential role that local mechanical and biochemical cues play in shaping the interactions between fungal pathogens and alveolar cells. Understanding how lung boundary conditions change in disease states will provide important insights into fungal infection outcomes.
Complete genomes of DNA viruses in faecal samples from small terrestrial mammals in Spain
Authors: Buigues Jaime , Viñals Adrià , Martínez-Recio Raquel , Monrós Juan S. , Sanjuán Rafael , Cuevas José M. 
Published: November 2024

AbstractViromics studies are allowing us to understand not only the enormous diversity of the virosphere, but also the potential threat posed by emerging viruses. Regarding the latter, the main concern lies in monitoring the presence of RNA viruses, but the zoonotic potential of some DNA viruses, on which we have focused in the present study, should also be highlighted. For this purpose, we analysed 160 faecal samples from 14 species belonging to three orders of small terrestrial mammals (i.e.Rodentia, LagomorphaandEulypotyphla). This allowed us to identify a total of 25 complete or near-complete genomes belonging to the familiesPapillomaviridae, Polyomaviridae, Adenoviridae, CircoviridaeandGenomoviridae, 18 of which could be considered new species or types. Our results provide a significant increase in the number of complete genomes of DNA viruses of European origin with zoonotic potential in databases, which are at present clearly under-represented compared to RNA viruses.
Chromatin architecture mapping by multiplex proximity tagging
Authors: Delamarre Axel , Bailey Benton , Yavid Jennifer , Koche Richard , Mohibullah Neeman , Whitehouse Iestyn 
Published: November 2024

AbstractChromatin plays a pivotal role in genome expression, maintenance, and replication. To better understand chromatin organization, we developed a novel proximity-tagging method which assigns unique DNA barcodes to molecules that associate in 3D space. Using this method – Proximity Copy Paste (PCP) – we mapped the connectivity of individual nucleosomes in Saccharomyces cerevisiae. By analyzing nucleosome positions and spacing on single molecule fibers, we show that chromatin is predominantly organized into regularly spaced nucleosome arrays that can be positioned or delocalized. Basic features of nucleosome arrays are generally explained by gene size and transcription. PCP can also map long-range, multi-way interactions and we provide the first direct evidence supporting a model that metaphase chromosomes are compacted by cohesin loop clustering. Analyzing single-molecule nuclease footprinting data we define distinct chromatin states within a mixed population to show that non-canonical nucleosomes, notably Overlapping-Di-Nucleosomes (OLDN) are a stable feature of chromatin. PCP is a versatile method allowing the detection of the connectivity of individual molecules locally and over large distance to be mapped at high-resolution in a single experiment.
Proteomic characterization ofMycobacterium tuberculosissubjected to carbon starvation
Authors: Devlin Kaylyn L. , Leach Damon T. , Stratton Kelly G. , Lamichhane Gyanu , Lin Vivian S. , Beatty Kimberly E. 
Published: November 2024

AbstractMycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis (TB), the leading cause of infectious-disease related deaths worldwide. TB infections present as a spectrum from active to latent disease. In the human host,Mtbfaces hostile environments, such as nutrient deprivation, hypoxia, and low pH. Under these conditions,Mtbcan enter a dormant, but viable, state characterized by a lack of cell replication and increased resistance to antibiotics. These dormantMtbpose a major challenge to curing infections and eradicating TB globally. In the current study, we subjectedMtbto carbon starvation (CS), a culture condition that induces growth stasis and mimics nutrient-starved conditions associated with dormancyin vivo. We provide a detailed analysis of the proteome in CS compared to replicating samples. We observed extensive proteomic reprogramming, with 36% of identified proteins significantly altered in CS. Many enzymes involved in oxidative phosphorylation and lipid metabolism were retained or upregulated in CS. The cell wall biosynthetic machinery was present in CS, although numerous changes in the abundance of peptidoglycan, arabinogalactan, and mycolic acid biosynthetic enzymes likely result in pronounced remodeling of the cell wall. Many clinically approved anti-TB drugs target cell wall biosynthesis, and we found that these enzymes were largely retained in CS. Lastly, we compared our results to those of other dormancy models and propose that CS produces a physiologically-distinct state of stasis compared to hypoxia inMtb.
Molecular determinants of protein pathogenicity at the single-aggregate level
Authors: Urbanek Agnieszka , Garland Emma F. , Prescott Emily E. , King Marianne C. , Olerinyova Anna , Wareing Hollie E. , Georgieva Nia , Bradshaw Ellie L. , Tzokov Svetomir B. , Knight Alexander , Tartakovskii Alexander I. , Malm Tarja , Highley J Robin , De Suman 
Published: November 2024

AbstractDetermining the structure-function relationships of protein aggregates is a fundamental challenge in biology. These aggregates, whether formedin vitro, within cells, or in living organisms, present significant heterogeneity in their molecular features such as size, structure, and composition, making it difficult to determine how their structure influences their functions. Interpreting how these molecular features translate into functional roles is crucial for understanding cellular homeostasis and the pathogenesis of various debilitating diseases like Alzheimer’s and Parkinson’s. In this study, we introduce a bottom-up approach to explore how variations in protein aggregates’ size, composition, post-translational modifications and point mutations profoundly influence their biological functions. Applying this method to Alzheimer’s and Parkinson’s associated proteins, we uncover the mechanism of novel disease-relevant pathways and demonstrate how subtle alterations in composition and morphology can shift the balance between healthy and pathological states. Our findings establish a broadly applicable framework for investigating protein dysfunctions in various proteinopathies.
Respi-Radar – a tool to monitor respiratory infections in Belgium during the winter season 2023- 2024
Authors: De Muylder Géraldine , Couvreur Simon , Stefani Giulietta , Brugerolles Claire , Dockx Yinthe , Callies Milena , Janssens Raphaël , De Mot Laurane , Bossuyt Nathalie , Stassijns Jorgen 
Published: November 2024

AbstractFollowing the experience gathered during the COVID-19 crisis, the Respi-Radar was developed by the Belgian Risk Assessment Group (RAG) in the summer of 2023, with the aim of assessing the epidemiological situation of respiratory infections and informing public health preparedness and response in Belgium.The Respi-Radar consisted of four levels (green, yellow, orange and red) which indicated the extent of viral circulation and/or pressure on the healthcare system. Depending on the level, specific measures would apply to reverse the trend. The Respi-Radar used six indicators, from the Influenza-Like Illness and Severe Acute Respiratory Infection sentinel surveillances in nursing homes, primary and secondary care, as well as from the wastewater surveillance. Additional information, such as data from the national reference laboratories, also contributed to assessing the situation.Based on the Respi-Radar tool, the RAG regularly evaluated the epidemiological situation of respiratory infections between September 2023 and March 2024.The Respi-Radar tool appeared useful for following trends and effectively communicating on the epidemiological situation of respiratory infections. Applying specific measures depending on a level was less straightforward. The experience gained using the Respi-Radar tool was key to determine the best approach to assess and manage the epidemiological situation for future respiratory seasons.
Inverse Cherenkov dielectric laser accelerator with alternating phase focusing for subrelativistic particles
Authors: Zhang Liwen , Xu Hongliang , Liu Weihao 
Published: November 2024

In this paper, we propose a dielectric laser acceleration scheme based on the inverse Cherenkov effect, which uses the principle of alternating phase focusing to accelerate, confine, and bunch the subrelativistic electron beam over an extended distance. In this scheme, the reference electron is always synchronized with the acceleration wave and is thus continuously accelerated. Electrons around it are alternately subjected to focusing and defocusing forces by alternately jumping its phase. Optimizing the focusing period can achieve stable beam confinement. Simulations show that a 100 keV electron bunch can be coherently accelerated with the average acceleration gradient of 220.8  MV/m, and it can travel nearly 200  μm without loss in a channel only 500 nm wide. This approach is scalable, potentially enabling the development of millimeter-scale MeV particle accelerators for ground-breaking use in medical, scientific, and materials research.

Published by the American Physical Society
2024