bluuebunny/crossref_metadata_2025 huggingface dataset:
Protective antigen-mediated delivery of an anti-CRISPR protein for precision genome editing
Authors: Vera Axel O. , Truex Nicholas L. , Sreekanth Vedagopuram , Pentelute Bradley L. , Choudhary Amit , Raines Ronald T.
Published: February 2025

Precise control over the dosage of Cas9-based technologies is essential because off-target effects, mosaicism, chromosomal aberrations, immunogenicity, and genotoxicity can arise with prolonged Cas9 activity. Type II anti-CRISPR proteins (Acrs) inhibit and control Cas9 but are generally impermeable to the cell membrane due to their size (6–54 kDa) and anionic charge. Moreover, existing Acr delivery methods are long-lived and operate within hours (e.g., viral and non-viral vectors) or are not applicable in vivo (e.g., nucleofection), limiting therapeutic applications. To address these problems, we developed the first protein-based anti-CRISPR delivery platform, LFN-Acr/PA, which delivers Acrs into cells within minutes. LFN-Acr/PA is a nontoxic, two-component protein system derived from anthrax toxin, where protective antigen proteins bind receptors widespread in human cells, forming a pH-triggered endosomal pore that LFN-Acr binds and uses to enter the cell. In the presence of PA, LFN-Acr enters human cells at concentrations as low as 2.5 pM to inhibit up to 95% of Cas9-mediated knockout, knock-in, transcriptional activation, and base editing. Timing LFN-Acr delivery reduces off-target base editing and increases Cas9 specificity by 41%. LFN-Acr/PA is the most potent known cell-permeable CRISPR-Cas inhibition system, significantly improving the utility of CRISPR for genome editing.
Increasing dengue outbreaks in temperate Brazil is linked toAedes aegyptiinvasion and infestation level driving widespread virus transmission
Authors: Bermann Thales , Gregianini Tatiana Schaffer , Godinho Fernanda Marques , Baethgen Ludmila Fiorenzano , Martiny Fernanda Letícia , Möllmann Erica Bortoli , Ruivo Amanda Pellenz , dos Santos Franciellen Machado , do Nascimento Ferreira Caroline , de Lima Gustavo Barbosa , Barbosa Danielly Alves Mendes , Dezordi Filipe Zimmer , Bauermann Milena , Selayaran Taina Machado , da Silva Loreto Elgion Lucio , Naveca Felipe Gomes , de Oliveira André Luiz Sá , da Veiga Ana Beatriz Gorini , Santos Paiva Marcelo Henrique , Campos de Lima Tulio , Bello Gonzalo , Bezerra Matheus Filgueira , de Oliveira Felipe Valter , Maciel-de-Freitas Rafael , Gräf Tiago , Salvato Richard Steiner , Wallau Gabriel Luz
Published: February 2025

Dengue fever, caused by the dengue virus (DENV), is the most important mosquito-borne disease impacting human health globally, it is particularly prevalent in tropical regions whereAedesvectors thrive. However, due to a recent expansion of the main dengue vectors to subtropical and temperate zones in the last decades there is an increasing human population at risk. Brazil is a global hotspot for dengue, accounting for 70% of all dengue cases reported worldwide in 2024. Noteworthy, dengue became endemic even in the southernmost Brazilian state of Rio Grande do Sul, which until recently had only imported cases. In this study, we integrated entomological, epidemiological, and high-resolution genomic data to investigate DENV transmission dynamics in Southern Brazil over nine years. From 2015 to 2023, we detected a partial to full invasion of the state municipalities byAedes aegypti, with dengue cases increasing substantially from 2020 onwards. The suitability index for transmission effectively predict the intensity of the outbreaks in the region, providing a two-month lead time before the surge in cases, representing an interesting proxy to forecast the outbreak size in the next few years. Invaded municipalities that surpassed a given case incidence level also increased, and by 2023, nearly half of the municipalities of the state surpassed that threshold, suggesting that dengue became endemic in the region. By analyzing 665 newly generated DENV genomes, we observed persistent overwintering lineages driving seasonal outbreaks, with the Northwest and Metropolitan regions serving as the main transmission hubs for dengue spread in the state. These regions were also the first to experience the endemic establishment of dengue lineages, making them key areas for targeted control efforts to mitigate further local outbreaks and the virus spread to other regions. These findings underscore the expansion of DENV-affected areas and increasing outbreaks into temperate zones, likely driven by the spread of the vector, associated with increased infestation level of the vector and widespread viral transmission in an immunologically naive population. In this context, enhanced control efforts are critical to mitigate the dengue burden in previously non-endemic areas.
Perceptions of Telerehabilitation Among Patients Receiving Physical Therapy for Spine Pain
Authors: McLaughlin Kevin H. , Caan Olivia , Skolasky Richard L.
Published: February 2025

Importance

Telerehabilitation was widely used during the COVID-19 pandemic to maintain access to physical therapy. However, its use has declined since the pandemic, potentially due to changes in patient demand.

Objective

To explore patients’ beliefs, attitudes, and preferences regarding telerehabilitation for spine pain treatment.

Design

Email or telephone administered survey.

Setting

Outpatient physical therapy network affiliated with an academic healthcare system.

Participants

Patients recently evaluated for spine pain by a physical therapist (n=100).

Main Outcomes and Measures

Survey items addressed patients’ perceptions of telerehabilitation effectiveness, preferences for care delivery, barriers to telerehabilitation, and factors influencing telerehabilitation use.

Results

Patients viewed telerehabilitation as effective for treating spine pain but not as effective as in-clinic physical therapy. Patients reported a preference for receiving care in-clinic care or using a hybrid model, rather than receiving care through telerehabilitation alone. Barriers to telerehabilitation included a lack of awareness of who offers telerehabilitation and uncertainty about its effectiveness. Patients indicated that evidence supporting telerehabilitation effectiveness would increase their likelihood of using telerehabilitation in the future. Patients also reported that transportation challenges or increased COVID-19 rates would encourage them to use telerehabilitation in the future.

Conclusions

The results of this survey suggest that patients with spine pain believe telerehabilitation may be an effective treatment approach, but they are skeptical about using telerehabilitation instead of in-clinic physical therapy. These results also suggest that patients are open to hybrid approaches that incorporate telerehabilitation, as well as using telerehabilitation if circumstances prevented them from receiving their care in-clinic. The largest patient concern surrounding telerehabilitation seems to be the lack of evidence supporting its effectiveness.

Relevance

This study suggests that patients believe telerehabilitation will continue to play an important role post-pandemic. However, comparative effectiveness research is needed to address patient concerns surrounding the effectiveness of telerehabilitation and guide informed decision-making.
DUNE: a versatile neuroimaging encoder captures brain complexity across three major diseases: cancer, dementia and schizophrenia
Authors: Barba Thomas , Bagley Bryce A. , Steyaert Sandra , Carrillo-Perez Francisco , Sadée Christoph , Iv Michael , Gevaert Olivier
Published: February 2025

Magnetic resonance images (MRI) of the brain exhibit high dimensionality that pose significant challenges for computational analysis. While models proposed for brain MRIs analyses yield encouraging results, the high complexity of neuroimaging data hinders generalizability and clinical application. We introduce DUNE, a neuroimaging-oriented encoder designed to extract deep-features from multisequence brain MRIs, thereby enabling their processing by basic machine learning algorithms. A UNet-based autoencoder was trained using 3,814 selected scans of morphologically normal (healthy volunteers) or abnormal (glioma patients) brains, to generate comprehensive low-dimensional representations of the full-sized images. To evaluate their quality, these embeddings were utilized to train machine learning models to predict a wide range of clinical variables. Embeddings were extracted for cohorts used for the model development (n=21,102 individuals), along with 3 additional independent cohorts (Alzheimer’s disease, schizophrenia and glioma cohorts, n=1,322 individuals), to evaluate the model’s generalization capabilities. The embeddings extracted from healthy volunteers’ scans could predict a broad spectrum of clinical parameters, including volumetry metrics, cardiovascular disease (AUROC=0.80) and alcohol consumption (AUROC=0.99), and more nuanced parameters such as the Alzheimer’s predisposing APOE4 allele (AUROC=0.67). Embeddings derived from the validation cohorts successfully predicted the diagnoses of Alzheimer’s dementia (AUROC=0.92) and schizophrenia (AUROC=0.64). Embeddings extracted from glioma scans successfully predicted survival (C-index=0.608) and IDH molecular status (AUROC=0.92), matching the performances of previous task-oriented models. DUNE efficiently represents clinically relevant patterns from full-size brain MRI scans across several disease areas, opening ways for innovative clinical applications in neurology.

One Sentence Summary

We propose a brain MRI-specialized encoder, which extracts versatile low-dimension embeddings from full-size scans.
Analysis of the current state of frailty indexes and their implementation for aging intervention studies
Authors: Frost Oliver G , Barkovskaya Anna , Rae Michael , Rebbaa Abdelhadi , Sharma Amit
Published: February 2025

Animal lifespan studies are foundational to developing interventions against the biological aging process. In recent years, there has been rising interest in characterizing the effects of longevity therapeutics on health span. Frailty indexes, originally developed to assess clinical frailty in aging humans, have shown promise as measurements of biological age and have been adopted for use in rodent aging biology. This perspective looks at the current state of rodent frailty indexes and how they are implemented. The differences in frailty parameters used to calculate these indexes have led to inconsistencies between studies defining frailty. In this perspective, we have highlighted those differences and made recommendations for implementing protocols for frailty index measurement.
Profiling brain morphology for autism spectrum disorder with two cross-culture large-scale consortia
Authors: Fan Xue-Ru , He Ye , Wang Yin-Shan , Li Lei ,   Lifespan Brain Chart Consortium (LBCC),   China Autism Brain Imaging Consortium (CABIC), Duan Xujun , Zuo Xi-Nian
Published: February 2025

We explore neurodevelopmental heterogeneity in Autism Spectrum Disorder (ASD) through normative modeling of cross-cultural cohorts. Leveraging large-scale datasets from Autism Brain Imaging Data Exchange (ABIDE) and China Autism Brain Imaging Consortium (CABIC), the model identifies two ASD subgroups with distinct brain morphological abnormalities: subgroup "L" is characterized by generally smaller brain region volumes and higher rates of abnormality, while subgroup "H" exhibits larger volumes with less pronounced deviations in specific areas. Key areas, such as the isthmus cingulate and transverse temporal gyrus, were identified as critical for subgroup differentiation and ASD trait correlations. In subgroup H, the regional volume of the isthmus cingulate cortex showed a direct correlation with individuals’ autistic mannerisms, potentially corresponding to its slower post-peak volumetric declines during development. These findings offer insights into the biological mechanisms underlying ASD and support the advancement of subgroup-driven precision clinical practices.
Splanchnic and pelvic spinal afferent pathways relay sensory information from the mouse colorectum into distinct brainstem circuits
Authors: Wang QingQing , McGovern Alice E. , Kyloh Melinda , Rychkov Grigori , Spencer Nick J. , Mazzone Stuart B. , Brierley Stuart M. , Harrington Andrea M.
Published: February 2025

This study aimed to identify where the sensory information relayed by the two spinal afferent pathways innervating the distal colon and rectum (colorectum), the splanchnic and pelvic spinal afferent pathways, integrates within the brainstem. Localised injections of transneuronal viral tracer (herpes simplex virus H129 strain expressing EGFP (H129-EGFP)) into the distal colon was used to assess the brainstem structures receiving ascending input from the colorectum. H129-EGFP+ cells were distributed in structures involved in ascending sensory relay, descending pain modulation and autonomic regulation in the medulla from 96 hours and in pontine and caudal midbrain 120 hours after inoculation. In a separate cohort of mice,in vivonoxious colorectal distension (CRD) followed by brainstem immunolabelling for phosphorylated MAP kinase ERK 1/2 (pERK) showed that many of the structures in which H129-EGFP+ labelling was observed were relevant to colorectal sensory processing. Surgical removal of dorsal root ganglia (DRG) containing cell bodies of splanchnic colorectal afferent neurons, significantly reduced CRD evoked neuronal activation within the caudal ventrolateral medulla, rostral ventromedial medulla and the lateral parabrachial nuclei. Whilst, removal of DRG containing cell bodies of pelvic colorectal afferent neurons significantly reduced CRD evoked neuronal activation within the rostral ventromedial medulla, lateral parabrachial nuclei, the locus coeruleus, Barrington’s nucleus and periaqueductal gray. Collectively, this study showed that the two spinal afferent pathways innervating the colorectum differentially shape colorectal processing within the brainstem and provides new insight into their unique roles to mediating visceromotor responses and defecation associated with colorectal nociception.
Evaluation of the antioxidant activity of biologically-active compositions based on plant metabolites produced byin vitrocell cultures
Authors: Mikhailovna Fedorova Anastasia , Sergeevna Milentyeva Irina , Konstantinovna Asyakina Lyudmila , Yuryevich Prosekov Alexander
Published: February 2025

Free radicals can cause oxidative stress in the body, which, in turn, leads to various diseases such as cardiovascular diseases, diabetes, Alzheimer’s disease, Parkinson’s disease, and others. To protect against the destructive effects of radicals, living organisms utilize antioxidants. One of the most important classes of antioxidants is polyphenols. The primary effect of polyphenols on the body is associated with their ability to capture and neutralize free radicals, as well as reactive oxygen and nitrogen species. This study focuses on investigating the antioxidant activity (AA) of polyphenols and their compositions based on rutin, quercetin, and trans-cinnamic acid, produced byin vitrocell cultures, with the aim of developing dietary supplements with geroprotective properties. The AA of the studied substances was assessed using the ABTS and DPPH free radical scavenging methods. The study established that, according to the ABTS method, AA decreases in the order of quercetin > rutin > trans-cinnamic acid, while according to the DPPH method, the order is rutin > quercetin > trans-cinnamic acid. Among the tested mixtures, the highest AA was observed in mixture No. 8 and mixture No. 3, regardless of the assessment method. Consequently, to achieve the highest AA in a mixture, a higher content of quercetin and a minimal amount of trans-cinnamic acid should be included, while the optimal amount of rutin could not be determined. It is assumed that the amount of rutin should be at least equal to the amount of trans-cinnamic acid and ideally equal to the amount of quercetin. Thus, when developing dietary supplements with high AA, it is more advisable to include only quercetin rather than mixtures that also contain rutin and trans-cinnamic acid.
NtLLG4-mediated unconventional polar exocytosis of NtPPME1 coordinates cell wall rigidity and membrane dynamics to control pollen tube integrity
Authors: Weng Xun , Wang Hao , Jiang Yifeng , Wang Ziheng , Liu Chuanhao , Chen Zhiheng , Yang Zhiyuan , Gao Jiayang , Jiang Liwen , Zhao Lifeng , Huang Jilei , Wang Hao
Published: February 2025

Plant fertilization relies on controlled pollen tube growth that integrates membrane dynamics and cell wall expansion. We previously identified an unconventional exocytic pathway wherein Golgi-derived secretory vesicles (GDSVs) bypass thetrans-Golgi network to deliverNicotiana tabacumpectin methylesterase 1 (NtPPME1), thereby modulating cell wall rigidity. However, the mechanisms linking this patwhay with membrane dynamics and signaling remain elusive. Here, we used cryo-FIB-SEM and 3D tomography to identified GDSVs as a distinct vesicle population at the pollen tube tip. We further demonstrated that tobacco LORELEI-like-GPI-anchored protein 4 (NtLLG4), a key signaling molecule controlling membrane dynamics and integrity, functions as a receptor for NtPPME1, regulating its polar exocytosisviaGDSVs to control cell wall stiffness. Furthermore, we identified trafficking signals which direct the unconventional exocytosis of NtPPME1 across intracellular organelles. Our findings reveal a crucial mechanism coupling cell wall rigidity with membrane signaling to control pollen tube growth and integrity during fertilization.

Teaser

We reveal a mechanism coupling cell wall rigidity with member signaling to control pollen tube growth and integrity during plant fertilization.
A novel expression system for imaging single-molecule fluorescence in Haloferax volcanii WR806 enables visualization of Cas1 involvement in UV-light associated DNA repair
Authors: Schrage Paula R , Afonina Uliana , Wörtz Julia , Marchfelder Anita , Martens Koen JA , Sáenz James P , Endesfelder Ulrike
Published: February 2025

Fluorescence microscopy has become an indispensable tool in biological research, offering powerful approaches to study protein dynamics and molecular biochemistryin vivo. Among archaea,Haloferax volcaniihas emerged as a particularly well-suited model organism for imaging studies, with a growing toolkit of established fluorescent markers, plasmids, and promoter systems. Recent advances in single-molecule imaging techniques have created new opportunities through WR806, a carotenoid-free strain providing reduced autofluorescence background. However, existing plasmid-based expression systems in WR806 show critical limitations in protein expression control and challenges with protein aggregation.

To address these limitations, we developed pUE001, a novel expression system specifically designed for WR806. This system achieves precise expression control by decoupling selection and induction through strategic implementation of thetrpAselection marker. Through comprehensive characterization, we demonstrate that pUE001 provides superior control over protein expression compared to the previously established pTA962 system. It enables linear, titratable expression of diverse proteins — from the highly regulated CRISPR-Cas component Cas1 to the abundant structural protein FtsZ1 — while preventing protein aggregation that could compromise native cellular functions. Additionally, we performed a comprehensive analysis of WR806 to show that carotenoid depletion does not affect native cellular physiology. Finally, to demonstrate the system’s utility, we investigated the role of Cas1 in UV-induced DNA repair using single-particle tracking photoactivated localization microscopy (sptPALM). Our findings reveal significant, dose-dependent changes in Cas1 mobility following UV-light induced damage, providing evidence for its involvement in DNA repair processes and offering new insights into the expanding roles of CRISPR-Cas systems beyond adaptive immunity.
Understanding bottlenecks in the microbial production of partially acetylated chitooligosaccharides
Authors: Snoeck Sofie , Malik Hamza , Demeester Wouter , Duchi Dries , Lips Wies , Guidi Chiara , De Mey Marjan
Published: February 2025

Chitooligosaccharides (COS) are versatile biomolecules with applications across food, pharmaceutical, and cosmetic industries. Expanding the COS portfolio, particularly with partially acetylated COS (paCOS) of defined degree and pattern of acetylation, is essential to unlocking their full potential. This study investigates the co-expression of chitin deacetylases (CDAs) with a chitooligosaccharide synthase (CHS)RhNodC inE. coliforin vivopaCOS production. While this approach shows promise, it is hampered by reduced overall (pa)COS yields and incomplete conversion of fully acetylated COS to paCOS. Our findings reveal thatRhNodC and CDAs co-localize, suggesting potential interactions that influence production efficiency. Additionally, CDA expression induces significant stress responses, including upregulation ofibpA andcpxP promoters linked to inclusion body formation and membrane stress, respectively. This is accompanied by pronounced cellular elongation, further indicating cellular distress. These bottlenecks highlight the need for deeper exploration ofRhNodC-CDA interactions and stress mitigation strategies to optimize scalablein vivopaCOS production.

Highlights

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Co-expression of rhizobial NodC and chitin deacetylases reduces chitooligosaccharide yield.

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Conversion of COS into paCOS remains incomplete upon co-expression.

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Upregulation of stress responses suggests protein misfolding and membrane stress.

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NodC and chitin deacetylases possibly co-localize and affect cellular localization.

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Chitin deacetylase expression causes cell elongation up to 30 micrometers.

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Further study needed on rhizobial NodC-chitin deacetylase and substrate interactions.
Dengue virus susceptibility inAedes aegyptilinked to natural cytochrome P450 variants
Authors: Merkling Sarah H. , Couderc Elodie , Crist Anna B. , Dabo Stéphanie , Daron Josquin , Jupatanakul Natapong , Burckbuchler Myriam , Sismeiro Odile , Legendre Rachel , Pain Adrien , Varet Hugo , Jiolle Davy , Ayala Diego , Paupy Christophe , Marois Eric , Lambrechts Louis
Published: February 2025

The mosquitoAedes aegyptiis the primary vector for dengue virus (DENV), which infects millions of people annually. Variability in DENV susceptibility among wildAe. aegyptipopulations is governed by genetic factors, but specific causal variants are unknown. Here, we identify a cytochrome P450-encoding gene (CYP4G15) whose variants drive differences in DENV susceptibility in a naturalAe. aegyptipopulation.CYP4G15is transiently upregulated in DENV-resistant midguts, while knockdown increases susceptibility, and transgenic overexpression enhances resistance. A naturally occurring 18-base-pair promoter deletion reducesCYP4G15expression and confers higher DENV susceptibility. The unexpected role of a cytochrome P450 in DENV susceptibility challenges the long-standing focus on canonical immune pathways and opens new avenues for understanding antiviral defense and DENV transmission in mosquitoes.
Endocytosis sculpts distinct cAMP signal transduction by endogenously coexpressed GPCRs
Authors: Blythe Emily E , Fagan Rita R , von Zastrow Mark
Published: February 2025

Many G protein-coupled receptors (GPCRs) trigger a second phase of G protein-dependent signaling from internal membranes after agonist-induced endocytosis. However, individual GPCRs differ significantly in their ability to internalize, and it remains unclear if this confers selectivity on cellular signaling through natively coexpressed GPCRs. We addressed this question by examining the activation of the cyclic AMP (cAMP) / cAMP-dependent protein kinase (PKA) pathway by three ligands that stimulate three distinct, endogenously coexpressed GPCRs in HEK293 cells: isoproterenol (Iso) which primarily activates the β2-adrenergic receptor (β2AR), vasoactive intestinal peptide (VIP) which primarily activates the VIP receptor 1 (VIPR1/VPAC1), and 5’-N-ethylcarboxamidoadenosine (NECA) which primarily activates the adenosine 2B receptor (A2BR). Using location-targeted biosensors and a transcriptional reporter, we demonstrate that each ligand triggers a unique cellular signaling profile and that these responses are differentially sensitive to endocytic inhibition. VIP elicited a response that was endocytosis-dependent at every level in the pathway, from upstream global cAMP elevation to downstream activation of nuclear PKA, while Iso elicited a response that was dependent on endocytosis selectively at downstream steps. In contrast, NECA robustly activated the entire cAMP signaling cascade independently of endocytosis, consistent with our observation that human A2BR does not robustly internalize after activation. We conclude that endocytosis indeed sculpts downstream cAMP signaling by GPCRs in a receptor-specific manner. Our results add to the evolving view of compartmentalized signaling in the cAMP / PKA pathway and suggest that differences in GPCR trafficking can encode receptor-specific signaling profiles through a shared signal transduction pathway.
Dysfunction-specific Mechanisms Critically Influence Seizure Onset and Termination in Epilepsy
Authors: Kamaraj Aravind Kumar , Szuromi Matthew Parker
Published: February 2025

Epileptic seizures arise from an abnormal synchronous firing of neurons, driven by an imbalance between excitatory and inhibitory neurotransmission. Understanding how various dysfunctions influence brain dynamics is essential for uncovering seizure mechanisms and developing effective treatments. Here, we present a neural mass model that combines an intuitive mathematical formulation with a clear biophysical interpretation to examine the role of excitatory and inhibitory dysfunctions in seizure onset and termination. We model the propagation of action potentials in the brain like the spread of an epidemic and establish a framework examining the interaction between one excitatory and one inhibitory population. Our model captures equilibria that correspond to different levels of neuronal activity: the equilibrium with maximal excitatory activity represents a seizure, and the equilibrium with minimal, non-zero neuronal activity represents normal brain activity. We then introduce various dysfunctions into the model such as an excessive drive to the excitatory population, depletion of inhibitory neurotransmitters, and depolarizing GABAergic neurotransmission and demonstrate that these dysfunctions can facilitate the transition from normal activity to seizure. Crucially, we show that interventions that only target the inhibitory neurotransmitter GABA fail to terminate a seizure when GABA is depolarising, whereas interventions targeting excitatory neurotransmission, such as levetiracetam, are more effective. Our findings highlight the importance of tailoring interventions to the specific underlying dysfunctions for effective seizure termination.
Additive manufacturing of patient-specific intracranial aneurysm cell culture models
Authors: de Nys Chloe M. , Murphy Ashley R. , Wood Jaimee-Lee , Novak James I. , Carluccio Danilo , Winter Craig D. , Allenby Mark C.
Published: February 2025

Intracranial aneurysms (IAs) are present in 2-6% of the global population. While rare, rupture results in mortality rates of 30-50% and lifelong disabilities in survivors. While treatment of unruptured IAs carries its own risk of mortality, there are no rigid guidelines indicating which IA presentation is at greater risk of rupture. We develop and evaluate the suitability of various additive manufacturing processes to fabricate patient-specific IA culture models for understanding IA pathophysiology and thereby support future development of a rupture risk prediction tool.

Material compatibility of several 3D printed resins, polydimethylsiloxane (PDMS) and collagen gel with immortalised human brain endothelial cells (HBECs) were investigated. Patient angiograms were segmented to producein vitromodels via two fabrication approaches: stereolithography (SLA) 3D printing versus chocolate injection moulding of a sacrificial core embedded in PDMS. These 3D arterial models were then cellularised with HBECs, and geometric accuracy and distension properties evaluated.

PDMS, collagen gel and the elastic50A resin materials supported cellularisation on material surfaces with high cell viability and proliferation. Both the 3D printed resin and injection moulding techniques successfully fabricated patient-specific basilar artery IA models with a Dice-Sørensen coefficient of over 90%. However, only PDMS models offered complete cell coverage in 3D geometries. This exceeds current benchmarks on IA fabrication accuracy. Through controlling IA model wall thickness, we demonstrate the ability to create localised distension under pressure in the context of thin– and thick-walled aneurysms.

In vitroIA models present a promising platform for investigating IA pathophysiology and rupture risk. The novel chocolate sacrificial core technique offers a biocompatible, support-free fabrication method suitable for 3D cultures. Given the independent effects of fluid dynamics and mechanical strain on cell behaviour, it is essential to characterise distension under pressure and ensure accurate fabrication for reliable analysis into cell behaviour.
Glucose-dependent metabolism of hippocampal primary neurons in response to chemically induced long-term potentiation
Authors: Pudelko-Malik Natalia , Drulis-Fajdasz Dominika , Fydryszewski Mateusz , Burgess Shawn , Mlynarz Piotr , Rakus Dariusz , Deja Stanislaw
Published: February 2025

Glucose is a predominant fuel for the brain supporting its high energy demand associated with neuronal signaling and synaptic activity. Long-term potentiation (LTP) is required for learning and memory formation by generating long lasting increase in synaptic strength and signal transmission between two neurons. While the electrophysiological bases of LTP are well established, much less is known about the metabolic demands of neurons involved in LTP. Common protocols used to examine synaptic activity rely on high glucose concentrations which are far from physiological glucose levels found in the brain. Here we used primary hippocampal neurons cultured under physiological (2.5 mM) and high (25 mM) glucose to investigate the metabolic effects of chemically induced LTP. Physiological glucose was associated with neuronal survival while high glucose promoted “PAS granule” accumulation. Changes in glucose altered extracellular lactate and pyruvate concentrations and affected key intracellular metabolic intermediates and neurotransmitter levels in neuronal cells without depleting the TCA cycle. LTP induction was comparable, but mitochondrial and neurotransmitter response to LTP was differentially affected physiological and high glucose conditions. Glycogen phosphorylase inhibition had minimal effects in physiological glucose but impaired synaptic responses and altered metabolite dynamics in high glucose. Our findings demonstrate that neuronal mitochondrial metabolism is closely linked to synaptic plasticity and highlight the importance of studying neurophysiological activity physiologically relevant glucose conditions.
The Stop Signal Stepping Task: how action cancellation commands disrupt step initiation in young and healthy older adults
Authors: Healey Rebecca , Wells Marlee J. , Salomoni Sauro E. , Puri Rohan , Hinder Mark R. , St George Rebecca J.
Published: February 2025

Action cancellation– the ability to rapidly cancel an initiated movement in response to unexpected events – has been extensively studied in the upper limb using the stop signal task (SST). During gait, action cancellation is needed to stop and modify steps to avoid hazards and prevent falls. By adapting the SST to step initiation, this study investigated how the anticipatory postural adjustment (APA) and foot-lift phases of forward stepping were affected by action cancellation commands, and whether this changed with healthy ageing. The SST was performed in stepping, foot tap, and finger button conditions in 27 young (Mage= 28.7 years) and 29 healthy older adults (Mage= 70.1 years).

Across conditions, older adults exhibited slowerresponsespeed compared to young adults and greater proactive slowing of responses when stop cues were anticipated. However, there was no significant difference instoppingspeed between young and older adults. Stopping speed was fastest in the finger tap condition, and slowest in the step condition. When an APA was initiated in a step cancellation trial, the magnitude of the weight shift toward the step leg did not differ between successful and unsuccessful foot-lift cancellations. Foot-lift could be cancelled when stop cues were presented at similar phases of step preparation for young and older adults.

These results suggest that the initial loading of the step leg is a ballistic process, however as weight is shifted toward the stance leg, action cancellation commands responding to external stimuli can decouple the APA and foot-lift step phases.

Key Points

The stop signal task (SST) – which allows an estimation of stopping speed independently of response speed – was applied to voluntary stepping in young and older adults.

While response speed was slower for older than young adults, stopping speed was not significantly different between age groups in the upper limb, lower limb when seated, and during forward stepping.

When stop cues were introduced, response speed slowed more in older than young adults, and more in the upper than the lower limb (i.e., Foot Tap and Step conditions).

The initial preparatory weight shift toward the stepping foot was not significantly different between successfully cancelled steps and normal steps, highlighting the ballistic nature of the early phase of step preparation.

Prior to foot-lift, action cancellation commands could decouple the preparatory weight shift phase from foot-lift at similar stages of step initiation in young and healthy older adults.
Compact and highly efficient plasmonic mode conversion in a metal slab waveguide with asymmetric subwaveguides
Authors: Ho Kum-Song , Jong Myong-Song , Kang Jin , Im Song-Jin , Kim Kum-Dong , Song Kil-Song , Pae Ji-Song , Ri Chol-Song
Published: February 2025

Compact plasmonic devices have paved a way to achieve highly integrated photonic circuit for the next-generation information technology. In this Letter, we proposed compact and highly efficient plasmonic mode conversion between symmetric and antisymmetric modes in metal slab waveguides containing asymmetric dielectric substructures. We derived intuitive analytical formulations concerning the mode asymmetry and intermode coupling in the asymmetric subwaveguide. And we estimated a conversion efficiency and compactness of the proposed plasmonic mode conversion. As a result, we confirmed the compact and high-efficiency plasmonic mode converter with conversion efficiency as high as 90% and a compact size up to one wavelength. The suggested device will give us potential possibilities to construct on-chip photonic computing networks.

Published by the American Physical Society
2025
Filgotinib Improves Experimental Pulmonary Fibrosis by Modulating JAK1/STAT3/SOCS3/IL‐17A Signalling
Authors: Lv Yunying , Zhang Guanghua , Kong Dexin , Jiang Wanglin
Published: February 2025

Background

Regulatory agencies in Europe and Japan have approved filgotinib, a selective JAK1 inhibitor, for use in treating rheumatoid arthritis, but its effect and mechanism of action in treating pulmonary fibrosis remain unclear.

Methods

We performed an in vivo investigation in rats on filgotinib's effect on pulmonary fibrosis resulting from the intratracheal infusion of bleomycin (BLM). Then, we focused on the mechanisms by which filgotinib inhibits experimentally induced pulmonary fibrosis in vitro by determining its effect on TGF‐β1‐induced proliferation of mouse lung fibroblasts.

Results

Continuous gavage of filgotinib at 20 mg/kg for 14 days elicited protective effects in the BLM‐induced rat experimental pulmonary fibrosis model, as reflected in changes in Hounsfield units as an indicator of overall pulmonary function and in the lung coefficient and lung microscopic pathology scores as indicators of gross pulmonary pathology. Protein expression levels of IL‐17A, phosphorylated tyrosine kinase (p‐JAK1), p‐STAT3 and cytokine signal transduction inhibitor 3 (SOCS3) were also changed. In in vitro studies, filgotinib at 1 μM reduced TGF‐β1‐induced fibroblast proliferation and produced lower levels of IL‐17A, p‐JAK1 and p‐STAT3, but higher SOCS3.

Conclusions

Filgotinib appeared to alleviate experimental pulmonary fibrosis by reducing fibroblast proliferation via inhibition of the JAK1/STAT3/SOCS3/IL‐17A pathway.
Influence of Hydrocolloids on the Drying and Functional Properties of Facheiro (Pilosocereus pachycladus) Fruit Pulp Powders
Authors: Silva Aline Priscila de França , Queiroz Alexandre José de Melo , de Figueirêdo Rossana Maria Feitosa , Silva Eugênia Telis de Vilela , Moura Henrique Valentim , da Silva Gabriel Monteiro , Andrade Fabrícia Santos , Gregório Mailson Gonçalves , Carvalho Raniza de Oliveira , Moreira Inácia dos Santos
Published: February 2025

Numerous native fruits with technological, nutritional, and economic potential remain largely unexplored in Brazil. Among these is the facheiro fruit (Pilosocereus pachycladus F. Ritter), a tree‐like cactus native to the Brazilian semi‐arid region. When ripe, this fruit yields a dark purple pulp characterized by a mildly sweet and slightly acidic flavor. This study aimed to produce and characterize powders derived from facheiro fruit pulp. The powders were prepared with different hydrocolloids—carboxymethylcellulose (CMC), guar gum, and xanthan gum—at varying concentrations and were labeled as follows: FI (pulp without additive), FC (pulp + 1% CMC), FG (pulp + 0.5% guar gum), and FX (pulp + 0.5% xanthan gum). These formulations were dried in a thin layer at 70°C in a forced‐air oven until reaching hygroscopic equilibrium. The powders were subsequently analyzed for their physical, physicochemical, technological, and hygroscopic properties. The analyses included water adsorption isotherms at 20°C, 30°C, and 40°C, as well as thermodynamic, thermal, and morphological evaluations. The powders exhibited a predominance of sugars, low protein content, and low acidity (pH > 5.0). The addition of hydrocolloids enhanced water, oil, and milk absorption capacities without significantly affecting flowability or cohesiveness but led to a reduction in porosity. Notably, xanthan gum also reduced the angle of repose. Water adsorption isotherms exhibited a type II sigmoid shape and were effectively described by the Oswin, Peleg, and GAB models. Thermodynamic analysis indicated that the adsorption process was entropy‐driven and spontaneous. FTIR and UV–vis analyses confirmed the presence of lipids, proteins, phenolics, flavonoids, alkaloids, polysaccharides, and glycosides in the powders.
Multidimensional plasticity of phenology: assessing the effects of population density on plastic responses of breeding time to temperature
Authors: Purushotham Vaishnavi , Cuchot Paul , Teplitsky Celine , Matthysen Erik
Published: February 2025

Phenotypic plasticity is the key adaptive mechanism behind annual adjustment of breeding time in response to temperature. In nature, organisms are not only subjected to variation in temperature but encounter multiple fluctuating environmental factors that affect phenotypic expression, including conspecific density, which affects individual performances through resource competition. We examined the interactive effects of temperature and conspecific density at two spatial scales (territory and patch level) on breeding time and success utilizing data obtained from long‐term monitoring of a wild great tit Parus major population in a fragmented woodland. As expected, we detected earlier breeding in response to warmer spring temperatures. We report earlier laying at low territory level density (i.e. a larger available area per breeding pair), but no evidence of density effects at patch level (breeding pairs per hectare). Birds experiencing low territory level density throughout their life bred on average earlier, and this response was also seen at the within‐individual level (earlier laying in years when individuals experienced a lower density than average). We found no context‐dependence of plastic responses to warmer springs as we detected no interactive effects between density and temperature. In terms of breeding success, earlier laying decreased the risk of brood failure and increased the number of fledglings. The number of fledglings was higher at low territory level density, while higher patch level density increased the probability of brood failure. Altogether, these results indicate that density‐related responses were likely mediated by food competition rather than by increased numbers of low‐quality birds or increased occupation of poorer territories at higher densities. This study highlights the importance of examining parameters at different spatial scales, along with the study of individual responses to multivariate cues for a comprehensive understanding of the variations in phenological plasticity.
The Hybrid Pathway to Flexible Power Turbines: Part III, Enabling Live Thermal Boundary Prediction Using Real-Time Plant Measurements And Lstm Neural Networks
Authors: Baker Mark , Rosic Budimir
Published: February 2025

The global drive towards renewable energy is imposing challenging operating requirements on power turbines. Flexible load-leveling applications must accept frequent and demanding start-stop cycles. Full transient analyses are too computationally expensive for real-time simulation so monitoring relies on sparse physical measurements. Alone, these sparse data lack the fidelity for real-time prediction of a complex thermal field. A new hybrid methodology is proposed, coupling data across a range of fidelities to bridge the limitations in the individual analyses. Combining several methods in parallel: low-order models, corrected by real-time physical measurements, are calibrated with high-fidelity simulations. The multi-faceted hybrid approach enables the real-time speed of low-order analysis at high resolution. This paper series develops the critical enabling features of the hybrid method. Real-time definition of the simulation thermal boundary condition is fundamental to the methodology. A novel Long-Short-Term-Memory (LSTM) neural network is presented, enabling time series prediction of the turbine thermal profile. The remote sensing method utilizes standard plant measurements to reconstruct the turbine temperature history, allowing reliable thermal prediction whilst removing the need for direct monitoring of the casing temperature. Calculations within the training region demonstrated high accuracy, achieving a mean square error of 3.1 K and maximum instantaneous peak error of 7.6 K. Combining a reduced feature space and efficient two-step predictor-corrector structure, the LSTM method offers high-speed temperature calculation, successfully predicting one month of operating data in under a minute.
Optimizing Coronary Artery Bypass Grafting Parameters for Failure Prevention using Computational Fluid Dynamics
Authors: Maiti Shraman , Kumar Mukesh , Mallick Adarsha , Kumar Mahir , Sahani Ashish
Published: February 2025

Coronary artery bypass grafting (CABG) is a surgical procedure aimed at improving blood circulation to the heart muscle in individuals with significant coronary artery disease. This involves transplanting a healthy artery from elsewhere in the body to bypass a blocked coronary artery. In this study, a computational fluid dynamics (CFD) simulation was performed using Ansys Fluent software to examine the impact of CABG on coronary arteries that are either entirely or partially blocked. This analysis considered laminar flow conditions with the application of the no-slip boundary condition and took into account the Reynolds number parameter, considering momentum and transport properties within the specified geometric, material, and physical constraints of blockage. By leveraging insights from failure studies, this paper aim to mitigate coronary artery failure by optimizing surgical techniques. Here, the chosen model contributes to establishing optimal surgical protocols for CABG, ensuring the long-term patency of the graft. To minimize the risk of heart failure, factors such as reduced flow, velocity, and wall shear stress by precise linear positioning of the graft, and accurate assessment of blockage size and shape should be enhanced. Through CFD analysis, blood flow dynamics in the artery post-grafting has been evaluated, for the given parameters such as blockage size, and position. Optimal outcomes are achieved when the graft is positioned appropriately with blockages minimized in size and positioned strategically to maintain laminar flow conditions within the artery.
Role of sequence length and functionalization in interactions of bioconjugated peptides with mitomembranes
Authors: Nguyen Son V. , Planalp Roy P. , Vashisth Harish
Published: February 2025

Cell-penetrating peptides are efficient tools for intracellular delivery of a variety of cargoes. In this study, we explored the effect of chain length, side chain chemistry, and the locations of conjugated molecules on the interaction between iron-chelating peptides and a mitochondrial-mimicking membrane. We report that a longer chain length enhanced peptide/membrane interactions, and conjugation at the N-terminus lowered the free-energy barrier for peptide translocation across the membrane. Peptides containing Phe side chains and those containing modified Phe (cyclohexane) side chains showed comparable peptide/membrane energetics and translocation energy barriers. Using steered molecular dynamics (SMD) simulations, we further probed the mechanistic details of translocation of each N-terminated peptide across the membrane and compared their metastable states. At a higher steering velocity, the peptide adopted a compact structure due to frequent π–π interactions among conjugated molecules, but at lower steering velocities, each N-terminated peptide adopted an extended structure. This structure allowed cationic residues to maximize their interactions with phosphate headgroups in the mitomembrane. The hydrophobic residues also formed interactions with the lipid acyl tails, facilitating the passage of peptides across the membrane with decreased free energy barriers. Our results highlight the significance of peptide chain length and conjugation in facilitating peptide transport across the membrane.