bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional RNA mining using random high-throughput screening
Authors: Liu Li-Hua , Chen Jinde , Lai Shijing , Zhao Xuemei , Yang Min , Wu Yi-Rui , Zhang Zhiqian , Jiang Ao
Published: December 2024

Functional RNA participates in various life processes in cells. However, there is currently a lack of effective methods to screen for functional RNA. Here, we developed a technology named random high-throughput screening (rHTS). rHTS uses a random library of ∼250-nt synthesized RNA fragments, with high uniformity and abundance. These fragments are circularized into circular RNA by an auto-cyclizing ribozyme to improve their stability. Using rHTS, we successfully screened and identified three RNA fragments contributing significantly to the growth of Escherichia coli, one of which possesses coding potential. Moreover, we found that two noncoding RNAs (ncRNAs) effectively inhibited the growth of E. coli, in vivo rather than in vitro. Subsequently, we applied the rHTS to a coenzyme-dependent screening platform. In this context, two ncRNAs were identified that could effectively promote the conversion from NADPH to NADP+. Exogenous expression of these two ncRNAs was able to increase the conversion rate of glycerol dehydrogenase from glycerol to 1,3-dihydroxyacetone from 18.3% to 21.8% and 23.2%, respectively. These results suggest that rHTS is a powerful technology for functional RNA mining.
Influenza a virus antiparallel helical nucleocapsid-like pseudo-atomic structure
Authors: Chenavier Florian , Zarkadas Eleftherios , Freslon Lily-Lorette , Stelfox Alice J , Schoehn Guy , Ruigrok Rob W H , Ballandras-Colas Allison , Crépin Thibaut
Published: December 2024

Influenza A viruses are responsible for human seasonal epidemics and severe animal pandemics with a risk of zoonotic transmission to humans. The viral segmented RNA genome is encapsidated by nucleoproteins (NP) and attached to the heterotrimeric polymerase, forming the viral ribonucleoproteins (vRNPs). Flexible helical vRNPs are central for viral transcription and replication. In this study, we present an advanced biological tool, the antiparallel helical RNP-like complex, assembled from recombinant N-terminally truncated NP and short synthetic RNA. The 3.0 Å cryo-electron microscopy structure details for the first time the whole RNA pathway across NP as well as NP-NP interactions that drive the antiparallel helical assembly accommodating major and minor grooves. Our findings show that the surface of the protein can harbour several conformations of the RNA, confirming that the number of nucleobases that binds to NP is not fixed, but ranges probably between 20 and 24. Taking all together, our data provide details to further understand the genome encapsidation and explain the inherent flexibility of influenza A virus vRNPs.
Lig3-dependent rescue of mouse viability and DNA double-strand break repair by catalytically inactive Lig4
Authors: Medina-Suárez David , Han Li , O’Reilly Sandra , Liu Jiali , Wei Chao , Brenière Manon , Goff Noah J , Chen Chen , Modesti Mauro , Meek Katheryn , Harrington Bonnie , Yu Kefei
Published: December 2024

Recent studies have revealed a structural role for DNA ligase 4 (Lig4) in the maintenance of a repair complex during non-homologous end joining (NHEJ) of DNA double-strand breaks. In cultured cell lines, catalytically inactive Lig4 can partially alleviate the severe DNA repair phenotypes observed in cells lacking Lig4. To study the structural role of Lig4 in vivo, a mouse strain harboring a point mutation to Lig4’s catalytic site was generated. In contrast to the ablation of Lig4, catalytically inactive Lig4 mice are born alive. These mice display marked growth retardation and have clear deficits in lymphocyte development. We considered that the milder phenotype results from inactive Lig4 help to recruit another ligase to the repair complex. We next generated a mouse strain deficient for nuclear Lig3. Nuclear Lig3-deficient mice are moderately smaller and have elevated incidences of cerebral ventricle dilation but otherwise appear normal. Strikingly, in experiments crossing these two strains, mice lacking nuclear Lig3 and expressing inactive Lig4 were not obtained. Timed mating revealed that fetuses harboring both mutations underwent resorption, establishing an embryonic lethal genetic interaction. These data suggest that Lig3 is recruited to NHEJ complexes to facilitate end joining in the presence (but not activity) of Lig4.
A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance
Authors: Sun Nan , Chen Qun , Chen Hao , Sun Penggang , Liu Yuxiang , Song Dan , Yu Daohan , Wang Pandeng , Song Yu , Qin Jie , Tian Kaifu , Zhong Junzhe , Ma Wenbin , Xuan Hanwen , Qian Da , Yuan Ye , Chen Tongzheng , Wang Xin , Jiang Chuanlu , Cai Jinquan , Meng Xiangqi
Published: December 2024

Background

Temozolomide (TMZ) is used in the treatment of glioblastoma (GBM). However, the primary obstacle remains the emergence of TMZ chemotherapy resistance. Non-POU domain-containing octamer-binding protein (NONO) and splicing factor proline/glutamine rich (SFPQ) are multifunctional nuclear proteins involved in genome stability and gene regulation. However, the specific role of NONO and SFPQ in TMZ resistance of GBM remains to be explored.

Methods

RNA-binding protein immunoprecipitation-microarray and RNA microarray of TMZ-resistant and parental cells were performed for the gain of HSD52. The effects of HSD52 on TMZ resistance were investigated through in vitro assays, intracranial xenograft, and GBM organoid models. The underlying mechanisms were explored by DNA methylation chip, RNA immunoprecipitation, RNA pull-down assays, among others. GBM clinical samples were rolled in to investigate the clinical significance of HSD52.

Results

We identified a novel noncoding RNA, HSD52, that was highly expressed in TMZ-resistant GBM and facilitated the interaction between NONO and SFPQ. H3 ubiquitination attenuation and reduced DNA methyltransferase 1 (DNMT1) recruitment increased HSD52 transcription via DNA hypo-methylation. HSD52 formed an RNA duplex with UFM1 specific ligase 1 (UFL1) mRNA, thereby promoting NONO/SFPQ complex binding to UFL1 mRNA and enhancing its stability, and then contributed to TMZ resistance through activating the ataxia telangiectasia mutated signaling pathway. In vivo xenograft and GBM organoid models showed significant repression in tumor growth after HSD52 knockout with TMZ treatment. In GBM clinical samples, HSD52 was responsible for the malignant progression and TMZ resistance.

Conclusions

Our results revealed that HSD52 could serve as a promising therapeutic target to overcome TMZ resistance, improving the clinical efficacy of TMZ chemotherapy in GBM.
Phase II trial of blood–brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma
Authors: Dmello Crismita , Brenner Andrew , Piccioni David , Wen Patrick Y , Drappatz Jan , Mrugala Maciej , Lewis Lionel D , Schiff David , Fadul Camilo E , Chamberlain Marc , Kesari Santosh , Ahluwalia Manmeet , Ghosh Debora , Sonabend Adam M , Kumthekar Priya
Published: December 2024

Background

This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood–brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).

Methods

Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).

Results

Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.

Conclusion

A dose of 600 mg/m2 was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.
Atomically precise silver-based bimetallic clusters for electrocatalytic urea synthesis
Authors: Chen Hong , Liu Lin , Ma Xiao-Hong , Zheng Su-Jun , Dong Xiao-Yu , Huang Ren-Wu , Wang Zhao-Yang , Cai Jinmeng , Zang Shuang-Quan
Published: December 2024

Electrocatalytic urea synthesis from CO2 and nitrate holds immense promise as a sustainable strategy, but its complicated synthesis steps and controversial C–N coupling mechanism restrict the design of efficient catalysts. Atomically precise metal cluster materials are ideal model catalysts for investigating the C–N coupling issues. Here we synthesize two atomically precise bimetallic clusters, Ag14Pd(PTFE)6(TPP)8 and Ag13Au5(PTFE)10(DPPP)4, both with icosahedral cores and similar ligands. We demonstrate that both clusters have good performance for electrocatalytic urea synthesis, with the production rates at the maximum Faradaic efficiency of 143.3 and 82.3 mg h−1 gcat−1, respectively. Bimetallic structures can induce charge polarization at the active sites of metal clusters, thereby influencing the selectivity. In mechanistic investigations, we propose that *NOH and *COOH are the rate-limiting steps for the reduction of nitrate and CO2, respectively, and that the key intermediates formed thereafter can significantly affect the C–N coupling process. This approach offers a deep understanding into C–N coupling through the utilization of atomically precise metal clusters.
Concentration and mergers: evidence from Italian labor markets
Authors: Passerini Filippo
Published: December 2024

This article investigates the effects of labor market concentration on employment, job security, and wages. By constructing a flow-based index, I find that concentration is generally low across markets but varies across industries. Then, I use a Two-Stage Least Squares (TSLS) strategy based on the different exposures of industries to horizontal mergers. I find that mergers increase concentration, which in turn reduces wages by −0.14 and −0.07 and hires by −0.77 and −0.68%age points. I also find that (1) concentration does not affect the likelihood of a permanent hire but increases the probability that, when a temporary worker is renewed, the contract is again temporary; (2) men are affected by concentration only through wages, while women are less affected but also through job security; (3) estimates magnitude increases in concentration levels.
Safety and quality of life with maintenance olaparib plus bevacizumab in older patients with ovarian cancer: subgroup analysis of PAOLA‑1/ENGOT-ov25
Authors: Montégut Coline , Falandry Claire , Cinieri Saverio , Cropet Claire , Montane Laure , Rousseau Frédérique , Joly Florence , Moubarak Malak , Mosconi Anna M , Guerra-Alía Eva M , Schauer Christian , Fujiwara Hiroyuki , Vergote Ignace , Parma Gabriella , Lindahl Gabriel , Anota Amélie , Canzler Ulrich , Marmé Frederik , Pujade-Lauraine Eric , Ray-Coquard Isabelle , Sabatier Renaud
Published: December 2024

Background

In PAOLA-1/ENGOT-ov25, the addition of olaparib to bevacizumab maintenance improved overall survival in patients with newly diagnosed advanced ovarian cancer. We describe the safety profile and quality of life (QoL) of this combination in older patients in PAOLA-1.

Methods

Safety (CTCAE v4.03) and QoL (EORTC QoL Questionnaires Core 30 and Ovarian 28) data were collected. We compared safety by age (≥70 vs <70 years) in the olaparib-containing arm. QoL by treatment arm was assessed in older patients. Geriatric features, including Geriatric Vulnerability Score (GVS), were also gathered.

Results

Of 806 patients randomized, 142 were ≥70 years old (olaparib-containing arm: n = 104; placebo arm: n = 38). Older patients treated with olaparib exhibited a similar safety profile to younger patients, except for higher rates of all grades of lymphopenia and grade ≥3 hypertension (31.7% vs 21.6%, P =.032 and 26.9% vs 16.7%, P =.019, respectively). No hematological malignancy was reported. Two years after randomization, mean Global Health Status and cognitive functioning seemed better with olaparib than bevacizumab alone (adjusted mean difference: +4.47 points [95% CI, −0.49 to 9.42] and +4.82 [−0.57 to 10.21], respectively), and other QoL items were similar between arms. In the olaparib-containing arm, older patients with baseline GVS ≥ 1 (n = 48) exhibited increased toxicity and poorer QoL than those with GVS of 0 (n = 34).

Conclusion

Among older patients in PAOLA-1, olaparib plus bevacizumab had a manageable safety profile and no adverse impact on QoL. Additional data are required to confirm these results in more vulnerable patients.

(ClinicalTrials.gov Identifier: NCT02477644).
Feeding selectivity and niche characteristics in Southern Ocean salps
Authors: Fender Christian K , Décima Moira , Gutiérrez-Rodríguez Andres , Selph Karen E , Safi Karl A , Stukel Michael R
Published: December 2024

Salps are a group of pelagic tunicates with widespread distribution and the potential to strongly impact ecosystem dynamics through their rapid reproduction, carbon export and filtration rates. Like most filter feeders, they are considered to be nonselective in their feeding, although recent reports of differences in the proportions of prey types in salp diets compared to their availability have challenged this paradigm. We investigate the potential for selective feeding and its impacts on salp niche breadth and overlap using scanning electron microscopy of the gut contents of 58 salps from the Southwest Pacific east of New Zealand representing seven species: Salpa thompsoni, Thetys vagina, Thalia democratica, Salpa fusiformis, Ihlea magalhanica, Soestia zonaria and Pegea confoederata. We then compare their diet to water column plankton communities via FlowCam and flow cytometry. While most prey types were consumed without preference as expected, dinoflagellates were positively selected across five of the seven salp species regardless of water column prey compositions. Large, spinous diatoms and submicron particles were consistently negatively selected. These selectivities resulted in high niche breadths that still fell short of true generalists, highlighting that selectivity is a spectrum rather than a dichotomy.
Kiwifruit spatiotemporal multiomics networks uncover key tissue-specific regulatory processes throughout the life cycle
Authors: Zeng Zhebin , Li Yawei , Zhu Man , Wang Xiaoyao , Wang Yan , Li Ang , Chen Xiaoya , Han Qianrong , Nieuwenhuizen Niels J , Ampomah-Dwamena Charles , Deng Xiuxin , Cheng Yunjiang , Xu Qiang , Xiao Cui , Zhang Fan , Atkinson Ross G , Zeng Yunliu
Published: December 2024

Kiwifruit (Actinidia chinensis), a recently commercialized horticultural crop, is rich in various nutrient compounds. However, the regulatory networks controlling the dynamic changes in key metabolites among different tissues remain largely unknown. Here, high-resolution spatiotemporal datasets obtained by ultraperformance liquid chromatography-tandem mass spectrometry methodology and RNA-seq were employed to investigate the dynamic changes in the metabolic and transcriptional landscape of major kiwifruit tissues across different developmental stages, including from fruit skin, outer pericarp, inner pericarp, and fruit core. Kiwifruit spatiotemporal regulatory networks (KSRN) were constructed by integrating the 1,243 identified metabolites and co-expressed genes into 10 different clusters and 11 modules based on their biological functions. These networks allowed the generation of a global map for the major metabolic and transcriptional changes occurring throughout the life cycle of different kiwifruit tissues and discovery of the underlying regulatory networks. KSRN predictions confirmed previously established regulatory networks, including the spatiotemporal accumulation of anthocyanin and ascorbic acid (AsA). More importantly, the networks led to the functional characterization of three transcription factors: an A. chinensis ethylene response factor 1, which negatively controls sugar accumulation and ethylene production by perceiving the ripening signal, a basic-leucine zipper 60 (AcbZIP60) transcription factor, which is involved in the biosynthesis of AsA as part of the L-galactose pathway, and a transcription factor related to apetala 2.4 (RAP2.4), which directly activates the expression of the kiwi fruit aroma terpene synthase gene AcTPS1b. Our findings provide insights into spatiotemporal changes in kiwifruit metabolism and generate a valuable resource for the study of metabolic regulatory processes in kiwifruit as well as other fruits.
Designed to breathe: synthetic biology applications in plant hypoxia
Authors: Lavilla-Puerta Mikel , Giuntoli Beatrice
Published: December 2024

Over the past years, plant hypoxia research has produced a considerable number of new resources to monitor low oxygen responses in model species, mainly Arabidopsis thaliana. Climate change urges the development of effective genetic strategies aimed at improving plant resilience during flooding events. This need pushes forward the search for optimized tools that can reveal the actual oxygen available to plant cells, in different organs or under various conditions, and elucidate the mechanisms underlying plant hypoxic responses, complementing the existing transcriptomics, proteomics, and metabolic analysis methods. Oxygen-responsive reporters, dyes, and nanoprobes are under continuous development, as well as novel synthetic strategies that make precision control of plant hypoxic responses realistic. In this review, we summarize the recent progress made in the definition of tools for oxygen response monitoring in plants, either adapted from bacterial and animal research or peculiar to plants. Moreover, we highlight how adoption of a synthetic biology perspective has enabled the design of novel genetic circuits for the control of oxygen-dependent responses in plants. Finally, we discuss the current limitations and challenges toward the implementation of synbio solutions in the plant low-oxygen biology field.
The role of emotional and cultural intelligences on police leaders’ perceptions of reform
Authors: White David R , Schafer Joseph A
Published: December 2024

Police leaders’ support for policing reform is an important consideration because this population serves in some ways as gatekeepers of their respective organizations, setting organizational priorities and operationalizing change. Using survey data from 731 US police leaders who attended the FBI National Academy program in 2023, we evaluate the salience of emotional intelligence and cultural intelligence as key leadership contexts. Specifically, this study examines whether emotional and cultural intelligence relates to participants’ support for civilian oversight boards, and the belief that de-escalation and implicit bias training have a positive impact on policing. Controlling for other factors, the results indicate that emotional and cultural intelligence are significantly related to reform attitudes. Notably, we control for participants’ perceptions that systemic racism poses a problem in criminal justice and find that views of systemic racism also remain significant with most outcomes. Implications for police leadership training and policing reform are discussed.
The pattern of anti-IL-6 versus non-anti-IL-6 biologic disease modifying anti-rheumatic drugs use in patients with rheumatoid arthritis in Wales, UK: a real-world study using electronic health records
Authors: Cooksey Roxanne , Kennedy Jonathan , Rahman Muhammad , Brophy Sinead , Choy Ernest
Published: December 2024

Objective

Investigating factors associated with drug initiation and discontinuation in patients treated with anti-IL-6 biologic DMARDs (bDMARDs) (tocilizumab or sarilumab) vs non-anti-IL-6 (anti-TNF, B or T cell therapies) bDMARDs for RA.

Methods

A retrospective cohort study of patients with the diagnosis of RA in the Secure Anonymised Information Linkage Databank, comprising primary and secondary care and specialist rheumatology clinic records for >90% of the population in Wales, UK. Patients initiated on first bDMARD treatment, discontinuation and clinical outcomes including infection and hospitalisation were analysed using Cox regression analysis.

Results

Of patients identified with RA in their primary care records, 95.7% (4691/4922) received conventional synthetic DMARDs (csDMARDs). More than one-third (36.2%) were treated with bDMARDs (1784/4922). Of these biologic-naïve patients, 6.5% (116) were treated with anti-IL-6 bDMARDs; this treatment was associated with a previous history of infection [difference 8.8% (95% CI 1.1, 17.8)] and kidney disease [14.3% (95% CI 8.0, 22.5)]. Treatment discontinuation was significantly higher in the non-anti-IL-6 bDMARD-treated patients (23.1%) compared with the anti-IL-6 bDMARD-treated individuals (18.1%) [difference 9.4% (95% CI 1.1, 15.7)]. For those discontinuing a first line of treatment, 385 patients (23%) and 21 patients (18%) switched to an alternative bDMARD from the non-anti-IL-6 and anti-IL-6 groups, respectively.

Conclusion

Comorbidities, history of infection and kidney disease were associated with choosing anti-IL-6 bDMARDs in biologic-naïve RA patients in Wales. Anti-IL-6 bDMARD-treated biologic-naïve patients were more likely to continue treatment than non-IL-6 bDMARD-treated patients.
Microchannel plate response to solar energetic particles and consequences for solar-wind measurements on ESA’s Vigil mission
Authors: Parent P-Y , Verscharen D , Nicolaou G , Owen C J
Published: December 2024

Space weather forecasting aims at predicting the impacts of the Sun, interplanetary space, and the planetary environment on biological and technological systems. To monitor space weather, the European Space Agency is developing the Vigil mission. Vigil will carry the Plasma Analyser (PLA) instrument. We investigate the expected impact of Solar Energetic Particles (SEPs) on PLA. We analyse previous measurements from Solar Orbiter’s Solar Wind Analyser (SWA) Electron Analyser System (EAS) that, like PLA, uses a microchannel plate (MCP) as its detector. Using a fitting algorithm, we extract the number of erroneous counts created by the interaction between SEPs and the MCP. Using SEP flux measurements from Solar Orbiter’s Energetic Particle Detector (EPD) and multilinear regression, we establish a linear relationship between the number of erroneous counts and SEP fluxes. We define an SEP index, characterizing the impact of SEP events on EAS measurements. We then simulate PLA measurements during SEP events characterized by their SEP index. We show that moderate SEP events cause significant discrepancies in PLA plasma moment estimations under common solar-wind conditions. Based on our results, we propose a correction method for erroneous counts created by SEPs in instruments such as EAS and PLA.
A multifunctional photothermal electrospun PLGA/MoS2@Pd nanofiber membrane for diabetic wound healing
Authors: Chen Zhengrong , Mo Quansheng , Mo Dandan , Pei Xiaomin , Liang Anru , Cai Jinhong , Zhou Bo , Zheng Li , Li Hongmian , Yin Feiying , Zhao Jinmin
Published: December 2024

Injury caused by excess reactive oxygen species (ROS) may lead to susceptibility to bacterial infection and sustained inflammatory response, which are the major factors impeding diabetic wound healing. By utilizing optimal anti-inflammatory, antioxidant and antibacterial biomaterials for multifunctional wound dressings is critical in clinical applications. In this study, a novel electrospun PLGA/MoS2@Pd nanofiber membrane was synthesized by encapsulating antioxidant and near-infrared (NIR) responsive MOS2@Pd nanozymes in PLGA nanofibers to form a multifunctional dressing for diabetic wound repair. With excellent biocompatibility and hemostatic ability, this novel PLGA/MoS2@Pd nanofiber membrane can effectively reduce oxidative stress damage and intracellular inflammatory factors expression in fibroblasts by scavenging ROS. Additionally, the PLGA/MoS2@Pd nanofiber membrane exhibited favorable NIR-mediated photothermal antibacterial activity in vitro, with inhibition rates of 97.14% and 97.07% against Staphylococcus aureus (S.aureus) and Escherichia coli (E.coli), respectively. In a diabetic rat wound infection model, NIR-assisted PLGA/MoS2@Pd nanofiber membrane effectively inhibited bacterial growth in the wound, reduced infection-induced inflammatory response, and promoted tissue epithelialization and collagen deposition, resulting in a wound healing rate of up to 98.5% on Day 14. This study highlighted the construction of a multifunctional nanofiber membrane platform and demonstrated its promising potential as a clinical dressing for diabetic wounds.
Neutrophil-derived apoptotic body membranes-fused exosomes targeting treatment for myocardial infarction
Authors: Wang Jingjing , Li Jingjing , Su Gang , Zhang Youbin , Wang Zhu , Jia Yujuan , Yu Qian , Shen Zhenya , Zhang Yanxia , Yu Yunsheng
Published: December 2024

Myocardial infarction (MI) poses a substantial threat to human health, prompting extensive research into effective treatment modalities. Preclinical studies have demonstrated the therapeutic potential of mesenchymal stem cell-derived exosomes for cardiac repair. Despite their promise, the inherent limitations of natural exosomes, mainly their restricted targeting capabilities, present formidable barriers to clinical transformation. To address this, it is proposed to enhance their targeting specificity and retention in infarcted myocardium by fusing exosomes with neutrophil-derived apoptotic body membranes (NAM). These NAM inherit the surface signals from neutrophils, which allow them to home in on the damaged tissues and participate in regulating inflammatory responses. In this current work, we utilized a membrane fusion technique to create NAM-fused exosomes (NAM-Exo) for MI treatment. Compared to their native counterparts, NAM-Exo demonstrated enhanced adhesion to inflammatory endothelial cells, replicating the neutrophil recruitment mechanism at sites of myocardial injury in MI. Furthermore, our findings revealed that NAM-Exo not only significantly modulated inflammation responses but also promoted angiogenesis in a mouse model of MI, ultimately leading to improved cardiac function and ventricular remodeling post-treatment. These results underscore the potential of membrane fusion as an effective strategy to enhance the therapeutic efficacy of exosome-based cardiac repair and regeneration therapies, thereby paving the way for their translation into clinical practice.
Elevated Fcy receptor expression augments pro-inflammatory macrophage phagocytosis in systemic sclerosis and associated rheumatic diseases
Authors: Hukara Amela , Bonazza Gino A , Tabib Tracy , Micheroli Raphael , Jordan Suzana , Bürki Kristina , Rudnik Michal , Ciurea Adrian , Distler Oliver , Lafyatis Robert , Błyszczuk Przemysław , Kania Gabriela
Published: December 2024

Objectives

To investigate the pro-phagocytic phenotype of macrophages in SSc and other rheumatic diseases by examining their activation, signalling pathways and treatment responses, with the goal of uncovering mechanisms that drive enhanced phagocytosis.

Methods

Single-cell RNA sequencing (scRNA-seq) datasets (GSE138669/GSE212109) from skin and lung macrophages of healthy controls (HC) and SSc patients were analysed. Human monocyte-derived macrophages (hMDMs) were differentiated from CD14+ monocytes from HC, SSc, RA, PsA, and axSpA patients. In selected experiments, hMDMs were pretreated with 0.1 μM nintedanib. Phagocytic activity was quantified using pHrodo bioparticles and flow cytometry. Macrophage surface markers were evaluated by flow cytometry, NF-κB signalling by Western blot and gene expression by RT-qPCR.

Results

Analysis of scRNA-seq datasets revealed a pro-phagocytic signature in SSc-affected organs. SSc macrophages, particularly the FCGR3Ahi cluster in skin, exhibited elevated expression of FCGR genes and enriched FcγR-mediated phagocytosis pathways, accompanied by pro-inflammatory markers. This phenotype extended to FCN1hi lung macrophages in SSc patients with interstitial lung disease, indicating a systemic pro-inflammatory and phagocytic profile. hMDMs from SSc, RA and PsA patients demonstrated enhanced phagocytic activity in vitro. Elevated FcγRI and FcγRII levels were identified as key drivers of increased phagocytic activity and subsequent IL-6-driven inflammation. Nintedanib showed reduction in FcγRI expression, suggesting its potential therapeutic benefit in attenuating the phagocytic process.

Conclusion

This study highlights FcγR-expressing macrophages as drivers of phagocytosis and inflammatory responses in SSc. Dysregulated activation of these macrophages could lead to persistent inflammation and fibrosis in rheumatic diseases, highlighting new potential therapeutic approaches.
The evolution of Industry 4.0 capacities across regions in EU research programmes
Authors: Ciffolilli Andrea , Lopolito Antonio , Muscio Alessandro , Reid Alasdair
Published: December 2024

European policy supports cutting-edge research on Industry 4.0, aiming to promote excellence and ensure a balanced distribution of regional Industry 4.0 capacities. We analyse Industry 4.0 research projects financed by the European Union’s framework programmes over a 14-year period, investigating whether less developed regions benefit from interaction with more advanced regions that have a stronger capacity to diversify their Industry 4.0 technologies. We find a strong path-dependency in technological diversification between programming periods. Moreover, while national Industry 4.0 programmes negatively affect the capacity of regions to diversify technologies, possibly generating a substitution effect, we find that regional networking does not support less diversified regions in mastering multiple technologies.
Pupillometric and perceptual approaches provide independent estimates of melanopsin activity in humans
Authors: Woelders Tom , Didikoglu Altug , Bickerstaff Lucien , Brown Timothy M , Lucas Robert J
Published: December 2024

Study Objectives

Melanopsin-expressing retinal ganglion cells, which provide light information to time sleep and entrain circadian clocks, also influence perceived brightness raising the possibility that psychophysical paradigms could be used to explore the origins and implications of variability in melanopic sensitivity. We aimed to develop accessible psychophysical tests of melanopic vision and relate outcomes with a pupillometric measure of melanopsin function (post-illumination pupil response) and prior light exposure.

Methods

Individually calibrated pairs of isoluminant stimuli differing in melanopic radiance from a four primary source were presented sequentially with superimposed random color offsets in a two alternative forced choice brightness preference paradigm to 41 naïve adult participants with personal light exposure data for the prior 7 days and post-illumination pupil response measures defined by comparing maintained pupil constriction for luminance matched “red” vs “blue” pulses.

Results

Across participants we observed the expected tendency to report positive melanopsin contrast stimuli as “brighter” (one-tailed t-test p < 0.001), but with substantial inter-individual variability in both sensitivity (melanopsin contrast at criterion preference p = 0.75) and amplitude (preference at maximum melanopic contrast). There was little correlation between these psychophysical outcomes and post-illumination pupil response magnitude, or between either psychophysical or post-illumination pupil response measures and light history metrics (pairwise Pearson correlation coefficients -0.5> < 0.5). Random forest machine learning failed to satisfactorily predict outcome for either psychophysical or post-illumination pupil response measures based upon these inputs.

Conclusions

Our findings reveal that estimates of melanopic function provided by perceptual and pupillometric paradigms can be largely independent of one another and of recent history of light exposure.
O005 Age related changes in sleep quantitative EEG and longitudinal relationship to cognitive function
Authors: Stumbles E , Appleton S , Adams R , Yee B , Parker J , Vakulin A , Wittert G , Marshall N , D’Rozario A
Published: December 2024

Objectives

Altered sleep microarchitecture including sleep spindles and decline in cognitive function occurs with advancing age. However, the longitudinal relationship between changes in sleep neurophysiology and cognition in middle-to-late life is currently unclear. This study examined sleep micro-architecture measured by electroencephalography (EEG) and cognitive performance in middle-aged and older men over a 10-year period.

Methods

156 participants from the Florey Adelaide Male Ageing Study who reported no previous obstructive sleep apnoea diagnosis underwent home-based polysomnography and cognitive testing including mini mental state examination (MMSE) and trail-making tests A (visual attention) and B (executive function) at baseline (2010-2011) and follow up (2019-2020). Power spectral analysis of single-channel EEG (F4-M1) recordings at follow up (n=142) was performed. Baseline and follow-up sleep parameters including spindle metrics, and cognition were compared using paired t-tests, and associations examined with Pearson’s correlations.

Results

NREM (267.6 vs 299.2 minutes) and REM (57.0 vs 77.7 minutes) sleep was higher during follow up compared to baseline (p <0.001). NREM sleep spindle events (257.5 vs 351.7) and spindle density (0.95 to 1.17 events/minute) was higher at follow-up (p <0.001). Performance on the TMT was worse (TMT-A: 15.4 vs. 38.7 seconds, TMT-B: 74.9 vs. 93.7 seconds, p <.001), indicating cognitive decline in these domains. There was no change in MMSE. The change in sleep spindles and cognition were not correlated.

Conclusions

In this community-dwelling cohort of men, no longitudinal relationship between sleep spindles and cognitive function was observed. The unexpected increase in spindle activity across the 10-year follow-up warrants further exploration.
O007 Menstrual cycle phase classification methods and the relationship with sleep, mood, and performance in elite female athletes
Authors: Mascaro L , Leota J , Sammak S , Rajaratnam S , Drummond S , Facer-Childs E
Published: December 2024

Introduction

Female athletes are often excluded from sports-science research due to hormonal variations across the menstrual cycle. Effects of menstrual cycle phase on outcomes are inconclusive likely due to between-study variation in phase classification. We aimed to test if the relationship between menstrual cycle phase and sleep, mood, and performance differed depending on whether a continuous, 2-phase, 3-phase, or 4-phase approach was used to classify cycle phase.

Methods

Elite Australian Rules footballers reporting a regular menstrual cycle and not on contraception (N=18, M-age=24.9±5.1) were recruited. Over two weeks, they completed continuous sleep/wake monitoring via actigraphy and sleep diaries, daily self-reported sleep quality, mood, and performance ratings, and five sessions of cognitive (vigilant attention) and physical (ecological kicking task) performance testing. Using baseline self-report data, menstrual cycle phase for each day of the study was inferred using a continuous (percentage through the cycle), 2-phase (follicular, luteal), 3-phase (menses, mid-late follicular, luteal), and 4-phase (menses, mid-late follicular, early-mid luteal, pre-menses) model.

Results

No outcome was consistently predicted by all phase-models. Objective sleep efficiency was lower in menses according to the 3- and 4-phase models. Subjective mood and performance were higher in the mid-late follicular according to the 3-phase model.

Discussion

The relationships between menstrual cycle phase and sleep, mood, and performance depend on how menstrual cycle phases are classified. Discordant findings highlight the importance of methodological differences in athlete menstrual cycle research. The effects of the menstrual cycle phase need to be further studied using consistent and standardised classifications across studies.
O011 Loss of sleep due to high ambient temperatures and its impact on healthy life years: Implications for global warming
Authors: Lechat B , Toson B , Scott H , Nguyen D , Kaambwa B , Escourrou P , Catcheside P , Eckert D
Published: December 2024

Introduction

The summer of 2023 in the northern hemisphere saw the highest global temperatures in over 2000 years. This study uses big data from an under-mattress sensor and global ambient temperature records to estimate the impact of high temperatures on poor sleep and associated wellbeing costs.

Methods

Data were from 219,808 consumers who used an under-mattress sensor (Withings Sleep Analyzer; 89,219) or a smartwatch (Withings ScanWatch; 130,589) regularly between January 2020 and September 2023. Generalized non-linear mixed effect models tested the effects of 24h average ambient temperature on sleep duration and poor sleep (<6h) adjusting for potential confounders. Health economics models quantified wellbeing cost due to sleep loss from high temperatures.

Results

Extreme temperatures were associated with a ~30 to 300% increase in the prevalence of poor sleep and a 10-40 min average sleep duration loss compared to median temperatures, depending on the country, and this effect was stronger in older participants. The global burden (35 locations; 3.5 billion total population) associated with sleep loss due to higher than historical average temperatures in 2023 was ~2.2 million disability adjusted life years, including 82,000 years of life lost, which was 2.5-fold higher compared to 2000.

Conclusions

High ambient temperatures are associated with reduced sleep duration and a marked increase in poor sleep prevalence. Wellbeing cost associated with sleep loss due to high temperatures is substantial – equivalent to medical conditions such as bipolar disorders, chronic kidney diseases, and alcohol use disorders.
O015 Autonomic Activations in Sleep: Tachycardic responses to nocturnal swallows and arousals in people with OSA
Authors: Lung K , Bilston L , Burke P
Published: December 2024

Introduction

Nocturnal swallowing and cortical arousals from sleep both produce rapid transient heartrate increases driven by autonomic activation. Obstructive Sleep Apnoea (OSA) is associated with autonomic dysfunction and cardiovascular diseases, however, the underpinning mechanisms remain unclear. Here, we examine autonomic activation associated with swallowing and arousals during sleep in OSA.

Methods

Overnight sleep with epiglottic pressure data from a previous study were analyzed using custom semi-automated analysis scripts to extract variables for swallows and arousals during sleep. The following variables were extracted: average heartrate 30 seconds prior to a swallow or arousal and, peak heartrate 10 seconds afterwards, plus data on associated arousals and arousal duration, respiratory events preceding the swallow(s).

Results

53 datasets were analyzed, including 6 controls, 12 mild, 17 moderate and 18 severe OSA subjects, in total: 2794 swallows and 9147 arousals.

Across all samples, heartrate elevation was greater when swallows occurred in close succession (21.4bpm vs 14.7bpm, p<0.0001). Arousals with swallows produced larger heartrate elevations (17.0bpm vs 10.7bpm, p<0.0001) and prolonged duration by 6 seconds compared to arousals without swallows. Arousals during Rapid Eye Movement (REM) sleep also produced a higher heartrate increase (16.4bpm vs 12bpm, p<0.0001). Notably, the severe OSA group exhibited reduced magnitude of swallow and arousal heartrate increases (18.4bpm vs 22.3bpm and 11.9bpm vs 12.9bpm, p<0.0001).

Discussion

Individuals with severe OSA exhibited diminished magnitude of heartrate elevation responses to swallows and arousals. This finding potentially advances our comprehension of the underlying mechanisms of OSA with association with cardiovascular diseases.
O020 A novel method to demask non-circadian effects on core body temperature to enhance daily circadian timing and amplitude estimation
Authors: Nguyen P , Dunbar C , Scott H , Lechat B , Manners J , Micic G , Lovato N , Reynolds A , Lack L , Adams R , Eckert D , Vakulin A , Catcheside P
Published: December 2024

Introduction

Circadian disruption contributes to adverse effects on sleep, performance and health. One of the most practical methods to track continuous daily changes in circadian timing is to measure core body temperature (CBT) to identify the CBT minimum time (Tmin), usually via cosine-model fits to measured data in controlled studies. However, this method ignores large effects of activity, sleep and wake on CBT that confound and mask the circadian component of primary interest. This study introduces a novel physiology-grounded analytic approach to separate circadian from non-circadian effects on CBT.

Methods

The dataset comprised 33 healthy participants (mean±SD 32±13 years old) attending a 39-hour in-laboratory study with an initial overnight sleep followed by extended wake. CBT data were collected at 30-second intervals via ingestible capsules. A physiology-guided generalized additive model was constructed to model the combined circadian and non-circadian effects of sleep, wake, and activity on CBT. Model fits and estimated Tmin inferred from extended wake without sleep were compared with traditional cosine-based models fits.

Results

Compared to the traditional cosine model, the new model exhibited superior fits to CBT (Pearson R 0.90 [95%CI; [0.83,0.96] versus 0.81 [0.55-0.93]) and better estimation of Tmin (difference of 0.2 [-0.5,0.3] hours versus 1.4 [1.1 to 1.7] hours).

Conclusions

This new method provides superior demasking of non-circadian influences compared to traditional cosine fits, including the removal of a sleep related bias towards an earlier estimate of the circadian component of Tmin.
O021 Distinguishing Circadian from Sleep Effects on Cognitive Performance During a Simulated Night Work Lighting Intervention
Authors: Guyett A , Lovato N , Manner J , Stuart N , Toson B , Nguyen D , Scott H , Catcheside P
Published: December 2024

Introduction

We previously found that a circadian-informed lighting intervention accelerated circadian retiming, improved cognitive performance and sleep during 4-days of simulated nightwork. This study explores the independent and combined effects of circadian retiming and sleep duration on cognitive performance improvements with circadian-informed lighting.

Methods

Data were from 19 healthy sleepers (12 male; mean±SD aged 29 ±10 y) underwent two 8-day in-lab protocols with circadian and control lighting. On days 3-7, participants transitioned to day sleeps (10:00–19:00) and underwent cognitive tests simulating nightwork (00:00–08:00). Cognitive performance was measured by psychomotor vigilance task (PVT) lapses. Polysomnography measured total sleep time (TST) during each sleep. Core body temperature minimum (Tmin) was estimated via ingestible capsules. Multilevel generalized structural equation modelling tested the mediation effect of TST on the relationship between Tmin and PVT lapses, and the moderating effect of lighting intervention on all three pathways.

Results

For both mediating pathways between Tmin and TST, TST and PVT are not moderated by lighting intervention (B = 16.81, SE = 8.99, p =.062 and B = 0.00, SE = 0.97, p =.332 respectively) so we can conclude there is no moderated mediation effect. There was a moderated direct effect of lighting intervention on Tmin time and worse PVT time (B = -0.64, SE = -3.74, p<.001).

Discussion

While homeostatic and circadian processes impact sleep and cognitive performance, PVT performance improvements from circadian-informed lighting appear to be dominated by circadian retiming effects rather than longer sleep under night shift work conditions.
O025 Impact of Temporal Rhythms on Blood Pressure Variability: Daily, Weekly, and Seasonal Effects
Authors: Manners J , Scott H , Lechat B , Pinilla L , Perlis M , Adams R , Escourrou P , Eckert D
Published: December 2024

Introduction

High blood pressure (BP) and BP variability are associated with increased risk of cardiovascular events and mortality. Despite known impacts of daily, weekly, and seasonal fluctuations on BP and BP variability, the independent temporal impacts are not well quantified, particularly in sleep research.

Methods

Participants comprised users of the Withings Sleep Analyzer and home blood pressure monitors, with ≥6 months of measurements, ≥3 times/week and at 3 unique hours of the day. Mixed models tested non-linear associations between mean-arterial pressure (MAP) and hour of the day, day of the week, and hemisphere-adjusted month of the year, adjusting for wake time, sleep duration, apnea-hypopnea index, age, and sex.

Results

Results included 40,332 participants (mean±SD 59±12 years old, 87/13% male/female) with 9.5 million BP measurements (median[IQR]=97[43,245] measurements per participant). MAP was independently associated with time since wake (range=1.14mmHg), peaking at wake and declining over the day, and the hour of the day (range=2.36mmHg), typically peaking at 6AM. Significant weekday (range=0.96mmHg) and monthly variability (range=2.14mmHg) resulted in the highest MAP on Monday, in winter months. The greatest variation, Monday morning in winter vs Friday evening in summer, accounted for a 6.69±0.08mmHg difference in MAP.

Conclusion

Measured BP varied considerably by time of day, day of week, and season, independently from sleep duration and timing. The significant variability imposed by these rhythms has important clinical implications. Without accounting for this temporal aspect, measurements of BP changes due to external factors like sleep disorders or treatment interventions could yield misleading or incorrect associations.