Research Foundation Research Articles

Recent advances in osteoarthritis research: A review of treatment strategies, mechanistic insights, and acupuncture.

Osteoarthritis (OA) is a chronic joint condition affecting millions worldwide, characterized by the gradual degeneration of joint cartilage, leading to pain, stiffness, and functional impairment. Although the pathogenesis of OA is not fully understood, the roles of inflammation, metabolic dysregulation, and biomechanical stress are increasingly recognized. Current treatments, including pharmacotherapy, physical therapy, and surgical interventions, aim to alleviate symptoms and improve quality of life, yet they face limitations and challenges. In recent years, researchers have explored a variety of new treatment strategies, such as molecular targeted therapy, biologic treatments, regenerative medicine, and lifestyle modifications, aiming to directly address the root causes and complex mechanisms of OA. This review aims to summarize the latest research advancements to provide fresh perspectives for clinical treatment and lay the foundation for future research and development of treatment strategies for OA.

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits.

Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability. We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches. We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout. This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.

Theoretical foundations for service innovation research in sport management – insights from nonprofit sport organisations

ABSTRACT Research question: Research on service innovation in sport is not theoretically aligned with service innovation theory. To address this, we conduct an empirical study utilising major service innovation theoretical approaches. We address the question: How do nonprofit sport organisations engage in service innovation? Research methods: We combine existing service innovation frameworks to guide service innovation research in the nonprofit sport context. We apply it in a qualitative study, collecting data via 20 semi-structured interviews with Australian golf club managers. Data analysis relied on an inductive–deductive strategy. Results and findings: We found evidence for practices following service innovation archetypes, with a propensity for the output-based and process-based archetypes, and less evidence for the systemic and experiential service innovation archetypes. Service innovation practices centred on provision and representational practices and were less dependent on management and organisational practices. Implications: First, we demonstrate the complementary nature of the dominant and diverging theoretical approaches to service innovation. Second, we propose and provide empirical support for a combined conceptual framework for analysing service innovation. Finally, our research provides concrete managerial recommendations for stimulating service innovation within organisations and beyond.

Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer

BackgroundThe best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy.MethodsIn this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2–4a cN+, or cT2–4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival.ResultsFrom February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P=0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative-chemoradiotherapy group.ConclusionsPerioperative chemotherapy with FLOT led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy. (Funded by the German Research Foundation; ESOPEC ClinicalTrials.gov number, NCT02509286.)

Inhibition of acyl-CoA synthetase long-chain isozymes decreases multiple myeloma cell proliferation and causes mitochondrial dysfunction.

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long-chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose- and time-dependent manner. RNA-sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma.

Machine Learning Analysis of Glutamate Receptor Activity in Developing Locus Coeruleus Neurons

: The developing brain undergoes a remarkable process of synapse production and maturation, particularly in glutamatergic synapses. In this study, we focused on the locus coeruleus (LC) nucleus, a brain region crucial for cognitive functions, to investigate the developmental changes in glutamatergic synaptic connections. Using the whole-cell patch clamp method, we recorded evoked excitatory postsynaptic currents (eEPSCs) from LC neurons in rats at ages 7, 14, and 21 days. To assess the developmental changes, we employed fractal analysis to compute fractal dimensions of AMPA and NMDA receptors, serving as markers for synaptic maturation. Our findings revealed a significant increase in fractal dimensions during the third postnatal week, indicating a developmental progression in the complexity and organization of synaptic connections. Pearson correlation analysis demonstrated a strong positive correlation between amplitude and fractal dimensions (p < 0.001), suggesting that the synaptic currents' amplitude is closely related to the fractal properties of the receptors. Furthermore, linear regression analysis showed a linear relationship between fractal dimensions and age (R2 = 0.843, p < 0.001), indicating that fractal analysis can be a robust tool for predicting age-dependent developmental changes. Additionally, we employed machine learning techniques to predict developmental changes based on AMPA and NMDA receptors. Support Vector Machine (SVM) models outperformed random forest models in accurately predicting age-dependent developmental changes, as indicated by the area under the curve (AUC) values. SVM achieved an AUC of 0.89 for AMPA receptors and 0.86 for NMDA receptors, demonstrating the effectiveness of fractal-based features in characterizing synaptic maturation. This study offers valuable insights into synaptic development in the LC nucleus and demonstrates the potential of fractal analysis as a tool to understand brain plasticity and early development. Fractal dimensions play a crucial role in characterizing the maturation of glutamatergic synapses, providing a foundation for further research in neural circuitry development.

Automated Laser-Assisted Single-Cell Sorting for Cell Functional and RNA Sequencing.

Accurate and efficient sorting of single target cells is crucial for downstream single-cell analysis, such as RNA sequencing, to uncover cellular heterogeneity and functional characteristics. However, conventional single-cell sorting techniques, such as manual micromanipulation or fluorescence-activated cell sorting, do not match current demands and are limited by low throughput, low sorting efficiency and precision, or limited cell viability. Here, we report an automated, highly efficient single-cell sorter, integrating laser-induced forward transfer (LIFT) with a high-throughput picoliter micropore array. The micropore array was surface-functionalized to manipulate liquid surface tension, facilitating the formation of single-cell picoliter droplets in the micropores to realize automated and highly efficient (>80%) single-cell isolation. Using an in-house built microscopic system, rare target cells were identified and automatically retrieved by LIFT with precise sorting efficiency (about 100%) for downstream single-cell analysis while maintaining high cell viability (about 80%). As a case demonstration, we demonstrated the accurate sorting of rare transfected PC-9 cells and post-transfection cell culture, minimizing cell loss and the risk of contamination. Furthermore, we performed single-cell RNA sequencing and showed that high-quality single-cell transcriptome information was efficiently and reliably obtained during cell sorting, preventing additional costs due to low sorting accuracy. The single-cell sorter will become invaluable for single-cell analysis, laying the foundation for multiomics analysis and precision medicine research.

Social Network Analysis of Self-Management Behavior Among Older Adults With Diabetes.

This study explores the influence of social network structures on self-management behaviors among older adults with diabetes in rural Korean villages, focusing on dietary management, physical activity, and blood glucose monitoring. Employing social network analysis (SNA), the study assessed network structures in three villages, focusing on variations in degree, closeness, and betweenness centralities to understand their impact on health behavior dissemination and adoption. The analysis identified significant differences in network configurations across the villages. Village C, characterized by the highest closeness centrality, facilitated the efficient diffusion of health-related information, thereby promoting the rapid adoption of self-management behaviors. In contrast, Village B exhibited a prominent central node with considerable influence, underscoring its potential as a strategic focal point for targeted health interventions. Social network analysis is useful for identifying influential nodes within community structures to enhance chronic disease management strategies. By tailoring interventions to the unique attributes of a community's network, significant improvements in diabetes self-care efficacy can be achieved. This approach presents a scalable and sustainable framework for community-oriented health interventions. It provides a foundation for further research into the structural and functional dynamics of diabetes self-management networks.

Precise modelling of mitochondrial diseases using optimized mitoBEs.

The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE)binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.

The Role of ROS and Its Sources in Tumorigenesis: Friend or Foe?

Ponicidin has demonstrated effectiveness against HCC by promoting mitochondria apoptosis and generating ROS through the stabilization of the Keap1-PGAM5 complex. However, ROS can exhibit both tumor-promoting and tumor-suppressing activities in cancers, and exhibit different effects depending on its source-mtROS vs non-mtROS. Additionally, since ROS from different sources possesses distinct functions, mitochondria-targeted antioxidants, and non-targeted antioxidants may have entirely different effects on cancer progression. To address this complexity, novel measurement techniques such as MitoSOX, MitoPY1, and siDMA are used to specifically assess mtROS, providing deeper insights into mitochondrial function during treatment. Therefore, distinguishing the sources of ROS and separately detecting and targeting mtROS and non-mtROS can further clarify the anti-tumor mechanisms of ponicidin and provide a foundation for subsequent research.

Enhancing the efficacy of near-infrared photoimmunotherapy through intratumoural delivery of CD44-targeting antibody-photoabsorber conjugates.

Photoimmunotherapy (PIT) is a potent modality for cancer treatment. The conventional PIT regimen involves the systemic delivery of an antibody-photoabsorber conjugate, followed by a 24-h waiting period to ensure adequate localisation on the target cells. Subsequent exposure to near-infrared (NIR) light selectively damages the target cells. We aimed to improve the efficacy of PIT invivo by evaluating the effects of the different routes of conjugate administration on treatment outcomes. Subcutaneous Lewis lung carcinoma tumours were established in mice, targeting cluster of differentiation (CD)44 with an anti-CD44 antibody conjugated to IRDye700DX (IR700). The conjugate was administered via the intravenous or intratumoural route followed by the assessment of antibody binding and therapeutic effects of PIT. Compared to intravenous administration, intratumoural delivery of the CD44-IR700 conjugate significantly increased the number of cells binding to the conjugate by >five-fold. This method, combined with NIR light irradiation, halved tumour growth when compared to intravenous delivery. Reducing the interval between intratumoural injection and NIR light exposure to 30min did not diminish efficacy, thereby demonstrating the feasibility of a 1-h procedure. Intratumoural administration of the antibody-photoabsorber conjugate enhanced the efficacy of PIT invivo. A simplified, 1-h procedure involving conjugate tumour injection followed by irradiation emerged as a potent cancer treatment strategy. This study was supported by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, Japan Science and Technology Agency, and the Osaka Medical Research Foundation for Intractable Diseases.

Application of structural equation modelling (SEM) to evaluate reworks in sustainable buildings

PurposeSustainable buildings are designed to minimise the adverse impacts of buildings on users, occupants, communities and the environment while enhancing client investment, contractors’ productivity and profit margins. However, sustainable buildings often experience significant rework. This research aims to evaluate the complex interrelationships among the causes of rework in sustainable buildings using structural equation modeling (SEM) techniques. By testing the theory and validating a framework addressing the causes of rework in sustainable buildings, the construction sector can make a meaningful contribution towards a sustainable future.Design/methodology/approachThe study developed a questionnaire comprising 24 identified causes of rework in sustainable buildings, derived from an extensive literature review and field observations. The causes were evaluated using a 4-point Likert scale, ranging from less occurrence to very high occurrence. The survey was administered to construction professionals via online platforms and direct hand delivery.FindingsThe identified causes of rework were grouped into four components through exploratory factor analysis (EFA) and subsequently validated using SEM. These components are competency, information, framework and plan. While the measurement model demonstrated robustness, the structural model indicated the need for further refinement. The study provides actionable strategies to mitigate rework, supporting the advancement of sustainable practices within the construction sector.Originality/valueThe findings of this research carry substantial theoretical and practical significance for advancing knowledge and practices in the sustainable buildings market. Theoretically, the study enriches the understanding of rework causes and their interrelationships, providing a foundation for future research. Practically, the results serve as a vital resource for stakeholders in the construction sector and offer actionable insights to enhance decision-making, improve project outcomes and foster sustainable building practices.

Unveiling cell-type-specific microRNA networks through alternative polyadenylation in glioblastoma

BackgroundGlioblastoma multiforme (GBM) is characterized by its cellular complexity, with a microenvironment consisting of diverse cell types, including oligodendrocyte precursor cells (OPCs) and neoplastic CD133 + radial glia-like cells. This study focuses on exploring the distinct cellular transitions in GBM, emphasizing the role of alternative polyadenylation (APA) in modulating microRNA-binding and post-transcriptional regulation.ResultsOur research identified unique APA profiles that signify the transitional phases between neoplastic cells and OPCs, underscoring the importance of APA in cellular identity and transformation in GBM. A significant finding was the disconnection between differential APA events and gene expression alterations, indicating that APA operates as an independent regulatory mechanism. We also highlighted the specific genes in neoplastic cells and OPCs that lose microRNA-binding sites due to APA, which are crucial for maintaining stem cell characteristics and DNA repair, respectively. The constructed networks of microRNA-transcription factor-target genes provide insights into the cellular mechanisms influencing cancer cell survival and therapeutic resistance.ConclusionsThis study elucidates the APA-driven regulatory framework within GBM, spotlighting its influence on cell state transitions and microRNA network dynamics. Our comprehensive analysis using single-cell RNA sequencing data to investigate the microRNA-binding sites altered by APA profiles offers a robust foundation for future research, presenting a novel approach to understanding and potentially targeting the complex molecular interplay in GBM.

Analysis and optimization of threaded shear energy absorbing components of collision resistance hydraulic support columns

Conventional energy-absorbing components have limitations in terms of performance and functionality, including significant variability in reaction forces, inherent instability, and inadequate energy absorption capabilities. This paper presents a threaded shear-type energy-absorbing component designed for anti-impact hydraulic support columns, specifically for ZQL advancing support roadway hydraulic supports. The component operates based on the principle of threaded shear energy absorption. Its key structural parameters—such as thread shape, outer diameter, and pitch—are optimized using single-factor and response surface experimental design methods. Shear simulations are performed to analyze the deformation and force-displacement characteristics across various structural configurations. The impact of different thread parameters on energy absorption performance is evaluated, with quasistatic shear tests and simulations validating the results. The optimized design enhances energy absorption efficiency and provides a foundation for future research on integrating these components into hydraulic support systems to improve overall performance.

A near-complete genome assembly of Cinchona calisaya

Rubiaceae plants are globally widespread and possess significant economic and medicinal value. Such as the globally important crop of coffee, and Cinchona calisaya Wedd., which is rich in alkaloids, is an important medicinal resource for treating malaria. In recent years, several genome resources of Rubiaceae have been reported. However, the comprehensive phylogenetic relationships of Rubiaceae are still unknown. In this study, we present a nearly complete diploid genome assembly of C. calisaya, characterized by a genome size of 869.93 Mb, and contig N50 length of 44.34 Mb. Notably, 99.75% of the sequences have been successfully anchored to 17 chromosomes, with only 12 gaps remaining. BUSCO assessment indicates that 97.40% of complete core genes are present in the assembly. We identified a total of 42,741 protein-coding genes, among which 38,022 (89.00%) have received functional annotation. The high continuity and integrity of the C. calisaya genome provide a robust foundation for functional genomics research, varietal improvement, and the conservation of genomic resources in medicinal plants.

Modeling of magnetic vestibular stimulation experienced during high-field clinical MRI

BackgroundHigh-field magnetic resonance imaging (MRI) is a powerful diagnostic tool but can induce unintended physiological effects, such as nystagmus and dizziness, potentially compromising the comfort and safety of individuals undergoing imaging. These effects likely result from the Lorentz force, which arises from the interaction between the MRI's static magnetic field and electrical currents in the inner ear. Yet, the Lorentz force hypothesis fails to explain observed eye movement patterns in healthy adults fully. This study explores these effects and tests whether the Lorentz force hypothesis adequately explains magnetic vestibular stimulation.MethodsWe developed a mathematical model integrating computational fluid dynamics, fluid-structure interaction solvers, and magnetohydrodynamic equations to simulate the biomechanical response of the cristae ampullares. Using high-resolution micro-CT data of the human membranous labyrinth, we ensured anatomical accuracy. Experimental validation involved measuring horizontal, vertical, and torsional slow-phase eye movements in healthy subjects exposed to varying magnetic field intensities and head positions.ResultsOur model accurately replicates observed nystagmus patterns, predicting slow-phase eye velocities that match experimental data. Results indicate that Lorentz force-induced stimulation of individual cupulae explains variability in eye movements across different magnetic field intensities and head orientations.ConclusionsThis study empirically supports the Lorentz force hypothesis as a valid explanation for magnetic vestibular stimulation, offering new insights into the effects of high-field MRI on the vestibular system. These findings provide a foundation for future research and improved clinical practices.

Summary of the Best Evidence for Non-Pharmacological Management of Sleep Disturbances in Intensive Care Unit Patients.

To retrieve, evaluate and summarise the best evidence for non-pharmacological management of sleep disturbances in ICU patients, and to provide basis for clinical nursing practice. This study was an evidence summary followed by the evidence summary reporting standard of Fudan University Center for Evidence-based Nursing. All evidence on non-pharmacological management of sleep disturbances in ICU patients from both domestic and international databases and relevant websites was systematically searched, including guidelines, expert consensuses, best practice, clinical decision-making, evidence summaries and systematic review. UpToDate, BMJ Best Practice, Joanna Briggs Institute, Scottish Intercollegiate Guidelines Network, National Guideline Clearinghouse, National Institute for Health and Clinical Excellence, Yi Maitong Guidelines Network, Registered Nurses Association of Ontario, Canadian Medical Association: Clinical Practice Guideline, Guidelines International Network, WHO, the Cochrane Library, CINAHL, Embase, PubMed, Web of Science, CNKI, WanFang database, VIP database, SinoMed, The American Psychological Association, European Sleep Research Society, American Academy of Sleep Medicine and National Sleep Foundation were searched from the establishment of the databases to June 1, 2024. A total of 18 pieces of literature were included, involving 4 guidelines, 2 expert consensuses, 1 best practice and 11 systematic reviews. 25 pieces of evidence covering 4 categories of risk factors, sleep monitoring, non-pharmaceutical intervention, education and training were summarised. This study summarises the best evidence for non-pharmacological management of sleep disturbances in ICU patients. In clinical application, medical staff should make professional judgements and fully combine clinical situations and patient preferences to select evidence, laying a theoretical foundation for later empirical research to reduce the incidence of sleep disturbances in ICU patients and improve the sleep quality of critically ill patients. Medical staff can refer to the best evidence to provide reasonable non-pharmacological management plans for sleep disturbances in ICU patients, improving their sleep quality and life satisfaction. The management of sleep disturbances in critically ill patients has not received sufficient attention and standardisation. This study summarises 25 pieces of the best evidence for non-pharmacological management of sleep disturbances in critically ill patients. Accurate and standardised evaluation and monitoring are the foundation of sleep management for ICU patients. This summary of evidence can help ICU nurses enhance their clinical practice. This evidence summary followed the evidence summary reporting specifications of Fudan University Center for Evidence-based Nursing, which were based on the methodological process for the summary of the evidence produced by the Joanna Briggs Institute. This study was based on the evidence summary reporting specifications of the Fudan University Center for the Evidence-based Nursing; the registration number is 'ES20231708'. No Patient or Public Contribution.

Characterisation of pregnancy-induced alterations in apolipoproteins and their associations with maternal metabolic risk factors and offspring birth outcomes: apreconception and longitudinal cohort study.

Apolipoproteins as an integral part of lipoproteins are crucial for the transport and metabolism of lipids. However, there is a lack of longitudinal studies to quantify the concentrations of maternal apolipoproteins from preconception to postpartum and their associations with maternal metabolic health and offspring birth outcomes. Quantification of apolipoproteins was performed on maternal plasma samples (N=243 trios) collected at preconception, 26-28 weeks' pregnancy, and three months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. Linear regression models and network analysis were implemented to investigate the association of apolipoproteins with maternal genetic variants, biochemical measures, metabolic risk factors, and offspring birth outcomes. The concentrations of ApoC-III, ApoB and ApoL1 substantially increased in pregnancy compared to preconception and postpartum. Genome-wide association studies (GWAS) identified multiple single-nucleotide polymorphisms (SNPs) associated with plasma apolipoproteins (P<5.00E-08), including APOE-rs7412 for ApoE, LPA-rs56393506 for Apo(a), APOM-rs707921 for ApoM, ABCC4-rs117797426 for ApoJ, THSD7B-rs575613 for ApoA-II, and LOC102724443-rs140433245 for ApoA-IV. Plasma apolipoproteins were strongly associated with biochemical measures including lipidomic profiles, lipoprotein features and fat-soluble vitamins, as well as metabolic risk factors including glycaemic traits, liver enzymes, inflammatory markers, albumin, and blood pressure. Integrative network analysis of apolipoproteins and their correlates/determinants revealed both shared and specific associations, with the strongest relationships observed among apolipoproteins, cholesterol, triglycerides, alpha tocopherol, and GlycA (Padj<0.05). Higher maternal ApoC-I and ApoC-III concentrations at preconception were significantly associated with shorter gestational age of the offspring. We describe the longitudinal landscape of maternal circulating apolipoproteins from preconception to postpartum and their associations with maternal metabolic risk factors and offspring birth outcomes. This multi-omics characterisation of biochemical correlates and genetic determinants of maternal apolipoproteins will deepen our understanding of the molecular basis of metabolic flexibility in expectant mothers, leading to better assessment of pregnancy-related outcomes. This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. The Singapore Lipidomics Incubator (SLING) is supported by grants from the National University of Singapore via the Life Sciences Institute, the National Research Foundation (NRF, NRFI2015-05 and NRFSBP-P4) and A∗STAR IAF-ICP I1901E0040. Additional funding is provided by Institute for Human Development and Potential (IHDP)-Agency for Science, Technology and Research (A∗STAR), Singapore.

Emerging role of PANoptosis in kidney diseases: molecular mechanisms and therapeutic opportunities.

Kidney diseases represent a significant global public health challenge, characterized by complex pathogenesis, high incidence, low awareness, insufficient early screening, and substantial treatment disparities. Effective therapeutic options remain lacking. Programmed cell death (PCD), including apoptosis, pyroptosis, and necroptosis, play pivotal roles in the pathogenesis of various kidney diseases. In 2019, PANoptosis, a novel form of inflammatory cell death, was introduced, providing new insights into innate immunity and PCD research. Although research on PANoptosis in kidney diseases is still limited, identifying key molecules within PANoptosomes and understanding their regulatory roles is critical for disease prevention and management. This review summarizes the various forms of PCD implicated in kidney diseases, along with PANoptosomes activated by Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), NOD-like receptor family CARD domain containing 12 (NLRP12), and NOD-like receptor family member C5 (NLRC5). It also reviews the advancements in PANoptosis research in the field of kidney diseases, particularly in renal tumors and acute kidney injuries (AKI). The goal is to establish a foundation for future research into the role of PANoptosis in kidney diseases.

Phosphoproteomic analysis of X-ray-irradiated planarians provides novel insights into the DNA damage response.

Phosphorylation plays a crucial role in the cellular response to radiation and cancer therapies, yet phosphoproteomics studies in planarians remain underexplored despite the organism's remarkable regenerative capacities. This study utilized advanced ion mobility mass spectrometry for 4D-label-free quantitative proteomics to identify phosphorylation sites associated with irradiation in planarians. A total of 33,284 phosphorylation sites from 15,505 phosphorylated peptides and 4710 unique phosphoproteins were identified. In the sub-lethal dose irradiation group, 1695 phosphoproteins with 3483 phosphorylation sites exhibited significant changes, while exposure to lethal doses of radiation led to significant changes in 2308 phosphoproteins with 6112 phosphorylation sites, including many kinases, transcription factors, and cytoskeletal proteins. Functional enrichment analysis revealed that the altered phosphoproteins were primarily involved in transcription, RNA biosynthesis, mRNA processing regulation, and spliceosomal complex assembly. Functional validation of five differentially phosphorylated proteins revealed that their depletion impaired stem cell regeneration after irradiation by disrupting DNA repair, suggesting that these proteins are critical to planarian biology and their radiation response. By identifying the phosphorylation state and specific sites of planarian proteins, our study lays the foundation for further research on protein phosphorylation in the radiation-induced DNA damage response. In addition, our findings provide preliminary insights into the role of calnexin, a protein involved in interacting with newly synthesized N-linked glycoproteins, in planarians.