Unhealthy lifestyles are linked to epilepsy, but the underlying mechanisms involving metabolism and brain structure are unclear. This prospective study analyzed 130,530 UK Biobank participants with multimodal data including lifestyle factors, genotyping, metabolomics, and brain MRI. We examined associations between a composite healthy lifestyle score and incident epilepsy using Cox regression, stratified by polygenic risk score (PRS). We derived a metabolic signature using elastic net regression and identified causal metabolites using Mendelian randomization. Mediation analyses and structural equation modeling (SEM) were performed to elucidate the lifestyle-metabolite-brain-epilepsy axis. During 15.87 years of follow-up, a healthy lifestyle was associated with a lower risk of epilepsy (HR, 0.89; 95% CI: 0.84-0.95), even among individuals with high genetic risk. We identified 94 metabolites characterizing a healthy lifestyle, including specific lipid subclasses and inflammatory markers like GlycA. This metabolic signature was strongly associated with reduced epilepsy risk (HR, 0.75; 95% CI: 0.62-0.91) and mediated 20.51% of the protective effect of lifestyle. Furthermore, neuroimaging analysis revealed that a healthy lifestyle correlated with larger volumes in specific brain structures, such as the hippocampus. Specifically, hippocampal volume partially mediated the link between the metabolic signature and epilepsy. SEM revealed that lifestyle influences epilepsy through metabolic and structural brain alterations. A healthy lifestyle is a robust protective factor against epilepsy, even in genetically susceptible individuals. This protection is mechanistically linked to metabolic signature and brain structure, offering novel targets for prevention.
Obesity is a well-known heart failure (HF) risk factor, yet the biological pathways linking adiposity indices to HF remain unclear. This study aimed to identify proteomic mediators for five novel indices-waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHTR), body roundness index (BRI), weight-adjusted waist index (WWI), and translate mechanistic differences into clinical practice. Using UK Biobank data, we applied Cox regression and linear regression to identify proteins associated with both HF and each index, followed by mediation and GO enrichment analyses. All five indices were associated with HF, with WHR and WHTR showing the strongest links. Shared pathways included angiogenesis and cardiac development. Each index occupied a distinct position along a pathological continuum: BRI (cell surface-related) as the upstream driver of early adipose dysfunction; WHR (inflammatory-fibrotic cascade) and WHTR (developmental-metabolic-inflammatory-hormonal) as intermediate downstream markers; WWI (vascular development) and WC (extracellular matrix remodeling) as terminal downstream markers of established organ damage. Each indicator occupies a distinct position in HF progression, offering unique mechanistic insights into its onset, and thus enabling individualized risk assessment and mechanism-based interventions for obese patients.
Cue-reactivity and impaired inhibitory control represent well-established mechanisms contributing to substance use relapse, which, in turn, increases the risk of criminal reoffending in forensic populations whose offending behavior is closely linked to substance use. In Germany, such individuals may be mandated to custodial addiction treatment under Section 64 of the Criminal Code (§ 64 StGB). To date, it remains largely unexplored whether inhibitory control deficits under substance-cue exposure relate more directly to indicators of criminal recidivism risk in forensic addiction populations. The present work addresses this gap by examining the relationship between cue-induced inhibitory control and a validated proxy of reoffending risk. Fifty-one abstinent male forensic patients (24 with alcohol use disorder (AUD), 27 with other substance use disorders (SUD)) undergoing treatment under Section 64 completed two Go/NoGo tasks assessing inhibitory control under alcohol-related and neutral stimulus conditions. Controlling for relevant covariates, inhibitory performance (adjusted d ' ) was used to predict scores on Factor 2 of the Psychopathy Checklist: Screening Version (PCL:SV). Among patients with AUD, weaker inhibitory control in the alcohol-cued condition was strongly associated with higher PCL:SV Factor 2 scores (β = -0.79, p = .004), whereas no such association emerged for the neutral condition or for patients with other SUDs. These findings suggest a context-specific link between cue-elicited inhibitory deficits and criminogenic risk in forensic patients with AUD. Cue-related inhibitory impairments may represent a key cognitive mechanism connecting substance use to criminal (re-)engagement. If replicated longitudinally, such measures may inform future approaches to risk assessment and intervention in forensic addiction treatment.
Understanding how fungal biogeography shapes ecosystem processes is central to predicting biogeochemical responses to environmental change. However, the properties of saprotrophic fungi that link their distribution patterns to belowground carbon cycling remain unclear. Here, we provide a comprehensive assessment linking widespread (high-occurrence) and narrowly distributed (low-occurrence) saprotrophic fungi (saprotrophs) to carbon decomposition processes across a broad latitudinal gradient from tropical to boreal zones. Our results show that the diversity of saprotrophic fungi is shaped by distinct community assembly processes, which in turn generate contrasting geographic patterns across latitudes. Widespread saprotrophs are mainly structured by large-scale climatic and local soil variables (environmental filtering) and show increasing diversity toward higher latitudes, whereas narrow-ranged saprotrophs are primarily constrained by the regional species pool (dispersal filtering), leading to declining diversity with latitude. By integrating large-scale biogeographic data with DNA stable isotope probing experiment, we provide evidence that fungal taxa actively participating in straw decomposition are dominated by widespread saprotrophs, underscoring their essential role in carbon cycling. Our findings highlight occupancy as a key biogeographic attribute regulating fungal contributions to carbon cycling and provide a predictive framework for understanding how belowground biodiversity shapes soil carbon dynamics under global change.
The Random Vector Functional Link (RVFL) network provides an efficient and quick method of training feedforward single hidden neural networks. It solves major disadvantages of classical neural networks, i.e. dealing with slow convergence and overfitting by exploiting fixed random weights and closed-form output computation. DenseNet121 architecture has huge potential in the artificial intelligence field and more specifically in object recognition tasks. The major drawback, however, is its inability to provide insights into its intermediate levels of analysis of classification, which is why this algorithm offers limited flexibility to analyze the training procedure. To resolve this problem, we offer a combined solution by integrating DenseNet121 with RVFL. Within the framework described, deep features are obtained in relation to the input leaf pictures with the pre-trained DenseNet121 model that captures important texture and contour structure. To, firstly, minimize the dimension of these features and, secondly, remove superfluous redundancies, Principal Component Analysis (PCA) is used, and only the most informative components are retained. This smaller feature set is then marked to the RVFL classification, whose responsibility is a final classification. Understanding how the proposed DenseNet121-RVFL approach performs, we have conducted some comparative experiments against several baseline classifiers, such as DenseNet121- Support Vector Machine, DesnseNet121-Twin Support Vector Machine, DenseNet121-Extreme Learning Machine, DenseNet121 and DenseNet 121-Kernel Ridge Regression. The findings of the experiment reveal that the hybrid DenseNet121-RVFL model has the best effect in comparison to the other methods, as it provided the highest accuracy of 94.45, F1-Score is 0.955, Geometeric Mean(G-Mean) of 0.898 and Area Under Curve (AUC) of 0.961 on the test dataset.
Pregnancy represents a critical juncture for intergenerational transmission of stress-related health vulnerabilities when child-bearers' history of maltreatment may precipitate stress responses that adversely impact maternal and fetal outcomes. We aimed to shed light on this path by testing hypotheses that (1) childhood maltreatment would predict oral inflammatory responses to acute stress in late pregnancy, and (2) these inflammatory responses would relate to subsequent obstetric complications. Hypotheses were tested in a community sample of women (n = 158) from a larger longitudinal study. Participants reported a history of maltreatment and completed the Trier Social Stress Test during the third trimester of pregnancy. Five saliva samples collected before and after the task were assayed for pro-inflammatory cytokines (IL1β, IL6, TNFα) and C-reactive protein (CRP) to index oral inflammation. At 3 months postnatal, women reported pregnancy and birth complications, and birth outcomes. Multilevel models of inflammatory response trajectories supported hypothesized paths: Greater childhood maltreatment-especially physical neglect and sexual abuse-predicted higher and/or extended inflammatory stress responses. In turn, higher inflammatory stress responses related to greater pregnancy and birth complications, and extended inflammatory responses related to a greater likelihood of preterm birth. Findings support oral inflammatory response to stress as a potential link to target in intergenerational health risk transmission.
Pediatric-onset multiple sclerosis is associated with high inflammatory activity early in the disease course, yet sensitive biomarkers of early disease pathology are limited. Hyper-reflective foci on optical coherence tomography have been proposed as markers of inflammation in adult multiple sclerosis, but their relevance in pediatric populations remains unclear. We aimed to identify and quantify retinal layer-specific hyper-reflective foci burden in children with pediatric-onset multiple sclerosis and evaluate associations with MRI markers of disease severity. In this cross-sectional study, 53 children with pediatric-onset multiple sclerosis and 36 age- and sex-matched healthy controls underwent spectral-domain optical coherence tomography and MRI, including three-dimensional T1-weighted and fluid-attenuated inversion recovery sequences, near disease onset. Patients with a history of optic neuritis were excluded. Hyper-reflective foci were quantified within the ganglion cell-inner plexiform layer and inner nuclear layer as counts and as a normalized hyper-reflective foci index (count divided by retinal layer volume). Brain MRIs underwent parcellation and multiple sclerosis lesion segmentation. Generalized estimating equation models accounted for inter-eye correlation and adjusted for demographic and retinal structural covariates. Linear regression assessed associations between hyper-reflective foci burden and magnetic resonance imaging measures, including thalamic volume, cortical volume, and white matter lesion volume. Hyper-reflective foci counts and indexes were significantly increased in pediatric-onset multiple sclerosis compared with controls across both retinal layers. Higher ganglion cell-inner plexiform layer hyper-reflective foci index correlated with greater white matter lesion volume (r = 0.38, P = 0.006) and lower thalamic volume (r = -0.35, P = 0.012), but not cortical volume. In adjusted models, multiple sclerosis was independently associated with higher ganglion cell-inner plexiform and inner nuclear layer hyper-reflective foci counts and indexes (both P < 0.001). Inner nuclear layer hyper-reflective foci were negatively associated with macular retinal nerve fiber layer thickness and volume (β = -0.18, P < 0.01; β = -0.006, P < 0.01). Higher ganglion cell-inner plexiform layer hyper-reflective foci index remained associated with lower thalamic volume (β = -0.321, P = 0.024), greater lesion volume (β = 5.253, P = 0.011), and lower cortical volume (β = -6.403, P = 0.016). Children with multiple sclerosis demonstrate increased retinal hyper-reflective foci burden early in disease, in the absence of optic neuritis. The observed relationships between ganglion cell-inner plexiform layer hyper-reflective foci burden, thalamic and cortical atrophy, and white matter lesion volume suggest that hyper-reflective foci capture aspects of both inflammatory and neurodegenerative disease activity. Hyper-reflective foci represent a promising non-invasive biomarker of disease severity in pediatric-onset multiple sclerosis.
Chronic suppurative otitis media (CSOM) with cholesteatoma is a potentially dangerous condition that can lead to extracranial and intracranial complications. Bacteria associated with CSOM cholesteatoma frequently produce biofilms, which contribute to antibiotic resistance and accelerate disease progression. This cross-sectional study was conducted at the tertiary teaching hospital of Hasanuddin University, its affiliated hospitals, and the Hasanuddin University Medical Research Center (HUM-RC) between March 2024 and April 2025. Patients diagnosed with CSOM cholesteatoma who underwent mastoidectomy were enrolled. Bacterial isolates obtained from cholesteatoma tissue were evaluated for biofilm formation using crystal violet staining. Data were analyzed using SPSS software. A total of 49 patients were included: 46.9% male and 53.1% female; age range 9-66 years. Of the bacterial isolates, 40 demonstrated biofilm formation. Pseudomonas aeruginosa was the most frequently identified species (42.5%), followed by 12 other species, all of which exhibited weak to moderate biofilm production. Based on the Telmesani grading system, 47% of patients presented with severe disease. However, the limited sample size restricted the ability to establish a statistically significant correlation between biofilm presence and clinical severity. Biofilm formation was detected in the majority of bacterial isolates, with Pseudomonas aeruginosa emerging as the predominant species. Although nearly half of the patients presented with severe disease, most isolates demonstrated only weak to moderate biofilm production. The limited sample size restricted the ability to establish a statistically significant correlation between biofilm presence and clinical severity. Nevertheless, these findings highlight the importance of biofilm in the pathogenesis of CSOM and underscore the need for larger multicenter studies to clarify its role and inform the development of biofilm-targeted therapeutic strategies. Kolesteatomla ilişkili kronik süpüratif otitis media (KSOM), ekstrakraniyal ve intrakraniyal komplikasyonlara yol açabilen, potansiyel olarak tehlikeli bir hastalıktır. KSOM kolesteatomu ile ilişkili bakteriler sıklıkla biyofilm oluşturur; bu durum antibiyotik direncine katkıda bulunur ve hastalığın ilerlemesini hızlandırır. Bu kesitsel çalışma, Mart 2024 ile Nisan 2025 tarihleri arasında Hasanuddin Üniversitesi Tıp Fakültesi üçüncü basamak eğitim hastanesi, bağlı hastaneleri ve Hasanuddin Üniversitesi Tıbbi Araştırma Merkezi’nde gerçekleştirildi. Mastoidektomi uygulanan ve kolesteatomlu KSOM tanısı alan hastalar çalışmaya dahil edildi. Kolesteatom dokusundan elde edilen bakteriyel izolatlar, kristal viyole boyama yöntemi kullanılarak biyofilm oluşturma açısından değerlendirildi. Veriler SPSS yazılımı kullanılarak analiz edildi. Çalışmaya toplam 49 hasta dahil edildi; bunların %46,9’u erkek, %53,1’i kadındı ve yaşları 9 ile 66 arasında değişmekteydi. Elde edilen bakteriyel izolatların 40’ında biyofilm oluşumu saptandı. En sık izole edilen bakteri Pseudomonas aeruginosa (%42,5) olup, bunu toplam 12 farklı bakteri türü izledi. Bu türlerin tamamı zayıf ile orta düzey arasında biyofilm üretimi gösterdi. Telmesani evreleme sistemine göre hastaların %47’sinde hastalık şiddetli olarak değerlendirildi. Ancak örneklem büyüklüğünün sınırlı olması nedeniyle biyofilm varlığı ile klinik hastalık şiddeti arasında istatistiksel olarak anlamlı bir ilişki gösterilemedi. Bakteriyel izolatların büyük çoğunluğunda biyofilm oluşumu saptanmış olup en baskın tür Pseudomonas aeruginosa olarak belirlenmiştir. Hastaların yaklaşık yarısında hastalık şiddetli seyretmesine rağmen, izolatların çoğu yalnızca zayıf veya orta düzeyde biyofilm üretimi göstermiştir. Örneklem büyüklüğünün sınırlı olması, biyofilm varlığı ile klinik hastalık şiddeti arasında istatistiksel olarak anlamlı bir ilişkinin ortaya konulmasını engellemiştir. Bununla birlikte, elde edilen bulgular biyofilmin KSOM patogenezindeki önemini vurgulamakta ve biyofilme yönelik tedavi stratejilerinin geliştirilmesine katkı sağlayacak daha geniş örneklemli, çok merkezli çalışmalara ihtiyaç olduğunu göstermektedir.
[This retracts the article DOI: 10.1155/2022/9450393.].
Ionising radiation (IR) is a recognised risk factor for cardiovascular disease (CVD), yet the mechanisms linking it to exposure remain incompletely understood. We show that IR drives a pro-atherogenic phenotype in human coronary artery endothelial cells (HCAECs) through the induction of cellular senescence, and that rapamycin attenuates these effects. IR triggered hallmark senescence features, including elevated senescence-associated-β-galactosidase activity, nuclear enlargement, and increased Cyclin dependent kinase inhibitor 1 A and p53 expression. Functionally, irradiated HCAECs displayed impaired barrier integrity and heightened monocyte adhesion. Transcriptomic and proteomic profiling revealed broad IR-induced alterations enriched in DNA damage response, cell-cycle arrest, senescence, proteostasis, and immune-related pathways. These findings establish a mechanistic link between radiation-induced endothelial senescence and early atherogenic-associated dysfunction, demonstrating that senescence is a driver of pro-atherogenic phenotypes in HCAECs in vitro. Importantly, mTOR inhibition is identified as a promising strategy to counteract radiation-associated endothelial dysfunction. This work positions senescence as a tractable therapeutic target in radiation-induced vascular injury.
Mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease (AD), shows pronounced clinical heterogeneity poorly explained by pathology burden, representing a gap complicating prognosis. As the brain operates as a complex network for information integration, we hypothesized that connectome architecture mediates the link between AD pathology and clinical expression. We developed a framework integrating structural and functional connectomes from multi-center cohorts, performing connectome-based subtyping in MCI, with analyses of upstream pathology, downstream phenotypes, and transcriptomic associations. This approach identified an "MCI-compromised" (MCI-C) subgroup characterized by extensive structural-functional connectomic disruption and an "MCI-preserved" (MCI-P) subgroup with relatively preserved connectome integrity. Despite comparable pathology, MCI-C demonstrated more severe neurodegeneration, accelerated cognitive decline, and elevated progression risk. Multiscale analyses linked these patterns to transcriptomic profiles of mitochondrial, synaptic, and neuroimmune processes. These findings demonstrate that the connectome acts as a critical mediator, rather than a passive endophenotype, shaping AD clinical expression.
Sepsis-associated acute kidney injury (SA-AKI) commonly affects critically ill patients, but its early detection remains difficult. Biomarkers that facilitate early detection of patients susceptible to SA-AKI remain essential. This investigation seeks to evaluate the independent association between early serum S100A8/A9 levels and SA-AKI, considering 28-day all-cause mortality as a secondary endpoint. This single-center observational cohort investigation employed a hybrid (ambidirectional) design, enrolling 211 adult sepsis patients per the Sepsis-3 criteria. Among them, 118 developed SA-AKI within 7 days, while 93 did not. Serum S100A8/A9 levels were assessed within 2 h of intensive care unit (ICU) admission and again on days 1, 3, and 7. Demographic, clinical, and laboratory data were gathered. Multivariable logistic regression and restricted cubic spline analyses assessed the independent relationship between S100A8/A9 at ICU admission and SA-AKI, and receiver operating characteristic curves evaluated its discriminatory ability. Generalized estimating equations were utilized to compare longitudinal S100A8/A9 changes between groups, while Cox proportional hazards models evaluated the connection between S100A8/A9 and 28-day all-cause mortality. Serum S100A8/A9 levels within 2 h of ICU admission demonstrated significant elevation in patients developing SA-AKI versus those without AKI [3981.9 (3355.5, 5007.9) pg/mL vs. 3411.8 (2781.5, 3922.5) pg/mL; P < 0.001] and remained elevated on days 1, 3, and 7, despite an overall decline. Generalized estimating equation analysis revealed significant time and group effects (both P < 0.001). At ICU admission, S100A8/A9 was independently associated with SA-AKI (adjusted OR 1.13 per 100 pg/mL; 95% CI 1.08-1.19; P < 0.001), with restricted cubic spline analysis indicating an approximately linear relationship. The area under the curve of S100A8/A9 at ICU admission for identifying SA-AKI was 0.721 (95% CI 0.653-0.788), with optimal threshold at 3732.1 pg/mL (sensitivity 61.9%, specificity 68.8%). The combined model (SOFA + S100A8/A9) demonstrated enhanced discrimination relative to SOFA alone (area under the curve 0.861 vs. 0.771; DeLong P = 0.0001). In Cox models, S100A8/A9 showed no independent link to 28-day all-cause mortality. Elevated serum S100A8/A9 levels were independently associated with SA-AKI, but no independent link to 28-day all-cause mortality was observed.
Following ischemic stroke (IS), endogenous protective mechanisms are activated to mitigate brain injury. Adenosine (ADO), a key endogenous immunomodulator, is implicated in this response, yet the precise regulatory pathways linking upstream ischemic injury to ADO-mediated protection remain incompletely elucidated. We integrated single-cell RNA sequencing (scRNA-seq) data (GSE174574) and bulk RNA-seq data (GSE140275) from IS models. After preprocessing and t-SNE-based clustering, we conducted analyses of cell communication and differential expression. Differentially expressed genes were intersected with ADO metabolism-related genes from the GeneCards database to identify candidate regulators. The roles of these candidates in modulating ADO metabolism, oxidative stress, and apoptosis were functionally validated in vitro using qRT-PCR, Western blot, ELISA, and gene silencing in BV2 cells. Unsupervised clustering of scRNA-seq data identified 14 cell types, with microglia displaying extensive intercellular communication, particularly via the CCL and TNF signaling pathways. Cross-database analysis identified four candidate molecules: HMBS, UCP2, POR, and TNF. These were positively correlated with pro-ADO metabolic genes in middle cerebral artery occlusion (MCAO) models and were upregulated in LPS-stimulated BV2 cells, coinciding with increased inflammation, oxidative stress, and ADO levels. Silencing HMBS or POR reversed these effects. Exogenous ADO reduced oxidative stress and apoptosis in BV2 cells and promoted M2 microglia polarization. Our findings suggest that ischemic injury upregulates specific molecules (HMBS, UCP2, POR, and TNF) potentially associated with ADO metabolism, which may, in turn, alleviate oxidative stress and apoptosis while favoring anti-inflammatory microglial polarization. This supports the hypothesis that enhanced adenosine metabolism represents a potential endogenous protective mechanism activated in response to upstream ischemic insult. HMBS or POR silencing upregulated adenosine deaminase/adenosine kinase (ADA/ADK) and downregulated SLC29A1/A2 in LPS-stimulated BV2 cells. The protective effects of ADO were abolished by A2aR antagonist SCH 58261, confirming the functional link between HMBS/POR and ADO-mediated neuroprotection.
Lipid storage myopathy (LSM) is characterized by abnormal lipid accumulation in skeletal muscle. Emerging evidence suggests that environmental factors, including the use of antidepressants such as sertraline, may trigger LSM. Given the established link between hyperhomocysteinemia (HHcy) and disrupted lipid metabolism, we investigated its potential role in skeletal muscle lipid deposition. We enrolled six patients with HHcy undergoing muscle biopsy and explored their clinical and pathological characteristics of skeletal muscle. The mechanistic link was explored in muscle tissues from patients through transcriptomic profiling, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzymatic assays, and validated in C2C12 myotubes. Four of the six patients presented with clinical myopathic manifestations, including progressive muscle weakness and exercise intolerance, which resolved completely after B-vitamin supplementation, while abnormal skeletal muscle lipid deposition was observed in all six patients. Transcriptome and qRT-PCR analyses demonstrated a significant upregulation of the acetyl-CoA carboxylase β (ACACB) gene (p < 0.001), which encodes acetyl-CoA carboxylase 2 (ACC2), in the muscle tissues from patients. Furthermore, ACC2 protein expression was markedly elevated (p < 0.01), thereby raising cellular malonyl-CoA levels (p < 0.01). This metabolite potently inhibits carnitine palmitoyltransferase 1 (CPT1), impairing fatty acid oxidative metabolism in skeletal muscle. The key molecular cascade involving ACACB upregulation and subsequent CPT1 inhibition (p < 0.05), was further verified in C2C12 myotubes. This study indicates that HHcy is closely associated with abnormal skeletal muscle lipid deposition. HHcy may correlate with increased ACC2 expression, which elevates malonyl-CoA levels. This, in turn, suppresses CPT1 activity and facilitates abnormal lipid accumulation in skeletal muscle.
The origin of superconductivity in oxide interfaces and its relation to ferroelectricity remains an open question. At LaAlO3/SrTiO3 interfaces, quantum confinement and inversion symmetry breaking create a two-dimensional electron gas near a ferroelectric quantum critical point, yet direct evidence linking phonon dynamics to electron pairing has been lacking. Here we directly probe lattice vibrations and atomic structure at LaAlO3/SrTiO3 interfaces across the superconducting phase diagram using vibrational spectroscopy with momentum selectivity in a scanning transmission electron microscope. We find that superconductivity across the doping series correlates with inversion symmetry breaking and the appearance of high-frequency localized phonons. These tunable, polar vibrations-confined near the interface-exhibit strong electron-phonon coupling and evolve systematically with carrier density. Our findings establish a link between lattice instability, superconductivity and strong electron-phonon coupling mediated by tunable localized phonons, providing new insights into possible microscopic pairing pathways in quantum paraelectric systems.
The electrical power systems are facing rising challenges of stability and control with increasing share of intermittent renewable energy power sources. This work presents application of Twin-Delayed Deep Deterministic Policy Gradient (TD3) algorithm in single unified controller for multi-objective control of DFIG-Solar PV system connected to power grid. The commonly used Proportional-Integral (PI) controllers are not suitable to address nonlinearities of single controller based hybrid DFIG and solar PV systems. At times, the latest reinforcement learning-based controllers like DDPG can be erratic and aggressive due to overestimation of the actor's control action. These aggressive actions, which cause overshoot and oscillation, can be overcome by adopting the TD3 algorithm. The TD3 algorithm provides improved learning capabilities and performance by mitigating overestimation by using dual critic networks. A single TD3-based controller is implemented to simultaneously control the Rotor Side Converter (RSC), Grid Side Converter (GSC) and solar PV system integrated at the DC link. OPAL-RT real-time hardware-in-the-loop (HIL) simulation results demonstrate that the TD3 controller achieves a 10.3% reduction in power overshoot, 8% improvement in DC link voltage regulation, 15.3% faster response time, and 16.9% faster settling time compared to conventional PI control, and also outperforms the DDPG-based controller across all metrics.
The growing penetration of electric vehicles (EVs) necessitates the design of high-reliability, high power quality and efficient charging systems that can control regulated DC power extracted from an AC utility source. Conventional power factor correction (PFC) converters usually have serious limitations in terms of voltage regulation, harmonic distortion and switching losses. This paper presents a high-efficiency hybrid boost-buck power factor correction converter for electric vehicle (EV) charger applications to tackle these problems. The proposed topology consists of the cascaded boost and buck conversion stages with resonant soft-switching elements and a high-frequency transformer to achieve both step-up/step-down voltage regulation that can be used in applications where high efficiency and improved power quality need to be maintained. An accurate control over the DC-link voltage regulation and the input current shaping is achieved by implementing a dual-loop control strategy with an outer voltage regulation loop and an inner current control loop utilizing proportional-integral (PI) controllers. The converter switches at 15 kHz with an input supply of 190 V AC and generates a regulated output voltage of 270 V DC for EV battery charging. MATLAB/Simulink simulations to validate the maximum performance of the proposed converter were performed and finally, which were validated by a laboratory prototype. The experimental results show a power factor of 0.998, a total harmonic distortion (THD) of about 2.1% for the input current, and peak efficiency close to 97%. The results validate the capability of the enhanced hybrid boost-buck PFC converter in achieving high efficiency, reduced harmonic distortion and maintaining tight voltage regulation compared to previously reported PFC topologies, which makes it attractive for modern EV charging systems.
Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with diverse prognosis. The underlying mechanisms remain unknown, resulting in limited risk stratification and therapeutic strategies. This study aimed to elucidate molecular subtypes of HCM through integrated proteogenomic analysis and explore subtype-specific therapeutic strategies. We conducted an integrated proteogenomic analysis of 132 patients with HCM using myocardial samples, incorporating whole-exome sequencing, RNA sequencing, and proteomics. Unsupervised clustering was used to identify HCM subtypes, which were validated in heart tissues and human induced pluripotent stem cell-derived cardiomyocytes from 2 independent HCM subsets. Subtype-specific signatures and pathways were explored, and their causal link with HCM pathogenesis was established by genetic evidence. A subtype-specific drug was screened using in silico drug prediction, followed by in vitro and in vivo therapeutic effect assessments. Integrated multi-omics analysis identified 2 proteome-based molecular subtypes, severe and mild. We identified 550 subtype-signature proteins, and enrichment analysis based on which revealed that the reduction in fatty acid metabolism and oxidative phosphorylation pathways in HCM versus healthy controls was predominantly driven by the severe subtype, with more severe clinical characteristics and poorer prognosis compared with the mild subtype. Validation in independent cohorts confirmed the robustness of the proteomic subtypes and their association with clinical severity. Additionally, key proteins in fatty acid oxidation and oxidative phosphorylation exhibited consistent expression differences among healthy controls and 2 HCM subtypes. Furthermore, genetic evidence established a causal link between reduced fatty acid oxidation and HCM pathogenesis. Baicalin, identified as a fatty acid oxidation facilitator, improved metabolic and hypertrophic phenotypes in severe subtype human induced pluripotent stem cell-derived cardiomyocytes and Myh6R404Q/+ mice. Our analysis demonstrates the metabolic heterogeneity of HCM and enables the development of risk stratification and subtype-specific therapeutic strategies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03076580.
Interstitial lung disease (ILD) comprises diverse chronic inflammatory and fibrotic disorders with poorly understood mechanisms and limited diagnostic biomarkers. Growing evidence implicates lipid metabolic reprogramming in ILD pathogenesis, yet integrated metabolomic-transcriptomic analyses remain scarce. We performed combined metabolomic and transcriptomic analysis using publicly available datasets. Plasma metabolite profiles of ILD and lobar pneumonia (LOB) patients were analyzed by NMR-based metabolomics. Multivariate analyses (PCA, PLS-DA, OPLS-DA) identified discriminatory metabolites. KEGG enrichment revealed associated pathways. Transcriptomic data from lung tissue were analyzed for differentially expressed genes, identifying 345 differentially expressed genes (|log2FC| > 0.585, adjusted p < 0.05), integrated with metabolomic data to identify shared pathways. ROC curves evaluated diagnostic performance of key metabolites. To validate the bioinformatic findings, we established a bleomycin (BLM)-induced ILD mouse model with or without high-cholesterol diet (HCD) intervention. RT-qPCR, Western blotting, H&E staining, and Masson's trichrome staining were performed to assess gene expression and histopathological changes in lung tissue. Metabolomic profiling showed clear separation between ILD and LOB samples, driven by alterations in triglyceride-rich lipoproteins, phospholipids, and cholesterol fractions. Seven metabolites were significantly increased in ILD (p < 0.05). Integrated multi-omics identified "lipid and atherosclerosis" as a key shared pathway, encompassing six differential genes (CD36, NFKBIA, PIK3R1, SELP, CCL2, VCAM1) and one differential metabolite (Cholesterol [HDL4]). ROC analysis showed a combined metabolite model achieved AUC of 0.810. Experimental validation confirmed SELP, CCL2, and VCAM1 were upregulated while NFKBIA was downregulated in BLM-treated mice. HCD further aggravated BLM-induced pulmonary fibrosis and markedly elevated the expression of inflammatory cytokines (TNF-α, IL-6, IL-1β) as well as key pathway proteins (SELP, CCL2, VCAM1). This integrated multi-omics analysis reveals a strong link between lipid dysregulation and ILD pathogenesis. Cholesterol fractions, triglycerides, and phospholipids may serve as potential non-invasive biomarkers for ILD, while the lipid and atherosclerosis pathway represents a promising target for therapeutic intervention. Animal experiments further validated that HCD exacerbates ILD via the lipid and atherosclerosis pathway, reinforcing the clinical relevance of cholesterol dysregulation in ILD progression. Our findings provide new insights into the metabolic mechanisms of ILD and establish a foundation for future diagnostic and therapeutic development.
Plants are constantly challenged by environmental stressors, yet their sessile nature demands highly flexible developmental programs to maintain growth and survival. With the advent of single-cell technologies, developmental plasticity can now be dissected at cellular resolution. Two recent Populus studies show that both mechanical and drought stress induce xylem remodeling by shifting cell-type ratios or altering differentiation speed, while preserving the underlying developmental lineages. Highly similar patterns have been recently observed in Arabidopsis and cabbage, in which osmotic and salt stress alter the tempo of root hair differentiation without changing lineage identity. The recurrence of this developmental program across woody and herbaceous species, spanning distinct taxonomic orders, suggests that lineage-stable yet flexible stress responses are evolutionarily conserved in plants. Moreover, these insights were enabled by the application of advanced single-cell and spatially resolved approaches, with several of these studies incorporating single-cell/nucleus transcriptomics with spatial multi-omics analyses to link developmental dynamics with tissue context. This balance between flexibility and developmental order may represent a fundamental principle by which plants maintain resilience under diverse environmental challenges and may offer a valid framework for this field of study. 植物在生長過程中持續面臨各種環境逆境挑戰；然而，由於其固著性的生長特性，植物必須仰賴高度可塑性的發育調控，以維持生存與適應環境變化。隨著單細胞技術的快速發展，植物發育可塑性如今已能在單細胞層級被深入解析。近期兩篇以楊樹為研究對象的研究顯示，機械應力與乾旱逆境皆可透過改變細胞類型比例，或調節細胞分化速度，誘導木質部發育重塑；然而，這些變化仍維持既有的發育譜系結構。類似現象近期亦在阿拉伯芥與不結球白菜中被觀察到，分別顯示滲透壓與鹽逆境可改變根毛分化的發育節奏，但不改變其原有細胞譜系。此類現象同時出現在木本與草本植物中，且橫跨不同演化類群，顯示「維持細胞譜系穩定、同時保有發育可塑性」的逆境反應模式，為植物適應環境變化時的一種演化保守策略。此觀點的建立亦有賴於先進單細胞與空間解析技術的應用；透過結合單細胞/細胞核及空間轉錄體學，或是應用質譜多體學於獲取空間分子資訊，得以將發育動態與組織空間脈絡相互連結，進一步理解植物如何在逆境下維持發育進程與生長韌性。.