Search Results (226)

C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe complement-mediated kidney diseases. In a substantial proportion of these patients, C3 nephritic factors (C3NeFs) are detected; these autoantibodies stabilize the complement alternative pathway (AP) C3 convertase. Previous studies have investigated and distinguished properdin-dependent and properdin-independent C3NeFs. In this study, we investigated a distinct subset of C3NeFs that are exclusively active in the absence of properdin: properdin-inhibited C3NeFs. A two-step hemolytic AP convertase activity assay was employed to examine convertase activity in patient serum in the presence versus absence of properdin using the properdin inhibitor Salp20. In 7/16 patients and 1/23 healthy controls, who showed no convertase stabilization in full serum, convertase stabilization was observed upon properdin inhibition, indicating properdin-inhibited C3NeF activity. Consistent findings were obtained when purified patient Igs were added to properdin-depleted serum. Moreover, in an ELISA-based C3bBb binding assay, 6/7 patients with properdin-inhibited C3NeFs showed increased convertase binding, which decreased upon addition of properdin. Complement levels in patients with properdin-inhibited C3NeFs were not significantly different from those in the C3NeF-negative group, and properdin levels were generally within the refence range. In conclusion, our results support the existence of properdin-inhibited C3NeFs, thereby further expanding the functional heterogeneity of these autoantibodies. Although their functional relevance under physiological conditions remains unclear, these findings may have important implications for complement-targeted therapies, particularly strategies aimed at properdin inhibition, as the presence of these C3NeFs may predispose to unintended effects. Full article

Multiple sclerosis (MS) is a chronic central nervous system disease with heterogeneous symptoms, including gait disturbances and motor fatigue, affecting daily functioning and quality of life. Episodic assessments may miss within-day functional fluctuations, whereas home-like monitoring may characterize them. This technical proof-of-concept case study quantified gait parameters (velocity, step length, and variability) during natural walking, explored temporal changes in gait and activity as potentially fatigue-relevant motor-performance patterns, and examined the feasibility of deriving candidate digital measures in MS. Three individuals with MS (one EDSS 1; two EDSS 3) were monitored in an instrumented apartment for 6.5–9.0 h using three LiDAR sensors. Gait parameters, region transitions, activity patterns, EDSS, FSMC, VAS-F, and available data-yield indicators were summarized descriptively. Compared with published healthy-adult references, P01 and P03 showed lower walking velocity, and P03 showed reduced step length. P01 maintained stable gait, P02 increased afternoon walking velocity, and P03 showed an afternoon velocity decline and a smaller step length decrease. The behavioral profiles described different spatial activity patterns, and the activity levels remained low during monitoring. LiDAR-based monitoring may provide a privacy-preserving approach to capture gait and activity variations as candidate variables for future validation without establishing fatigue specificity, clinical validity, or diagnostic thresholds. Full article

Biosensing performance in graphene-derived field-effect transistors (BioFETs) is widely attributed to surface chemistry, yet the role of the underlying charge transport mechanism remains poorly understood. This work establishes a direct correlation between disorder-driven transport and biosensing transduction in vertical graphene (VG) and nanocrystalline graphite (NCG) FET devices. Temperature-dependent electrical characterization (15–500 K) reveals a hybrid transport regime: three-dimensional Mott variable-range hopping below 240 K, transitioning to thermally activated Arrhenius-type conduction above 240 K. The extracted VRH parameters characteristic temperature T₀, localization length ξ, and density of states N(E_F) quantify fundamentally distinct disorder landscapes: VG operates in a strongly localized, edge-dominated regime, while NCG forms a continuous percolative network with greater transport stability. Surface functionalization via PASE and amine-terminated ssDNA probes, followed by DNA hybridization across four nucleobase systems, demonstrates that the sequence-dependent electrical response is mechanistically interpretable within the VRH–transconductance framework. NCG transduces biomolecular binding through direct charge transfer and hopping pathway perturbation, whereas VG responds through interfacial electrostatic reorganization. These results introduce a unified VRH–transconductance–sensing framework, providing a rational physical basis for next-generation graphene BioFET design. Full article

Environmental disasters demand structured monitoring systems capable of linking ecological responses to adaptive governance. This study proposes an integrated indicator framework designed to support ecosystem preservation and environmental risk mitigation following large-scale contamination events. The proposed framework combines multi-source environmental data, intrinsic risk classification, multivariate statistical validation, and a dashboard-based decision-support architecture. When the model was applied to Restinga ecosystems impacted by mining tailings deposition, the results revealed significant spatial heterogeneity between the monitoring stations, with ~33% of sites classified under high or critical ecological risk during at least one monitoring period. Of the metals evaluated, 46.15% were above the reference levels, while for biological response indicators such as primary productivity, a 23.53% reduction in danger alerts was observed in 2019 across the evaluated sites when comparing the rainy and dry seasons. The composite “Danger Alert” indicator was triggered in all sampling campaigns during the evaluated period, demonstrating persistent ecological pressure throughout seasonal cycles. Sensitivity analyses confirmed the robustness of the risk classifications under alternative baseline and aggregation scenarios, and an uncertainty assessment indicated stable trends across temporal variability ranges. The proposed framework enhances the interpretability of complex environmental datasets by structuring inferential ecological associations between environmental pressures and biological responses, which can then be translated into actionable governance outputs. Beyond the case study, the architecture is structurally transferable to other ecosystems, provided that ecological indicators and thresholds are contextually recalibrated. The proposed approach contributes to sustainability-oriented environmental governance by integrating statistical validation, adaptive risk thresholds, and decision-support visualization within a unified monitoring system. Full article

Background/Objectives: African Swine Fever (ASF) represents one of the most serious threats to animal health and global food security. The causative agent of ASF is the African swine fever virus (ASFV), a DNA virus belonging to the Asfarviridae family. Here, we describe ex vivo results for an original anti-ASFV vaccine approach based on the cellular immune response induced by extracellular vesicles (EVs) engineered to express four ASFV proteins. EV engineering was achieved by expressing a DNA vector encoding a biologically inactive HIV-1 Nef protein (Nef^mut), which exhibits unusually high efficiency of incorporation into EVs, even when fused to foreign proteins. Previous studies have demonstrated that intramuscular injection of Nef^mut-based vectors leads to the engineering of Evs, spontaneously released by muscle cells, and induction of antigen-specific CD8⁺ T cell immunity. Methods: We designed DNA vectors expressing the fusion products between Nef^mut and each of the four ASFV structural proteins p30, p54, pp62, and p72. Engineered EVs were molecularly characterized by Western blot and nanotrack analysis, and their potential immunogenicity was assessed by priming and cross-presentation assays. Results: We assessed that the four fusion proteins were successfully expressed in transfected mammalian cells, with the release of valuable amounts of engineered EVs. When immature swine dendritic cells were challenged with the engineered EVs and then co-cultivated with autologous peripheral blood lymphocytes in priming assays, lymphocyte subpopulations specifically reacting against each ASFV antigen were elicited, as detected by an IFN-γ ELISpot assay. In addition, we provide evidence that the Nef^mut-based fusion products incorporated into the engineered EVs can be cross-presented by professional antigen-presenting cells, leading to cross-priming of autologous lymphocytes. Conclusions: These results represent the best premise to go forward with experiments examining immunogenicity and antiviral efficiency in pigs. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1), driven by high mutation and recombination rates, poses significant challenges for diagnostics, therapy, and vaccine development. While variable regions enable immune escape, hyperconserved regions are critical for viral function and represent promising targets for novel therapeutic interventions. This study aimed to develop and validate a bioinformatic algorithm for quantitative assessment of sequence conservation and automated identification of functionally significant conserved regions across all major HIV-1 proteins. A total of 1119 full-length HIV-1 genome sequences representing major subtypes (A1, A2, A6, B, C, D, F1, F2, G, H, J, K) were analyzed. Normalized Shannon entropy (S-index) was calculated for each alignment column. Statistical thresholds for conserved regions were established using 95% confidence intervals derived from bootstrap resampling. Two complementary algorithms, clustering and local maxima detection, were applied to identify conserved regions, which were subsequently mapped to known functional domains based on literature data. Protein conservation varied markedly, with S_m values ranging from 0.784 (Vpu) to 0.920 (Pol). Gag, Pol, and Vpr demonstrated the highest overall conservation, while Env, Rev, Tat, and Vpu exhibited pronounced variability interspersed with conserved domains. In total, 25 conserved regions in Gag, 49 in Pol, 28 in Env, and 6–4 regions in accessory proteins (Vif, Vpr, Rev, Tat, Nef, Vpu) were identified. These regions corresponded to critical functional elements including enzyme catalytic centers, zinc fingers, receptor-binding sites, protein interaction interfaces, and membrane-anchoring domains. The developed computational framework enables statistically grounded identification of evolutionarily constrained regions across analyzed HIV-1 subtypes. The identified conserved regions represent candidate sites for further investigation and may inform downstream studies focused on antiviral target prioritization, immunogen design, and diagnostic assay development. However, their translational applicability requires additional analytical, structural, and experimental validation. Full article

Monitoring center-of-mass is crucial for assessing postural control, but field measurements are often impractical or cost-prohibitive. This study investigates the feasibility of predicting center-of-mass kinematics from the motion of an unstable base—the Sensopro Luna—using deep learning, eliminating the need for wearable sensors. We conducted a cross-sectional study in which 64 participants were recorded performing three coordination exercises (Single-Leg Stance, Stepping, and Waves). Marker-based motion capture and auxiliary inertial sensors were used to record reference and tape kinematics. The model inputs consisted of IMU- and motion-capture-derived tape segment orientations, IMU accelerations and angular velocities, and algorithmic estimates of the lowest tape positions. Nine axis-specific exercise models were developed using a hybrid Encoder–LSTM–Decoder architecture and compared against linear regression baselines. Our results indicate that the deep learning models successfully predicted horizontal center-of-mass displacements (DNN Mean Absolute Errors of 16.1–23.7 mm for X-axis and 4.4–31.3 mm for Y-axis) and exhibited descriptively lower errors than linear models in mean absolute error and signal morphology. However, vertical predictions were less reliable, likely due to the physical constraints inherent to the kinematics of the unstable base. Error analysis revealed that prediction accuracy was highest within common postural ranges, but decreased for extreme displacements. These findings provide a proof-of-concept for wearable-free postural monitoring, particularly for movement along the mediolateral and sagittal axes. Such a system could facilitate automated, cost-effective postural feedback and performance tracking in rehabilitation and fitness environments, supporting autonomous coordination training without the practical constraints of traditional measurement systems. Full article

Endogenous safety and security (ESS), which advocates for designing systems that are inherently safe and secure by nature, has emerged as a pivotal paradigm for addressing the inherent vulnerabilities of information systems. The Dynamic Heterogeneous Redundancy (DHR) architecture serves as its typical implementation by introducing dynamic, heterogeneous, redundant executors with equivalent function (EF) into the information system. However, the functional equivalence property explicitly connects the system’s output to that of the individual executors, thereby creating potential security risks that adversaries could exploit. In addition, EF-DHR faces an inherent contradiction between functional equivalence and heterogeneous implementations (HIS), leading to high engineering costs and limited applicability. To address these problems, this paper proposes the Non-Equivalent Functional DHR (NEF-DHR) architecture, leveraging function secret sharing (FSS) theory to replace EF executors with NEF components, which fundamentally eliminates the EF-HIS contradiction. Specifically, we propose the concept of ‘terminal executor output information entropy loss’ to formalize the risk of output information interception by adversaries and theoretically prove that NEF-DHR improves unpredictability and resistance to attacks. Experimental results further validate that NEF-DHR exhibits lower error rates under various attack levels, with enhanced robustness and superior ESS performance. Additionally, we generalize the DHR architecture based on three core properties (indistinguishability, output recoverability, verification) and classify ESS into three types with corresponding DHR variants. This work advances the application of entropy theory in ESS and provides a novel entropy-enhanced solution for the large-scale deployment of DHR security systems. Full article

Reducing food waste and promoting green consumption have emerged as critical priorities in the transition toward a more sustainable food system. Purchasing near-expired food (NEF) offers a pathway to address both issues simultaneously, yet the mechanisms underlying consumers’ intentions toward such products remain underexplored. This research investigates these mechanisms through two complementary studies conducted in China, focusing on near-expired bread as a representative product category. Study 1 (N = 1154) draws on the stimulus–organism–response (SOR) framework to examine how key factors shape consumers’ purchase intentions toward near-expired bread. The results show that price discounts and longer remaining shelf life increase purchase intentions by enhancing perceived value and reducing perceived risk. Moreover, consumers’ normative beliefs with regard to food waste avoidance positively predict purchase intentions through heightened moral satisfaction. Study 2 (N = 746) employs a 2 × 3 between-subjects factorial experiment to test two types of retail interventions for near-expired bread: discount messages (50% vs. 10% off) and information framing (gain-framed vs. loss-framed). Extending Study 1, this experiment introduces two additional dependent variables—product attitudes and perceived environmental external benefits—to capture a broader range of consumer responses. ANCOVA results reveal that consumers with higher environmental concern exhibit stronger purchase intentions, more favorable product attitudes, and greater perceived environmental external benefits. Price discount messages significantly influence purchase intentions and product attitudes, whereas information framing affects purchase intentions and environmental external benefits. Notably, the two interventions interact to shape consumers’ perceptions of environmental external benefits. Together, these studies advance a comprehensive understanding of near-expired bread purchases and offer empirical guidance for designing effective retail communication strategies to promote green consumption and reduce food waste. Full article

Background: People living with HIV (PLWH) have a substantially increased risk of both AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs), which remain a major cause of morbidity despite effective antiretroviral therapy (ART); this review aims to integrate current epidemiological, molecular, and clinical evidence on HIV-associated oncogenesis. Methods: A structured literature search was conducted in PubMed (2000–2026) using predefined keywords, including “HIV”, “cancer”, “oncogenesis”, and “immune dysregulation”, with inclusion of original studies, systematic reviews, and meta-analyses meeting predefined quality criteria. Results: Available evidence indicates that HIV contributes to cancer development through both direct and indirect mechanisms: viral proteins such as Tat, Nef, and Vpr disrupt apoptosis, DNA repair, and cell cycle regulation, while chronic immune activation, persistent inflammation, and immunosuppression impair tumor immune surveillance and facilitate oncogenic viral co-infections, including Epstein–Barr virus, human papillomavirus, and human herpesvirus 8. Emerging pathways, such as epigenetic alterations, microRNA dysregulation, metabolic reprogramming, and the contribution of HIV reservoirs to pro-tumorigenic microenvironments, further modulate cancer risk. Conclusions: HIV may function as a cofactor that enhances the effects of oncogenic viruses by promoting viral persistence and immune dysregulation; while biologically plausible, direct evidence linking HIV to amplification of tumorigenesis in humans remains limited. Full article

A novel HIV-1 vaccine candidate under development targeting the highly conserved protease cleavage regions reduced viral acquisition and delayed disease progression in a macaque SIV-challenge model. Breakthrough virus isolated from vaccinees and control animals were sequenced in the regions surrounding the SIV protease cleavages. We identified unique viral mutations that were associated with alterations in viral load and maintenance of CD4+ T cell counts in vaccinees. To evaluate whether the vaccine-elicited mutations were detrimental to virus fitness, we produced 11 mutant constructs and transfection-derived viral stocks harboring mutations in both PCS2 (in CA/p2) and PCS12 (in Nef) that had emerged at high frequency during breakthrough viremia. Virus preparations harboring mutations displayed impaired proteolytic Gag processing, reduced viral RNA incorporation and p27-CA content. These mutants were also compromised in their ability to replicate in primary cells and cell lines. Interestingly, we observed only partial compensation of these PCS2 defects by downstream mutation at PCS12. In sum, we demonstrate that vaccine-elicited immunity directed to viral protease cleavage regions impair viral escape, and breakthrough virus cannot easily restore replicative fitness. Full article

Breast cancer represents a persistent global health burden, marked by extensive molecular heterogeneity and frequent therapeutic resistance in aggressive subtypes, particularly triple-negative breast cancer (TNBC). These clinical challenges underscore the urgency for alternative therapeutic strategies. Bioactive alkaloids isolated from Nelumbo nucifera, especially the bisbenzylisoquinoline compounds liensinine (LIE), isoliensinine (ISO), and neferine (NEF), have emerged as promising candidates due to their ability to disrupt oncogenic signaling pathways and inhibit malignant cellular transformation. The present study conducted a systematic investigation of LIE, ISO, and NEF across multiple breast cancer cell lines, including highly aggressive TNBC models. Results revealed potent growth-inhibitory effects mediated through apoptosis induction and cell cycle arrest at both the G1 and G2/M phases. Furthermore, transcriptomic profiling and molecular analysis identified LIE as a principal effector, driving extensive transcriptional reprogramming and targeting the MAPK and mTOR pathways as core regulators of its anti-cancer efficacy. Collectively, these findings define a mechanistic framework for the anti-cancer potential of N. nucifera-derived alkaloids and provide a compelling foundation for their development as therapeutic candidates for advanced breast cancer. Full article

Due to the application of antiretroviral therapy, HIV has become a manageable chronic disease, and people living with HIV/AIDS (PLWHA) experience several comorbidities, including cardiovascular disease. Although antiretroviral therapy suppresses the viral load to an undetectable level, HIV proteins can still be detected in the circulation and in different organs. In our previous study, we found that the expression of the Nef protein causes cardiac dysfunction and heart failure in a transgenic mouse model. We also observed inhibition of autophagy along with the upregulation of the senescence marker Bcl2. To further understand the metabolic changes related to Nef in cardiac tissue, we examined nicotinamide adenine dinucleotide (NAD) metabolism in the heart. Our metabolic study with cardiac tissue revealed that Nef expression decreases NAD+ levels in the heart. Additionally, we explored whether replenishing cellular NAD+ could be a potential therapeutic target for HIV-associated cardiovascular disease. Interestingly, our study found that NMN treatment can improve cellular autophagy, decrease the senescence marker Bcl2, and reduce fibrosis in the heart. Overall, our study suggests that NMN could serve as a promising therapeutic molecule for the treatment of HIV-associated cardiovascular comorbidities. Full article

Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but may become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently characterized. We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to stimulation of Toll-like receptors (TLR) were measured. We further examined whether TRIM influenced susceptibility to HIV infection in MDMs derived from monocytes exposed to extracellular vesicles carrying the HIV-1 Nef protein (Nef EVs). Baseline IL-6 production did not differ between unstimulated MDMs from PLWH and uninfected controls. Although sex-associated differences were initially observed, these effects were no longer significant after adjustment for infection duration. IL-6 responses following TLR2 and TLR7 stimulation, but not TLR4 stimulation, were significantly amplified in PLWH-derived MDMs, consistent with a trained phenotype. Similar trends were observed in sex-stratified analyses but did not reach statistical significance. The magnitude of unstimulated IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting over time. Despite heightened inflammatory responsiveness, TRIM did not reduce susceptibility to HIV infection in Nef EV-exposed MDMs, indicating functional maladaptation rather than protective priming. These findings provide evidence of maladaptive TRIM in PLWH, characterized by preserved basal cytokine output but exaggerated inflammatory responses to innate immune stimulation without antiviral benefit. The association with infection duration supports progressive innate immune reprogramming as a contributor to HIV-associated inflammation. No statistically significant differences in trained immune responses were observed between male and female PLWH after accounting for duration of infection. Further studies are needed to define the mechanisms underlying this maladaptation and its clinical consequences. Full article