Search Results (978)

This study develops a reduced-order predictive model of the Sit-To-Stand (STS) task to examine whether a simplified biomechanical representation can reproduce key STS patterns reported in the literature and to investigate the role played in movement by a flexible trunk. The model represents the human body as a planar multibody system and formulates STS as an optimization problem within a discrete mechanics framework. This formulation combines reduced model complexity, explicit torso flexibility, and a structure-preserving numerical approach for trajectory generation. Simulations were used to evaluate the effects of movement duration, reduced joint strength, and seat height on joint torques, kinematics, trunk motion, and ground reaction forces (GRFs). The results reproduced several qualitative trends reported in previous experimental studies, including increased peak joint torques and GRFs with shorter movement duration, lower joint strength, and reduced seat height, as well as greater compensatory trunk motion under more demanding conditions. These findings suggest that the proposed framework captures key adaptive features of STS mechanics and may provide useful insights for rehabilitation analysis and the design of assistive technologies such as lower-limb exoskeletons and rehabilitation devices. At the same time, the present work should be regarded as an initial methodological study, since validation is currently qualitative and further experimental calibration, quantitative validation, and sensitivity analysis remain part of ongoing work. Full article

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria (NSM) and synaptosomal fractions containing synaptic mitochondria from adult male rats exposed to six weeks of CSIS, an animal model of depression, compared to controls. The compartment-specific proteomic alterations reveal mechanisms underlying mitochondrial dysregulation, providing molecular insights into the depression-like phenotype. Hippocampal NSM exhibit changes in energy metabolism-related proteins, including components of the tricarboxylic acid cycle and oxidative phosphorylation, as well as mitochondrial transport proteins and alterations in chaperones, structural and translational proteins, and monoamine oxidase, further elucidating how these proteomic changes contribute to mitochondrial dysregulation. In contrast, synaptosomal proteomics reveal predominantly increased protein abundance associated with energy metabolism, signaling, cytoskeletal organization, protein quality control, and vesicle trafficking, suggesting compensatory adaptations. Together, these findings highlight compartment-specific mitochondrial proteomic changes that may underlie depression-like behaviors and represent potential targets for therapeutic intervention. Full article

The high incidence of thrombosis in lymphoma is largely due to chronic inflammation and endothelial dysfunction. To elucidate the mechanisms underlying thrombus formation and fibrinolysis, we investigated interactions between circulating endothelial cells and peripheral blood mononuclear cells (MNCs), along with inflammatory signaling pathways, in patients with follicular lymphoma (FL), Hodgkin lymphoma (HL), and diffuse large B-cell lymphoma (DLBCL), independent of the presence of thrombosis, compared to healthy controls by flow cytometry, immunoblotting, and fluorometric assays. We observed increased tissue factor (TF) expression on CD31+ endothelial cells in DLBCL and FL. In DLBCL, inducible nitric oxide synthase expression was elevated in MNCs, while reduced nitrite levels correlated with an advanced clinical stage in patients with thrombosis. In lymphoma, nuclear factor kappa B (NFκB) signaling was activated in MNCs, while signal transducer and activator of transcription 3 (STAT3) activation was increased in DLBCL with thrombosis. Trans-endothelial migration of MNC was enhanced in HL, FL and DLBCL with thrombosis and reduced by inflammatory cytokine tumor necrosis factor alpha (TNF-α) that promoted platelet aggregation like interleukin-6 (IL-6) in HL and FL. Fibrinolytic analyses showed reduced tissue type plasminogen activator in lymphoma, whereas increased urokinase-type plasminogen activator (uPA) was linked to poorer total survival in DLBCL with thrombosis, suggesting a compensatory role in early thrombus resolution. These findings indicate that chronic inflammation promotes endothelial activation, dysregulated fibrinolysis, and increased vascular permeability, contributing to heightened thrombotic risk. This study provides mechanistic insight into lymphoma-associated thrombosis and identifies TF, uPA, and the inflammatory signaling pathways as potential biomarkers and therapeutic targets. Full article

The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored. Full article

Objective: This study aims to investigate the protective effect of Shengmai San (SMS) against high-glucose (HG)-induced injury in neonatal rat ventricular myocytes (NRVMs) and to elucidate the underlying pharmacological molecular mechanisms. We hypothesize that SMS ameliorates HG-induced calcium homeostasis imbalance in NRVMs by improving mitochondrial energy metabolism disorder, and this protective effect is associated with the downregulation of oxidized and phosphorylated CaMKII expression to inhibit CaMKII signaling pathway overactivation. Herein, we verify this hypothesis by assessing mitochondrial function, calcium transients, sarcoplasmic reticulum (SR) calcium handling and CaMKII phosphorylation levels in NRVMs. Methods: First, ultra-high performance liquid chromatography–high resolution mass spectrometry was used to identify the chemical components of SMS to clarify its material basis. Primary NRVMs were then cultured under low-glucose (LG) or HG conditions, with 2% SMS-medicated serum (SMS-MS) as the experimental intervention, and NAC (ROS scavenger) and KN93 (CaMKII inhibitor) as positive controls. Following intervention, we sequentially detected key indicators corresponding to the proposed pathological pathway: intracellular reactive oxygen species (ROS) levels (oxidative stress), mitochondrial ROS, mitochondrial function indices including oxygen consumption rate (OCR) (energy metabolism), calcium transients and diastolic intracellular free calcium concentration (global calcium homeostasis), sarcoplasmic reticulum (SR) calcium leak (calcium handling disorder), and, finally, the phosphorylation, oxidation levels of CaMKII and RyR2 phosphorylation (Ser2814) (p-RyR2) (key regulatory pathway) via Western blot to systematically elucidate the mechanistic link between SMS intervention and HG-induced NRVM injury. Results: Quantitative analysis revealed that high-glucose (HG) induction significantly reduced calcium transient amplitude and prolonged the decay time constant (tau) in NRVMs at 72 h (p < 0.01 vs. LG), with these parameters normalizing by 120 h—an effect indicative of a compensatory adaptive response. The 2%SMS-MS markedly ameliorated HG-induced calcium transient abnormalities at 72 h (p < 0.01 vs. HG). Additionally, 2%SMS-MS significantly enhanced mitochondrial basal oxygen consumption rate, spare respiratory capacity, ATP production, and maximal respiration in HG-exposed NRVMs (p < 0.01 vs. HG). SMS also significantly reduced intracellular reactive oxygen species (ROS) levels (p < 0.01 vs. HG), mitochondrial ROS levels (p < 0.01 vs. HG), diastolic intracellular free calcium concentration (p < 0.01 vs. HG), and SR calcium leak (p < 0.05 vs. HG). Western blot analysis revealed that 2%SMS-MS intervention effectively downregulated the expression of oxidized CaMKII (Ox-CaMKII) (p < 0.01 vs. HG), phosphorylated CaMKII (p-CaMKII) (p < 0.01 vs. HG), and RyR2 phosphorylation (Ser2814) (p < 0.05 vs. HG), which may be the potential mechanism in maintaining calcium homeostasis in HG-induced NRVMs. Conclusions: This study suggests that SMS enhances mitochondrial energy metabolism and exerts a protective effect against high-glucose-induced calcium homeostasis imbalance in NRVMs, which supports our proposed hypothesis. Its potential mechanism indicates that the protective effects of SMS are associated with its ability to downregulate the expression of oxidized and phosphorylated CaMKII. These findings highlight SMS as a potential therapeutic candidate for alleviating HG-related myocardial injury and provide evidence for its application in the prevention of early diabetic cardiomyopathy. Full article

The maintenance mechanisms underlying community temporal stability represent a pivotal concern in ecology. However, empirical evidence on how multiple mechanisms independently or synergistically stabilize natural communities, and how their importance responds to external factors and evolves over time, remains limited. Leveraging a 12-year (2007–2018) manipulative experiment involving clipping and fertilization in an alpine meadow, we assessed the relative contributions of four mechanisms, namely, species asynchrony (compensatory dynamics among species), the portfolio effect (statistical averaging of species’ fluctuations), the selection effect (dominance of stable species), and interspecific interactions, across treatments and temporal scales. Stability was quantified as the reciprocal of the coefficient of variation in community coverage. Asynchrony was a ubiquitous foundation of stability across all treatments and time periods. The portfolio effect was a critical positive driver in the initial phase but was suppressed by fertilization over time. In contrast, interspecific interactions and the selection effect emerged as central determinants of long-term stability in later stages. Fertilization amplified the portfolio effect and fostered weak interactions while reducing the fluctuation disparity between dominant and non-dominant species. Clipping enhanced stability mechanisms by preserving species richness and asynchrony. Structural equation modelling revealed that treatments indirectly influenced stability by “reprogramming” the causal pathways among these mechanisms. Our study demonstrates that community stability is upheld by multiple coordinated mechanisms, whose relative importance is contingent on treatment and time scale. Grassland management should therefore move beyond a singular focus on species richness and adopt strategies that promote the synergistic functioning of multiple stability mechanisms. Full article

The fall armyworm (Spodoptera frugiperda) is a major global migratory pest. Its increasing insecticide resistance poses a severe threat to food security. Developing biopesticides such as SfMNPV is critical for sustainable control. Nevertheless, the early molecular mechanisms underlying the S. frugiperda midgut response to oral SfMNPV challenge remain poorly understood. This study utilized high-throughput transcriptome sequencing to systematically characterize the dynamic transcriptional profiles of the larval midgut at 1, 12, and 24 h after oral SfMNPV inoculation. Results showed that the midgut transcriptional response to SfMNPV is time and stage-specific. During this period, the physical midgut barrier underwent remodeling, with core components of the peritrophic matrix downregulated at 1 h, followed by the basal lamina at 12 h, alongside the activation of cytoskeleton genes during 12–24 h. Concurrently, sustained endoplasmic reticulum stress, autophagy, and ubiquitin system responses occurred from 12 to 24 h. At the metabolic level, the defense system exhibited a functional succession, shifting from ABC transporters and UDP-glycosyltransferases at 1 h to glutathione S-transferases and superoxide dismutase at 12–24 h. Additionally, the midgut tissue exhibited a cascade transition from pro-apoptotic signaling at 1 h to compensatory regenerative repair mediated by the Wnt, mTOR, and Hippo pathways at 12–24 h. This study elucidates the molecular process of barrier damage, homeostatic imbalance, and tissue remodeling during early oral SfMNPV challenge. These findings provide a global perspective on baculovirus-host interactions and establish a theoretical foundation for designing novel biopesticides targeting the midgut interaction. Full article

This study investigated neural oscillatory dynamics underlying visual word recognition in university students with dyslexia using a portable brain–computer interface (BCI) EEG system. The sample included university students with dyslexia (N = 12) and matched controls (N = 14) who completed auditory discrimination and visual word recognition tasks, with and without musical accompaniment. Through these experimental conditions, the researchers assessed (a) the cortical activation across frequency bands, (b) the modulatory effect of background music, and (c) the relationship between emotional states and brain activity. Results revealed significant group differences in oscillatory patterns, with reduced β- and γ-band activity in the left occipito-temporal cortex among participants with dyslexia, confirming disrupted temporal coordination in posterior reading networks. Compensatory right-hemisphere activation was observed, particularly under musical conditions, accompanied by increased α-band power and reduced δ activity, indicating enhanced attentional engagement and reduced cognitive fatigue. Emotional assessment using the DASS-21 revealed higher stress and anxiety scores in the dyslexic group, suggesting that affective factors may modulate oscillatory dynamics. The presence of background music appeared to attenuate these effects, supporting improved emotional regulation and cognitive focus. These findings demonstrate that dyslexia reflects a distributed disruption in neural synchrony and cross-frequency coupling, influenced by both cognitive and affective mechanisms. The integration of portable EEG technology with rhythmic auditory stimulation offers new insights into the neurophysiological and emotional aspects of dyslexia, highlighting the potential of rhythm- and music-based approaches for both diagnostic and therapeutic applications. Full article

Neurogranin (Ng) is a postsynaptic calmodulin-binding protein highly enriched in forebrain neurons and widely implicated in synaptic plasticity. However, whether Ng contributes more broadly to neuronal network maturation and cellular homeostasis remains unclear. Here, we examined the consequences of silencing or restoring Ng to adult physiological levels in primary hippocampal neurons. Ng expression promoted dendritic expansion, increased synaptic number, and shifted the axon initial segment toward the soma, consistent with structural adaptations to enhanced connectivity. Calcium (Ca²⁺) imaging revealed a marked increase in spontaneous neuronal activity and network synchronization, which was confirmed by electrophysiological recordings showing enhanced burst firing and spike synchrony. At the molecular level, Ng altered Ca²⁺/calmodulin (CaM) signaling by increasing total CaM levels, reducing Ca²⁺/CaM-dependent protein kinase II (CaMKII) abundance while increasing its relative autophosphorylation, and downscaling specific ionotropic glutamate receptors. Despite elevated network activity, Ng expression enhanced neuronal metabolic competence and viability, reduced cellular stress signaling and induced modest caspase-3 activation without engagement of apoptotic pathways. Together, these results indicate that Ng promotes neuronal maturation and coordinated network activity while engaging compensatory mechanisms that preserve excitatory balance and neuronal resilience. Our findings identify Ng as a molecular integrator linking Ca²⁺/CaM signaling with the structural and functional maturation of neuronal networks. Full article

Community social capital (CSC) and the community-built environment (CBE) are key resources associated with residents’ health, yet their combined associations with multidimensional health and well-being remain insufficiently understood. Drawing on large-scale data from the 2018 China Labor-force Dynamics Survey, this study analyzed a filtered sample of 14,127 respondents nested within 326 communities and employed multilevel models to examine the direct, interactive, and combined associations of CSC and CBE on four outcomes: residents’ self-rated health, subjective well-being, loneliness, and mental health. The results identified two CSC indicators: neighborhood mutual support and resident relationship quality, and two CBE indicators: community type and residential density, as key factors associated with multidimensional health, each showing significant associations with multiple health outcomes, with CSC indicators demonstrating relatively stronger and more consistent effect sizes than CBE indicators. The study further identified a dual mechanism involving key indicators of CSC (relationship quality and neighborhood mutual support) and CBE (community type and residential density). When one dimension was constrained, the other was associated with compensatory patterns in residents’ health, whereas high levels of both social and physical resources were associated with synergistic advantages. Stratified analyses revealed that individuals with low external social engagement appeared more sensitive to these environmental associations. This study emphasizes that sustainable community planning and governance should consider key social and physical indicators to support both social sustainability and built-environment sustainability. Depending on the level of community resources, it may be beneficial to leverage the compensatory and synergistic patterns among different community attributes to support improvements in residents’ health benefits. Particular attention may be warranted for individuals with low social engagement to build healthier and more sustainable communities. This research advances an integrated resource configuration framework that contributes to a shift in urban health governance from isolated environmental interventions toward an adaptive, balanced approach. Full article

Antibody–drug conjugates (ADCs) represent a paradigm shift in precision oncology, ingeniously coupling the targeting capability of monoclonal antibodies with the lethal potency of cytotoxic payloads to selectively eradicate tumor cells. While ADCs have demonstrated transformative efficacy across a spectrum of malignancies, the emergence of intrinsic and acquired resistance remains a formidable obstacle, frequently culminating in treatment failure and disease progression. The landscape of ADC resistance is highly complex, governed by a diverse array of molecular mechanisms. These range from alterations in antigen dynamics—such as downregulation or impaired trafficking—to intracellular adaptations, including the upregulation of multi-drug resistance efflux pumps, enhanced DNA damage repair capacity, and the blockade of apoptotic cell death. Moreover, tumor cells often exploit compensatory signaling networks to bypass therapeutic inhibition. Consequently, elucidating the intricate signaling cascades that drive these resistance phenotypes is critical for clinical advancement. This review comprehensively examines the pivotal signaling pathways underpinning ADC resistance and evaluates novel therapeutic strategies designed to circumvent these molecular barriers, aiming to optimize patient outcomes. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Serotonin is a critical morphogen in early development, yet the mechanisms regulating its homeostasis in the preimplantation embryo remain unclear, particularly under conditions of maternal antidepressant exposure. Here, we investigated embryonic serotonergic autonomy using mouse models of pharmacological transport blockade (maternal fluoxetine treatment) and in vitro treatment with the monoamine oxidase inhibitor pargyline. We employed immunofluorescence, RT-qPCR, and live-cell imaging to assess metabolic flux, gene expression, and physiological health. We demonstrate that monoamine oxidase functions as a metabolic firewall, progressively maturing from zygote to blastocyst to degrade excess amines. Paradoxically, maternal serotonin transporter blockade triggered significant intracellular serotonin hyper-accumulation in blastocysts, associated with a trend toward a compensatory upregulation of the biosynthetic gene Ddc. While this serotonin overload did not compromise morphology, mitochondrial function, or pluripotency marker expression, it induced a robust epigenetic response. Excess serotonin promoted elevated H3Q5ser immunoreactivity in both nuclear and cytoplasmic compartments via a transglutaminase-dependent mechanism. These findings reveal that the preimplantation embryo possesses a resilient, autonomous serotonergic system capable of compensatory synthesis. However, environmental fluctuations are chemically recorded via transglutaminase-mediated serotonylation, representing an epigenetic mark that warrants further long-term study within the Developmental Origins of Health and Disease (DOHaD) framework. Full article

Glioblastoma cells sustain tumor growth by releasing inflammatory cytokines that modulate the tumor microenvironment (TME). Targeting the cytokine expression profile of glioblastoma multiforme (GBM) and tumor-supportive cells represents a promising therapeutic strategy. Lactoferrin, a natural compound with recognized anticancer properties, has been poorly investigated regarding its role in modulating GBM cytokine profiles and TME cellular activity. This study evaluated lactoferrin’s ability to modulate GBM inflammatory signaling and pro-tumorigenic functions of tumor-associated astrocytes. U87MG glioblastoma cells were treated with human lactoferrin (10 μg/mL) for 72 h, and DI-TNC1 astrocytes were exposed to conditioned medium from treated and untreated U87MG cells for 24 h. Results demonstrate that lactoferrin inhibits GBM cell proliferation, migration, and stemness-related pathways while modulating inflammatory profiles through NF-κB pathway interference, downregulating pro-tumorigenic cytokines IL-6, IL-1β, IL-4, and IL-10. Increased TGF-β expression in lactoferrin-treated cells likely reflects a compensatory mechanism rather than enhanced malignancy. Furthermore, lactoferrin attenuates pro-tumorigenic effects of tumor-associated astrocytes by reducing NF-κB activation and expression of TGF-β, TNF-α, IL-4, and IL-10. This innovative study provides evidence supporting non-cytotoxic approaches targeting GBM-TME interactions, highlighting lactoferrin’s potential to attenuate glioblastoma malignancy and astrocyte inflammatory signaling, suggesting its therapeutic potential for GBM treatment. Full article

Background: The effect of fluid thickening in older patients with oropharyngeal dysphagia (OD) is not settled in the case of mild OD or OD caused by structural abnormalities. Objective: To assess the therapeutic effect and mechanism of action of the xanthan-gum-based thickener Tsururinko Quickly in older patients with structural OD and those with mild OD (Penetration–Aspiration Score < 3). Patients and Methods: We included 25 participants in each group (81.8 ± 7.1 vs. 77.4 ± 7.2 yr, respectively). Participants underwent videofluoroscopy (VFS) while swallowing 10 mL boluses at <50 mPa·s, 100, 200, 400, 800, and 1600 mPa·s to evaluate the safety and efficacy of swallowing and the biomechanics of the swallowing response at each viscosity level. After 30 s oral incubation, the effect of salivary α-amylase on shear viscosity was assessed using viscometer measurements. Results: (a) For the <50 mPa·s liquid series, no aspirations occurred in either group; however, 44% of patients with structural OD and 30% of patients with mild OD showed PAS 2 penetrations. (b) Fluid thickening reduced prevalence of penetrations with a maximal effect at 800 mPa·s and without affecting oral or pharyngeal residue in either group. (c) Increasing shear viscosity did not affect timing of airway protection mechanisms nor bolus kinematics. (d) Oral incubation decreased viscosity by 1.7–1.8% at 800 mPa·s. Conclusions: Fluid thickening with TQ enhances swallowing safety in older patients with structural causes of OD and those with mild OD through compensatory mechanisms and without a consistent increase in pharyngeal residue across the tested viscosity range. Full article