Search Results (589)

Recent studies in murine disease models have identified Siglec-F⁺ neutrophils, which express a marker traditionally associated with eosinophils, as a functionally distinct population characterized by extended lifespans and context-dependent roles. While conventional neutrophils typically return to the bone marrow or undergo apoptosis at the site of inflammation, these cells remain in tissues for extended periods. These cells demonstrate remarkable functional plasticity, promote bacterial clearance and immune activation during infections, foster immunosuppression and tumor progression in cancer, and contribute to tissue remodeling in fibrotic diseases. In this review, we examine the key features governing Siglec-F⁺ neutrophil differentiation and function—including Siglec-F signaling, metabolic programming, and upstream cytokine cues—and explore how targeting these pathways may offer promising avenues for precision immunomodulation. Full article

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates metabolic and environmental signals to regulate cell growth and survival. In the central nervous system, mTOR plays a pivotal role in neuronal development, plasticity, and circuit homeostasis. In diffusely infiltrating gliomas, including glioblastomas, mTOR signaling is frequently dysregulated and contributes to malignant progression, therapeutic resistance, and metabolic adaptation. Beyond tumor-intrinsic effects, recent evidence reveals that gliomas actively reprogram peritumoral neurons via mTOR-dependent mechanisms, leading to synaptic remodeling, hyperexcitability, and neurological symptoms such as seizures and cognitive dysfunction. These results position mTOR as a central mediator of both oncogenesis and neurological dysfunction in diffusely infiltrating glioma. While clinical trials of mTOR inhibitors in gliomas have so far shown limited efficacy, emerging data suggest these agents may ameliorate tumor-associated neurological dysfunction. This review synthesizes current knowledge of mTOR signaling across tumor and neuronal compartments in diffusely infiltrating glioma and highlights its potential as a therapeutic target at the intersection of cancer biology and neuroscience. Full article

Compaction quality control in earthworks and pavements still relies mainly on density-based acceptance referenced to laboratory Proctor tests, which are costly, time-consuming, and spatially sparse. Lightweight dynamic cone penetrometer (LDCP) provides rapid indices, such as $q_{d0}$ and $q_{d1}$, yet acceptance thresholds commonly depend on ad hoc, site-specific calibrations. This study develops and validates a supervised machine learning framework that estimates $q_{d0}$, $q_{d1}$, and $Z_c$ directly from readily available soil descriptors (gradation, plasticity/activity, moisture/state variables, and GTR class) using a multi-campaign dataset of $n=360$ observations. While the framework does not remove the need for the standard soil characterization performed during design (e.g., W, ${\gamma }_{d,\mathrm{field}}$, and $R{C}_{\mathrm{SPC}}$), it reduces reliance on additional LDCP calibration campaigns to obtain device-specific reference curves. Models compared under a unified pipeline include regularized linear baselines, support vector regression, Random Forest, XGBoost, and a compact multilayer perceptron (MLP). The evaluation used a fixed 80/20 train–test split with 5-fold cross-validation on the training set and multiple error metrics ($R^2$, RMSE, MAE, and MAPE). Interpretability combined SHAP with permutation importance, 1D partial dependence (PDP), and accumulated local effects (ALE); calibration diagnostics and split-conformal prediction intervals connected the predictions to QA/QC decisions. A naïve GTR-average baseline was added for reference. Computation was lightweight. On the test set, the MLP attained the best accuracy for $q_{d1}$ ($R^2=0.794$, RMSE $=5.866$), with XGBoost close behind ($R^2=0.773$, RMSE $=6.155$). Paired bootstrap contrasts with Holm correction indicated that the MLP–XGBoost difference was not statistically significant. Explanations consistently highlighted density- and moisture-related variables (${\gamma }_{d,\mathrm{field}}$, $R{C}_{\mathrm{SPC}}$, and W) as dominant, with gradation/plasticity contributing second-order adjustments; these attributions are model-based and associational rather than causal. The results support interpretable, computationally efficient surrogates of LDCP indices that can complement density-based acceptance and enable risk-aware QA/QC via conformal prediction intervals. Full article

Pathological vascular remodeling—central to restenosis, atherosclerosis, and vasculo-proliferative diseases—depends on the phenotypic switching of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a synthetic, proliferative program. Although the receptor tyrosine kinase c-Kit is implicated in proliferation, migration, and tissue repair, its role in VSMC plasticity has yet to be fully understood. Using c-Kit haploinsufficient mice subjected to right carotid artery ligation (CAL) and primary aortic VSMC cultures, we show that c-Kit is required for the contractile-to-synthetic transition. In vitro, c-Kit haploinsufficiency halved c-Kit expression, reduced 5-bromo-2′-deoxyuridine (BrdU) incorporation, and blunted platelet-derived growth factor BB (PDGF-BB)-induced repression of contractile genes. c-Kit–deficient VSMCs exhibited a senescence program with increased p16^INK4a/p21 expression and upregulated senescence-associated secretory phenotype (SASP) mediators. RNA-Seq of carotid arteries 7 days post-ligation revealed that wild-type arteries activated cell-cycle pathways and suppressed contractile signatures, whereas c-Kit-deficient carotid arteries failed to fully engage proliferative programs and instead maintained contractile gene expression. At 28 days post CAL in vivo, c-Kit haploinsufficiency produced markedly reduced neointima, fewer Ki67+ VSMCs, more p16^INK4a+ cells, and impaired re-endothelialization. Because progenitor-to-VSMC differentiation contributes to remodeling, we tested adult cardiac stem/progenitor cells (CSCs) as a model system of adult progenitor differentiation. Wild-type CSCs efficiently generated induced VSMCs (iVSMCs) with appropriate smooth-muscle gene upregulation; c-Kit–deficient rarely did so. Restoring c-Kit with a BAC transgene rescued both the smooth-muscle differentiation and proliferative competence of c-Kit-deficient iVSMCs. Collectively, our data identified c-Kit as a gatekeeper of reparative VSMC plasticity. Adequate c-Kit enables progenitor-to-VSMC commitment and the expansion of newly formed VSMCs while permitting injury-induced proliferation and matrix synthesis; reduced c-Kit locks cells in a hypercontractile, senescence-prone state and limits neointima formation. Modulating the c-Kit axis may therefore offer a strategy to fine-tune vascular repair while mitigating pathological remodeling. Full article

Epithelial-mesenchymal transition (EMT) and inflammasome signalling are intercon-nected processes which underpin tumour progression, metastasis, and therapeutic re-sistance. Inflammasomes such as NLRP3 encourage pro-inflammatory states (IL-1β, IL-18, NF-κB) and the activation of signalling pathways like TGF-β that promote mes-enchymal traits crucial for EMT. EMT transcriptional programmes can then in turn modulate the inflammasome via NF-κB/TGF-β signalling, creating self-perpetuating mechanisms of cellular plasticity and dysregulated therapeutic response. We have re-viewed the mechanistic evidence for EMT–inflammasome crosstalk in cancer and discussed the potential therapeutic implications. The function of the EMT-inflammasome axis is clearly context-dependent, with the cancer type, stage, and the complexity of the tumour microenvironment heavily contributing. The crosstalk between EMT and the inflammasome is an overlooked mechanism of tumour evolution, and targeting inflammasomes like NLRP3, or their downstream signalling pathways, offers a promising therapeutic avenue, with the objective of inhibiting metastasis and overcoming drug resistance. Full article

17β-estradiol (E2) enhances the cerebellar molecular layer interneurons (MLIs)—Purkinje cells (PCs) synaptic transmission via activation of the Erβ in vivo in mice. Whether E2 regulates cerebellar MLI-PC synaptic plasticity is unknown. To investigate the mechanism of E2, we evaluated the modulation of facial stimulation-evoked MLI-PC long-term plasticity in mice. Cell-attached recordings from PCs of Crus II were performed using an Axopatch-700B patch-clamp amplifier. The MLI-PC synaptic transmission was evoked by facial stimulation. Immunohistochemistry was used to detect the expression of ERβ. Under control conditions, 1 Hz facial stimuli induced long-term depression (LTD) at MLI-PC synapses, characterized by a sustained reduction in P1 amplitude and a simple spike (SS) pause. The facial stimulus-induced MLI-PC LTD was completely prevented by E2, but this effect was reversed by a selective ERα/ERβ antagonist, ICI182780. Blockade of cannabinoid receptor 1 (CB1R) eliminated the MLI-PC LTD under control conditions, but revealed an E2-triggered long-term potentiation (LTP). The E2-triggered MLI-PC LTP persisted in the presence of an ERα antagonist but was absent in the presence of an ERβ antagonist PHTPP. The E2-triggered MLI-PC LTP remained unaffected by protein kinase A inhibition but was abolished by inhibition of protein kinase C (PKC) and intracellular Ca²⁺ depletion. Moreover, ERβ immunoreactivity was abundantly distributed around dendrites and somas of PCs in the Crus II region of the mouse cerebellar cortex. The present results suggest that E2 activates ERβ, thereby triggering facial stimulation-induced MLI-PC LTP via the PKC signaling cascade, which occludes CB1R-dependent MLI-PC LTD in the cerebellar cortex of mice in vivo. Full article

Rising ocean temperatures due to climate change, combined with the intensification of anthropogenic activity, may lead to changes in the physiology and distribution of native species. Compounding climate stress, microplastic particles (MPs) enter the oceans through wastewater and the breakdown of macroplastics. Depending on their composition, they can be harmful and act as a vehicle for toxic substances, although their effects on native Antarctic and subantarctic species are unknown. Notothenioid fish are members of this group and are found inside and outside Antarctica, such as the Harpagifer, which has adapted to the cold and is particularly sensitive to thermal increases. Here, we aimed to evaluate the innate immune response in the head kidney, spleen, and foregut of two notothenoid fish, Harpagifer antarcticus and Harpagifer bispinis, exposed to elevated temperatures and PVC (polyvinyl chloride) microplastics. Adults from both species were collected on King George Island (Antarctica) and Punta Arenas (Chile), respectively. Specimens were assigned to a control group or exposed to a temperature increase (TI) or PVC microplastics (MPs), separately or in combination (MPs + TI). MP exposures were oral (gavage) for 24 h or aqueous (in a bath) for 24 and 48 h. Using real-time qPCR, we evaluated the relative gene expression of markers involved in the innate immune response, including tlr2 (toll-like receptor 2), tlr4 (toll-like receptor 4), myd88 (myeloid differentiation factor 88), nfkb (nuclear factor kb), il6 (interleukin 6), and il8 (irterleukin 8). We found differences between treatments when H. antarcticus and H. bispinis were exposed independently to MPs or thermal increase (TI) in the experiment with a cannula, showing an up-regulation in transcripts. In contrast, a down-regulation was observed when exposed in combination to MP + TI, which looked to be tissue-dependent. However, transcripts related to innate immunity in the bath experiment increased when exposure to both stressors was combined, mostly at 48 h. These results highlight the importance of evaluating the effects of multiple stressors, both independently and in combination, and whether these species will have the capacity to adapt or survive under these conditions, especially in waters where temperature is increasing and pollution is also rising, primarily from MP-PVC, a plastic widely used in various industries and among the population. Full article

Nanoparticle superlattices, periodic assemblies of nanoscale building blocks, offer opportunities to tailor mechanical behavior through controlled lattice geometry and interparticle interactions. Here, classical molecular dynamics simulations were performed to investigate the compressive responses of copper nanoparticle superlattices with face-centered cubic (FCC), hexagonal close-packed (HCP), body-centered cubic (BCC), and simple cubic (SC) arrangements, as well as disordered assemblies. The flow stresses span 0.5–1.5 GPa. Among the studied configurations, the FCC and HCP superlattices exhibit the highest strengths (~1.5 GPa), followed by the disordered assembly (~1.0 GPa) and the SC structure (~0.8 GPa), while the BCC superlattice exhibits the lowest strength (~0.5 GPa), characterized by pronounced stress drops and recoveries resulting from interfacial sliding. Atomic-scale analyses reveal that plastic deformation is governed by two coupled geometric factors: (i) the number of interparticle contact patches, controlling the density of dislocation sources, and (ii) their orientation relative to the loading axis, which dictates stress transmission and slip activation. A combined parameter integrating particle coordination number and contact orientation is proposed to rationalize the structure-dependent strength, providing mechanistic insight into the deformation physics of metallic nanoparticle assemblies. Full article

Histone deacetylases (HDACs) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. In recent years, HDACs have emerged as therapeutic targets for neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, given their role in modulating neuronal plasticity, neuroinflammation, and neuronal survival. HDAC inhibitors (HDACi) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. Preclinical and clinical studies have demonstrated that HDACi can mitigate neurodegeneration, reduce neuroinflammatory markers, and improve cognitive and motor functions, positioning them as promising therapeutic agents for NDDs. Given the complexity and multifactorial nature of NDDs, therapeutic success will likely depend on multi-target drugs as well as new cellular and molecular therapeutic targets. Emerging evidence suggests that HDACi can modulate the function of astrocytes, a glial cell type critically involved in neuroinflammation, synaptic regulation, and the progression of neurodegenerative diseases. Consequently, HDACi targeting astrocytic pathways represent a novel approach in NDDs therapy. By modulating HDAC activity specifically in astrocytes, these inhibitors may attenuate pathological inflammation and promote a neuroprotective environment, offering a complementary strategy to neuron-focused treatments. This review aims to provide an overview of HDACs and HDACi in the context of neurodegeneration, emphasizing their molecular mechanisms, therapeutic potential, and limitations. Additionally, it explores the emerging role of astrocytes as targets for HDACi, proposing that this glial cell type could enhance the efficacy of HDACs-targeted therapies in NDD management. Full article

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia. Full article

This study investigates the effect of hydrogen charging time on the mechanical properties and microstructural evolution of low-carbon ferrite–pearlite steel that has been in service for over 30 years in natural gas transmission. Specimens were subjected to in-situ electrochemical hydrogen charging for varying durations, followed by tensile testing. Detailed microstructural analysis was performed using scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Despite negligible changes in the overall hydrogen content ($C_H$≈ 4.0 wppm), significant alterations in fracture morphology were observed. Fractographic and TEM analyses revealed a clear transition from ductile fracture in uncharged specimens to a predominance of brittle fracture modes (quasi-cleavage, intergranular, and transgranular) in hydrogen-charged samples. The results show time-dependent microstructural changes, including increased dislocation density and the formation of prismatic loop debris, particularly within the ferrite phase. Prolonged charging leads to localized embrittlement, which is explained by enhanced hydrogen trapping at ferrite-cementite boundaries, grain boundaries, and dislocation cores. TEM investigations further indicated a sequential activation of hydrogen embrittlement mechanisms: initially, Hydrogen-Enhanced Localized Plasticity (HELP) dominates within ferrite grains, followed by Hydrogen-Enhanced Decohesion (HEDE), particularly at ferrite-cementite interfaces in pearlite colonies. These findings demonstrate that extended hydrogen charging promotes defect localization, dislocation pinning, and interface decohesion, ultimately accelerating fracture propagation. The study provides valuable insight into the degradation mechanisms of ferrite-pearlite steels exposed to hydrogen, highlighting the importance of charging time. The results are essential for assessing the reliability of legacy pipeline steels and guiding their safe use in future hydrogen transport infrastructure. Full article

Marine pollution incidents pose significant threats to marine ecosystems and coastal communities across Pacific Island nations, necessitating advanced predictive capabilities for effective environmental management. This study analyzes 8133 marine pollution incidents from 2001–2014 across 25 Pacific Island nations to develop predictive models for pollution type classification, hotspot identification, and seasonal pattern forecasting. Our analysis reveals Papua New Guinea as the dominant pollution hotspot, experiencing 51.9% of all regional incidents, with plastic waste dumping comprising 78.8% of pollution events and exhibiting pronounced seasonal peaks during June (coinciding with critical fish breeding periods). Machine learning classification achieved 99.1% accuracy in predicting pollution types, with material composition emerging as the strongest predictor, followed by seasonal timing and geographic location. Temporal analysis identified distinct seasonal dependencies, with June representing peak pollution activity (755 average incidents), coinciding with vulnerable marine ecological periods. The predictive framework successfully distinguishes between persistent geographic hotspots and episodic pollution events, enabling targeted conservation interventions during high-risk periods. These findings demonstrate that pollution type and location are highly predictable from environmental and temporal variables, providing marine conservationists with tools to anticipate when and where pollution will most likely impact fish populations and ecosystem health. The study establishes the first comprehensive baseline for Pacific Island marine pollution patterns and validates machine learning approaches for proactive pollution monitoring, offering scalable solutions for protecting ocean ecosystems and supporting evidence-based policy formulation across the region. Full article

Calcium-dependent cysteine proteases, known as calpains, emerge as important regulators of spinal cord physiology, plasticity, and pathology. First characterized in the brain, they influence a wide range of processes in the spinal cord, maintaining neuronal homeostasis, shaping both synaptic and intrinsic plasticity, and modulating glial responses. When dysregulated, calpains contribute to the pathophysiology of traumatic and neurodegenerative spinal cord disorders, as well as to their associated motor and sensory complications, including spasticity and neuropathic pain. A recurring feature of these conditions is calpain-mediated proteolysis of ion channels, transporters, and cytoskeletal proteins, which promotes disinhibition and neuronal hyperexcitability. The resultant protein fragments are examined as prospective biomarkers for damage and disease progression. Meanwhile, promising strategies for neuroprotection and functional recovery in the clinic emerge as a result of innovative pharmacological and genetic approaches to modulate calpain activity. In this review, we present the current state of knowledge regarding the functions and regulation of calpains in the spinal cord and assess their translational potential as both therapeutic targets and effectors in spinal cord disorders. Full article

Pediococcus pentosaceus is a lactic acid bacterium used inter alia for the fermentation of milk, meat, vegetables, fruits, and even for brewing beer. Several health-promoting effects, such as antibacterial and antifungal activities or microphage and immune system stimulation, have been attributed. Apart from refining foods during the fermentation process, P. pentosaceus strains are added to meat and meat products as protective cultures to improve food safety, while leaving the organoleptic properties untouched. Since knowledge on the latter issue is still limited, we investigated 32 isolates from milk samples and teat canal biofilms regarding their antibacterial efficacy as a prerequisite for possible application as protective cultures. P. pentosaceus strains were unequivocally identified by DNA sequencing of the rrnA gene encoding 16S rRNA. Binary matrices obtained from random amplification of polymorphic DNA experiments showed that all isolates differed by more than 5% and thus represented subspecies. The antibacterial profiles against eight food-borne pathogens and food spoilage bacteria were determined. They efficiently combatted, although to various extents, Gram-negative bacteria such as Pseudomonas aeruginosa or Salmonella enterica, and Gram-positive bacteria such as Staphylococcus aureus and Listeria monocytogenes. Interestingly, acid production was dependent on the presence of the challenged pathogen and did not correlate with the extent of inhibition. Bioinformatic analyses of the genomes of the three top-ranked isolates revealed a pronounced genomic plasticity with a core genome of 1460 genes and additional 91, 130, and 161 unique genes, respectively. Each strain included a set of three, five, or six plasmids and was equipped with different genes encoding bacteriocins. The data suggest that multiple strains of P. pentosaceus should be included in order to optimize the selection of a culture for food preservation. The approach could also be applicable to other bacterial species. Full article

Background/Objectives: Synaptic plasticity is fundamental to learning and memory, yet classical models such as Hebbian learning and spike-timing-dependent plasticity often overlook the distributed and wave-like nature of neural activity. We present a computational framework grounded in Scale Relativity Theory (SRT), which describes neural propagation along fractal geodesics in a non-differentiable space-time. The objective is to link nonlinear wave dynamics with the emergence of structured memory representations in a biologically plausible manner. Methods: Neural activity was modeled using nonlinear Schrödinger-type equations derived from SRT, yielding complex wave solutions. Synaptic plasticity was coupled through a reaction–diffusion rule driven by local activity intensity. Simulations were performed in one- and two-dimensional domains using finite difference schemes. Analyses included spectral entropy, cross-correlation, and Fourier methods to evaluate the organization and complexity of the resulting synaptic fields. Results: The model reproduced core neurobiological features: localized potentiation resembling CA1 place fields, periodic plasticity akin to entorhinal grid cells, and modular tiling patterns consistent with V1 orientation maps. Interacting waveforms generated interference-dependent plasticity, modeling memory competition and contextual modulation. The system displayed robustness to noise, gradual potentiation with saturation, and hysteresis under reversal, reflecting empirical learning and reconsolidation dynamics. Cross-frequency coupling of theta and gamma inputs further enriched trace complexity, yielding multi-scale memory structures. Conclusions: Wave-driven dynamics in fractal space-time provide a hypothesis-generating framework for distributed memory formation. The current approach is theoretical and simulation-based, relying on a simplified plasticity rule that omits neuromodulatory and glial influences. While encouraging in its ability to reproduce biological motifs, the framework remains preliminary; future work must benchmark against established models such as STDP and attractor networks and propose empirical tests to validate or falsify its predictions. Full article