Search Results (217)

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

Background: We recently reported sex-dependent impairment in cognitive functions in male and female mice exposed for 24 h, 48 h or 15 days to 2G hypergravity (HG). Methods: In the present study, we investigated brain functional correlates by analyzing synaptic activity and plasticity in the CA1 area of the hippocampus in both genders of mice previously exposed to 2G for the same duration. This was assessed by electrophysiological extracellular recordings in ex vivo slice preparations. Results: Basal synaptic transmission and glutamate release were unchanged regardless of HG duration. However, plasticity was altered in a sex- and time-specific manner. In males, long-term potentiation (LTP) induced by strong high-frequency stimulation and NMDA receptor (NMDAr) activation was reduced by 26% after 24 h of exposure but recovered at later timepoints. This deficit was reversed by D-serine or glycine, suggesting decreased activation at the NMDAr co-agonist site. In females, LTP deficits (23%) were found only after 15 days following mild theta burst stimulation and were not reversed by D-serine. Long-term depression (LTD) was unaffected in both sexes. Conclusions: This study highlights, for the first time, sex-dependent divergence in the CA1 hippocampal plasticity timeline following 2G exposure. The synaptic changes depend on exposure duration and the stimulation protocol and could underlie the previously observed cognitive deficits. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

The application of artificial intelligence through the brain–computer interface (BCI) is proving to be one of the great advances in neuroscience today. The development of surface electrodes over the cortex and very fine electrodes that can be stereotactically implanted in the brain have moved the science forward to the extent that paralyzed people can play chess and blind people can read letters. However, the introduction of foreign bodies into deeper parts of the central nervous system results in foreign body reaction, scarring, apoptosis, and decreased signaling. Implanted electrodes activate microglia, causing the release of inflammatory factors, the recruitment of systemic inflammatory cells to the site of injury, and ultimately glial scarring and the encapsulation of the electrode. Recordings historically fail between 6 months and 1 year; the longest BCI in use has been 7 years. This article proposes a biomolecular strategy provided by angiogenic cell precursors (ACPs) and nerve cell precursors (NCPs), administered intrathecally. This combination of cells is anticipated to sustain and promote learning across the BCI. Together, through the downstream activation of neurotrophic factors, they may exert a salutary immunomodulatory suppression of inflammation, anti-apoptosis, homeostasis, angiogenesis, differentiation, synaptogenesis, neuritogenesis, and learning-associated plasticity. Full article

Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized ¹³C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized ¹³C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) ¹H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response. Full article

Mangrove wetlands, acting as significant traps for marine debris, have received insufficient attention in previous research. Here, we conduct the first comprehensive investigation into the magnitude, accumulation, source, and fate of marine debris across seven mangrove areas in the northern South China Sea (MNSCS) during 2019–2020. Systematic field surveys employed stratified random sampling, partitioning each site by vegetation density and tidal influence. Marine debris were collected and classified in sampling units by material (plastic, fabric, styrofoam), size (categorized into small, medium, and large), and origin (distinguishing between land-based and sea-based). Source identification and potential risk assessment were achieved through the integration of debris feature analysis. The results indicate relatively low debris levels in MNSCS mangroves, with plastics dominant. More than 70% of all debris weight with plastics (48.34%) and fabrics (14.59%) is land-based, and more than 70% comes from coastal/recreational activities. More than 90% of all debris items with plastics (52.50%) and Styrofoam (36.32%) are land-based, and more than 90% come from coastal/recreational activities. Medium/large-sized debris are trapped in mangrove wetlands under the influencing conditions of local tidal level, debris item materials, and sizes. Our study quantifies marine debris characteristics, sources, and ecological potential risks in MNSCS mangroves. From environmental, economic, and social sustainability perspectives, our findings are helpful for guiding marine debris management and mangrove conservation. By bridging research and policies, our work balances human activities with ecosystem health for long-term sustainability. Full article

Rapid economic growth has led to an increase in the use of multilayer plastic packaging, which involves complex polymer compositions and hinders recycling. This study investigated the catalytic pyrolysis of plastic packaging waste in a 3000 cm³ semibatch reactor, aiming to optimize kerosene-like hydrocarbon production. The temperature (420–500 °C), N₂ flow rate (25–125 mL/min), and catalyst loading (5–20 wt.%) were examined individually and in combination with activated carbon and an Fe-doped dolomite (Fe/DM) catalyst. Central composite design (CCD) and response surface methodology (RSM) were used to identify the optimal conditions and synergistic effects. Pyrolysis product analysis involved simulation distillation gas chromatography (Sim-DGC), gas chromatography/mass spectrometry (GC/MS), and Fourier transform infrared (FT-IR) spectroscopy. The optimal conditions (440 °C, 50 mL/min N₂ flow, catalyst loading of 10 wt.% using a 5 wt.% Fe-doped dolomite-activated carbon 0.6:0.4 mass/molar ratio) yielded the highest pyrolysis oil (79.6 ± 0.35 wt.%) and kerosene-like fraction (22.3 ± 0.22 wt.%). The positive synergistic effect of Fe/DM and activated carbon (0.6:0.4) enhanced the catalytic activity, promoting long-chain polymer degradation into mid-range hydrocarbons, with secondary cracking yielding smaller hydrocarbons. The pore structure and acid sites of the catalyst improved the conversion of intermediate hydrocarbons into aliphatic compounds (C₅–C₁₅), increasing kerosene-like hydrocarbon production. Full article

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. Full article

Microplastic pollution presents a significant and rising risk to both ecological integrity and the long-term viability of economic activities reliant on marine ecosystems. The Black Sea, a region sustaining economic sectors such as fisheries, tourism, and maritime transport, is increasingly vulnerable to this form of contamination. Mytilus galloprovincialis, a well-established bioindicator, accumulates microplastics, providing a direct measure of environmental pollution and indicating potential economic consequences deriving from degraded ecosystem services. While previous studies have documented microplastic pollution in the Black Sea, our paper specifically quantified microplastic contamination in M. galloprovincialis collected from four sites along the western Black Sea coast, each characterised by distinct levels of anthropogenic influence: Midia Port, Constanta Port, Mangalia Port, and 2 Mai. We used statistical analysis to quantify site-specific microplastic contamination in M. galloprovincialis and employed machine learning to develop models predicting accumulation patterns based on environmental variables. Our findings demonstrate the efficacy of mussels as bioindicators of marine plastic pollution and highlight the utility of machine learning in developing effective predictive tools for monitoring and managing marine litter contamination in marine environments, thereby contributing to sustainable economic practices. Full article

Although some GABA_A receptor subtypes are involved in both the passive permeability of anions and the ATP-dependent recovery of neuronal anion concentrations, the molecular mechanisms that ensure the coordination of passive and active transport processes remain unclear. Here we used fluorescence measurements to investigate the role of genistein (tyrosine kinase inhibitor) and vanadate (tyrosine phosphatase and ATPase inhibitor) in modulating GABA_AR-mediated [Cl⁻]_i/[HCO₃⁻]_i changes and ATPase activity in rat cortical neurons and HEK 293FT cells expressing the heteropentameric α2β3γ2 GABA_AR isoform. We found that genistein plays an important role in the inhibition of passive GABA_AR-mediated Cl⁻ influx and Cl⁻ATPase activity, whereas vanadate plays an important role in the inhibition of Cl⁻, HCO₃⁻ATPase activity and ATP-dependent recovery of [HCO₃⁻]_i via changes in the formation of the phosphorylated intermediate. The effect of blockers was significantly restored in the presence of phenol. In behavioral experiments, the administration of phenol has been established to induce tremors and head twitching in rats, with the involvement of GABA_AR/ATPase in these behavioral responses. Genistein can reduce the adverse effects of phenol, thereby confirming the interaction of these chemicals when binding to binding receptor sites. While our data demonstrate the opposing roles of genistein and vanadate in modulating GABA_AR/ATPase function in a bicarbonate-dependent manner. Such multidirectional systems are considered to be bistable elements involved in the regulatory mechanisms of synaptic plasticity. Full article

Climate change has negatively impacted species worldwide. Ectotherms, including reptiles, are at particular risk of local extirpation. Numerous reptile species vary in their climate response across latitude and altitude; therefore, understanding how climate change impacts populations is vital. Thermoregulation trades off with hydroregulation; therefore, both must be included when investigating response to microclimate. Here we investigated behavioural responses to temperature and relative humidity in three latitudinally distinct lineages of Tiliqua adelaidensis, a cryptic, burrow-dwelling endangered lizard endemic to South Australia. A monthly field-based approach distance method was adopted in the spring of 2022 in the wild and at a southerly trial translocation site. The behaviour of wild northern latitude lizards was linked with the microclimate, prioritising surface activity under moderate conditions. Wild and translocated northern lizards reduced approach distance and were only observed on the surface when base-of-burrow humidity was high, suggesting a plasticity lag or limit for this population. There was some evidence of translocation acclimatisation; however, our results suggest acclimatisation may take longer than two years and may vary with latitude of origin. While lineages may be limited in their ability to adjust to increasing temperatures under climate change, these lizards may cope with translocation as a mitigation strategy in the longer term. Full article

The Clonostachys genus is a saprophytic soil microfungus (Ascomycota). It exhibits significant ecological adaptability and plays a crucial role in maintaining the balance of soil microorganisms. Species within this genus are natural antagonists of insects and nematodes, and they also combat phytopathogenic fungi through mycoparasitism. This process involves producing lytic enzymes and competing for space and nutrients. Clonostachys species are effective biocontrol agents in agriculture and have been utilized to manage pests affecting many high-value commercial crops, acting as a natural biopesticide. They inhabit plant tissues, boosting plant defenses and activating genes for water and nutrient uptake, enhancing plant performance. Additionally, they produce enzymes and bioactive metabolites with antimicrobial, antifungal, nematocidal, anticancer, and antioxidant properties. Clonostachys species can degrade plastic waste and remove hydrocarbons from crude oil-contaminated sites when functioning as endophytes, positioning Clonostachys as a promising candidate for reducing environmental pollution. There are still challenges and limitations, such as the continuous surveillance of the safety of Clonostachys species on plants, the establishment of commercial applications, formulation viability, and variability due to field conditions. These issues will have to be addressed. This review provides an overview of Clonostachys ecology, morphology, classification, and biotechnological applications, emphasizing its significance in various fields. Full article

Chemical recycling of plastic waste, especially polyolefins, into valuable liquid fuels is of considerable significance to address the serious issues raised by their threat on environmental and human health. Nevertheless, the construction of efficient and economically viable catalytic systems remains a significant hurdle. Herein, we developed an efficient bifunctional catalyst system comprising γ-Al₂O₃-supported ruthenium nanoparticles (Ru/γ-Al₂O₃) and β-zeolite for the conversion of polyolefins into gasoline-range hydrocarbons. A yield of C_5–12 paraffins up to 73.4% can be obtained with polyethene as the reactant at 250 °C in hydrogen. The Ru sites primarily activate the initial cleavage of C–H bonds of polymer towards the formation of olefin intermediates, which subsequently go through further cracking and isomerization over the acid sites in β-zeolite. Employing in situ infrared spectroscopy and probe–molecule model reactions, our investigation reveals that the optimized proportion and spatial distribution of the dual catalytic sites are pivotal in the tandem conversion process. This optimization synergistically regulates the cracking kinetics and accelerates intermediate transfer, thereby minimizing the production of side C_1–4 hydrocarbons resulting from over-cracking at the Ru sites and enhancing the yield of liquid fuels. This research contributes novel insights into catalyst design for the chemical upgrading of polyolefins into valuable chemicals, advancing the field of plastic waste recycling and sustainable chemical production. Full article

The plastic profile of construction waste is varied and complex, particularly when compared to other waste streams such as timber, concrete, metals, and plasterboard. There are fewer incentives for recycling this low-density, low-value waste stream. Plastic waste generated by construction activities remains poorly characterised, obstructing efforts to optimise reduction, reuse, and recycling practices. To understand its types and sources, and better address plastic waste management, this study audited plastic waste produced across six new-build construction sites in Auckland, New Zealand. A total of 7.2 tonnes of plastic construction waste was collected on-site and audited. Plastics were separated, weighed, and categorised by function and construction stage. Polymer type was determined using Fourier transform infrared (FTIR) spectroscopy. In total, 62% of plastic waste was diverted from landfill through reuse or recycling. On average, 0.61 kg of plastic was generated per m² of construction. Soft plastics were the most generated by mass (33%), followed by PVC and HDPE pipes (22%), shrink wrap (12%), and expanded polystyrene (5%). The majority of plastic waste was generated in the final stages of the projects. The authors recommend the separation of soft plastic, pipes, shrink wrap, and polystyrene on construction sites, particularly towards the finishing stages of construction. Full article

The Squamosa promoter-binding protein-like (SPL) family proteins plays pivotal roles in plant development and stress adaptation. In this study, we functionally characterized MaSPL8 in mulberry (Morus alba) and investigated its regulatory roles in biotic and abiotic stress responses. MaSPL8 encodes a 364-amino acid protein with a conserved SBP domain and lacks miR156/157 binding sites. Phylogenetic analysis confirmed its orthology to Arabidopsis AtSPL8, albeit with functional divergence. Downregulation of MaSPL8 via virus-induced gene silencing (VIGS) resulted in more susceptibility to Ciboria shiraiana infection, but significantly enhanced resistance to drought and salt stress, as evidenced by reduced oxidative damage, elevated proline accumulation, and increased antioxidant enzyme activities. Transcriptomic profiling of MaSPL8-silenced plants revealed enrichment of differentially expressed genes (DEGs) in brassinosteroid biosynthesis, jasmonic acid metabolism, and oxidative stress responses, suggesting hormone signaling interplay. Furthermore, bioinformatic predictions identified miR5658 and miR4221 as potential post-transcriptional regulators of MaSPL8. This study highlights MaSPL8 as a negative regulator of abiotic stress tolerance and positive regulator of biotic (C. shiraiana) stress tolerance in mulberry and provides insights into its integration with phytohormone pathways. Our findings underscore the evolutionary plasticity of SPL8 genes and propose MaSPL8 as a target for enhancing mulberry’s resilience in challenging environments. Full article