Substantial Release Research Articles

Pharmaceutical prospects of pomegranate antioxidants in combating microbial infections

ABSTRACT Pomegranates, which are renowned for their diverse bioactive phytochemicals with antioxidant, anti-inflammatory, and antimicrobial properties, have garnered significant interest in the field of natural medicine. This study aimed to systematically investigate the phytochemical content, bioavailability, and antimicrobial effects of extracts derived from different parts of three Jordanian pomegranate cultivars, Kodari, Qerati, and Black. Comprehensive quantitative analyses revealed significantly higher phenolic content and antioxidant capacities in peel extracts, particularly in the Black and Qerati cultivars. The total phenolic content was determined using the Folin-Ciocalteu colorimetric assay, and the antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Bioavailability was determined using stimulated gastrointestinal digestion assays, revealing controlled release in gastric fluid compared to more substantial release in intestinal fluid, thereby suggesting potential implications for bioavailability. Furthermore, antimicrobial assays showed promising antibacterial effects against Staphylococcus aureus in a time-dependent manner, although the efficacy varied among the cultivars and components. These findings underscore the multifaceted bioactive potential of pomegranate extracts, particularly those derived from optimized peel extracts, positioning them as promising natural preservatives or functional ingredients. However, further research is warranted to delve into specific bioactive constituents, absorption mechanisms, and their potential applications in diverse fields, such as foods, nutraceuticals, and pharmaceuticals. By expanding the current understanding of the factors influencing pomegranate bioactivities, this study lays the groundwork for tailored utilization of pomegranate fractions based on ideal phytochemical profiles and targeted effects.

Design and evaluation of a multi-epitope DNA vaccine against HPV16

ABSTRACT Cervical cancer, among the deadliest cancers affecting women globally, primarily arises from persistent infection with high-risk human papillomavirus (HPV). To effectively combat persistent infection and prevent the progression of precancerous lesions into malignancy, a therapeutic HPV vaccine is under development. This study utilized an immunoinformatics approach to predict epitopes of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) using the E6 and E7 oncoproteins of the HPV16 strain as target antigens. Subsequently, through meticulous selection of T-cell epitopes and other necessary elements, a multi-epitope vaccine was constructed, exhibiting good immunogenic, physicochemical, and structural characteristics. Furthermore, in silico simulations showed that the vaccine not only interacted well with toll-like receptors (TLR2/TLR3/TLR4), but also induced a strong innate and adaptive immune response characterized by elevated Th1-type cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL2). Additionally, our study investigated the effects of different immunization intervals on immune responses, aiming to optimize a time-efficient immunization program. In animal model experiments, the vaccine exhibited robust immunogenic, therapeutic, and prophylactic effects. Administered thrice, it consistently induced the expansion of specific CD4 and CD8 T cells, resulting in substantial cytokines release and increased proliferation of memory T cell subsets in splenic cells. Overall, our findings support the potential of this multi-epitope vaccine in combating HPV16 infection and signify its candidacy for future HPV vaccine development.

Potential high-risk release sources of thallium and arsenic from surrounding rocks of a typical thallium and arsenic mining area in southwest China

Abundant naturally and anthropogenically exposed surrounding rocks (NESRs and AESRs) in mining areas may pose persistent threats as sources of potentially toxic elements (PTEs), but this has been historically overlooked, especially for thallium (Tl) and arsenic (As). Here, the release risks of Tl and As from both NESRs and AESRs in a typical TlAs sulfide mining area were investigated. In a single leaching process, AESRs released 10.4 % of total Tl (157 μg L−1) and 32.5 % of total As (4089 μg L−1), 2–3 orders of magnitude higher than NESRs. Prolonged multiple leaching tests revealed notable and long-term risks of release of Tl and As from AESRs, associated with oxidation and dissolution of iron/sulfur-bearing minerals. Substantial release of PTEs was linked to the transformation/degradation of the -OH functional group and extensive dissolution of secondary sulfate minerals in AESRs. Ultrafiltration and STEM-EDS indicate that 18.4 % of water-extracted As released from AESRs existed as natural nanoparticles consisting of iron/sulfur-bearing minerals. This study highlights the high risks of Tl and As release from anthropogenically exposed surrounding rocks and the importance of nanoparticles in PTE transport, and provides insights into the control of PTEs in mining areas.

Understanding Demographic Factors Influencing Open Burning Incidents in Kentucky

Open burning poses a significant threat to human health and the environment by releasing hazardous chemicals and exacerbating plastic pollution. Urgent action is required to address its pervasive impact and the substantial release of gaseous pollutants. Limited research has explored the demographic aspect of open burning behavior, with none specifically conducted in Kentucky. An analysis of open burning complaints reported to the Kentucky Division for Air Quality in 2015, 2019, and 2021 revealed no significant differences in reported incidents by month and county. Binary logistic regression analyses identified the urban vs rural divide as significant predictors of open burning incidents, while violations were influenced by both urban and rural factors and average household income. Unemployment rates and the percentage of individuals with less than a high school diploma did not significantly predict open burning violations. Targeted interventions at the state and local level, focusing on rural areas and economically disadvantaged communities, can effectively address and mitigate open burning issues.

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion.

The pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that treating damaged rat lungs by a transient heat stress during ex-vivo lung perfusion (EVLP) to elicit a pulmonary heat shock response could protect the endothelium from severe reperfusion injury. Rat lungs damaged by 1h warm ischemia were reperfused on an EVLP platform for up to 6h at a constant temperature (T°) of 37°C (EVLP37°C group), or following a transient heat stress (HS) at 41.5°C from 1 to 1.5h of EVLP (EVLPHS group). A group of lungs exposed to 1h EVLP only (pre-heating conditions) was added as control (Baseline group). In a first protocol, we measured lung heat sock protein expression (HSP70, HSP27 and Hsc70) at selected time-points (n=5/group at each time). In a second protocol, we determined (n=5/group) lung weight gain (edema), pulmonary compliance, oxygenation capacity, pulmonary artery pressure (PAP) and vascular resistance (PVR), the expression of PECAM-1 (CD31) and phosphorylation status of Src-kinase and VE-cadherin in lung tissue, as well as the release in perfusate of cytokines (TNFα, IL-1β) and endothelial biomarkers (sPECAM, von Willebrand Factor -vWF-, sE-selectin and sICAM-1). Histological and immunofluorescent studies assessed perivascular edema and formation of 3-nitrotyrosine (a marker of peroxinitrite) in CD31 lung endothelium. HS induced an early (3h) and persisting expression of HSP70 and HSP27, without influencing Hsc70. Lungs from the EVLP37°C group developed massive edema, low compliance and oxygenation, elevated PAP and PVR, substantial release of TNFα, IL-1β, s-PECAM, vWF, E-selectin and s-ICAM, as well as significant Src-kinase activation, VE-cadherin phosphorylation, endothelial 3-NT formation and reduced CD31 expression. In marked contrast, all these alterations were either abrogated or significantly attenuated by HS treatment. The therapeutic application of a transient heat stress during EVLP of damaged rat lungs reduces endothelial permeability, attenuates pulmonary vasoconstriction, prevents src-kinase activation and VE-cadherin phosphorylation, while reducing endothelial peroxinitrite generation and the release of cytokines and endothelial biomarkers. Collectively, these data demonstrate that therapeutic heat stress may represent a promising strategy to protect the lung endothelium from severe reperfusion injury.

Deflagration characteristics of N2 diluted propanal/air mixtures at elevated pressures

Hydrocarbon fuels, in addition to being direct sources of energy, also serve as crucial raw materials for numerous industrial processes. In this study, the oxidation of propanal to propionic acid under elevated pressures has garnered our attention due to the substantial heat release during the mixing of propanal and oxidants, posing considerable hazards to production. Fortunately, the introduction of N2 effectively mitigates these risks by reducing the laminar burning speed (SL) and peak deflagration pressure (Pm), and even preventing the ignition of mixtures. On this basis, the deflagration characteristics of propanal/N2/air mixtures were investigated in a 20 L spherical vessel at 348 K under various equivalent ratios (φ, 0.5 - 2.0), dilution rates (D, 0 - 0.5) and initial pressures (P0, 0.1 - 1.0 MPa). The combustion characteristics of propanal/N2/air were also analyzed through the 1-D laminar flame speed model, and the sensitivity analysis was performed to elucidate the effect of φ, D and P0 on the combustion of propanal. Results reveal that the addition of N2 stabilizes the flame propagation, and the Pm of propanal/N2/air mixtures decreases with the increasing D, with a sudden drop observed at a certain D level. However, the reduction of SL does not undergo an abrupt decrease across the entire dilution rate range. Furthermore, Pm exhibits a linear relationship with P0 at lower D, but this linear trend disappears once D approaches the critical suppression concentration. Interestingly, the critical suppression concentration of N2 increases with P0 at fuel-rich conditions, yet remains unaffected by P0 at fuel-lean conditions. Near the critical suppression concentration, a limiting burning speed (Slim) emerges, below which the flame is incapable of spontaneous propagation. Notably, Slim is not a fixed value, but varies according to the composition and initial state of the mixture. For a given gas component, an increase in P0 leads to a decline in Slim, while for gases with varying components, Slim is observed to be lower under fuel-rich conditions compared to fuel-lean scenarios. Also, both the addition of N2 and the augmentation of P0 significantly reduce the SL. When SL is comparable to the gas rise speed due to natural convection, the flame propagation becomes vulnerable to buoyancy instability. Meanwhile, the flame propagation may also be influenced by thermal diffusion instability and hydrodynamic instability. Under the combined effect of these instabilities, the flame is prone to be unstable. More importantly, when the flame contacting the upper wall of the is in a critical state where it can or cannot propagate downward, the irregularity of the disturbed flame may introduces uncertainty into the subsequent propagation, resulting in markedly different Pm even among mixtures with identical compositions.

Terbuthylazine induces oxidative stress and mitophagy through activating cGAS-STING pathway in chicken jejunum

Terbuthylazine (TBA) is a widely employed pesticide that has been found to be a significant source of food and environmental pollution. Excessive exposure to TBA raises considerable apprehension regarding its potential impact on biological health, but its underlying toxic mechanisms have not been reported. Our findings indicated that TBA exposure could cause intestinal damage, as evidenced by decrease in the quantity of cupped cells and decrease in the expression of intestinal barrier-related proteins (Claudin-1, Occludin, ZO-1, and JAM-1). Additionally, exposure to TBA resulted in a significant decrease in the expression levels of oxidative stress-related genes and proteins. Furthermore, the expression of 8-hydroxy-2′-deoxyguanosine was significantly upregulated. Additionally, excessive exposure to TBA led to a substantial release of mitochondrial DNA, which further activated the cGAS-STING pathway and caused TBK1 and IRF3 phosphorylation. Meanwhile, mitophagy was activated under TBA exposure, as evidenced by decrease in the protein and gene levels of p62 and increase in the levels of PINK1, PARKIN and LC3 II. Therefore, our results suggested that TBA exposure induced oxidative stress in the jejunum and caused mtDNA leakage, for activating the cGAS-STING pathway, which in turn promoted mitophagy. These findings revealed the toxicity mechanisms of TBA, which provided new insights into food safety caused by pesticide contamination.

Perforation performance and mechanism of a torch utilizing Al/PTFE/Fe2O3/CuO thermite composites

Aluminum-based thermite containing fluorine oxidizers exhibits excellent performance characteristics such as substantial heat release and tunable gas production. In this study, a torch loaded with Al/PTFE/Fe2O3/CuO thermite composites was recently designed to eject high-temperature jets and penetrate 10 mm-thick Q235 steel plates. The reactivity of the loading composites was systematically studied to analyze the perforation mechanism. The microstructure, the flame temperature, and pressure properties of the thermites were tested. The device’s perforation capacity was quantified. The research confirmed the application potential of fluoropolymer-based thermites in the field of metal perforation. The results of the pressure tests suggest that the composites have a synergistic effect on pressure properties, resulting in better peak pressure than single thermite. The fuel-rich thermite exhibited a higher flame temperature and heat of combustion. It is observed that the perforation velocity increased with the increase in flame temperature and peak pressure. By adjusting the Al and PTFE content of the near fuel-rich thermites, the torch with different equivalence ratios exhibited a tunable perforation time ranging from 0.4 s to 5.21 s. It is hypothesized that the formation of the alloy layer on the surface of the metal targets plays a significant role in the perforation process by weakening the strength of the plates and improving the mobility of the molten area. The results provide a new and practical path to designing efficient perforation agents.

Divergent effects of copper oxide nanoparticles on methanotrophs: Stimulation at low concentrations and inhibition at high concentrations

Methanotrophs represent pivotal microorganisms, integral to the regulation of global methane emissions. Upon introduction into the environment, copper oxide nanoparticles (CuO NPs), a frequently employed category of inorganic nanomaterials, possess the potential to exert influences on methanotrophs. This study investigated the impact of CuO NPs on methanotrophs, showing a clear concentration-dependent response. Under high concentrations, exposure of methanotrophs to CuO NPs induced the production of reactive oxygen species, compromised cell membrane integrity, and resulted in the substantial release of lactate dehydrogenase. The expressions of genes encoding methane monooxygenase were obviously down-regulated. Whereas under low concentrations, a distinct enhancement of bacterial growth and metabolism was observed. The presence of methanotrophs facilitated the release of Cu2+ from CuO NPs, and the Cu2+ stimulated the biosynthesis of particulate methane monooxygenase reversely. Compared to the cellular toxicity of CuO NPs as nanoparticles, the released Cu2+ exerted a more pronounced promoting effect on methanotrophs growth, resulting in an overall strengthened methane metabolism. Significant alterations were observed in genes encoding copper uptake and resistance, cytochrome-related and heme-related proteins. This study provides novel insights into interactions between methanotrophs and nanoparticles, thereby advancing our comprehension of the impact of CuO NPs on methane emissions within an environmental context.

Methotrexate-loaded manganese nitrogen dual-doped carbon quantum dots as targeted nano drug-delivery system for potential use in cancer theranostics

The present work highlights manganese nitrogen dual-doped carbon quantum dots as a novel pH-sensitive drug delivery system, for the delivery of methotrexate, targeted to cancer cells, along with the simultaneous real-time monitoring of cellular uptake and drug delivery using fluorescence imaging. Briefly, methotrexate was conjugated with the as-prepared quantum dots to form a nano drug-delivery system through non-covalent interactions. The developed material demonstrated drug loading efficiency of ∼91 % and a very efficient (∼80 %) pH-responsive drug release at pH 5.5. The cytotoxic properties of the developed nano-platform viz. manganese, nitrogen dual-doped carbon quantum dots, and methotrexate conjugated manganese nitrogen dual-doped carbon quantum dot complex were evaluated in cancer cells (HeLa) and healthy human cells (L929). The conjugated complex demonstrated excellent biocompatibility, high cellular uptake, and a substantial drug release. Healthy human cells were largely unaffected when incubated with both the MTX-conjugated Mn-, N-CQD and the free drug. Additionally, in vitro, the fluorescence bio-imaging potential of the developed nano-platform was also assessed, where the unconjugated (free) quantum dots exhibited better blue fluorescence imaging potential compared to that of the conjugated complex, which can be attributed to fluorescence quenching due to the presence of methotrexate. This study highlights the manganese nitrogen dual-doped carbon quantum dots capable of pH-responsive methotrexate drug delivery selective to cancer cells. The combination of drug delivery and fluorescence imaging creates an efficient platform for targeted therapy, allowing very precise drug release while accessing non-invasive monitoring of therapeutic response. This method holds a great promise for advancing cancer treatment strategies, with the potential for increased efficacy and decreased side effects.

Can China Reach Its Carbon Peak Before 2030? An Empirical Study Based on China's Carbon Emission Data

The global surge in the warming trend is predominantly attributed to the substantial release of greenhouse gases, notably carbon dioxide. Despite continuous international efforts to curb these emissions, our country, marked by the largest population and energy consumption, stands as a major contributor to carbon dioxide emissions. Unlike developed nations, we face a more formidable challenge in reducing emissions, demanding intensified endeavors. To address climate change, our nation has set a crucial carbon emission target: achieving a carbon peak before 2030 and attaining carbon neutrality by 2060. The "14th Five-Year Plan" of each province underscores the significance of "carbon peaking and carbon neutrality," tailoring emission reduction policies to individual economic landscapes. Current research inadequacies hinder theoretical guidance needed to meet the 2030 carbon peak. Crafting province-specific emission reduction strategies is thus imperative. This study aims to scrutinize national and regional carbon dioxide emissions in four distinct Chinese regions, utilizing the STIRPAT model to predict emissions from 2020 to 2030 under the "low development and strong low carbon" paradigm. Initial analysis from 2004 to 2019 showed an annual increase in national and provincial carbon dioxide emissions, revealing significant regional differences. Six prominent factors influencing emissions were identified. The STIRPAT model predicted emissions for 2020 to 2030, indicating that achieving carbon peaking before 2030 is unfeasible under the baseline scenario. However, within the "low development and strong low carbon" framework, attaining this goal becomes plausible.

Peptidoglycan fragment release and NOD activation by commensal Neisseria species from humans and other animals.

Neisseria gonorrhoeae, a human restricted pathogen, releases inflammatory peptidoglycan (PG) fragments that contribute to the pathophysiology of pelvic inflammatory disease. The genus Neisseria is also home to multiple species of human- or animal-associated Neisseria that form part of the normal microbiota. Here we characterized PG release from the human-associated nonpathogenic species Neisseria lactamica and Neisseria mucosa and animal-associated Neisseria from macaques and wild mice. An N. mucosa strain and an N. lactamica strain were found to release limited amounts of the proinflammatory monomeric PG fragments. However, a single amino acid difference in the PG fragment permease AmpG resulted in increased PG fragment release in a second N. lactamica strain examined. Neisseria isolated from macaques also showed substantial release of PG monomers. The mouse colonizer Neisseria musculi exhibited PG fragment release similar to that seen in N. gonorrhoeae with PG monomers being the predominant fragments released. All the human-associated species were able to stimulate NOD1 and NOD2 responses. N. musculi was a poor inducer of mouse NOD1, but ldcA mutation increased this response. The ability to genetically manipulate N. musculi and examine effects of different PG fragments or differing amounts of PG fragments during mouse colonization will lead to a better understanding of the roles of PG in Neisseria infections. Overall, we found that only some nonpathogenic Neisseria have diminished release of proinflammatory PG fragments, and there are differences even within a species as to types and amounts of PG fragments released.

Dual Self-Assembly of Puerarin and Silk Fibroin into Supramolecular Nanofibrillar Hydrogel for Infected Wound Treatment.

The treatment of infected wounds remains a challenging biomedical problem. Some bioactive small-molecule hydrogelators with unique rigid structures can self-assemble into supramolecular hydrogels for wound healing. However, they are still suffered from low structural stability and bio-functionality. Herein, a supramolecular hydrogel antibacterial dressing with a dual nanofibrillar network structure is proposed. A nanofibrillar network created by a small-molecule hydrogelator, puerarin extracted from the traditional Chinese medicine Pueraria, is interconnected with a secondary macromolecular silk fibroin nanofibrillar network induced by Ga ions via charge-induced supramolecular self-assembly. The resulting hydrogel features adequate mechanical strength for sustainable retention at wounds. Good biocompatibility and efficient bacterial inhibition are obtained when the Ga ion concentration is 0.05%. Otherwise, the substantial release of Ga ions and puerarin endows the hydrogel with excellent hemostatic and antioxidative properties. In vivo, evaluation of a mouse-infected wound model demonstrates that its healing effect outperformed that of a commercially available silver-containing wound dressing. The experimental group successfully achieves a 100% wound closure rate on day 10. This study sheds new light on the design of nanofibrillar hydrogels based on supramolecular self-assembly of naturally derived bioactive molecules as well as their clinical use for treating chronic infected wounds.

Regulating Effect of Exogenous α-Ketoglutarate on Ammonium Assimilation in Poplar.

Extensive industrial activities and anthropogenic agricultural practices have led to substantial ammonia release to the environment. Although croplands can act as ammonia sinks, reduced crop production under high concentrations of ammonium has been documented. Alpha-ketoglutarate (AKG) is a critical carbon source, displaying pleiotropic physiological functions. The objective of the present study is to disclose the potential of AKG to enhance ammonium assimilation in poplars. It showed that AKG application substantially boosted the height, biomass, and photosynthesis activity of poplars exposed to excessive ammonium. AKG also enhanced the activities of key enzymes involved in nitrogen assimilation: glutamine synthetase (GS) and glutamate synthase (GOGAT), elevating the content of amino acids, sucrose, and the tricarboxylic acid cycle (TCA) metabolites. Furthermore, AKG positively modulated key genes tied to glucose metabolism and ATP synthesis, while suppressing ATP-depleting genes. Correspondingly, both H+-ATPase activity and ATP content increased. These findings demonstrate that exogenously applying AKG improves poplar growth under a high level of ammonium treatment. AKG might function through sufficient carbon investment, which enhances the carbon-nitrogen balance and energy stability in poplars, promoting ammonium assimilation at high doses of ammonium. Our study provides novel insight into AKG's role in improving poplar growth in response to excess ammonia exposure.

Research on enhancing sewage sludge lysis and bioreactor initiation through composite thermophilic strains

Returning lysed sludge to biochemical tanks to achieve in-situ sludge reduction is promising. A novel approach for regulating and initiating the sludge lysis process utilizing thermophilic strains is proposed. In this study, three strains were isolated from sludge, and sequencing of the 16 S rDNA amplicon revealed that the three thermophilic strains were the closest relatives to the genus Geobacillus, and they were designated as Geobacillus sp. DX5, Geobacillus sp. DX8 and Geobacillus sp. DX11. Sludge lysis experiments demonstrated that composite thermophilic strains (CTS) were dosed at 65°C, and the sludge VSS removal efficiency after 24 h was 37.8%, significantly surpassing individual strains. Moreover, 65.8% of proteins and 52.0% of polysaccharides in Extracellular polymeric substances (EPS) of sludge were degraded. Furthermore, Three-dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy results revealed a substantial release of dissolved organic matter during sludge lysis. Inoculation of CTS under optimal conditions (65°C, pH 7, 4 × 1010cfu/L) resulted in VSS removal efficiency and protease activity of 42.7% and 2584 U/L, respectively. After 20 days of inoculation with CTS to initiate sludge lysis reactor, VSS removal efficiency reached 46%. Additionally, it stimulated the growth of the thermophilic bacterial community, engaging indigenous thermophilic strains in the sludge lysis process.

Performance of microbial inoculation and tricalcium phosphate on nitrogen retention and conversion: Core microorganisms and enzyme activity during kitchen waste composting

The substantial release of NH3 during composting leads to nitrogen (N) losses and poses environmental hazards. Additives can mitigate nitrogen loss by adsorbing NH3/NH4, adjusting pH, and enhancing nitrification, thereby improving compost quality. Herein, we assessed the effects of combining bacterial inoculants (BI) (1.5%) with tricalcium phosphate (CA) (2.5%) on N retention, organic N conversion, bacterial biomass, functional genes, network patterns, and enzyme activity during kitchen waste (KW) composting. Results revealed that adding of 1.5%/2.5% (BI + CA) significantly (p < 0.05) improved ecological parameters, including pH (7.82), electrical conductivity (3.49 mS/cm), and N retention during composting. The bacterial network properties of CA (265 node) and BI + CA (341 node) exhibited a substantial niche overlap compared to CK (210 node). Additionally, treatments increased organic N and total N (TN) content while reducing NH4+-N by 65.42% (CA) and 77.56% (BI + CA) compared to the control (33%). The treatments, particularly BI + CA, significantly (p < 0.05) increased amino acid N, hydrolyzable unknown N (HUN), and amide N, while amino sugar N decreased due to bacterial consumption. Network analysis revealed that the combination expanded the core bacterial nodes and edges involved in organic N transformation. Key genes facilitating nitrogen mediation included nitrate reductase (nasC and nirA), nitrogenase (nifK and nifD), and hydroxylamine oxidase (hao). The structural equation model suggested that combined application (CA) and microbial inoculants enhance enzyme activity and bacterial interactions during composting, thereby improving nitrogen conversion and increasing the nutrient content of compost products.

Lithium isotope fractionation during submarine hydrothermal alteration processes

River water and submarine hydrothermal fluids are the two primary sources of lithium (Li) input to the ocean. However, compared to well-documented weathering processes, the behavior of Li isotopes during hydrothermal alteration processes remains obscure. In this research, we investigated the Li isotopic compositions (δ7Li) of hydrothermally altered sediments from two IODP drilling cores (C0013 and C0014) in the Iheya North Knoll of the middle Okinawa Trough. The sediments, primarily altered from volcanic clasts, exhibit a pristine δ7Li value (5.2 ± 0.7 ‰) similar to that of MORB (3.7 ± 1 ‰). Intense hydrothermal activity led to the complete conversion of primary feldspars into phyllosilicates, predominantly Mg-chlorite, at site C0013 and in the middle and deep parts of C0014. The altered samples showed a depletion of 7Li (ranging in δ7Li from −10.0 ‰ to 4.2 ‰) compared to background sediment, indicating the preferential incorporation of 6Li during the formation of secondary minerals. Furthermore, both drilling sites exhibited increasing trends in δ7Li values with depth, with the deepest samples approaching the pristine δ7Li values of unaltered volcanic rock. These trends were attributed to the significant thermal gradients present at both sites. The temperature-dependent fractionation factor of Li isotopes allowed us to estimate the alteration temperature, which yielded temperature values consistent with those obtained using the δ18O geothermometer. This finding underscores the potential of Li isotopes as a novel geothermometer tool, although further calibration work is required. Based on our research findings, we developed a dissolution-precipitation model (based on mass balance) that establishes a relationship between the δ7Li values of altered solids and hydrothermal fluids, with the aim of elucidating the relatively limited variation observed in global submarine hydrothermal fluids (ranging from 1.6 ‰ to 11.0 ‰, with an averaged value of 5.9 ± 3.0 ‰, mean ± SD). This model quantitatively depicted the strong restriction of the Li concentration in hydrothermal fluids on their isotopic compositions, as high concentrations of Li in the fluids necessitate a substantial release of Li from the solid phase, causing the fluids' δ7Li values to approach that of the bedrock. Additionally, limited fractionation factors at high temperatures further constrain the variations in the fluids' δ7Li values. Model predictions also suggest that the reported δ7Li values of hydrothermal fluids have encompassed the potential δ7Li variation, providing supporting evidence for the assumption that δ7Li values of submarine hydrothermal fluids have exhibited insignificant variations throughout Earth's history.

Scaffold hopping derived novel benzoxazepinone receptor-interacting protein kinase 1 (RIP1) inhibitors as anti-necroptosis agents: Anti-inflammatory effect in systemic inflammatory response syndrome (SIRS) and epilepsy

Necroptosis is a type of regulated cell death known for its pro-inflammatory nature due to the substantial release of cellular contents. The phosphorylation of key proteins, namely RIP1, RIP3, and mixed lineage kinase domain-like protein (MLKL), plays a pivotal role in the processes associated with necroptosis. Consequently, inhibiting the phosphorylation of any of these three key protein kinases could effectively block necroptosis. Utilizing a scaffold hopping strategy, we have successfully designed and synthesized a series of novel RIP1 inhibitors with selective and anti-necrotic properties, using compound o1 as the lead compound. In comparison to o1, SY1 has demonstrated heightened antinecroptosis activity and binding affinity in vitro studies. Moreover, SY1 has exhibited superior efficacy in both in vivo studies, specifically in the context of SIRS, and pharmacokinetic assessments. Furthermore, SY1 has proven effective in significantly suppressing the central inflammatory response induced by epilepsy.

EFFECT OF PEGYLATED POLYPROPYLENE IMINE DENDRITIC ARCHITECTURE ON PHARMACOKINETICS OF PYRAZINAMIDE ON RABBITS

Objective: This study sought to investigate the impact of pegylated polypropylene imine dendrimer-loaded pyrazinamide on drug delivery and assess this novel formulation's pharmacokinetic parameters. Methods: Various concentrations of pyrazinamide-loaded dendrimers were formulated in four distinct batches, with the most promising formulation selected for administration to New Zealand rabbits. Plasma concentrations of the drug were subsequently compared to those of the pure drug. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to reach Cmax (tmax), the area under the curve (AUC), the area under the first moment curve (AUMC), elimination rate constant (λz), biological half-life (t1/2), and mean residence time (MRT), were meticulously determined. Results: The plasma drug concentration Vs time profile illustrated a sustained release pattern for the pyrazinamide drug-loaded dendrimer formulation compared to the pure drug. While a minor alteration was observed in peak plasma concentration, a notable divergence was noted in all other pharmacokinetic parameters. The AUC demonstrated a fourfold increase for pyrazinamide drug-loaded dendrimers, rising from 8657.94±295.10 to 34663.89±702.89 (ng/ml/h), and the mean residence time nearly doubled when compared to the pure drug. Conclusion: Pyrazinamide drug-loaded dendrimers exhibit significant potential for enhancing drug release compared to the pure drug. This novel formulation promises a substantial and sustained drug release profile, holding promise for improving therapeutic outcomes and patient compliance in the treatment of relevant conditions.

Analysis of phase change material (PCM) melting utilizing environmentally friendly nanofluids in a double tube with spiral fins: A numerical study

Phase Change Materials (PCMs) show great potential for thermal energy storage applications due to their substantial latent heat release during the transition from solid to liquid phases. The objective of this numerical study is to assess the melting process of a phase change material (PCM) within a vertical helical coil designed as a latent heat storage system. Innovative enhancements to the system's performance are introduced through the utilization of environmentally friendly nanofluids, BH (Biogenic Hierarchical)–SiO2/water and OLE (Olive Leaf Extract)–TiO2/water, and three distinct configurations of spiral fins. A three-dimensional model is implemented to investigate the impact of the number of fins, nanoparticle concentration, initial temperature and velocity of the Heat Transfer Fluid (HTF), as well as various fin thicknesses. The porous enthalpy method within ANSYS-Fluent is employed to model the phase-changing process. The results indicate a significant reduction of 66.88 % in the melting time of solid PCM with the inclusion of three spiral fins compared to the configuration without fins. Furthermore, the thermal performance of BH–SiO2 is found to surpass that of OLE–TiO2, attributed to its higher thermal conductivity. Additionally, the analysis reveals that the melting time is more sensitive to the initial temperature of the HTF than its velocity.