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Stan Lee
A collection of comics that celebrates the career of prolific storyteller Stan Lee, Marvel Comics' primary creative leader for two decades and co-creator of numerous iconic superhero characters.
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Concepts and practices used to develop functional PLGA-based nanoparticulate systems
The functionality of bare polylactide-co-glycolide (PLGA) nanoparticles is limited to drug depot or drug solubilization in their hard cores. They have inherent weaknesses as a drug-delivery system. For instance, when administered intravenously, the nanoparticles undergo rapid clearance from systemic circulation before reaching the site of action. Furthermore, plain PLGA nanoparticles cannot distinguish between different cell types. Recent research shows that surface functionalization of nanoparticles and development of new nanoparticulate dosage forms help overcome these delivery challenges and improve in vivo performance. Immense research efforts have propelled the development of diverse functional PLGA-based nanoparticulate delivery systems. Representative examples include PEGylated micelles/nanoparticles (PEG, polyethylene glycol), polyplexes, polymersomes, core-shell-type lipid-PLGA hybrids, cell-PLGA hybrids, receptor-specific ligand-PLGA conjugates, and theranostics. Each PLGA-based nanoparticulate dosage form has specific features that distinguish it from other nanoparticulate systems. This review focuses on fundamental concepts and practices that are used in the development of various functional nanoparticulate dosage forms. We describe how the attributes of these functional nanoparticulate forms might contribute to achievement of desired therapeutic effects that are not attainable using conventional therapies. Functional PLGA-based nanoparticulate systems are expected to deliver chemotherapeutic, diagnostic, and imaging agents in a highly selective and effective manner.
Journal Article
Early upregulation of immune suppressors dominates the macrophage response to Toxoplasma gondii
The apicomplexan parasite Toxoplasma gondii is a master manipulator, subverting its host through secreted proteins, hormone disruption, and even behavioural changes. Macrophages, the immune system’s first responders, play a pivotal role in determining infection outcomes, yet the initial triggers shaping these complex responses remain elusive. This study unveils the earliest transcriptional shifts in a mouse macrophage-like cell line RAW264.7- T. gondii infection model. Using time-resolved transcriptomic profiling, we captured host and parasite gene expression dynamics within the critical 15–120 minute window — when the host mounts its first line of defence and the parasite secures its foothold. By leveraging inactivated parasites, we disentangled responses to active invasion from general immune activation. By 60 minutes, macrophages exhibited a trend of increased suppressor of cytokine signalling expression — uniquely tied to live infection — while stress and pro-growth genes became dysregulated. Meanwhile, T. gondii responded with a slow but strategic transcriptional shift: an early increase in transcription and growth capacity, followed by a delayed activation of secreted proteins. These findings reveal a tug-of-war at the transcriptional level, where macrophages show rapid upregulation, while T. gondii employs a measured, delayed strategy to carve out its replicative niche.
Journal Article
The Salmonella pathogenicity island 1 injectisome reprograms host cell translation to evade the inflammatory response
During bacterial infection both the host cell and its invader must rapidly divert resources to synthesize specific proteins. For the host, these factors may be needed for innate immune responses, including programmed cell death, and in the bacteria newly synthesized proteins may include survival factors that counteract host defences.
Salmonella
is an important bacterial pathogen that invades and multiplies within host cells. It is well established that epithelial cell invasion is dependent upon the
Salmonella
pathogenicity island 1 (SPI-1) type III injectisome, a biological needle that penetrates host cells and injects effectors that promote bacterial internalization. However, the importance of the SPI-1 injectisome in infection of professional phagocytes such as macrophages, the predominant host cell type supporting systemic infection, is less clear. Through time-resolved parallel transcriptomic and translatomic studies of macrophage infection, we reveal SPI-1 injectisome-dependent infection of macrophages triggers rapid translation of transcription factors, including Early Growth Response 1 (EGR1). Despite EGR1’s short half-life, its swift synthesis, driven by untranslated regions of its mRNA, is sufficient to inhibit the transcription of pro-inflammatory genes; this restrains inflammation and macrophage death which would otherwise abort systemic infection. This demonstrates the importance of translational activation in host–pathogen dynamics during bacterial infection.
In this work, authors show that
Salmonella
uses its SPI-1 injectisome to infect macrophages, triggering rapid translational upregulation of transcription factors, such as EGR1 which suppresses the inflammatory response, aiding the bacteria in establishing systemic infection
Journal Article
Characterization of a Nickel Sulfide Concentrate and Its Implications on Pentlandite Beneficiation
In anticipation of future demands, a comprehensive understanding of the chemical and mineralogical characteristics of nickel-bearing minerals is a prerequisite to devising effective nickel beneficiation methods. Of particular importance are markers in the mineralogy of the flotation concentrate that inform beneficiation strategies to improve concentrate grades, increasing both the marketability and cost of refining. In this work, a detailed characterization of a complex nickel sulfide flotation concentrate from a Western Australian deposit was carried out to determine the mode of occurrence and distribution of nickel and the associated gangue minerals, with the view of identifying prudent beneficiation strategies to improve concentrate grades. The concentrate was characterized via particle, chemical, and mineralogical techniques. Particle size analysis of the concentrate showed that it consisted predominantly of fine and ultra-fine particles (<20 μm), with the nickel value concentrated in the finer size fractions. Nickel mineralization in the ore (by quantitative X-ray diffraction) was found to be within pentlandite, violarite, millerite, and gersdorffite. The sulfide gangue was predominantly pyrrhotite, pyrite, chalcopyrite, sphalerite, arsenopyrite, and galena. Quantitative evaluation of minerals by scanning microscopy (QEMSCAN) analysis revealed that nickel minerals are at least 91% liberated, and the remaining portion (around 7%) is locked within binary iron (Fe) sulfides and 2% within complex minerals. Based on these findings, potential processing options, such as magnetic separation, gravity separation, and froth flotation, for recovering and upgrading nickel from this concentrate are discussed. Notably, with the significant presence of ultrafine/fine pyrrhotite content, averaging around 52% in the minus 38 µm fraction, novel flotation cells, including the Jameson cell, column flotation cells, and Reflux flotation cell (RFC), have been identified as potential candidates for fine/ultrafine pentlandite recovery. Overall, the characterization study conducted suggests that acquiring knowledge about the mineralogical characteristics of existing mineral concentrates can serve as a pathway to improving future concentrate grades.
Journal Article
Nebulization of Cyclic Arginine-Glycine-(D)-Aspartic Acid-Peptide Grafted and Drug Encapsulated Liposomes for Inhibition of Acute Lung Injury
PurposeAcute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo.MethodsIn vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (LcRGD) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-LcRGD). Formulations were nebulized in vivo in rats using micro-pump nebulizer.ResultsLiposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-LcRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels.ConclusionFrom the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.
Journal Article
Reprocessing of Sulphide Flotation Tailings for Copper Recovery: Characterisation
This study characterises low-grade copper ore tailings from a conventional flotation circuit to evaluate their feasibility for further processing. A suite of advanced analytical techniques, such as X-ray fluorescence (XRF), inductively coupled plasma (ICP), X-ray diffraction (XRD), and the quantitative evaluation of minerals by scanning electron microscopy (QEMSCAN), was employed to assess the elemental, chemical, and mineralogical composition of the tailings. Chalcopyrite was identified as the dominant copper-bearing mineral phase, predominantly locked within iron oxides and silicate gangue minerals. The QEMSCAN results showed that chalcopyrite was only partially liberated, which highlights the complex mineral intergrowths that hinder efficient recovery. Based on the mineralogical characteristics, the applicability of various processing techniques, including conventional froth flotation, advanced flotation methods [including HydrofloatTM, Jameson, and the Reflux Flotation Cell (RFC)], magnetic separation, and gravity separation, was evaluated. Overall, this study indicates that incorporating HydroFloat™, the Jameson Cell, and the RFC into the flotation circuit could greatly improve copper recovery from tailings. This study also identified rare earth elements (REEs) as potential by-products of copper recovery, so it is an additional opportunity for resource recovery. This paper contributes to sustainable mining practices and resource optimization by highlighting the characteristics and recovery of valuable minerals from tailings.
Journal Article
Building community resilience to prevent and mitigate community impact of gun violence: conceptual framework and intervention design
IntroductionThe USA has the highest rate of community gun violence of any developed democracy. There is an urgent need to develop feasible, scalable and community-led interventions that mitigate incident gun violence and its associated health impacts. Our community-academic research team received National Institutes of Health funding to design a community-led intervention that mitigates the health impacts of living in communities with high rates of gun violence.Methods and analysisWe adapted ‘Building Resilience to Disasters’, a conceptual framework for natural disaster preparedness, to guide actions of multiple sectors and the broader community to respond to the man-made disaster of gun violence. Using this framework, we will identify existing community assets to be building blocks of future community-led interventions. To identify existing community assets, we will conduct social network and spatial analyses of the gun violence episodes in our community and use these analyses to identify people and neighbourhood blocks that have been successful in avoiding gun violence. We will conduct qualitative interviews among a sample of individuals in the network that have avoided violence (n=45) and those living or working on blocks that have not been a location of victimisation (n=45) to identify existing assets. Lastly, we will use community-based system dynamics modelling processes to create a computer simulation of the community-level contributors and mitigators of the effects of gun violence that incorporates local population-based based data for calibration. We will engage a multistakeholder group and use themes from the qualitative interviews and the computer simulation to identify feasible community-led interventions.Ethics and disseminationThe Human Investigation Committee at Yale University School of Medicine (#2000022360) granted study approval. We will disseminate study findings through peer-reviewed publications and academic and community presentations. The qualitative interview guides, system dynamics model and group model building scripts will be shared broadly.
Journal Article
Lyophilized Iron Oxide Nanoparticles Encapsulated in Amphotericin B: A Novel Targeted Nano Drug Delivery System for the Treatment of Systemic Fungal Infections
We formulated and tested a targeted nanodrug delivery system to help treat life-threatening invasive fungal infections, such as cryptococcal meningitis. Various designs of iron oxide nanoparticles (IONP) (34–40 nm) coated with bovine serum albumin and coated and targeted with amphotericin B (AMB-IONP), were formulated by applying a layer-by-layer approach. The nanoparticles were monodispersed and spherical in shape, and the lead formulation was found to be in an optimum range for nanomedicine with size (≤36 nm), zeta potential (−20 mV), and poly dispersity index (≤0.2), and the drug loading was 13.6 ± 6.9 µg of AMB/mg of IONP. The drug release profile indicated a burst release of up to 3 h, followed by a sustained drug release of up to 72 h. The lead showed a time-dependent cellular uptake in C. albicans and C. glabrata clinical isolates, and exhibited an improved efficacy (16–25-fold) over a marketed conventional AMB-deoxycholate product in susceptibility testing. Intracellular trafficking of AMB-IONP by TEM and confocal laser scanning microscopy confirmed the successful delivery of the AMB payload at and/or inside the fungal cells leading to potential therapeutic advantages over the AMB-deoxycholate product. A short-term stability study at 5 °C and 25 °C for up to two months showed that the lyophilized form was stable.
Journal Article
Formulation, Development, and In Vitro Evaluation of a CD22 Targeted Liposomal System Containing a Non-Cardiotoxic Anthracycline for B Cell Malignancies
Doxorubicin cardiotoxicity has led to the development of superior chemotherapeutic agents such as AD 198. However, depletion of healthy neutrophils and thrombocytes from AD 198 therapy must be limited. This can be done by the development of a targeted drug delivery system that delivers AD 198 to the malignant cells. The current research highlights the development and in vitro analysis of targeted liposomes containing AD 198. The best lipids were identified and optimized for physicochemical effects on the liposomal system. Physiochemical characteristics such as size, ζ-potential, and dissolution were also studied. Active targeting to CD22 positive cells was achieved by conjugating anti-CD22 Fab’ to the liposomal surface. Size and ζ-potential of the liposomes was between 115 and 145 nm, and −8 to−15 mV. 30% drug was released over 72 h. Higher cytotoxicity was observed in CD22+ve Daudi cells compared to CD22−ve Jurkat cells. The route of uptake was a clathrin- and caveolin-independent pathway. Intracellular localization of the liposomes was in the endolysosomes. Upon drug release, apoptotic pathways were activated partly by the regulation of apoptotic and oncoproteins such as caspase-3 and c-myc. It was observed that the CD22 targeted drug delivery system was more potent and specific compared to other untargeted formulations.
Journal Article