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A non-canonical role of somatic Cyclin D/CYD-1 in oogenesis and in maintenance of reproductive fidelity, dependent on the FOXO/DAF-16 activation state
No full textFor the optimal survival of a species, an organism coordinates its reproductive decisions with the nutrient availability of its niche. Thus, nutrient-sensing pathways like insulin-IGF-1 signaling (IIS) play an important role in modulating cell division, oogenesis, and reproductive aging. Lowering of the IIS leads to the activation of the downstream FOXO transcription factor (TF) DAF-16 in Caenorhabditis elegans which promotes oocyte quality and delays reproductive aging. However, less is known about how the IIS axis responds to changes in cell cycle proteins, particularly in the somatic tissues. Here, we show a new aspect of the regulation of the germline by this nutrient-sensing axis. First, we show that the canonical G1-S cyclin, Cyclin D/CYD-1, regulates reproductive fidelity from the uterine tissue of wild-type worms. Then, we show that knocking down cyd-1 in the uterine tissue of an IIS receptor mutant arrests oogenesis at the pachytene stage of meiosis-1 in a DAF-16-dependent manner. We observe activated DAF-16-dependent deterioration of the somatic gonadal tissues like the sheath cells, and transcriptional de-regulation of the sperm-to-oocyte switch genes which may be the underlying reason for the absence of oogenesis. Deleting DAF-16 releases the arrest and leads to restoration of the somatic gonad but poor-quality oocytes are produced. Together, our study reveals the unrecognized cell non-autonomous interaction of Cyclin D/CYD-1 and FOXO/DAF-16 in the regulation of oogenesis and reproductive fidelity
Cleavable amphiphilic biocides with ester-bearing moieties: aggregation properties and antibacterial activity
No full textThe rise of multidrug-resistant bacterial infections and the dwindling supply of newly approved antibiotics have emerged as a grave threat to public health. Toward the ever-growing necessity of the development of novel antimicrobial agents, herein, we synthesized a series of cationic amphiphilic biocides featuring two cationic headgroups separated by different hydrophobic spacers, accompanied by the inclusion of two lipophilic tails through cleavable ester functionality. The detailed aggregation properties offered by these biocides were investigated by small-angle neutron scattering (SANS) and conductivity. The critical micellar concentration of the biocides and the size and shape of the micellar aggregates differed with variation of pendant and spacer hydrophobicity. Furthermore, the aggregation number and size of the micelles were found to vary with changing concentration and temperature. These easily synthesized biocides exhibited potent antibacterial properties against various multidrug-resistant bacteria. The optimized biocides with minimum hematotoxicity and potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii exhibited rapid killing kinetics against planktonic bacteria. Also, these membrane-active agents were able to eradicate preformed biofilms. The enzymatic and acidic degradation profile further offered proof of gradual degradation. Collectively, these cleavable amphiphilic biocides demonstrated excellent potency for combating the multidrug-resistant bacterial infection
Antimicrobial nanocomposite coatings for rapid intervention against catheter-associated urinary tract infections
No full textCatheter-associated urinary tract infections (CAUTIs) pose a significant challenge in hospital settings. Current solutions available on the market involve incorporating antimicrobials and antiseptics into catheters. However, challenges such as uncontrolled release leading to undesirable toxicity, as well as the prevalence of antimicrobial resistance reduce the effectiveness of these solutions. Additionally, conventional antibiotics fail to effectively eradicate entrenched bacteria and metabolically suppressed bacteria present in the biofilm, necessitating the exploration of alternative strategies. Here, we introduce a novel polymer–nanocomposite coating that imparts rapid antimicrobial and anti-biofilm properties to coated urinary catheters. We have coated silicone-based urinary catheters with an organo-soluble antimicrobial polymer nanocomposite (APN), containing hydrophobic quaternized polyethyleneimine and zinc oxide nanoparticles, in a single step coating process. The coated surfaces exhibited rapid eradication of drug-resistant bacteria within 10–15 min, including E. coli, K. pneumoniae, MRSA, and S. epidermidis, as well as drug-resistant C. albicans fungi. APN coated catheters exhibited potent bactericidal activity against uropathogenic strains of E. coli, even when incubated in human urine. Furthermore, the stability of the coating and retention of antimicrobial activity was validated even after multiple washes. More importantly, this coating deterred biofilm formation on the catheter surface, and displayed rapid inactivation of metabolically repressed stationary phase and persister cells. The ability of the coated surfaces to disrupt bacterial membranes and induce the generation of intracellular reactive oxygen species (ROS) was assessed through different techniques, such as electron microscopy imaging, flow cytometry as well as fluorescence spectroscopy and microscopy. The surface coatings were found to be biocompatible in an in vivo mice model. Our simple one-step coating approach for catheters holds significant potential owing to its ability to tackle multidrug resistant bacteria and fungi, and the challenge of biofilm formation. This work brings us one step closer to enhancing patient care and safety in hospitals
Unveiling the potent activity of a synthetic ion transporter against multidrug-resistant Gram-positive bacteria and biofilms
No full textThe increasing prevalence of drug-resistant infections caused by Gram-positive bacteria poses a significant threat to public healthcare. These pathogens exhibit not only smart resistance mechanisms but also form impenetrable biofilms on various surfaces, rendering them resilient to conventional therapies. In this study, we present the potent antibacterial activity of a synthetic ion transporter T against multi-drug resistant (MDR) Gram-positive pathogens, with minimum inhibitory concentration (MIC) values ranging from 0.5 to 2 μg mL−1. The compound demonstrates high selectivity with negligible toxicity towards mammalian cells (HC50 = 810 μg mL−1). It exhibits fast killing kinetics, completely eliminating >5 log bacterial cells within 12 h. Moreover, the compound displays efficacy against both planktonic bacteria and preformed biofilms of methicillin-resistant S. aureus (MRSA), reducing the bacterial burden within the biofilm by 2 log. Mechanistic investigations reveal that the ion transporter depolarizes the bacterial membrane potential and enhances membrane permeability. Additionally, it generates reactive oxygen species, contributing to its bactericidal activity. Notably, MRSA did not exhibit detectable resistance to the ion transporter even after serial passaging for 10 days. Collectively, this novel class of ion transporter holds promise as a therapeutic candidate for combating infections caused by multi-drug resistant Gram-positive bacteria
Integrated study on buried pipelines, co-seismic landslides, and magnitude conversion for 2023 Türkiye earthquake.
No full textTürkiye is known for its intricate tectonic structure and high seismic activity, which makes in-depth research on earthquakes necessary. This research paper presents a multifaceted examination of earthquake impact in Türkiye, encompassing critical elements of seismic vulnerability with a special focus on the latest twin earthquake of February 6, 2023. Firstly, a three-dimensional finite element (FE) analysis has been conducted to explore the buried pipeline behavior under left-lateral strike-slip faults. Secondly, making use of the earthquake data from 1976 to 2023, a new Newmark displacement-based model has been proposed which predicts co-seismic landslide displacement. Finally, new magnitude conversion relations are developed in the generalized moment magnitude scale (Mwg) for Türkiye using three statistical regression techniques. The maximum tensile strain was found to be around 2.0% based on the findings of the 3D numerical study of an underground pipe that was subjected to left-lateral strike-slip fault movement. The proposed co-seismic landslide displacement model was developed based on moment magnitude, yield acceleration, and peak ground acceleration, which yields an R-squared value of 0.93. Outcomes of the magnitude conversion study depicted that the improved general orthogonal regression (IGOR) relationships developed in this study performed better than the other conventional methods of regression. Also, the proposed regional relations based on Mwg scale perform better than global relations as they provide closer values to the observed ones. By offering a comprehensive perspective on seismic impact, the research lays the groundwork for upgraded predictive methods and refined seismic design considerations. The proposed models and conversion relations contribute to the strengthening of critical infrastructures, providing a forward-looking approach to enhance preparedness and resilience against earthquake disasters in Türkiye
Seismic response of tunnels in soft soil—status and future prospects.
No full textFor the safe functioning of tunnels, dynamic loading conditions, such as earthquakes, must be considered for design. The main idea here is to review tunnel responses under soft soil conditions and emphasize work done to date toward the seismic response of tunnels. Specifically, various parameters influencing tunneling, effects on tunnel structure, and ground failure due to seismic excitations are discussed. After that, a review of different closed-form solutions used for the transverse and longitudinal analysis of the response of tunnel structures is presented. Next is the study of various numerical models of tunnel systems with adjacent structures, both above and near the ground surface, like buildings, bridges, and buried pipelines. Here, the discussions are based on the different computational modeling procedures adopted by researchers and the effect of soil–tunnel structure interaction arising during seismic events. Subsequently, a review of interactions between underground tunnels and adjacent ground structures is also presented. The paper discusses the effects of segmental jointed tunnels under earthquake loads and the seismic vulnerability of tunnels. Finally, the article tries to stimulate ideas for new work in these areas for the researchers. Thus, emphasis is given to the identification of current gaps in understanding the seismic response of tunnels in soft soil
Density dependent survival drives variation in density dependent population growth of an insect pest
No full textSeveral ecological processes – from population dynamics to species co-existence – are driven by density dependence (DD) in population growth rate. Thus, to predict and manage ecological outcomes, we need a deep understanding of which factors and demographic traits drive variation in DD. In the insect pest Tribolium castaneum, we found large variation in DD across habitats but not across source populations. We modeled DD in population growth as the product of DD in fecundity and survival, experimentally estimating each parameter. Across habitats, survival parameters varied more than fecundity, including in simulations with varying parameter values. Thus, DD in survival drives variation in density-dependent population growth. Hence, under strong density-dependent selection, we expect evolutionary change in density-dependent survival, provided sufficient genetic variance. Our general framework combining detailed experiments and simulations with a simple model can be used for other species to better understand the causes and consequences of density dependent population growth
Antibacterial activity of hydrophobicity modulated cationic polymers with enzyme and pH-responsiveness.
No full textThe membrane lipid compositions of prokaryotic and eukaryotic cells are inherently different in many aspects, although some similarities exist in their structure and composition. Therefore, selective targeting of membrane lipids with a compound of therapeutic value, such as an antibacterial copolymer, is often challenging. Hence, developing an ideal copolymer with antibacterial properties demands hydrophobicity/hydrophilicity balance with a high biosafety profile. To integrate hydrophobic/hydrophilic balance and cationic charge in an alternating antibacterial copolymer with enzyme and pH-responsiveness, a lysine appended styrenic monomer was copolymerized with a fatty acid (octanoic acid (OA) or myristic acid (MA)) tethered maleimide monomer via reversible addition–fragmentation chain transfer (RAFT) polymerization. A range of microscopic analyses, including dynamic light scattering (DLS), confirmed the formation of nanoaggregates (size ∼30–40 nm) by these polymers in aqueous solution with positive zeta potential (cationic surface charge). Hydrophobic Nile red (NR) dye was successfully encapsulated in the nanoaggregates, and the in vitro release kinetics of the NR dye were monitored at different pHs and in the presence or absence of esterase/lipase. The in vitro release kinetics of NR revealed ∼85% dye release in the presence of pH 5.5 and lipase, suggesting their suitability for pH/enzyme-triggered therapeutic payload delivery. The standard broth microdilution assay showed significant bactericidal activity against both Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) bacteria with an MIC50 value <30 μg mL−1. The effect of polymeric nanoaggregates on bacterial morphology and in vitro survival was further confirmed by field emission scanning electron microscopy (FESEM), agar gel disk diffusion assay, and bacterial live/dead cell count. The significantly low hemolytic activity against red blood cells (RBCs) (HC50 >103 μg mL−1) and nontoxic effect on human intestinal epithelial cells (INT 407) (EC50 >500 μg mL−1) ensure that the polymer nanoaggregates are safe for in vivo use and can serve as a potent antibacterial polymer
Enzyme-triggered degradation of supramolecularly cross-linked polymersomes of azobenzene-based polyurethane: cell-selective anticancer drug release.
No full textEnzyme-responsive self-assembled nanostructures for drug delivery applications have gained a lot of attention, as enzymes exhibit dysregulation in many disease-associated microenvironments. Azoreductase enzyme levels are strongly elevated in many tumor tissues; hence, here, we exploited the altered enzyme activity of the azoreductase enzyme and designed a main-chain azobenzene-based amphiphilic polyurethane, which self-assembles into a vesicular nanostructure and is programmed to disassemble in response to a specific enzyme, azoreductase, with the help of the nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme in the hypoxic environment of solid tumors. The vesicular nanostructure sequesters, stabilizes the hydrophobic anticancer drug, and releases the drug in a controlled fashion in response to enzyme-triggered degradation of azo-bonds and disruption of vesicular assembly. The biological evaluation revealed tumor extracellular matrix pH-induced surface charge modulation, selective activated cellular uptake to azoreductase overexpressed lung cancer cells (A549), and the release of the anticancer drug followed by cell death. In contrast, the benign nature of the drug-loaded vesicular nanostructure toward normal cells (H9c2) suggested excellent cell specificity. We envision that the main-chain azobenzene-based polyurethane discussed in this manuscript could be considered as a possible selective chemotherapeutic cargo against the azoreductase overexpressed cancer cells while shielding the normal cells from off-target toxicity
Recent advancements in polymeric n-nitrosamine-based nitric oxide (no) donors and their therapeutic applications.
No full textNitric oxide (NO), a gasotransmitter, is known for its wide range of effects in vasodilation, cardiac relaxation, and angiogenesis. This diatomic free radical also plays a pivotal role in reducing the risk of platelet aggregation and thrombosis. Furthermore, NO demonstrates promising potential in cancer therapy as well as in antibacterial and antibiofilm activities at higher concentrations. To leverage their biomedical activities, numerous NO donors have been developed. Among these, N-nitrosamines are emerging as a notable class, capable of releasing NO under suitable photoirradiation and finding a broad range of therapeutic applications. This review discusses the design, synthesis, and biological applications of polymeric N-nitrosamines, highlighting their advantages over small molecular NO donors in terms of stability, NO payload, and target-specific delivery. Additionally, various small-molecule N-nitrosamines are explored to provide a comprehensive overview of this burgeoning field. We anticipate that this review will aid in developing next-generation polymeric N-nitrosamines with improved physicochemical properties