Amino Acid-Conjugated Polymer-Silver Bromide Nanocomposites for Eradicating Polymicrobial Biofilms and Treating Burn Wound Infections.

The rise in antimicrobial resistance, the increasing occurrence of bacterial, and fungal infections, and the challenges posed by polymicrobial biofilms necessitate the exploration of innovative therapeutic strategies. Silver-based antimicrobials have garnered attention for their broad-spectrum activity and multimodal mechanisms of action. However, their effectiveness against single-species or polymicrobial biofilms remains limited. In this study, we present the fabrication of polymer-silver bromide nanocomposites using amino acid conjugated polymers (ACPs) through a green and water-based in situ technique. The nanocomposite architecture facilitated prolonged and controlled release of the active components. Remarkably, the nanocomposites exhibited broad-spectrum activity against multidrug-resistant (MDR) human pathogenic bacteria (MIC = 2-16 µg/mL) and fungi (MIC = 1-8 µg/mL), while displaying no detectable toxicity to human erythrocytes (HC50 > 1024 µg/mL). In contrast to existing antimicrobials and silver-based therapies, the nanocomposite effectively eradicated bacterial, fungal, and polymicrobial biofilms, and prevented the development of microbial resistance due to their membrane-active properties. Furthermore, the lead polymer-silver bromide nanocomposite demonstrated a 99% reduction in the drug-resistant Pseudomonas aeruginosa burden in a murine model of burn wound infection, along with excellent in vivo biocompatibility.

Unveiling the potent activity of a synthetic ion transporter against multidrug-resistant Gram-positive bacteria and biofilms.

The 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.

Neurogenic and angiogenic poly(N-acryloylglycine)-co-(acrylamide)-co-(N-acryloyl-glutamate) hydrogel: preconditioning effect under oxidative stress and use in neuroregeneration.

Traumatic injuries, neurodegenerative diseases and oxidative stress serve as the early biomarkers for neuronal damage and impede angiogenesis and subsequently neuronal growth. Considering this, the present work aimed to develop a poly(N-acryloylglycine)-co-(acrylamide)-co-(N-acryloylglutamate) hydrogel [p(NAG-Ac-NAE)] with angiogenesis/neurogenesis properties. As constituents of this polymer modulate their vital role in biological functions, inhibitory neurotransmitter glycine regulates neuronal homeostasis, and glutamatergic signalling regulates angiogenesis. The p(NAG-Ac-NAE) hydrogel is a highly branched, biodegradable and pH-responsive polymer with a very high swelling behavior of 6188%. The mechanical stability (G', 2.3-2.7 kPa) of this polymeric hydrogel is commendable in the differentiation of mature neurons. This hydrogel is biocompatible (as tested in HUVEC cells) and helps to proliferate PC12 cells (152.7 ± 13.7%), whereas it is cytotoxic towards aggressive cancers such as glioblastoma (LN229 cells) and triple negative breast cancer (TNBC; MDA-MB-231 cells) and helps to maintain the healthy cytoskeleton framework structure of primary cortical neurons by facilitating the elongation of the axonal pathway. Furthermore, FACS results revealed that the synthesized hydrogel potentiates neurogenesis by inducing the cell cycle (G0/G1) and arresting the sub-G1 phase by limiting apoptosis. Additionally, RT-PCR results revealed that this hydrogel induced an increased level of HIF-1α expression, providing preconditioning effects towards neuronal cells under oxidative stress by scavenging ROS and initiating neurogenic and angiogenic signalling. This hydrogel further exhibits more pro-angiogenic activities by increasing the expression of VEGF isoforms compared to previously reported hydrogels. In conclusion, the newly synthesized p(NAG-Ac-NAE) hydrogel can be one of the potential neuroregenerative materials for vasculogenesis-assisted neurogenic applications and paramount for the management of neurodegenerative diseases.

Antimicrobial nanocomposite coatings for rapid intervention against catheter-associated urinary tract infections.

Catheter-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.

Visible-Light-Responsive Novel Ru(II)-Metallo-Antibiotics with Potential Antibiofilm and Antibacterial Activity.

Growing challenges with antibiotic resistance pose immense challenges in combating microbial infections and biofilm prevention on medical devices. Lately, antibacterial photodynamic therapy (aPDT) is now emerging as an alternative therapy to overcome this problem. Herein, we synthesized and characterized four Ru(II)-complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(dpq)Cl]PF6 (Ru2), [Ru(ph-tpy)(dppz)Cl]PF6 (Ru3), and [Ru(ph-tpy)(dppn)Cl]PF6 (Ru4) (where 4'-phenyl-2,2':6',2″-terpyridine = ph-tpy; 2,2'-bipyridine = bpy; dipyrido[3,2-f:2',3'-h]quinoxaline = dpq; dipyrido[3,2-a:2',3'-c]phenazine = dppz; and Benzo[I]dipyrido[3,2-a:2',3'-c]phenazine = dppn), among which Ru2-Ru4 are novel. Octahedral geometry of the complexes with a RuN5Cl core was evident from the crystal structure of Ru2. Ru1-Ru4 showed an MLCT absorption band in the 450-600 nm region, useful for aPDT performances. Further, optimum triplet excited state energy and excellent photostability of Ru1-Ru4 made them good photosensitizers for aPDT. Ru1-Ru4 demonstrated enhanced antimicrobial activity on visible-light exposure (400-700 nm, 10 J cm-2), confirmed using different antibacterial assays. Mechanistic studies revealed that inhibition of bacterial growth was due to the generation of oxidative stress (via NADH oxidation and ROS generation) upon treatment with Ru2-Ru4, resulting in destruction of the bacterial wall. Ru2 performed best killing performance against both Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtilis) bacteria when exposed to light. Ru2-Ru4, when coated on a polydimethylsiloxane (PDMS) disk, showed long-term reusability and durable antibiofilm properties. Molecular docking confirmed the efficient interaction of Ru2-Ru4 with FabH (regulates fatty acid biosynthesis of E. coli) and PgaB (gives structural stability and helps biofilm formation of E. coli), resulting in probable downregulation. In vivo studies with healthy Wistar rats confirmed the biocompatibility of Ru2. This study shows that these lead complexes (Ru2-Ru4) can be used as potent alternative antimicrobial agents in low concentrations toward bacterial eradication with photodynamic therapy (PDT).

Biosynthesized silver nanoparticles prevent bacterial infection in chicken egg model and mitigate biofilm formation on medical catheters.

Investigating the application of innovative antimicrobial surface coatings on medical devices is an important field of research. Many of these coatings have significant drawbacks, including biocompatibility, coating stability and the inability to effectively combat multiple drug-resistant bacteria. In this research, we developed an antibiofilm surface coating for medical catheters using biosynthesized silver nanoparticles (b-Cs-AgNPs) developed using leaves extract of Calliandra surinamensis. Various characterization techniques were employed to thoroughly characterize the synthesized b-Cs-AgNPs and c-AgNPs. b-Cs-AgNPs were compatible with human normal kidney cells and chicken embryos. It did not trigger any skin inflammatory response in in vivo rat model. b-Cs-AgNPs demonstrated potent zone of inhibition of 19.09 mm when subjected to the disc diffusion method in E. coli confirming strong antibacterial property. Different anti-bacterial assays including liquid growth curve, colony counting assay, biofilm formation assay supported the potent antimicrobial efficacy of b-Cs-AgNPs alone and when coated to medical grade catheters. Mechanistic studies reveal the presence of ferulic acid, that was important for the synthesis of b-AgNPs along with enhanced antibacterial effects of b-Cs-AgNPs compared to c-AgNPs, supported by molecular docking analysis. These results together demonstrated the effective role b-Cs-AgNPs in combating infections and mitigating biofilm formations, highlighting their need for further study in the field of biomedical applications.

Multifunctional (4-in-1) Therapeutic Applications of Nickel Thiocyanate Nanoparticles Impregnated Cotton Gauze as Antibacterial, Antibiofilm, Antioxidant and Wound Healing Agent.

The wounds, arises from accidents, burns, surgeries, diabetes, and trauma, can significantly impact well-being and present persistent clinical challenges. Ideal wound dressings should be flexible, stable, antibacterial, antioxidant and anti-inflammatory in nature, facilitating a scarless rapid wound healing. Initiatives were taken to create antibacterial cotton fabrics by incorporating agents like antibiotics and metallic nanoparticles. However, due to a lack of multifunctionality, these materials were not highly effective in causing scarless and rapid wound healing. In this article, nickel thiocyanate nanoparticle (NiSCN-NPs) impregnated cotton gauze wound dressing (NiSCN-CG) was developed. These nanoparticles were non-toxic to normal human cell lines till 1 mg/mL dose and did not cause skin irritation in the rat model. Further, NiSCN-NPs exhibited antimicrobial, antibiofilm and antioxidant activities confirmed using different in vitro experiments. In vivo wound healing studies in rat models using NiSCN-CG demonstrated rapid scarless wound healing. The nickel thiocyanate impregnated cotton gauze presents a novel approach in scarless wound healing, and as an antimicrobial agent, offering a promising solution for diverse wounds and infections in the future.

Evolving therapeutic interventions for the management and treatment of Alzheimer's disease.

Alzheimer's Disease (AD) patients experience diverse symptoms, including memory loss, cognitive impairment, behavioral abnormalities, mood changes, and mental issues. The fundamental objective of this review is to discuss novel therapeutic approaches, with special emphasis on recently approved marketed formulations for the treatment of AD, especially Aducanumab, the first FDA approved moiety that surpasses the blood-brain barrier (BBB) and reduces amyloid plaques in the brain, thereby reducing associated cognitive decline. However, it is still in the phase IV trial and is to be completed by 2030. Other drugs such as lecanemab are also under clinical trial and has recently been approved by the FDA and is also discussed here. In this review, we also focus on active and passive immunotherapy for AD as well as several vaccines, such as amyloid-beta epitope-based vaccines, amyloid-beta DNA vaccines, and stem cell therapy for AD, which are in clinical trials. Furthermore, ongoing pre-clinical trials associated with AD and other novel strategies such as curcumin-loaded nanoparticles, Crispr/ cas9, precision medicine, as well as some emerging therapies like anti-sense therapy are also highlighted. Additionally, we discuss some off-labeled drugs like non-steroidal anti-inflammatory drugs (NSAID), anti-diabetic drugs, and lithium, which can manage symptoms of AD and different non-pharmacological approaches are also covered which can help to manage AD. In summary, we have tried to cover all the therapeutic interventions which are available for the treatment and management of AD under sections approved, clinical phase, pre-clinical phase or futuristic interventions, off-labelled drugs, and non-pharmacological interventions for AD, offering positive findings and well as challenges that remain.

Small molecule conjugation reduces macrophage uptake and increases in vivo blood circulation of polystyrene nanoparticles.

Nanomedicine often failed clinically to show therapeutic efficacy due to reduced particle circulation and enhanced capture by the reticuloendothelial system (RES), including the liver. Developing novel immunomodulatory surface coating can prevent macrophage capture and increase the particle circulation of the nanomedicine, resulting in higher therapeutic efficiency. Herein, we demonstrate the development of immunomodulatory small molecule (RZA15) with triazole functionality using copper-catalyzed click chemistry to conjugate onto spherical polystyrene nanoparticles using amide coupling reactions, achieving higher blood circulation and lesser macrophage uptake of the nanoconjugates. In this work, we evaluated the effectiveness of RZA15 coating for the enhanced circulation of polystyrene nanoparticles of 100 nm size, which is commonly utilized for various drug delivery applications, and compared with poly(ethylene)glycol (PEG) coatings. Several polystyrene nanoconjugate formulations were analyzed in vitro in normal and macrophage cells for cell viability and cellular uptake studies. In vitro studies demonstrated lesser macrophage uptake of the nanoconjugates following RZA15 coating. Finally, in vivo, blood-circulation, pharmacokinetics, and biodistribution studies were performed in the C57BL/6J mouse model that endorsed the substantial role of RZA15 in preventing liver and spleen capture and results in extended circulation. Coating immunomodulatory small molecules to nanoparticles can severely enhance the potential therapeutic effects of nanomedicine at lower doses.

Augmenting Antimicrobial Resistance Surveillance: Rapid Detection of ß-Lactamase-Expressing Drug-Resistant Bacteria through Sensitized Luminescence on a Paper-Supported Hydrogel.

The emergence of antimicrobial resistance (AMR) in pathogenic bacteria, expedited by the overuse and misuse of antibiotics, necessitates the development of a rapid and pan-territorially accessible diagnostic protocol for resistant bacterial infections, which would not only enable judicious prescription of drugs, leading to infection control but also augment AMR surveillance. In this study, we introduce for the first time a "turn-on" terbium (Tb3+) photoluminescence assay supported on a paper-based platform for rapid point-of-care (POC) detection of ß-lactamase (BL)-producing bacteria. We strategically conjugated biphenyl-4-carboxylic acid (BCA), a potent Tb3+ sensitizer, with cephalosporin to engineer a BL substrate CCS, where the energy transfer to terbium is arrested. However, BL, a major resistance element produced by bacteria resistant to ß-lactam antibiotics, triggers a spontaneous release of BCA, empowering terbium sensitization within a supramolecular scaffold supported on paper. The remarkable optical response facilitates quick assessment with a binary answer, and the time-gated signal acquisition ensues improved sensitivity with a detection limit as low as 0.1 mU/mL. Furthermore, to ensure accessibility, particularly in resource-limited areas, we have developed an in loco imaging device as an affordable alternative to high-end instruments. The integration of the assay with the device readily identified the BL-associated drug-resistant strains in the mimic urinary tract infection samples within 2 h, demonstrating its excellent potential for in-field translation. We believe that this rapid paper-based POC assay, coupled with the in loco device, can be deployed anywhere, especially in developing regions, and will enable extensive surveillance on antibiotic-resistant infections.

Nonequilibrium steady states in coupled asymmetric and symmetric exclusion processes.

We propose and study a one-dimensional (1D) model consisting of two lanes with open boundaries. One of the lanes executes diffusive and the other lane driven unidirectional or asymmetric exclusion dynamics, which are mutually coupled through particle exchanges in the bulk. We elucidate the generic nonuniform steady states in this model. We show that in a parameter regime, where hopping along the TASEP lane, diffusion along the SEP lane, and the exchange of particles between the TASEP and SEP lanes compete, the SEP diffusivity D appears as a tuning parameter for both the SEP and TASEP densities for a given exchange rate in the nonequilibrium steady states of this model. Indeed, D can be tuned to achieve phase coexistence in the asymmetric exclusion dynamics together with spatially smoothly varying density in the diffusive dynamics in the steady state. We obtain phase diagrams of the model using mean field theories, and corroborate and complement the results with stochastic Monte Carlo simulations. This model reduces to an isolated open totally asymmetric exclusion process (TASEP) and an open TASEP with bulk particle nonconserving Langmuir kinetics (LK), respectively, in the limits of vanishing and diverging particle diffusivity in the lane executing diffusive dynamics. Thus, this model works as an overarching general model, connecting both pure TASEPs and TASEPs with LK in different asymptotic limits. We further define phases in the SEP and obtain phase diagrams and show their correspondence with the TASEP phases. In addition to its significance as a 1D driven, diffusive model, this model also serves as a simple reduced model for cell biological transport by molecular motors undergoing diffusive and directed motion inside eukaryotic cells.

Small molecular adjuvants repurpose antibiotics towards Gram-negative bacterial infections and multispecies bacterial biofilms.

Gram-negative bacterial infections pose a significant challenge due to two major resistance elements, including the impermeability of the outer membrane and the overexpression of efflux pumps, which contribute to antibiotic resistance. Additionally, the coexistence of multispecies superbugs in mixed species biofilms further complicates treatment, as these infections are refractory to most antibiotics. To address this issue, combining obsolete antibiotics with non-antibiotic adjuvants that target bacterial membranes has shown promise in combating antibacterial resistance. However, the clinical translation of this cocktail therapy has been hindered by the toxicity associated with these membrane active adjuvants, mainly due to a limited understanding of their structure and mechanism of action. Towards this goal, herein, we have designed a small molecular adjuvant by tuning different structural parameters, such as the balance between hydrophilic and hydrophobic groups, spatial positioning of hydrophobicity and hydrogen bonding interactions, causing moderate membrane perturbation in bacterial cells without any toxicity to mammalian cells. Moderate membrane perturbation not only enhances the internalization of antibiotics, but also increases the intracellular concentration of drugs by hampering the efflux machinery. This revitalises the efficacy of various classes of antibiotics by 32-512 fold, without inducing toxicity. The leading combination not only exhibits potent bactericidal activity against A. baumannii biofilms but also effectively disrupts mature multispecies biofilms composed of A. baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which is typically resistant to most antibiotics. Importantly, the combination therapy demonstrates good biocompatibility and excellent in vivo antibacterial efficacy (>99% reduction) in a skin infection model of A. baumannii. Interestingly, A. baumannii shows reduced susceptibility to develop resistance against the leading combination, underscoring its potential for treating multi-drug resistant infections.

Poly(N-acryloylglycine-acrylamide) Hydrogel Mimics the Cellular Microenvironment and Promotes Neurite Growth with Protection from Oxidative Stress.

In this work, the glycine-based acryloyl monomer is polymerized to obtain a neurogenic polymeric hydrogel for regenerative applications. The synthesized poly(N-acryloylglycine-acrylamide) [poly(NAG-b-A)] nanohydrogel exhibits high swelling (∼1500%) and is mechanically very stable, biocompatible, and proliferative in nature. The poly(NAG-b-A) nanohydrogel provides a stable 3D extracellular mimetic environment and promotes healthy neurite growth for primary cortical neurons by facilitating cellular adhesion, proliferation, actin filament stabilization, and neuronal differentiation. Furthermore, the protective role of the poly(NAG-b-A) hydrogel for the neurons in oxidative stress conditions is revealed and it is found that it is a clinically relevant material for neuronal regenerative applications, such as for promoting nerve regeneration via GSK3ß inhibition. This hydrogel additionally plays an important role in modulating the biological microenvironment, either as an agonist and antagonist or as an antioxidant. Furthermore, it favors the physiological responses and eases the neurite growth efficiency. Additionally, we found out that the conversion of glycine-based acryloyl monomers into their corresponding polymer modulates the mechanical performance, mimics the cellular microenvironment, and accelerates the self-healing capability due to the responsive behavior towards reactive oxygen species (ROS). Thus, the p(NAG-b-A) hydrogel could be a potential candidate to induce neuronal regeneration since it provides a physical cue and significantly boosts neurite outgrowth and also maintains the microtubule integrity in neuronal cells.

Noise cross correlations can induce instabilities in coupled driven models.

We study the effects of noise cross correlations on the steady states of driven, nonequilibrium systems, which are described by two stochastically driven dynamical variables, in one dimension. We use a well-known stochastically driven coupled model with two dynamical variables, where one of the variables is autonomous, being independent of the other, whereas the second one depends explicitly on the former. Introducing cross correlations of the two noises in the two dynamical equations, we show that depending upon the details of the nonlinear coupling between the dynamical fields, such cross correlations can induce instabilities in the models that are otherwise stable in the absence of any cross correlations. We argue that this is reminiscent of the roughening transition found in the Kardar-Parisi-Zhang equation in dimensions greater than two. Phenomenological implications of our results are discussed.

Recent advances of nanocrystals in cancer theranostics.

Emerging cancer cases across the globe and treating them with conventional therapies with multiple limitations have been challenging for decades. Novel drug delivery systems and alternative theranostics are required for efficient detection and treatment. Nanocrystals (NCs) have been established as a significant cancer diagnosis and therapeutic tool due to their ability to deliver poorly water-soluble drugs with sustained release, low toxicity, and flexibility in the route of administration, long-term sustainable drug release, and noncomplicated excretion. This review summarizes several therapies of NCs, including anticancer, immunotherapy, radiotherapy, biotheranostics, targeted therapy, photothermal, and photodynamic. Further, different imaging and diagnostics using NCs are mentioned, including imaging, diagnosis through magnetic resonance imaging (MRI), computed tomography (CT), biosensing, and luminescence. In addition, the limitations and potential solutions of NCs in the field of cancer theranostics are discussed. Preclinical and clinical data depicting the importance of NCs in the spotlight of cancer, its current status, future aspects, and challenges are covered in detail.

Reducing Peri-implant Capsule Thickness in Submuscular Rodent Model of Breast Reconstruction With Delayed Radiotherapy.

INTRODUCTION: Capsular contracture remains the most common complication following device-based breast reconstruction, occurring in up to 50% of women who also undergo adjuvant radiotherapy either before or after device-based reconstruction. While certain risk factors for capsular contracture have been identified, there remains no clinically effective method of prevention. The purpose of the present study is to determine the effect of coating the implant with the novel small molecule Met-Z2-Y12, with and without delayed, targeted radiotherapy, on capsule thickness and morphologic change around smooth silicone implants placed under the latissimus dorsi in a rodent model. METHODS: Twenty-four female Sprague Dawley rats each had 2 mL smooth round silicone breast implants implanted bilaterally under the latissimus dorsi muscle. Twelve received uncoated implants and twelve received implants coated with Met-Z2-Y12. Half of the animals from each group received targeted radiotherapy (20 Gray) on postoperative day ten. At three and 6 months after implantation, the tissue surrounding the implants was harvested for analysis of capsular histology including capsule thickness. Additionally, microCT scans were qualitatively analyzed for morphologic change. RESULTS: Capsules surrounding Met-Z2-Y12-coated implants were significantly thinner (P = 0.006). The greatest difference in capsule thickness was seen in the irradiated 6-month groups, where mean capsule thickness was 79.1 ± 27.3 µm for uncoated versus 50.9 ± 9.6 µm for Met-Z2-Y12-coated implants (P = 0.038). At the time of explant, there were no capsular morphologic differences between the groups either grossly or per microCT. CONCLUSIONS: Met-Z2-Y12 coating of smooth silicone breast implants significantly reduces capsule thickness in a rodent model of submuscular breast reconstruction with delayed radiotherapy.

Isoamphipathic antibacterial molecules regulating activity and toxicity through positional isomerism.

Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. However, optimization of these properties is not enough to circumvent unwanted toxicity towards mammalian cells. Hence, herein, we report new isoamphipathic antibacterial molecules (IAMs: 1-3) where positional isomerism was introduced as one of the guiding factors for molecular design. This class of molecules displayed good (MIC = 1-8 µg mL-1 or µM) to moderate [MIC = 32-64 µg mL-1 (32.2-64.4 µM)] antibacterial activity against multiple Gram-positive and Gram-negative bacteria. Positional isomerism showed a strong influence on regulating antibacterial activity and toxicity for ortho [IAM-1: MIC = 1-32 µg mL-1 (1-32.2 µM), HC50 = 650 µg mL-1 (654.6 µM)], meta [IAM-2: MIC = 1-16 µg mL-1 (1-16.1 µM), HC50 = 98 µg mL-1 (98.7 µM)] and para [IAM-3: MIC = 1-16 µg mL-1 (1-16.1 µM), HC50 = 160 µg mL-1 (161.1 µM)] isomers. Co-culture studies and investigation of membrane dynamics indicated that ortho isomer, IAM-1 exerted more selective activity towards bacterial over mammalian membranes, compared to meta and para isomers. Furthermore, the mechanism of action of the lead molecule (IAM-1) has been characterized through detailed molecular dynamics simulations. In addition, the lead molecule displayed substantial efficacy against dormant bacteria and mature biofilms, unlike conventional antibiotics. Importantly, IAM-1 exhibited moderate in vivo activity against MRSA wound infection in a murine model with no detectable dermal toxicity. Altogether, the report explored the design and development of isoamphipathic antibacterial molecules to establish the role of positional isomerism in achieving selective and potential antibacterial agents.

Differential Gene Expression Data Analysis of ASD Using Random Forest.

Autism spectrum disorder (ASD) is a developmental disability caused by differences in the brain regions. Analysis of differential expression (DE) of transcriptomic data allows for genome-wide analysis of gene expression changes related to ASD. De-novo mutations may play a vital role in ASD, but the list of genes involved is still far from complete. Differentially expressed genes (DEGs) are treated as candidate biomarkers and a small set of DEGs might be identified as biomarkers using either biological knowledge or data-driven approaches like machine learning and statistical analysis. In this study, we employed a machine learning-based approach to identify the differential gene expression between ASD and Typical Development (TD). The gene expression data of 15 ASD and 15 TD were obtained from the NCBI GEO database. Initially, we extracted the data and used a standard pipeline to pre-process the data. Further, Random Forest (RF) was used to discriminate genes between ASD and TD. We identified the top 10 prominent differential genes and compared them with the statistical test results. Our results show that the proposed RF model yields 5-fold cross-validation accuracy, sensitivity and specificity of 96.67%. Further, we obtained precision and F-measure scores of 97.5% and 96.57%, respectively. Moreover, we found 34 unique DEG chromosomal locations having influential contributions in identifying ASD from TD. We have also identified chr3:113322718-113322659 as the most significant contributing chromosomal location in discriminating ASD and TD. Our machine learning-based method of refining DE analysis is promising for finding biomarkers from gene expression profiles and prioritizing DEGs. Moreover, our study reported top 10 gene signatures for ASD may facilitate the development of reliable diagnosis and prognosis biomarkers for screening ASD.

Screening hydrogels for antifibrotic properties by implanting cellularly barcoded alginates in mice and a non-human primate.

Screening implantable biomaterials for antifibrotic properties is constrained by the need for in vivo testing. Here we show that the throughput of in vivo screening can be increased by cellularly barcoding a chemically modified combinatorial library of hydrogel formulations. The method involves the implantation of a mixture of alginate formulations, each barcoded with human umbilical vein endothelial cells from different donors, and the association of the identity and performance of each formulation by genotyping single nucleotide polymorphisms of the cells via next-generation sequencing. We used the method to screen 20 alginate formulations in a single mouse and 100 alginate formulations in a single non-human primate, and identified three lead hydrogel formulations with antifibrotic properties. Encapsulating human islets with one of the formulations led to long-term glycaemic control in a mouse model of diabetes, and coating medical-grade catheters with the other two formulations prevented fibrotic overgrowth. High-throughput screening of barcoded biomaterials in vivo may help identify formulations that enhance the long-term performance of medical devices and of biomaterial-encapsulated therapeutic cells.

Lipid Deposition Profiles Influence Foreign Body Responses.

Fibrosis remains a significant cause of failure in implanted biomedical devices and early absorption of proteins on implant surfaces has been shown to be a key instigating factor. However, lipids can also regulate immune activity and their presence may also contribute to biomaterial-induced foreign body responses (FBR) and fibrosis. Here it is demonstrated that the surface presentation of lipids on implant affects FBR by influencing reactions of immune cells to materials as well as their resultant inflammatory/suppressive polarization. Time-of-flight secondary ion mass spectroscopy (ToF-SIMS) is employed to characterize lipid deposition on implants that are surface-modified chemically with immunomodulatory small molecules. Multiple immunosuppressive phospholipids (phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin) are all found to deposit preferentially on implants with anti-FBR surface modifications in mice. Significantly, a set of 11 fatty acids is enriched on unmodified implanted devices that failed in both mice and humans, highlighting relevance across species. Phospholipid deposition is also found to upregulate the transcription of anti-inflammatory genes in murine macrophages, while fatty acid deposition stimulated the expression of pro-inflammatory genes. These results provide further insights into how to improve the design of biomaterials and medical devices to mitigate biomaterial material-induced FBR and fibrosis.