Polymeric Nanoparticles Active against Dual-Species Bacterial Biofilms.

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of Escherichia coli and Pseudomonas aeruginosa. This study highlights a potential clinical application of the presented polymeric platform.

Polymer-Based Bioorthogonal Nanocatalysts for the Treatment of Bacterial Biofilms.

Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.

Combatting antibiotic-resistant bacteria using nanomaterials.

The dramatic increase in antimicrobial resistance for pathogenic bacteria constitutes a key threat to human health. The Centers for Disease Control and Prevention has recently stated that the world is on the verge of entering the "post-antibiotic era", one where more people will die from bacterial infections than from cancer. Recently, nanoparticles (NPs) have emerged as new tools that can be used to combat deadly bacterial infections. Nanoparticle-based strategies can overcome the barriers faced by traditional antimicrobials, including antibiotic resistance. In this tutorial review, we have highlighted multiple nanoparticle-based approaches to eliminate bacterial infections, providing crucial insight into the design of elements that play critical roles in creating antimicrobial nanotherapeutics. In particular, we have focused on the pivotal role played by NP-surface functionality in designing nanomaterials as self-therapeutic agents and delivery vehicles for antimicrobial cargo.

Engineered Polymer Nanoparticles with Unprecedented Antimicrobial Efficacy and Therapeutic Indices against Multidrug-Resistant Bacteria and Biofilms.

The rapid emergence of antibiotic-resistant bacterial "superbugs" with concomitant treatment failure and high mortality rates presents a severe threat to global health. The superbug risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that render them refractory to available treatments. We hypothesized that efficient antimicrobial agents could be generated through careful engineering of hydrophobic and cationic domains in a synthetic semirigid polymer scaffold, mirroring and amplifying attributes of antimicrobial peptides. We report the creation of polymeric nanoparticles with highly efficient antimicrobial properties. These nanoparticles eradicate biofilms with low toxicity to mammalian cells and feature unprecedented therapeutic indices against red blood cells. Most notably, bacterial resistance toward these nanoparticles was not observed after 20 serial passages, in stark contrast to clinically relevant antibiotics where significant resistance occurred after only a few passages.

Biodegradable Nanocomposite Antimicrobials for the Eradication of Multidrug-Resistant Bacterial Biofilms without Accumulated Resistance.

Infections caused by multidrug-resistant (MDR) bacteria are a rapidly growing threat to human health, in many cases exacerbated by their presence in biofilms. We report here a biocompatible oil-in-water cross-linked polymeric nanocomposite that degrades in the presence of physiologically relevant biomolecules. These degradable nanocomposites demonstrated broad-spectrum penetration and elimination of MDR bacteria, eliminating biofilms with no toxicity to cocultured mammalian fibroblast cells. Notably, serial passaging revealed that bacteria were unable to develop resistance toward these nanocomposites, highlighting the therapeutic promise of this platform.

Emotional tones of voice affect the acoustics and perception of Mandarin tones.

Lexical tones and emotions are conveyed by a similar set of acoustic parameters; therefore, listeners of tonal languages face the challenge of processing lexical tones and emotions in the acoustic signal concurrently. This study examined how emotions affect the acoustics and perception of Mandarin tones. In Experiment 1, Mandarin tones were produced by professional actors with angry, fear, happy, sad, and neutral tones of voice. Acoustic analyses on mean F0, F0 range, mean amplitude, and duration were conducted on syllables excised from a carrier phrase. The results showed that emotions affect Mandarin tone acoustics to different degrees depending on specific Mandarin tones and specific emotions. In Experiment 2, selected syllables from Experiment 1 were presented in isolation or in context. Listeners were asked to identify the Mandarin tones and emotions of the syllables. The results showed that emotions affect Mandarin tone identification to a greater extent than Mandarin tones affect emotion recognition. Both Mandarin tones and emotions were identified more accurately in syllables presented with the carrier phrase, but the carrier phrase affected Mandarin tone identification and emotion recognition to different degrees. These findings suggest that lexical tones and emotions interact in complex but systematic ways.

Antimicrobial polymer-loaded hydrogels for the topical treatment of multidrug-resistant wound biofilm infections.

Integration of antimicrobial polymeric nanoparticles into hydrogel materials presents a promising strategy to address multidrug-resistant biofilm infections. Here we report an injectable hydrogel loaded with engineered cationic antimicrobial polymeric nanoparticles (PNPs) for the effective topical treatment of severe wound biofilm infections. The PNPs demonstrated biofilm penetration and disruption, resulting in the eradication of resistant and persister cells that reside within the biofilm. Significantly, PNPs did not elicit resistance development even after multiple exposures to sub-therapeutic doses. In vitro studies showed PNPs significantly reduced prolonged inflammation due to infection and promoted fibroblast migration. These PNPs were then incorporated into Poloxamer 407 (P407) hydrogels and utilized as an inert carrier for PNPs to provide a controlled and sustained topical release of the antimicrobial nanoparticles at the wound area. In vivo studies using a mature (4-day) wound biofilm infection in a murine model mimicking severe human wound infections demonstrated provided 99% bacterial biofilm clearance and significantly enhanced wound healing. Overall, this work demonstrated the efficacy and selectivity of the antimicrobial polymer-loaded hydrogel platform as a topical treatment for difficult-to-treat wound biofilm infections.

Antimicrobial-loaded biodegradable nanoemulsions for efficient clearance of intracellular pathogens in bacterial peritonitis.

Intracellular pathogenic bacteria use immune cells as hosts for bacterial replication and reinfection, leading to challenging systemic infections including peritonitis. The spread of multidrug-resistant (MDR) bacteria and the added barrier presented by host cell internalization limit the efficacy of standard antibiotic therapies for treating intracellular infections. We present a non-antibiotic strategy to treat intracellular infections. Antimicrobial phytochemicals were stabilized and delivered by polymer-stabilized biodegradable nanoemulsions (BNEs). BNEs were fabricated using different phytochemicals, with eugenol-loaded BNEs (E-BNEs) affording the best combination of antimicrobial efficacy, macrophage accumulation, and biocompatibility. The positively-charged polymer groups of the E-BNEs bind to the cell surface of macrophages, facilitating the entry of eugenol that then kills the intracellular bacteria without harming the host cells. Confocal imaging and flow cytometry confirmed that this entry occurred mainly via cholesterol-dependent membrane fusion. As eugenol co-localized and interacted with intracellular bacteria, antibacterial efficacy was maintained. E-BNEs reversed the immunosuppressive effects of MRSA on macrophages. Notably, E-BNEs did not elicit resistance selection after multiple exposures of MRSA to sub-therapeutic doses. The E-BNEs were highly effective against a murine model of MRSA-induced peritonitis with better bacterial clearance (99 % bacteria reduction) compared to clinically-employed treatment with vancomycin. Overall, these findings demonstrate the potential of E-BNEs in treating peritonitis and other refractory intracellular infections.

Dye molecular structure device open-circuit voltage correlation in Ru(II) sensitizers with heteroleptic tridentate chelates for dye-sensitized solar cells.

Dicarboxyterpyridine chelates with π-conjugated pendant groups attached at the 5- or 6-position of the terminal pyridyl unit were synthesized. Together with 2,6-bis(5-pyrazolyl)pyridine, these were used successfully to prepare a series of novel heteroleptic, bis-tridentate Ru(II) sensitizers, denoted as TF-11-14. These dyes show excellent performance in dye-sensitized solar cells (DSCs) under AM1.5G simulated sunlight at a light intensity of 100 mW cm(-2) in comparison with a reference device containing [Ru(Htctpy)(NCS)(3)][TBA](3) (N749), where H(3)tctpy and TBA are 4,4',4"-tricarboxy-2,2':6',2"-terpyridine and tetra-n-butylammonium cation, respectively. In particular, the sensitizer TF-12 gave a short-circuit photocurrent of 19.0 mA cm(-2), an open-circuit voltage (V(OC)) of 0.71 V, and a fill factor of 0.68, affording an overall conversion efficiency of 9.21%. The increased conjugation conferred to the TF dyes by the addition of the π-conjugated pendant groups increases both their light-harvesting and photovoltaic energy conversion capability in comparison with N749. Detailed recombination processes in these devices were probed by various spectroscopic and dynamics measurements, and a clear correlation between the device V(OC) and the cell electron lifetime was established. In agreement with several other recent studies, the results demonstrate that high efficiencies can also be achieved with Ru(II) sensitizers that do not contain thiocyanate ancillaries. This bis-tridentate, dual-carboxy anchor configuration thus serves as a prototype for future omnibearing design of highly efficient Ru(II) sensitizers suited for use in DSCs.

A task-specific cognitive domain decline is correlated with plasma and neuroimaging markers in patients with Parkinson's disease.

BACKGROUND: Cognitive impairment is a disabling non-motor symptom of Parkinson's disease (PD). It remains uncertain whether declines in specific cognitive domains relate to imaging or plasma biomarkers across the disease continuum. OBJECTIVE: We investigated whether neuroimaging and plasma biomarkers correlate with individual task-specific cognitive domain declines evidenced by computerized neuropsychological tests in PD patients. METHODS: A total of 107 participants, including 87 PD patients (30 with normal cognition [PD-NC], 30 with mild cognitive impairment [PD-MCI], 27 with dementia [PDD]), and 20 healthy controls, were recruited. All received the Cambridge Neuropsychological Test Automatic Battery (CANTAB) test, brain MRI, and assays of plasma biomarkers, including α-synuclein, tau, Aß42, and Aß40. RESULTS: PD patients had generally poorer cognitive performance than controls. Patients with PD-MCI and PDD had worse performance in visual, verbal, and working memory and executive function than those with PD-NC. After adjusting for covariates, PDD patients had global cortical thinning, especially in the temporal and parietal lobes, and higher plasma α-synuclein levels and tau:Aß42 ratios than PD-NC group. Plasma α-synuclein level was associated with frontal lobe-mediated tasks, while the tau:Aß42 ratio was associated with posterior cortical-mediated tasks. Facial emotion recognition tasks and visual pattern recognition associated with frontotemporal cortical thinning. The accuracy of predicting PDD using age alone (area under the curve [AUC] 0.756) increased by incorporating plasma biomarkers (AUC = 0.851, p = 0.025). CONCLUSIONS: Cognitive decline in PD patients has a task-specific correlation with neuroimaging and plasma biomarkers, which may implicate the underlying neuropathological process of PDD.

Retraction: Efficient in vivo wound healing using noble metal nanoclusters.

Retraction of 'Efficient in vivo wound healing using noble metal nanoclusters' by Kuo Li et al. Nanoscale, 2021, 13, 6531-6537. DOI: 10.1039/D0NR07176E.

Direct discrimination of cell surface glycosylation signatures using a single pH-responsive boronic acid-functionalized polymer.

Cell surface glycans serve fundamental roles in many biological processes, including cell-cell interaction, pathogen infection, and cancer metastasis. Cancer cell surface have alternative glycosylation to healthy cells, making these changes useful hallmarks of cancer. However, the diversity of glycan structures makes glycosylation profiling very challenging, with glycan 'fingerprints' providing an important tool for assessing cell state. In this work, we utilized the pH-responsive differential binding of boronic acid (BA) moieties with cell surface glycans to generate a high-content six-channel BA-based sensor array that uses a single polymer to distinguish mammalian cell types. This sensing platform provided efficient discrimination of cancer cells and readily discriminated between Chinese hamster ovary (CHO) glycomutants, providing evidence that discrimination is glycan-driven. The BA-functionalized polymer sensor array is readily scalable, providing access to new diagnostic and therapeutic strategies for cell surface glycosylation-associated diseases.

All-natural gelatin-based bioorthogonal catalysts for efficient eradication of bacterial biofilms.

Bioorthogonal catalysis mediated by transition metal catalysts (TMCs) presents a versatile tool for in situ generation of diagnostic and therapeutic agents. The use of 'naked' TMCs in complex media faces numerous obstacles arising from catalyst deactivation and poor water solubility. The integration of TMCs into engineered inorganic scaffolds provides 'nanozymes' with enhanced water solubility and stability, offering potential applications in biomedicine. However, the clinical translation of nanozymes remains challenging due to their side effects including the genotoxicity of heavy metal catalysts and unwanted tissue accumulation of the non-biodegradable nanomaterials used as scaffolds. We report here the creation of an all-natural catalytic "polyzyme", comprised of gelatin-eugenol nanoemulsion engineered to encapsulate catalytically active hemin, a non-toxic iron porphyrin. These polyzymes penetrate biofilms and eradicate mature bacterial biofilms through bioorthogonal activation of a pro-antibiotic, providing a highly biocompatible platform for antimicrobial therapeutics.

Dual antimicrobial-loaded biodegradable nanoemulsions for synergistic treatment of wound biofilms.

Wound biofilm infections caused by multidrug-resistant (MDR) bacteria constitute a major threat to public health; acquired resistance combined with resistance associated with the biofilm phenotype makes combatting these infections challenging. Biodegradable polymeric nanoemulsions that encapsulate two hydrophobic antimicrobial agents (eugenol and triclosan) (TE-BNEs) as a strategy to combat chronic wound infections are reported here. The cationic nanoemulsions efficiently penetrate and accumulate in biofilms, synergistically eradicating MDR bacterial biofilms, including persister cells. Notably, the nanoemulsion platform displays excellent biocompatibility and delays emergence of resistance to triclosan. The TE-BNEs are active in an in vivo murine model of mature MDR wound biofilm infections, with 99% bacterial elimination. The efficacy of this system coupled with prevention of emergence of bacterial resistance highlight the potential of this combination platform to treat MDR wound biofilm infections.

Integrated 18F-T807 Tau PET, Structural MRI, and Plasma Tau in Tauopathy Neurodegenerative Disorders.

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy. Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18F-T807 tau PET, brain MRI, and plasma tau assay. Results: The global cortical standard uptake value ratio (SUVR) of 18F-T807 PET was comparable between PD and control (p = 0.088). The cortical SUVR was significantly higher in AD group (p = 0.002) but was modestly increased in PSP group compared to the PD group (p = 0.044), especially in parietal and pallidal regions. Asymmetric 18F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level (p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = -0.092, p = 0.025; PSP: r = -0.114, p = 0.015). Conclusions: The 18F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.

Efficient in vivo wound healing using noble metal nanoclusters.

The wound healing process involves multiple steps including hemostasis, inflammation, proliferation, and tissue remodeling. Nanomaterials have been employed externally for healing wounds. However, their use as systemic therapeutics has not been extensively explored. We report the use of ultra-small noble metal nanoclusters (NCs) for the treatment of skin wounds. Both in vitro and in vivo studies indicate NCs have comprehensive therapeutic effects for wound healing, promoting cell proliferation and migration while decreasing inflammation.

In situ Generation of Antibiotics using Bioorthogonal "Nanofactories".

Prodrug strategies use chemical modifications to improve the pharmacokinetic properties and therefore therapeutic effects of parent drugs. Traditional prodrug approaches use endogenous enzymes for activation. Bioorthogonal catalysis uses processes that endogenous enzymes cannot access, providing a complementary strategy for prodrug uncaging. Site-selective activation of prodrugs to drugs (uncaging) using synthetic catalysts is a promising strategy for localized drug activation. We discuss here recent studies that incorporate metal catalysts into polymers and nanoparticle scaffolds to provide biocompatible "enzyme-like" catalysts that can penetrate bacterial biofilms and activate prodrug antibiotics in situ, affording a new strategy to treat bacterial biofilm infections with the potential for reduced off-target effects.

Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections.

Antibiotic-resistant bacterial infections arising from acquired resistance and/or through biofilm formation necessitate the development of innovative 'outside of the box' therapeutics. Nanomaterial-based therapies are promising tools to combat bacterial infections that are difficult to treat, featuring the capacity to evade existing mechanisms associated with acquired drug resistance. In addition, the unique size and physical properties of nanomaterials give them the capability to target biofilms, overcoming recalcitrant infections. In this Review, we highlight the general mechanisms by which nanomaterials can be used to target bacterial infections associated with acquired antibiotic resistance and biofilms. We emphasize design elements and properties of nanomaterials that can be engineered to enhance potency. Lastly, we present recent progress and remaining challenges for widespread clinical implementation of nanomaterials as antimicrobial therapeutics.

Activity of Biodegradable Polymeric Nanosponges against Dual-Species Bacterial Biofilms.

Infections caused by multidrug-resistant (MDR) bacteria present an emerging global health crisis, and the threat is intensified by the involvement of biofilms. Some biofilm infections involve more than one species; this can further challenge treatment using traditional antibiotics. Nanomaterials are being developed as alternative therapeutics to traditional antibiotics; here we report biodegradable polymer-stabilized oil-in-water nanosponges (BNS) and show their activity against dual-species bacterial biofilms. The described engineered nanosponges demonstrated broad-spectrum antimicrobial activity through prevention of dual-species biofilm formation as well as eradication of preformed biofilms. The BNS showed no toxicity against mammalian cells. Together, these data highlight the therapeutic potential of this platform.

Nanotherapeutics using all-natural materials. Effective treatment of wound biofilm infections using crosslinked nanoemulsions.

Bacterial wound infections are a threat to public health. Although antibiotics currently provide front-line treatments for bacterial infections, the development of drug resistance coupled with the defenses provided through biofilm formation render these infections difficult, if not impossible, to cure. Antimicrobials from natural resources provide unique antimicrobial mechanisms and are generally recognized as safe and sustainable. Herein, an all-natural antimicrobial platform is reported. It is active against bacterial biofilms and accelerates healing of wound biofilm infections in vivo. This antimicrobial platform uses gelatin stabilized by photocrosslinking using riboflavin (vitamin B2) as a photocatalyst, and carvacrol (the primary constituent of oregano oil) as the active antimicrobial. The engineered nanoemulsions demonstrate broad-spectrum antimicrobial activity towards drug-resistant bacterial biofilms and significantly expedite wound healing in an in vivo murine wound biofilm model. The antimicrobial activity, wound healing promotion, and biosafety of these nanoemulsions provide a readily translatable and sustainable strategy for managing wound infections.