Auriferous nanozymes: advances in diagnostic and therapeutic applications.

Nanozymes are a group of nanomaterials that garnered significant attention due to their enzyme-mimicking properties and their catalytic activities comparable to those of natural enzymes. The ability of nanozymes to emulate crucial biological processes which can conquer the drawbacks of natural enzymes, such as their restricted thermostability as well as substrate range. Auriferous (gold) nanozymes possess remarkable enzyme-like properties, such as reductase, peroxidase, superoxide dismutase, oxidase, and catalase. This characteristic makes them a strong competitor for possible applications in the fields of biomedicine as well as biochemical analysis, especially when compared to natural enzymes, along with their simple manufacturing, adaptable features, biocompatibility, and affordability. This review evaluates the factors that affect the catalytic activity of auriferous nanozymes. We offer a thorough investigation of their diagnostic applications, including detecting cancer, microorganisms, glucose, cysteine, and uric acid. Furthermore, we delve into the applications of gold nanozyme in therapeutics including chemodynamic therapy, radiotherapy, and photothermal therapy. In contrast to previous review, our review highlights various advantages of auriferous nanozymes in diagnostics and therapies and provides novel insights into the diverse applications of gold nanozymes encompassing current research studies.

Improving Antibiotic Use for Ventilator-Associated Pneumonia Through Diagnostic Stewardship: A Proof-of-Concept Mixed Methods Study.

Background: Overtreatment of ventilator-associated pneumonia (VAP) in the intensive care unit is driven by positive respiratory tract cultures in the absence of a clinical picture of pneumonia. We evaluated the potential for diagnostic stewardship at the respiratory culture reporting step. Methods: In this mixed methods study, we conducted a baseline evaluation of lower respiratory tract (LRT) culture appropriateness and antibiotic prescribing, followed by a nonrandomized intervention in 2 adult intensive care units. The intervention was a comment in the report to indicate potential colonization instead of organism identification when LRT cultures were inappropriate-that is, not meeting criteria for pneumonia as adjudicated by a physician using a standard algorithm. Results: At baseline, among 66 inappropriate LRT cultures, antibiotic treatment for VAP was more frequent with identification of potential pathogens in the index culture when compared with no growth/normal flora (16/35 [46%] vs 7/31 [23%], P = .049). In the intervention period, 28 inappropriate cultures with growth of potential pathogens underwent report modification. The proportion of episodes for which antibiotic therapy for VAP was completed was significantly lower in the intervention group vs the baseline group (5/28 [18%] vs 16/35 [46%], P = .02). Conclusions: Diagnostic stewardship for VAP could be facilitated by modification of LRT culture reporting guided by clinical features of pneumonia.

Exploring the potential of Bacillus for crop productivity and sustainable solution for combating rice false smut disease.

Rice false smut, which is caused by the soil-borne fungal pathogen Ustilaginoidea virens (U. virens), is one of the most threatening diseases in most of the rice-growing countries including India that causes 0.5-75% yield loss, low seed germination, and a reduction in seed quality. The assessment of yield loss helps to understand the relevance of disease severity and facilitates the implementation of appropriate management strategies. This study aimed to mitigate biotic stress in rice by employing a rhizobacterial-based bioformulation, which possesses diverse capabilities as both a plant growth promoter and a biocontrol agent against U. virens. Rhizobacteria were isolated from the soil of the rice rhizospheres from the healthy plant of the false smut affected zone. Furthermore, they were identified as Bacillus strains: B. subtilis (BR_4), B. licheniformis (BU_7), B. licheniformis (BU_8), and B. vallismortis (KU_7) via sequencing. Isolates were screened for their biocontrol potential against U. virens under in vitro conditions. The antagonistic study revealed that B. vallismortis (KU_7) inhibited U. virens the most (44.6%), followed by B. subtilis BR_4 (41.4%), B. licheniformis BU_7 (39.8%), and B. licheniformis BU_8 (43.5%). Various biochemical and plant growth promoting attributes, such as phosphate and Zn solubilization, IAA, ammonium, siderophore, and chitinase production, were also investigated for all the selected isolates. Furthermore, the potential of the isolates was tested in both in vitro and field conditions by employing talc-based bioformulation through bio-priming and root treatment. The application of bioformulation revealed a 20% decrease in disease incidence in plants treated with B. vallismortis (KU_7), a 60.5% increase in the biological yield, and a 45% increase in the grain yield. This eco-friendly approach not only controlled the disease but also improved the grain quality and reduced the chaffiness.

Click chemistry in the development of PROTACs.

Proteolysis-targeting chimeras or PROTACs are hetero-bifunctional molecules designed to mediate the disposal of a target protein via recruitment of the ubiquitination-proteasome degradation machinery. Because of the chimeric nature of such molecules, their synthesis requires a key step of "assembling" whether in the lab or in situ. Furthermore, targeted PROTACs often are hetero-trifunctional and require a second "assembling" step. Click chemistry has the unique advantages of tethering two or more molecular entities of choice under near physiological conditions and therefore has been applied to the development of PROTACs in various ways. This review provides a succinct summary of this field with a critical analysis of various factors that need to be considered for optimal results. Specifically, we examine issues including applications of click chemistry in in situ assembly for improved delivery, conjugation with a targeting group for selectivity, rapid synthesis for linker optimization, and lysosomal degradation of extracellular and membrane-associated proteins. We also examine reaction kinetics issues whenever possible or warranted.

Nanozymes: A comprehensive review on emerging applications in cancer diagnosis and therapeutics.

Nanozymes, a new class of nanomaterials-based artificial enzymes, have gained huge attraction due to their high operational stability, working efficiency in extreme conditions, and resistance towards protease digestion. Nowadays, they are effectively substituted for natural enzymes for catalysis by closely resembling the active sites found in natural enzymes. Nanozymes can compensate for natural enzymes' drawbacks, such as high cost, poor stability, low yield, and storage challenges. Due to their transforming nature, nanozymes are of utmost importance in the detection and treatment of cancer. They enable precise cancer detection, tailored drug delivery, and catalytic therapy. Through enhanced diagnosis, personalized therapies, and reduced side effects, their adaptability and biocompatibility can transform the management of cancer. The review focuses on metal and metal oxide-based nanozymes, highlighting their catalytic processes, and their applications in the prevention and treatment of cancer. It emphasizes their potential to alter diagnosis and therapy, particularly when it comes to controlling reactive oxygen species (ROS). The article reveals the game-changing importance of nanozymes in the future of cancer care and describes future research objectives, making it a useful resource for researchers, and scientists. Lastly, outlooks for future perspective areas in this rapidly emerging field have been provided in detail.

Review on interactions between nanomaterials and phytohormones: Novel perspectives and opportunities for mitigating environmental challenges.

Nanotechnology offers the potential to provide innovative solutions for sustainable crop production as plants are exposed to a combination of climate change factors (CO2, temperature, UV radiation, ozone), abiotic (heavy metals, salinity, drought), and biotic (virus, bacteria, fungi, nematode, and insects) stresses. The application of particular sizes, shapes, and concentration of nanomaterials (NMs) potentially mitigate the negative impacts in plants by modulation of photosynthetic rate, redox homeostasis, hormonal balance, and nutrient assimilation through upregulation of anti-stress metabolites, antioxidant defense pathways, and genes and genes network. The present review inculcates recent advances in uptake, translocation, and accumulation mechanisms of NMs in plants. The critical theme of this review provides detailed insights into different physiological, biochemical, molecular, and stress tolerance mechanism(s) of NMs action and their cross-talk with different phytohormones. The role of NMs as a double-edged sword for climate change factors, abiotic, and biotic stresses for nutrients uptake, hormones synthesis, cytotoxic, and genotoxic effects including chromosomal aberration, and micronuclei synthesis have been extensively studied. Importantly, this review aims to provide an in-depth understanding of the hormesis effect at low and toxicity at higher doses of NMs under different stressors to develop innovative approaches and design smart NMs for sustainable crop production.

Biotin conjugates in targeted drug delivery: is it mediated by a biotin transporter, a yet to be identified receptor, or (an)other unknown mechanism(s)?

Conjugation of drugs with biotin is a widely studied strategy for targeted drug delivery. The structure-activity relationship (SAR) studies through H3-biotin competition experiments conclude with the presence of a free carboxylic acid being essential for its uptake via the sodium-dependent multivitamin transporter (SMVT, the major biotin transporter). However, biotin conjugation with a payload requires modification of the carboxylic acid to an amide or ester group. Then, there is the question as to how/whether the uptake of biotin conjugates goes through the SMVT. If not, then what is the mechanism? Herein, we present known uptake mechanisms of biotin and its applications reported in the literature. We also critically analyse possible uptake mechanism(s) of biotin conjugates to address the disconnect between the results from SMVT-based SAR and "biotin-facilitated" targeted drug delivery. We believe understanding the uptake mechanism of biotin conjugates is critical for their future applications and further development.

Recent progress in biomarker-based diagnostics of Helicobacter pylori, gastric cancer-causing bacteria.

The progression of any disease and its outcomes depend on the complicated interaction between pathogens, host and environmental factors. Thus, complete knowledge of bacterial toxins involved in pathogenesis is necessary to develop diagnostic methods and alternative therapies, including vaccines. This review summarizes recently employed biomarkers to diagnose the presence of Helicobacter pylori bacteria. The authors review distinct types of disease-associated biomarkers such as urease, DNA, miRNA, aptamers and bacteriophages that can be utilized as targets to detect Helicobacter pylori and, moreover, gastric cancer in its early stage. A detailed explanation is also given in the context of the recent utilization of these biomarkers in the development of a highly specific and sensitive biosensing platform.

Developing a diagnosis calculator to estimate the probability of bacterial pneumonia.

Misdiagnosis of bacterial pneumonia increases risk of exposure to inappropriate antibiotics and adverse events. We developed a diagnosis calculator (https://calculator.testingwisely.com) to inform clinical diagnosis of community-acquired bacterial pneumonia using objective indicators, including incidence of disease, risk factors, and sensitivity and specificity of diagnostic tests, that were identified through literature review.

The UTH-UMB Global Health Education Collaboration: Building a Bidirectional Exchange Based on Equity and Reciprocity.

The global health exchange program between the University Teaching Hospitals (UTH) of Lusaka, Zambia and the University of Maryland, Baltimore (UMB) has been operating since 2015. As trainees and facilitators of this exchange program, we describe our experiences working in Lusaka and Baltimore, and strengths and challenges of the partnership. Since 2015, we have facilitated rotations for 71 UMB trainees, who spent four weeks on the Infectious Disease (ID) team at UTH. Since 2019 with funding from UMB, nine UTH ID trainee physicians spent up to six weeks each rotating on various ID consult services at University of Maryland Medical Center (UMMC). Challenges in global health rotations can include inadequate preparation or inappropriate expectations among high-income country trainees, low-value experiences for low- and middle-income country trainees, lack of appropriate mentorship at sites, and power imbalances in research collaborations. We try to mitigate these issues by ensuring pre-departure and on-site orientation for UMB trainees, cross-cultural mentored experiences for all trainees, and intentional sharing of authorship and credit on scientific collaborations. We present a description of our medical education collaboration as a successful model for building equitable and reciprocal collaborations between low- and middle-income countries and high-income countries, and offer suggestions for future program initiatives to enhance global health education equity among participants and organizations.

Toward "CO in a Pill": Silica-Immobilized Organic CO Prodrugs for Studying the Feasibility of Systemic Delivery of CO via In Situ Gastrointestinal CO Release.

Carbon monoxide (CO), an endogenous signaling molecule, is known to exert a range of pharmacological effects, including anti-inflammation, organ protection, and antimetastasis in various animal models. We have previously shown the ability of organic prodrugs to deliver CO systemically through oral administration. As part of our efforts for the further development of these prodrugs, we are interested in minimizing the potential negative impact of the "carrier" portion of the prodrug. Along this line, we have previously published our work on using benign "carriers" and physically trapping the "carrier" portion in the gastrointestinal (GI) tract. We herein report our feasibility studies on using immobilized organic CO prodrugs for oral CO delivery while minimizing systemic exposure to the prodrug and the "carrier portion." In doing so, we immobilize a CO prodrug to silica microparticles, which are generally recognized as safe by the US FDA and known to provide large surface areas for loading and water accessibility. The latter point is essential for the hydrophobicity-driven activation of the CO prodrug. Amidation-based conjugation with silica is shown to provide 0.2 mmol/g loading degree, effective prodrug activation in buffer with comparable kinetics as the parent prodrug, and stable tethering to prevent detachment. One representative silica conjugate, SICO-101, is shown to exhibit anti-inflammation activity in LPS-challenged RAW264.7 cells and to deliver CO systemically in mice through oral administration and GI CO release. We envision this strategy as a general approach for oral CO delivery to treat systemic and GI-specific inflammatory conditions.

Resistance strategies for defense against Albugo candida causing white rust disease.

Albugo candida, the causal organism of white rust, is an oomycete obligate pathogen infecting crops of Brassicaceae family occurred on aerial part, including vegetable and oilseed crops at all growth stages. The disease expression is characterized by local infection appearing on the abaxial region developing white or creamy yellow blister (sori) on leaves and systemic infections cause hypertrophy and hyperplasia leading to stag-head of reproductive organ. To overcome this problem, several disease management strategies like fungicide treatments were used in the field and disease-resistant varieties have also been developed using conventional and molecular breeding. Due to high variability among A. candida isolates, there is no single approach available to understand the diverse spectrum of disease symptoms. In absence of resistance sources against pathogen, repetitive cultivation of genetically-similar varieties locally tends to attract oomycete pathogen causing heavy yield losses. In the present review, a deep insight into the underlying role of the non-host resistance (NHR) defence mechanism available in plants, and the strategies to exploit available gene pools from plant species that are non-host to A. candida could serve as novel sources of resistance. This work summaries the current knowledge pertaining to the resistance sources available in non-host germ plasm, the understanding of defence mechanisms and the advance strategies covers molecular, biochemical and nature-based solutions in protecting Brassica crops from white rust disease.

De Novo Construction of Fluorophores via CO Insertion-Initiated Lactamization: A Chemical Strategy toward Highly Sensitive and Highly Selective Turn-On Fluorescent Probes for Carbon Monoxide.

Extensive studies in the last few decades have led to the establishment of CO as an endogenous signaling molecule and subsequently to the exploration of CO's therapeutic roles. In the current state, there is a critical conundrum in CO-related research: the extensive knowledge of CO's biological effects and yet an insufficient understanding of the quantitative correlations between the CO concentration and biological responses of various natures. This conundrum is partially due to the difficulty in examining precise concentration-response relationships of a gaseous molecule. Another reason is the need for appropriate tools for the sensitive detection and concentration determination of CO in the biological system. We herein report a new chemical approach to the design of fluorescent CO probes through de novo construction of fluorophores by a CO insertion-initiated lactamization reaction, which allows for ultra-low background and exclusivity in CO detection. Two series of CO detection probes have been designed and synthesized using this strategy. Using these probes, we have extensively demonstrated their utility in quantifying CO in blood, tissue, and cell culture and in cellular imaging of CO from exogenous and endogenous sources. The probes described will enable many biology and chemistry labs to study CO's functions in a concentration-dependent fashion with very high sensitivity and selectivity. The chemical and design principles described will also be applicable in designing fluorescent probes for other small molecules.

Ultrasensitive and selective colorimetric detection of uric acid using peroxidase mimetic activity of biogenic palladium nanoparticles.

Uric acid (2,6,8-trihydroxypurine) is a metabolic product of purine, which is one of the important markers of human health. The development of a rapid, facile, highly sensitive, and selective method for uric acid detection is critical for the diagnosis of related diseases and is still a strategic challenge. In this study, we developed a highly sensitive and selective colorimetric assay for the detection of uric acid using biogenic palladium nanoparticles (Pd NPs). The synthesized nanoparticles were shown to acquire peroxidase mimetic activity that oxidized 3,3',5,5'-tetramethylbenzidine and produced a blue colour in an assay. The developed colorimetric assay is instrument-free detection of uric acid with a limit of detection of 0.05 µM and a 1.11 µM limit of quantification (LOQ). This is the first report determining the LOQ for a colorimetric assay that gives the lowest quantity of analyte that can be evaluated with more precision under the specified conditions of the analysis. The developed assay had a linear response at low uric acid concentrations of 0.05 to 1 µM and a 0.99841 linear regression correlation coefficient. This colorimetric detection provides a rapid, cost-effective, and easy-to-use platform for the clinical diagnosis of uric acid biomarkers.

Continuous renal replacement therapy and extracorporeal membrane oxygenation: implications in the COVID-19 era.

The novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (coronavirus Disease 19 (COVID-19)) was identified as the causative agent of viral pneumonias in Wuhan, China in December 2019, and has emerged as a pandemic causing acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. Interim guidance by the World Health Organization states that extracorporeal membrane oxygenation (ECMO) should be considered as a rescue therapy in COVID-19-related ARDS. International registries tracking ECMO in COVID-19 patients reveal a 21%-70% incidence of acute renal injury requiring renal replacement therapy (RRT) during ECMO support. The indications for initiating RRT in patients on ECMO are similar to those for patients not requiring ECMO. RRT can be administered during ECMO via a temporary dialysis catheter, placement of a circuit in-line hemofilter, or direct connection of continuous RRT in-line with the ECMO circuit. Here we review methods for RRT during ECMO, RRT initiation and timing during ECMO, anticoagulation strategies, and novel cytokine filtration approaches to minimize COVID-19's pathophysiological impact.

Polymeric micelles and cancer therapy: an ingenious multimodal tumor-targeted drug delivery system.

Since the beginning of pharmaceutical research, drug delivery methods have been an integral part of it. Polymeric micelles (PMs) have emerged as multifunctional nanoparticles in the current technological era of nanocarriers, and they have shown promise in a range of scientific fields. They can alter the release profile of integrated pharmacological substances and concentrate them in the target zone due to their improved permeability and retention, making them more suitable for poorly soluble medicines. With their ability to deliver poorly soluble chemotherapeutic drugs, PMs have garnered considerable interest in cancer. As a result of their remarkable biocompatibility, improved permeability, and minimal toxicity to healthy cells, while also their capacity to solubilize a wide range of drugs in their micellar core, PMs are expected to be a successful treatment option for cancer therapy in the future. Their nano-size enables them to accumulate in the tumor microenvironment (TME) via the enhanced permeability and retention (EPR) effect. In this review, our major aim is to focus primarily on the stellar applications of PMs in the field of cancer therapeutics along with its mechanism of action and its latest advancements in drug and gene delivery (DNA/siRNA) for cancer, using various therapeutic strategies such as crossing blood-brain barrier, gene therapy, photothermal therapy (PTT), and immunotherapy. Furthermore, PMs can be employed as "smart drug carriers," allowing them to target specific cancer sites using a variety of stimuli (endogenous and exogenous), which improve the specificity and efficacy of micelle-based targeted drug delivery. All the many types of stimulants, as well as how the complex of PM and various anticancer drugs react to it, and their pharmacodynamics are also reviewed here. In conclusion, commercializing engineered micelle nanoparticles (MNPs) for application in therapy and imaging can be considered as a potential approach to improve the therapeutic index of anticancer drugs. Furthermore, PM has stimulated intense interest in research and clinical practice, and in light of this, we have also highlighted a few PMs that have previously been approved for therapeutic use, while the majority are still being studied in clinical trials for various cancer therapies.

Angle-resolved polarimetry of hybrid perovskite emission for photonic technologies.

Coupling between light and matter strongly depends on the polarization of the electromagnetic field and the nature of excitations in a material. As hybrid perovskites emerge as a promising class of materials for light-based technologies such as LEDs, LASERs, and photodetectors, it is critical to understand how their microstructure changes the intrinsic properties of the photon emission process. While the majority of optical studies have focused on the spectral content, quantum efficiency and lifetimes of emission in various hybrid perovskite thin films and nanostructures, few studies have investigated other properties of the emitted photons such as polarization and emission angle. Here, we use angle-resolved cathodoluminescence microscopy to access the full polarization state of photons emitted from large-grain hybrid perovskite films with spatial resolution well below the optical diffraction limit. Mapping these Stokes parameters as a function of the angle at which the photons are emitted from the thin film surface, we reveal the effect of a grain boundary on the degree of polarization and angle at which the photons are emitted. Such studies of angle- and polarization-resolved emission at the single grain level are necessary for future development of perovskite-based flat optics, where effects of grain boundaries and interfaces need to be mitigated.

Natural layered mercury antimony sulfosalt livingstonite with anisotropic optical properties.

Naturally occurring layered mineral livingstonite is identified as a new type of van der Waals (vdW) heterostructure based 2D material, consisting of two commensurately modulated alternating layers of HgSb2S4 and Sb2S4. The heterostructures of livingstonite crystal are prepared as thin flakes via mechanical exfoliation method. The prepared livingstonite crystals are further investigated in the context of vibrational, linear, and nonlinear optical properties, including anisotropic Raman scattering, wavelength-dependent linear dichroism (LD) transition effect, birefringence, and anisotropic third-harmonic generation (THG). Owing to the monoclinic crystal structure, livingstonite crystals exhibit strong anisotropic vibrational and optical responses. In contrast to conventional vdW heterostructures, the anomalous LD transition effect and the evolution of butterfly-shaped THG emission pattern in livingstonite crystals are demonstrated. Furthermore, the third-order nonlinear susceptibility is estimated for livingstonite crystal using the thickness-dependent THG emission response. Overall, the discussed outcomes establish livingstonite as a new type of naturally grown vdW heterostructure based 2D material and offer insights in tailoring linear and nonlinear light-matter interactions in such vdW heterostructures, which may find further relevance in polarized optical applications and on-chip integrated photonic circuits.

Anisotropic third-harmonic generation of exfoliated As2S3 thin flakes.

Van der Waals (vdW) materials have recently attracted significant interest in the context of orientation-dependent linear and nonlinear optical properties. Recently, arsenic trisulfide (As2S3) or orpiment is identified as a new vdW layered material having anisotropic vibrational and optomechanical responses due to the reduced in-plane crystal symmetry, but its nonlinear optical response is still not well understood yet. Herein, the anisotropic third-harmonic generation (THG) response of mechanically exfoliated As2S3 thin flakes is reported. The polarization-dependent evolution of THG emission from butterfly-shaped pattern to four-lobe pattern is comprehensively explored. Moreover, the third-order nonlinear susceptibility of As2S3 crystal is extracted by analyzing the thickness-dependent THG emission. We anticipate that the discussed results will not only update the existing understanding on the nonlinear light-matter interaction in anisotropic vdW materials, but also promote future applications in integrated photonic circuits, on-chip nonlinear signal processing, and polarization-sensitive optical devices.

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core.

Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumour-suppressor and thus leads to cancer progression. In recent years, anthraquinone analogs have received significant attention due to their ability to downregulate MDM2, thereby promoting p53-induced apoptosis. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both cell culture and animal models of acute lymphocytic leukaemia. Earlier work was focussed on mechanistic work, pharmacological validation of this class of compounds in animal models, and mapping out structural space that allows for further modification and optimisation. Herein, we describe our work in optimising the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet (IC50 = 0.19 ± 0.01 µM) which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.