RESUMO
Event-driven bifunctional molecules, typified by proteolysis targeting chimera (PROTAC) technology, have been successfully applied in degrading many proteins of interest (POI). Due to the unique catalytic mechanism, PROTACs will induce multiple cycles of degradation until the elimination of the target protein. Here, we propose a versatile "Ligation to scavenging" approach to terminate event-driven degradation for the first time. Ligation to the scavenging system consists of a TCO-modified dendrimer (PAMAM-G5-TCO) and tetrazine-modified PROTACs (Tz-PROTACs). PAMAM-G5-TCO can rapidly scavenge intracellular free PROTACs via an inverse electron demand Diels-Alder reaction and terminate the degradation of certain proteins in living cells. Thus, this work proposes a flexible chemical knockdown approach to adjust the levels of POI on-demand in living cells, which paves the way for controlled target protein degradation.
Assuntos
Proteínas , Ubiquitina-Proteína Ligases , Proteínas/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , LigaduraRESUMO
Heat shock protein 90 (Hsp90) as a molecular target for oncology therapeutics has attracted much attention in the last decade. The Hsp90 multichaperone complex has important roles in the growth and/or survival of cancer cells. Cdc37, as a cochaperone, associates kinase clients to Hsp90 and promotes the development of malignant tumors. Disrupting the Hsp90-Cdc37 interaction provides an alternative strategy to inhibit the function of Hsp90 for cancer therapy. Celastrol, as a natural product, can disrupt the Hsp90-Cdc37 interaction and induce degradation of kinase clients. The study conducted here attempted to elucidate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors and to improve the druglike properties. 23 celastrol derivatives were designed, synthesized, and the biological activities and physicochemical properties were determined. The derivative CEL20 showed improved Hsp90-Cdc37 disruption activity, anti-proliferative activities as well as druglike properties. Additionally, CEL20 induced clients degradation, cell cycle arrest and apoptosis in Panc-1 cells. This study can provide reference for the discovery of novel Hsp90-Cdc37 disruptors.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperoninas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/química , Humanos , Modelos Moleculares , Estrutura Molecular , Triterpenos Pentacíclicos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/químicaRESUMO
Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel-Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.
Assuntos
Ferroptose , Ferro , Coativadores de Receptor Nuclear , Animais , Humanos , Masculino , Camundongos , Descoberta de Drogas , Ferroptose/efeitos dos fármacos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/antagonistas & inibidores , Peptídeos/química , Peptídeos/efeitos dos fármacos , Peptídeos/metabolismoRESUMO
A gold nanoparticle-enhanced fluorescent nanocomposite was developed. The designed nanocomposite contained a spherical gold nanoparticle core, a thin PVP coating layer, a silica spacer, and a fluorescent dye layer in the silica matrix. The dye molecules were conjugated to a polymer to be effectively doped in the nanocomposites. Different sized gold nanoparticle cores were used while the spacer thickness was varied. The function of the PVP layer in the fabrication of the nanocomposites was discussed. The fluorescence enhancement effects of the metal core size (gold nanoparticles) and the distance between the fluorescent molecules and the metal core were systematically studied. A series of control experiments were conducted to ensure the accuracy of the fluorescence enhancement measurement. The results showed that the developed nanocomposite can effectively enhance the fluorescence signal of the doped dye conjugates. An enhancement factor of 9.2 was obtained when the nanocomposite contained a 13.7 ± 1.3 nm gold nanoparticle core and a 36.6 ± 4.4 nm silica spacer. It is expected that the developed nanocomposite could be an effective model for studying various effects and the mechanism of metal-enhanced fluorescence at the nanoscale.
Assuntos
Fluorescência , Ouro/química , Nanopartículas Metálicas/química , Nanocompostos/química , Povidona/químicaRESUMO
A target-induced fluorescent silica nanoparticle has been developed for the identification, enrichment and in situ determination of trace amounts of zinc(II). The nanoparticle combines the advantages of target-induced fluorescent compounds and the small size of the nanomaterial to produce a new, smarter nanosignaling material that is capable of selectively enriching a target and detecting a specific binding process in one step. As the target analyte, Zn(II), changes the fluorescence characteristics of the nanoparticle and effectively 'turns on' the fluorescence signal, no separation step is needed to confirm or quantify the binding process. The designed nanoparticle was characterized by several aspects prior to monitoring of Zn(II) in situ. The interferences from common metal ions were studied in detail. The photostability and reversibility of the sensing materials were investigated as well. The ability of this nanoparticle to detect the target Zn(II) provides a great advantage for in situ monitoring targets in biological samples under the fluorescence microscope.
Assuntos
Técnicas de Química Analítica/instrumentação , Corantes Fluorescentes/química , Nanopartículas/química , Zinco/análise , Zinco/química , Antracenos/química , Desenho de Fármacos , Dióxido de Silício/química , Propriedades de SuperfícieRESUMO
This study aimed to investigate the recognition mechanism of dextranase (PC-Edex) produced by Penicillium cyclopium CICC-4022 on dextran. Whole genome information of P. cyclopium CICC-4022 was obtained through genome sequencing technology. The coding information of PC-Edex was determined based on the annotation of the protein-coding genes using protein databases. The three-dimensional structure of PC-Edex was obtained via homology modelling. The active site and binding free energy between PC-Edex and dextran were calculated by molecular docking and molecular dynamics techniques. The results showed that the total sequence length and GC content of P. cyclopium CICC-4022 were 29,710,801 bp and 47.02 %, respectively. The annotation of protein-encoding genes showed that P. cyclopium CICC-4022 is highly active and has many carbohydrate transport and metabolic functions, and most of its proteases are glycolytic anhydrases. Furthermore, the gene encoding PC-Edex was successfully annotated. Molecular dynamics simulations indicated that van der Waals interaction was the main driving force of interaction. Residues Ile114, Asp115, Tyr332, Lys344, and Gln403 significantly promoted the binding between dextran and PC-Edex. In summary, this study explored the active site catalyzed by PC-Edex based on the binding pattern of PC-Edex and dextran. Therefore, this study provides genomic information on dextranase and data supporting the rational modification and enhancement of PC-Edex.
Assuntos
Dextranase , Penicillium , Simulação de Acoplamento Molecular , Dextranase/metabolismo , Dextranos , Alprostadil , Penicillium/genética , Penicillium/metabolismoRESUMO
Hydrogels are emerging as the most promising dressings due to their excellent biocompatibility, extracellular matrix mimicking structure, and drug loading ability. However, existing hydrogel dressings exhibit limited breathability, poor environmental adaptability, potential drug resistance, and limited drug options, which extremely restrict their therapeutic effect and working scenarios. Here, the current research introduces the first paradigm of hydrogel textile dressings based on novel gelatin glycerin hydrogel (glyhydrogel) fibers fabricated by the Hofmeister effect based wet spinning. Benefiting from the unique knitted structure, the textile dressing features excellent breathability (1800 times that of the commercially available 3 M dressing) and stretchability (535.51 ± 38.66%). Furthermore, the glyhydrogel textile dressing can also withstand the extreme temperature of -80 °C, showing the potential for application in subzero environments. Moreover, the introduction of glycerin endows the textile dressing with remarkable antibacterial property and expands the selection of loaded drugs (e.g., clindamycin). The prepared glyhydrogel textile dressing shows an excellent infected wound healing effect with a complete rat skin closure within 14 days. All these functions have not been achievable by traditional hydrogel dressings and provide a new approach for the development of hydrogel dressings.
RESUMO
This communication describes a new class of semiconducting polymer nanoparticle-quantum dot hybrid with high brightness, narrow emission, near-IR fluorescence, and excellent cellular targeting capability. Using this approach, we circumvented the current difficulty with obtaining narrow-band-emitting and near-IR-fluorescing semiconducting polymer nanoparticles while combining the advantages of both semiconducting polymer nanoparticles and quantum dots. We further demonstrated the use of this new class of hybrid nanomaterial for effective and specific cellular and subcellular labeling without any noticeable nonspecific binding. This hybrid nanomaterial is anticipated to find use in a variety of in vitro and in vivo biological applications.
Assuntos
Corantes Fluorescentes/análise , Nanopartículas/análise , Polímeros/química , Pontos Quânticos , Fluorescência , Corantes Fluorescentes/química , Células HeLa , Humanos , Microscopia Confocal , Nanopartículas/química , Nanopartículas/ultraestrutura , SemicondutoresRESUMO
Semiconducting polymer dots (Pdots) recently have emerged as a new class of ultrabright fluorescent probes with promising applications in biological detection and imaging. We developed photoswitchable Pdots by conjugating photochromic spiropyran molecules onto poly[9,9-dioctylfluorenyl-2,7-diyl)-co-1,4-benzo-{2,1'-3}-thiadiazole)] (PFBT). The modulation of fluorescence was achieved by ultraviolet irradiation, which converted spiropyran into its visible-absorbing merocyanine form. The merocyanine efficiently quenched the fluorescence of PFBT via Förster resonance energy transfer (FRET). We then reversed the quenching by subsequent irradiation with visible light to get back the fluorescence of PFBT. This FRET-based photomodulation of Pdot fluorescence could be repeated multiple times. We next conjugated biomolecules onto the surface of these photoswitchable Pdots and demonstrated their specific cellular and subcellular labeling to different types of cells without any noticeable nonspecific binding. We anticipate these photoswitchable and biocompatible Pdots will be useful in developing bioimaging techniques in the future.
Assuntos
Benzopiranos/química , Indóis/química , Luz , Nitrocompostos/química , Polímeros/química , Semicondutores , Fluorenos/química , Células HeLa , Humanos , Células MCF-7 , Imagem Molecular , Espectrometria de Fluorescência , Estreptavidina/químicaRESUMO
BACKGROUND: Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described. METHODS: We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000-2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p < 0.001), and peaked at 8.43 cases per 100,000 in 2005. The increase was mainly the result of an increase in the incidence of serogroup C disease. Serogroup C disease increased from 2/23 (9%) meningococcal cases and 0.11 cases per 100,000 in 2000 to 33/58 (57%) cases and 1.76 cases per 100,000 in 2003 (p < 0.01). Patients infected with serogroup C had serious complications more frequently than those infected with other serogroups. Specifically, 161/493 (32.7%) cases infected with serogroup C had at least one complication. The case-fatality rate of serogroup C meningitis was 11.4%, significantly higher than for serogroup A meningitis (5.3%, p = 0.021). Among patients with meningococcal disease, factors associated with death in univariate analysis were age of 15-24 years, infection with serogroup C, and meningococcemia. CONCLUSIONS: The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain.
Assuntos
Meningite Meningocócica/epidemiologia , Meningite Meningocócica/mortalidade , Neisseria meningitidis Sorogrupo C/classificação , Neisseria meningitidis Sorogrupo C/isolamento & purificação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China/epidemiologia , Análise por Conglomerados , Eletroforese em Gel de Campo Pulsado , Doenças Endêmicas , Feminino , Genótipo , Humanos , Incidência , Lactente , Masculino , Meningite Meningocócica/microbiologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Tipagem de Sequências Multilocus , Neisseria meningitidis Sorogrupo C/genética , Análise de Sobrevida , Adulto JovemRESUMO
Micron and nanometer size textured silicate glass surfaces are of interest in consumer electronics, photovoltaics, and biosensing applications. Typically, texturing glass surfaces requires applying a patterned mask or a pre-etching treatment (e.g. sandblasting) on the glass substrate, followed by a mask transferring or etching process using a fluoride-containing compound. The major challenges of such a process are the complexity and cost of masking, and the safety and environmental concerns around the usage and disposal of hydrofluoric acid. Here, we describe a template-free method to construct micron-sized and submicron-sized texture on isotropic glass surfaces in one step. The new texturing mechanisms are well supported by experimental data and peridynamic simulations. With this novel strategy, the etchant uses fluoride-free chemicals such as citric acid to texture silicate glass. Etchant concentration, etch temperature, time, and additives are the primary parameters that dictate the texturing process. Surface feature size and depth can be independently controlled by tuning the leaching and chemical polishing process. We hope this study can trigger more research on novel and more environmentally friendly texturing of isotropic materials.
RESUMO
The negative impact of COVID-19 on physical activity has been improved, while the research on changes in physical fitness that may be caused by physical inactivity is still scarce. This study aims to explore the impact of the COVID-19 pandemic lockdown on physical fitness, and the impact of initial physical fitness indicators on their changes during the lockdown in adolescents. A longitudinal study including 265 adolescents aged 14.1 ± 0.4 years old was conducted in China. Physical fitness measurement at baseline and follow-up were respectively measured before (November 2019) and after the lockdown (July 2020). Several physical fitness indicators including aerobic fitness (i.e., 800-m or 1000-m run) and explosive force (i.e., 50-m sprint) deteriorated during the lockdown. Whereas the performances of vital capacity, flexibility (i.e., sit and reach), and muscular strength (i.e., pull-ups) were significantly improved during the lockdown. Furthermore, the reduction in physical fitness for adolescents with higher physical fitness before the lockdown was greater than that for others. These findings may contribute to the development of targeted intervention strategies for physical fitness promotion during the lockdown caused by the public health emergency.
RESUMO
This communication describes ultrabright single-nanoparticle ratiometric temperature sensors based on semiconducting polymer dots (Pdots). We attached the temperature sensitive dye-Rhodamine B (RhB), whose emission intensity decreases with increasing temperature-within the matrix of Pdots. The as-prepared Pdot-RhB nanoparticle showed excellent temperature sensitivity and high brightness because it took advantage of the light harvesting and amplified energy transfer capability of Pdots. More importantly, the Pdot-RhB nanoparticle showed ratiometric temperature sensing under a single wavelength excitation and has a linear temperature sensing range that matches well with the physiologically relevant temperatures. We employed Pdot-RhB for measuring intracellular temperatures in a live-cell imaging mode. The exceptional brightness of Pdot-RhB allows this nanoscale temperature sensor to be used also as a fluorescent probe for cellular imaging.
Assuntos
Nanotecnologia/métodos , Polímeros , Rodaminas/química , Semicondutores , Temperatura , Transferência de Energia , Corantes Fluorescentes , NanopartículasRESUMO
Semiconducting polymer-based nanoparticles (Pdots) have recently emerged as a new class of ultrabright probes for biological detection and imaging. This paper describes the development of poly(2,5-di(3',7'-dimethyloctyl)phenylene-1,4-ethynylene) (PPE) Pdots as a platform for designing Förster resonance energy transfer (FRET)-based ratiometric pH nanoprobes. We describe and compare three routes for coupling the pH-sensitive dye, fluorescein, to PPE Pdots, which is a pH-insensitive semiconducting polymer. This approach offers a rapid and robust sensor for pH determination using the ratiometric methodology where excitation at a single wavelength results in two emission peaks, one that is pH sensitive and the other one that is pH insensitive for use as an internal reference. The linear range for pH sensing of the fluorescein-coupled Pdots is between pH 5.0 and 8.0, which is suitable for most cellular studies. The pH-sensitive Pdots show excellent reversibility and stability in pH measurements. In this paper, we use them to measure the intracellular pH in HeLa cells following their uptake by endocytosis, thus demonstrating their utility for use in cellular and imaging experiments.
Assuntos
Transferência Ressonante de Energia de Fluorescência/métodos , Nanopartículas/química , Polímeros/química , Semicondutores , Endocitose , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Espaço Intracelular/química , Espaço Intracelular/metabolismo , Modelos Lineares , Imagem Molecular , Polímeros/metabolismoRESUMO
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.
Assuntos
Compostos Azo/farmacologia , Dasatinibe/análogos & derivados , Dasatinibe/farmacologia , Lenalidomida/análogos & derivados , Lenalidomida/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Compostos Azo/síntese química , Compostos Azo/efeitos da radiação , Linhagem Celular Tumoral , Dasatinibe/efeitos da radiação , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Lenalidomida/efeitos da radiação , Ligantes , Proteólise/efeitos dos fármacos , Estereoisomerismo , Ubiquitina-Proteína Ligases , Ubiquitinação/efeitos dos fármacos , Raios UltravioletaRESUMO
In recent years, wildlife conservation has attracted great public attention. However, substantial distinctions can be found in the prevailing concepts of wildlife conservation, particularly with the recent notion that emphasizes animal rights. Wildlife welfare and wildlife rights are not synonymous, with welfare more compatible with the reasonable and legal utilization of wildlife. The key to scientific wildlife conservation is the appropriate awareness and appreciation of the relationship between wildlife conservation and utilization and the theoretical basis of holism. Nevertheless, rational biases regarding the public's understanding of wildlife conservation and the spread of information via social media still exist. As such, expansion of the concept of scientific wildlife conservation requires the application of several measures. Wildlife conservation researchers should be regarded as the most important disseminators of scientifically-based information, with education in schools and universities of growing importance. Furthermore, the media should shoulder the social responsibility for the accurate dissemination of conservation information.
Assuntos
Conservação dos Recursos Naturais/métodos , Disseminação de Informação/métodos , Ciência , Animais , Evolução Biológica , Educação , HumanosRESUMO
Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Células HCT116 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Corantes Fluorescentes/química , Polímeros/química , Células 3T3 , Alanina/análogos & derivados , Alanina/química , Animais , Química Click , Fluorenos/química , Corantes Fluorescentes/síntese química , Humanos , Camundongos , Estrutura Molecular , Tamanho da Partícula , Polímeros/síntese química , Proteínas/análise , Proteínas/metabolismo , Semicondutores , Coloração e Rotulagem , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
The rapid development and acceptance of PDots for biological applications depends on an in depth understanding of their cytotoxicity. In this paper, we performed a comprehensive study of PDot cytotoxicity at both the gross cell effect level (such as cell viability, proliferation and necrosis) and more subtle effects (such as redox stress) on RAW264.7 cells, a murine macrophage cell line with high relevance to in vivo nanoparticle disposition. The redox stress measurements assessed were inner mitochondrial membrane lipid peroxidation (nonyl-acridine orange, NAO), total thiol level (monobromobimane, MBB), and pyridine nucleotide redox status (NAD(P)H autofluorescence). Because of the extensive work already performed with QDots on nanotoxicity and also because of their comparable size, QDots were chosen as a comparison/reference nanoparticle for this study. The results showed that PDots exhibit cytotoxic effects to a much lesser degree than their inorganic analogue (QDots) and are much brighter, allowing for much lower concentrations to be used in various biological applications. In addition, at lower dose levels (2.5 nM to 10 nM) PDot treatment resulted in higher total thiol level than those found with QDots. At higher dose levels (20 nM to 40 nM) QDots caused significantly higher thiol levels in RAW264.7 cells, than was seen with PDots, suggesting that QDots elicit compensation to oxidative stress by upregulating GSH synthesis. At the higher concentrations of QDots, NAD(P)H levels showed an initial depletion, then repletion to a level that was greater than vehicle controls. PDots showed a similar trend but this was not statistically significant. Because PDots elicit less oxidative stress and cytotoxicity at low concentrations than QDots, and because they exhibit superior fluorescence at these low concentrations, PDots are predicted to have enhanced utility in biomedical applications.