RESUMO
Monoterpene pyridine alkaloids (MTPAs) are alkaloids derived from iridoid glycosides (IGs). The common molecular structure of MTPAs is the pyridine ring, while some of them have a cyclopenta[c]pyridine skeleton. Some compounds containing this structure are potentially bioactive medicinal agents. In this paper, seven drug candidates (A-G), ninety natural source products (1-90), thirty-seven synthesized compounds (91-127), as well as twenty-six key intermediates (S1-S26) were summarized. We categorized five types of MTPAs and one type of cyclopenta[c]pyridine alkaloids in all. Additionally, their possible genetic pathways were proposed. Then, the chemical transformation, biotransformation, chemical synthesis, as well as the bioactivity of MTPAs and cyclopenta[c]pyridine derivatives were analyzed and summarized. Cyclopenta[c]pyridine derivatives can be concisely and chirally synthesized, and they have shown potentials with antibacterial, insecticidal, antiviral, anti-inflammatory, and neuropharmacological activities.
Assuntos
Alcaloides , Produtos Biológicos , Monoterpenos , Alcaloides/farmacologia , Alcaloides/química , Estrutura Molecular , Piridinas/farmacologia , Piridinas/química , Produtos Biológicos/químicaRESUMO
(±)-Caryopterisines A (1) and B (2) featuring an unprecedented 6/5/5/5/6 pentacyclic rings system were isolated from Caryopteris glutinosa. The structures were determined by spectroscopic and X-ray crystallographic data analyses as well as theoretical calculations. Chiral HPLC resolution of both racemic 1 and 2 afforded their corresponding enantiotropic enantiomers. A plausible biogenesis for 1 and 2 may be originated from Diels-Alder reaction between pyridine-containing oxerine derivatives. The enantiotropic conversion mechanism of the enantiomers was demonstrated by H-D exchange and 18O incorporation studies. Compounds 1 and 2 showed moderate inhibition of estrogen E2 biosynthesis in human ovarian granulosa-like KGN cells. These two alkaloids reduced kynurenine biosynthesis at moderate level via inhibition of indoleamine 2,3-dioxygenase. Alkaloid 2 exhibited moderate inhibition of the release of interleukin-1ß.
Assuntos
Alcaloides/farmacologia , Receptor beta de Estrogênio/antagonistas & inibidores , Lamiaceae/química , Monoterpenos/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Linhagem Celular , Relação Dose-Resposta a Droga , Receptor beta de Estrogênio/metabolismo , Humanos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The SpyTag/SpyCatcher reaction has emerged as a powerful way for bioconjugation, but it leaves a folded complex in the product after the formation of the isopeptide bond. To vary the location of the reactive residue and reduce the size of the complex and its potential immunogenicity, we engineer two circularly permuted SpyCatcher variants, SpyCatcher-N and SpyCatcher-NTEV, the latter of which possesses a TEV-recognition site for removal of the fragment containing the catalytic site. Surprisingly, both variants are found to be disordered in solution, yet still retain the ability to form an ordered complex upon reaction with SpyTag with second-order rate constants of â¼10 M-1 s-1. Cellular expression of a telechelic protein bearing SpyCatcher-NTEV at the N-terminus and SpyTag at the C-terminus gives both cyclized and chain-extended products. Notably, the monomers exist almost exclusively in the cyclic form owing to its high reactivity in vivo. The fragment containing the catalytic site of SpyCatcher-NTEV can then be removed by TEV digestion, giving a circular protein with minimal trace from the ligation reaction. The plasticity of SpyTag/SpyCatcher reactive pair has promised an ever-expanding toolbox of genetically encoded peptide-protein reaction with versatile features.
Assuntos
Peptídeos/síntese química , Proteínas/síntese química , Sequência de Aminoácidos , Técnicas de Química Sintética/métodos , Ciclização , Endopeptidases/química , Escherichia coli/genética , Modelos Moleculares , Peptídeos/química , Peptídeos/genética , Plasmídeos/genética , Proteínas/química , Proteínas/genética , Proteólise , Transformação GenéticaRESUMO
Protein immobilization is critical to utilize their unique functions in diverse applications. Herein, we report that orthogonal peptide-protein chemistry enabled multilayer construction can facilitate the incorporation of various folded structural domains, including calmodulin in different states, affibody, and dihydrofolate reductase (DHFR). An extended conformation is found to be the most advantageous for steady film growth. The resulting protein thin films exhibit sensitive and selective responsive behaviors to biosignals, such as Ca2+, trifluoperazine, and nicotinamide adenine dinucleotide phosphate (NADPH), and fully maintain the catalytic activity of DHFR. The approach is applicable to different substrates such as hydrophobic gold and hydrophilic silica microparticles. The DHFR enzyme can be immobilized onto silica microparticles with tunable amounts. The multilayer setup exhibits a synergistic enhancement of DHFR activity with increasing numbers of bilayers and also makes the embedded DHFR more resilient to lyophilization. Therefore, this is a convenient and versatile method for protein immobilization with potential benefits of synergistic enhancement in enzyme performance and resilience.
Assuntos
Enzimas Imobilizadas/química , Tetra-Hidrofolato Desidrogenase/química , Cálcio/química , Estabilidade Enzimática , Enzimas Imobilizadas/metabolismo , Ouro/química , NADP/química , Nanopartículas/química , Dióxido de Silício/química , Tetra-Hidrofolato Desidrogenase/metabolismo , Trifluoperazina/químicaRESUMO
Protein-based materials call for innovative processing techniques to integrate their unique biologically enabled functions with other materials of complementary features. Herein, we report the covalent protein layer-by-layer assembly via orthogonal "Tag-Catcher" reactions as a facile and robust approach to make entirely protein-based multilayers on a variety of substrates. Programmed assembly of native telechelic proteins not only endows the materials valuable stimuli-sensitive behaviors, but also unique properties unparalleled by any synthetic counterparts. As proof of concept, super uranyl-binding protein (SUP) is immobilized on silica gel by this method with tunable capacity and enhanced capability for uranyl sequestration. Not only is the capturing performance enhanced in the multilayer setup, it also confers resilience to recycling, allowing efficient harvest of uranyl with an average of â¼90% and â¼60% recovery rate in over 10 cycles from water and synthetic seawater, respectively. The approach is the first entirely protein-based multilayers covalently assembled by the layer-by-layer method. It provides a platform for immobilizing proteins with synergistic enhancement of function and resilience and expands the scope and capability of genetically encoded protein-based materials.
Assuntos
Proteínas de Transporte/química , Escherichia coli/química , Urânio/química , Urânio/isolamento & purificação , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genéticaRESUMO
Cyanide ions are shown to interact with lanthanide complexes of phenacylDO3A derivatives in aqueous solution, giving rise to changes in the luminescence and NMR spectra. These changes are the consequence of cyanohydrin formation, which is favored by the coordination of the phenacyl carbonyl group to the lanthanide center. These complexes display minimal affinity for fluoride and can detect cyanide at concentrations less than 1â µm. By contrast, lanthanide complexes with DOTAM derivatives display no affinity for cyanide in water, but respond to changes in fluoride concentration.
RESUMO
Dopamine-modified poly(acrylic acid) (PAA-dopa) and poly(vinylpyrrolidone) (PVPON) was layer-by-layer (LbL) assembled to prepare thin film based on hydrogen bonding. The carboxylic group of acrylic acid and the phenolic hydroxyl group of dopamine can both act as hydrogen bond donors. The critical assembly and the critical disintegration pH values of PVPON/PAA-dopa film are enhanced compared with PVPON/PAA film. The hydrogen-bonded PVPON/PAA-dopa thin film can be cross-linked via catechol chemistry of dopamine. After cross-linking, the film can be exfoliated from the substrate in alkaline solution to get a free-standing film. Moreover, by tuning the pH value, deprotonation and protonation of PAA will make the hydrogen bond in the film break and reconstruct, which induces that the free-standing film has a reversible swelling-shrinking behavior.
Assuntos
Catecóis/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Membranas Artificiais , Estrutura MolecularRESUMO
Lycopene, a carotenoid with numerous physiological benefits, particularly in its Z-isomer form, faces challenges in its application due to low chemical stability. To address this limitation, high internal phase emulsion was successfully synthesized using ovalbumin-chitosan complexes. The aim was to enhance the stability of lycopene including Z-lycopene. The solubility, particle size, ζ-potential and uniformity of the mixture were dependent on pH value and biopolymer proportion. Notably, optimal ovalbumin-chitosan complex formation occurred at pH 2.5 with a ratio of 4:1 resulting in the highest solubility and optimal uniformity which contributed to its superior emulsification properties. Evaluation of encapsulating efficiency and loading amount revealed 98.19% and 1.7661 mg/g respectively for lycopene in ovalbumin-chitosan stabilized emulsions, inhibiting the transformation from Z-lycopene to (all-E)-lycopene. The encapsulated lycopene possessed UV stability where retention rate remained high at 81.86%. The retention rate was up to 65.37% and 41.82% at 45 °C and 80 °C, respectively.
RESUMO
Probabilistic computing is a computing scheme that offers a more efficient approach than conventional complementary metal-oxide-semiconductor (CMOS)-based logic in a variety of applications ranging from optimization to Bayesian inference, and invertible Boolean logic. The probabilistic bit (or p-bit, the base unit of probabilistic computing) is a naturally fluctuating entity that requires tunable stochasticity; by coupling low-barrier stochastic magnetic tunnel junctions (MTJs) with a transistor circuit, a compact implementation is achieved. In this work, by combining stochastic MTJs with 2D-MoS2 field-effect transistors (FETs), we demonstrate an on-chip realization of a p-bit building block displaying voltage-controllable stochasticity. Supported by circuit simulations, we analyze the three transistor-one magnetic tunnel junction (3T-1MTJ) p-bit design, evaluating how the characteristics of each component influence the overall p-bit output. While the current approach has not reached the level of maturity required to compete with CMOS-compatible MTJ technology, the design rules presented in this work are valuable for future experimental implementations of scaled on-chip p-bit networks with reduced footprint.
RESUMO
Highly diastereoselective self-assembly reactions give both enantiomers (Λ and Δ) of anti-parallel triple-stranded bimetallic Co(ii) and Co(iii) cationic helices, without the need for resolution; the first such reaction for Co. The complexes are water soluble and stable, even in the case of Co(ii). Studies in a range of cancer and healthy cell lines indicate high activity and selectivity, and substantial differences between enantiomers. The oxidation state has little effect, and correspondingly, Co(iii) compounds are reduced to Co(ii) e.g. by glutathione. In HCT116 colon cancer cells the Λ enantiomer induces dose-dependent G2-M arrest in the cell cycle and disrupts microtubule architectures. This Co(ii) Λ enantiomer is ca. five times more potent than the isostructural Fe(ii) compound. Since the measured cellular uptakes are similar this implies a higher affinity of the Co system for the intracellular target(s); while the two systems are isostructural they have substantially different charge distributions as shown by calculated hydrophobicity maps. In contrast to the Λ enantiomer, Δ-Co(ii) induces G1 arrest in HCT116 cells, efficiently inhibits the topoisomerase I-catalyzed relaxation of supercoiled plasmid DNA, and, unlike the isostructural Fe(ii) system, causes DNA damage. It thus seems very likely that redox chemistry plays a role in the latter.
RESUMO
Herein, 13 previously undescribed neo-clerodane diterpenoids (1-13) and 27 known analogs (14-40) were isolated from the aerial parts of Scutellaria barbata. Absolute configurations of undescribed compounds were assigned based on single-crystal X-ray diffraction analysis and comparison of experimental and circular dichroism. All isolates were evaluated for the inhibition of nitric oxide generation induced by lipopolysaccharide in RAW 264.7 macrophages. Compound 36 was found to be the most active with an IC50 value of 10.6 µM. Structure-activity relations of these neo-clerodane diterpenoids revealed that the α, ß-unsaturated-γ-lactone moiety with an exocyclic conjugated double bond was necessary for maintaining and increasing its activity. Further mechanistic studies show that compound 36 suppressed nitric oxide synthase enzymes (iNOS) expression without affecting iNOS activity. Additionally, compound 36 suppresses NF-κB signaling by inhibiting IκBα phosphorylation.
Assuntos
Diterpenos Clerodânicos , Scutellaria , Estrutura Molecular , Diterpenos Clerodânicos/farmacologia , Diterpenos Clerodânicos/química , Scutellaria/química , Lipopolissacarídeos/farmacologia , Macrófagos , Óxido NítricoRESUMO
Background: The gut microbiota has emerged as an intriguing and potentially influential factor in regulating bone health. However, the causal effect of the gut microbiota on bone mineral density (BMD) appears to differ throughout various life stages. Methods: We conducted a Mendelian randomization (MR) analysis to investigate the potential causal relationship between gut microbiota and BMD in five distinct age groups: 0-15, 15-30, 30-45, 45-60, and 60 years and older. The analysis employed three different methods, namely MR-Egger, weighted median, and Inverse-variance weighting, to ensure the robustness of our findings, a series of sensitivity analyses were also conducted, such as horizontal pleiotropy tests, heterogeneity tests, and leave-one-out sensitivity tests. Results: In the age group of 0-15 years, Eubacterium_fissicatena_group and Eubacterium_hallii_group were identified as risk factors for BMD. During the 15-30 age group, Phascolarctobacterium, Roseburia, and Ruminococcaceae_UCG_003 were found to be protective factors for BMD. In the 30-45 age group, Lachnospira genus demonstrated a protective effect on BMD, while Barnesiella and Lactococcus were identified as risk factors for BMD. Moving on to the 45-60 age group, Eubacterium_ventriosum_group, Lachnospiraceae_UCG_004, and Subdoligranulum were observed to be protective factors for BMD, while Eubacterium_coprostanoligenes_group, Fusicatenibacter, and Lactococcus were associated with an increased risk of BMD. In individuals aged 60 years and older, Fusicatenibacter and Ruminococcaceae_UCG_002 were also noted as risk factors for BMD. Conversely, Eubacterium_ruminantium_group, Ruminococcus_gauvreauii_group, Alistipes, and Coprococcus_3 were found to be protective factors for BMD, whereas Barnesiella and Sellimonas were identified as risk factors for BMD. Conclusion: A robust causal relationship between gut microbiota and bone mineral density (BMD) exists throughout all stages of life, with Firmicutes phylum being the primary group associated with BMD across age groups. Gut microbiota linked with BMD primarily belong to the Firmicutes phylum across age groups. The diversity of gut microbiota phyla associated with BMD depicts relatively stable patterns during the ages of 0-45 years. However, for individuals aged 45 years and above, there is an observed increase in the number of gut microbiota species linked with BMD, and by the age of 60 years, a trend toward an increase in the Bacteroidetes phylum categories is proposed.
RESUMO
Coal gasification fine slag is a by-product of the entrained-flow gasifier, which has caused some environmental pollution. Through acid dissolution and calcination at different temperatures, mesoporous spherical silica/porous carbon composite filler was prepared using coal gasification fine slag. The particle size and specific surface area of the composite filler decreased with the decrease of unburned carbon content. The analysis of X-ray photoelectron spectroscopy (XPS) indicated the decrease of oxygen-containing functional groups and the increase of C-C groups with the decrease of the content of carbon. The effects of mesoporous spherical silica/porous carbon with different carbon content on the comprehensive properties of filled polypropylene (PP) were studied. The tensile strength and interface interaction increased at first and then decreased with the decrease of carbon content, due to the synergistic effect of mesoporous spherical silica and rough amorphous carbon. The scanning electron microscope showed that the composite filler with the carbon content of 14.47 wt.% at the calcination temperature of 450 °C had the best compatibility with the matrix. Thermodynamic analysis of the PP composites indicated that thermal insulation properties and thermal stability improved with the incorporation of the composite filler. Differential scanning calorimetry (DSC) testing indicated the highest crystallinity of the matrix corresponding to the best comprehensive performances of the composites. XRD patterns revealed that the cooperation of fillers brought characteristic peaks and did not change the primary crystal structure of PP. Simultaneously, heavy calcium powders (CC) were used as comparative fillers, and the overall properties of the PP composites filled with the composite filler were better compared to those of the CC-filled PP composite. The results illustrated that mesoporous spherical silica/porous carbon particles can completely replace CC used in the PP composites, which can be used in auto bumpers, plastic pipes, display cases, and car air deflectors. The CGFS can be processed into a plastic filler for substituting heavy calcium powder particles, which can solve the environmental pollution caused by the accumulation of solid waste.
RESUMO
Three undescribed dimeric pyridine-containing alkaloids, caryopterisines C - E, and four unreported cyclopenta[c]pyridine-derived alkaloids, caryopterisines F - I, were identified from Caryopteris glutinosa Rehder (Lamiaceae), together with two known monoterpene alkaloids. Caryopterisine C, featuring with an unprecedented 6/5/6/6/5 pentacyclic rings scaffold, may biosynthetically stem from a Diels-Alder reaction of two cyclopenta[c]pyridine-containing monomers and a following aromatization rearrangement reaction. Caryopterisines D and E, possessing an unprecedented 6/6/6/6/5 fused rings framework, may originate from a same Diels-Alder reaction of two monomers and subsequent aromatization arrangement, Baeyer-Villiger oxidation, and a set of tailoring reactions. Caryopterisine C showed strong inhibition on collagen accumulation in NIH3T3 cells (IC50 = 14.26 ± 1.46 µM). Caryopterisines G and I reduce collagen accumulation with IC50 values 88.91 ± 0.95 µM and 33.09 ± 1.38 µM, respectively. The Western blotting of the transforming growth factor-ß-activated signaling pathways revealed that caryopterisine C inhibits collagen expression and accumulation via suppression of the phosphorylation of ERK1/2, P38, and SMAD2/3. The present works indicate caryopterisine C is a potential lead compound for the development of antifibrotic drugs.
Assuntos
Alcaloides , Lamiaceae , Alcaloides/farmacologia , Animais , Colágeno/metabolismo , Lamiaceae/metabolismo , Camundongos , Monoterpenos/farmacologia , Células NIH 3T3 , Piridinas , Fatores de Crescimento TransformadoresRESUMO
BiOCl hierarchical microspheres assembled from nanosheets with exposed {001} facets were successfully synthesized using PEG-2000 as template by a one-pot room-temperature hydrolysis method. The PEG-modified BiOCl photocatalyst exhibits a significantly enhanced RhB photosensitized degradation activity under visible light. After 10 min white LED irradiation, the degradation efficiency of RhB by the PEG-modified BiOCl sample S 0.07 reaches 99.5%. The degradation rate constant of the PEG-modified sample S 0.07 over RhB is 0.4568 min-1, which is 6.76 times that of the unmodified sample S 0 (0.0676 min-1). After 4 min of xenon lamp (λ ≥ 420 nm) irradiation, the degradation rate of RhB by S 0.07 is almost 100%. The exposed {001} facets with surface defects contribute to the superior adsorption capacity of BiOCl towards RhB, which immensely accelerates the electron transfer efficiency from the excited RhB into the conduction band of BiOCl, forming superoxide radical (ËO2 -) active species to degrade the pollutants. Moreover, the superior RhB-sensitized BiOCl system provides high photocatalytic degradation activity over MO. This work provides a facile and efficient BiOCl synthesis method that is conducive to large-scale production and simultaneously opens up new ideas for the synthesis of other photocatalysts.
RESUMO
OBJECTIVE: To determine the potent and broad neutralizing monoclonal antibody (mAb) against enterovirus A (EV-A) in vitro and in vivo induced by enterovirus A71(EVA71) and coxsackievirus 16 (CVA16) co-immunization. METHODS: The mAb was Generated by co-immunization with EVA71 and CVA16 through hybridomas technology. The characteristics and neutralizing ability of mAb were analysed in vitro and in mice. RESULTS: We screened three mAb, the IgM antibody M20 and IgG antibody B1 and C31. All three antibodies showed cross-reactivity against tetra-EV-As. However, M20 showed potent and broad neutralizing ability against tetra-EV-As than B1 and C31. Meanwhile, M20 provided cross-antiviral efficacy in tetra-EV-As orally infected mice. Moreover, M20 binds to a conserved neutralizing epitope within the GH loop of tetra-EV-As VP1. CONCLUSIONS: M20 and its property exhibited potent and broad antiviral activity against tetra-EV-As, and that is expected to be a potential preventive and therapeutic candidate against EV-As.
Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Animais , Anticorpos Neutralizantes , Imunização , Imunoglobulina M , CamundongosRESUMO
A novel heterogeneous Co-containing Fenton-like catalyst consisting of mesoporous reduction state cobalt (RSCo)-doped silica (SiO2) nanospheres (mp-RSCo-SiO2 NSs) was prepared by an enhanced hydrothermal process. The catalyst exhibited very high activity and stability for a series of refractory pollutant degradation in a very wide pH range of 3.1-10.9. The Fenton-like reaction rate constant of this Co-containing catalyst was approximately 290 times higher than that of Co3O4 for pollutant degradation under the neutral and mild conditions. Based on the characterization, the catalyst possessed a porous nanosphere morphology, and the reduction state cobalt species, including nano-zero-valent cobalt (nZVCo) and Co2+, were found to be generated in the SiO2 framework through forming CoOSi bonds. During the Fenton-like reaction, the electron donation effect of organic pollutants was successfully realized through the interaction of "Pollutants â Co2+/0-SiO2". The obtained electrons from pollutants were transferred to the catalyst surface and captured by H2O2, resulting in the generation of hydroxyl radicals (OH). Therefore, a dual-pathway degradation of the pollutants was realized: (I) oxidation and degradation as the electron donors for the system and (II) attacking and destruction by OH radicals. This work provided a new perspective on the effective utilization of the electrons of pollutants and the improvement of Fenton reaction efficiency.
RESUMO
Fourteen undescribed diterpenoids caryopterisoids D - Q, three undescribed iridoid glucoside derivatives caryopterisides F - H, and 8 known diterpenoids were isolated from the 95% aqueous ethanolic extract of Caryopteris glutinosa. Their structures were elucidated on the basis of spectroscopic data analysis and chemical derivation studies. The structure and absolute conï¬guration of caryopterisoid D were confirmed by X-ray crystallographic analysis. Caryopterisoids K and R, royleanone, 6α-hydroxydemethylcryptojaponol, and teuvincenone E were shown to reduce the biosynthesis of estrogen E2 with IC50 values from 0.25 to 3.06 µM in cell-based estrogen biosynthesis assays system.
Assuntos
Glucosídeos Iridoides , Lamiaceae , Diterpenos , Estrutura MolecularRESUMO
Natural, standard, and compound curing are adopted to study the effect of different curing systems on the reinforcement of carbon fiber in reactive powder concrete (RPC). This work systematically studies the changes in RPC compressive and tensile strengths under different curing systems. Taking age, fiber content, and curing system as parameters, Scanning electron microscope (SEM) and X-ray diffraction (XRD) microscopic methods are used to study the influencing mechanism of carbon-fiber content and curing systems on RPC. The calculation methods of the RPC strength of different carbon-fiber contents are studied. Results show that the optimum carbon-fiber content of carbon-fiber RPC is 0.75% under the natural, standard, and compound curing conditions. In comparison with standard curing, compound curing can improve the early strength of carbon-fiber RPC and slightly affect the improvement of late strength. The strength is slightly lower in natural curing than in standard curing, but the former basically meets the requirements of the project and is beneficial for the practical application of this project. The calculation formula of 28-day compressive and splitting tensile strengths of carbon-fiber content from 0% to 0.75% is proposed to select the carbon-fiber content flexibly to satisfy different engineering requirements.
RESUMO
Etherification of cellulose can get a series of water soluble derivatives, which can form hydrogen-bonded polymer complex with poly(acrylic acid) (PAA). Three cellulose ethers hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) and methyl cellulose (MC) are LbL assembled with PAA to fabricate thin films. The hydrogen bonding of the films is characterized with FT-IR. The film growth behaviors are monitored by a quartz crystal microbalance (QCM) and a spectroscopic interferometer, which shows a different growth rate for different system and a strong dependence on pH values. The stability of the films can be increased by heat treatment. Once the cross-linked structure is formed, and the dissolution of film can be prevented even in the high pH value. In addition, the films show good water adsorption ability from environment. Owing to pH responsive behavior and good water adsorption, CE/PAA films can be explored for various applications, especially for biomedical application.